有鉴于此,立法与司法实践开展了“数据权利”的技术探索。这种探索来自一个基本的认知,即数据是技术操作的产物,数据的来源和归属能够通过技术观察与测量予以描述,作为测量方法的数据机器和算法能够解释特定场景下的数据状态,技术处理的痕迹也成为追溯数据操作行为的重要依据。即便是最为初级、简易的数据,也经历了从物理世界转化为数据的过程,需要以一定的技术处理手段为基础。自然界的事件、人物和行为能够转化为可呈现、可陈述的数据元素,由计算机语言处理、记载和储存。联合国国际贸易法委员会(United Nations Commission on International Trade Law)从技术路径上定义“电子数据”,规定“电子数据”系指以电子技术手段生成、传递、接收或存储的信息,电子数据包括“如何对数据进行分类,以及如何通过自动化手段管理记录这些信息”等重要内容。沿着这一思路,欧盟委员会联合研究中心(the Joint Research Centre of the European Commission, JRC)2017年发布了《关于所有权、准入和贸易的数据经济学报告》。该报告主要在数据产权方面补充《通用数据保护条例》(General Data Protection Regulation, GDPR)的不足,认为“ GDPR没有给予数据主体完全的所有权,……在很大一个领域,数据的所有权或剩余权利没有得到法律规定,或者规定不完全”,数据产权成为“de facto right”,即法律尚未明确规定却在事实上已经存在的权利。
面对电子数据的基本特征,司法实务回归“谁拥有数据”的基础财产法问题,同时在数据的创造、控制和处理技术应用中做出“技术性的拟制”。早在1985年,美国印第安纳州法院已经承认数字资产是计算机技术产生的信息,并且“构成盗窃财务的目标财产。”2003年,美国联邦第九巡回法院在克莱蒙诉科恩案(Kremen v. Cohen)中,赋予网络域名数据作为财产的法律属性并认为,登记系统中的技术手段“使域名术语相关的权利类似于‘一块土地’能够提出的权利主张。”不仅如此,联邦第九巡回法院以技术使用的材料为证据,进一步判定应当赔偿的数据价值。在我国,技术性手段在实践中的应用,已经为数字产品权属纠纷的解决提供了重要线索。目前,数字技术支持数字资产登记、授权、交易、使用和维权的服务体系,尤其应用到数据存证、版权授予、数字产品防伪追溯等领域,可以规范音乐、视频、图片、文字作品等数字产品市场。
再次,进程确权须以特定技术应用能力和基础设施条件为前提。为进程确权提供支持的技术手段,需要凭借防篡改性和准确性使数据流动有据可循,还要在数据安全方面具有防御能力。这些确权效果的实现离不开区块链、智能合约等特定技术手段的应用。诸如区块链技术验证和审计的高要求增加了技术适用和处理的巨大成本,限制了数据权利主体实际控制的能力,也容易影响到数据流通的速度,这需要高水平信息基础设施建设的支持。考虑到这些前置条件,欧盟区块链观察组织(the EU Blockchain Observatory)对区块链适用的经验做出论证并认为,区块链等技术手段的应用需要考虑数据价值的创造和使用需求,以及数据加密、数据共享的程度等。应当看到,整体性确权模式的起步较早,在实践中有较大范围的普及,中心化数据存储系统和载体的技术已经相对成熟。如果对数据权属没有较高的实时记录需求,也没有刻意的防篡改需求,中心化的数据库存储仍可支持概括性的整体确权模式。可见,受到技术条件的客观限制,确权进程化的模式转变无法排斥整体确权的适用。
J.R. 麦蒂考特所写《英国议会的起源》 (Origins of the English Parliament) 堪称此一领域杰作。他在书中将贤人会议和其他欧洲议会 进行比较,得出结论:无论在代表构成、税收的决定权,还是其存在方 式上,贤人会议与其他会议都有着质的不同。他说:“在西方世界其他 地区,日耳曼式的立法传统到10世纪时已告终结。而这一传统在英格兰 得以保存并发展,实在是罕见的特例。”贤人会议不仅是王室立法的伙 伴,同时也是那些有可能制约国王的制定法的守护者。麦蒂考特说:“在英国例外论这一点上,不存在任何疑议。”
可以说,布莱克斯通和洛克一样,也是美国革命的教父。他的巨著 《英格兰法释义》 (Commentaries on the Laws of England) 被称为继 《圣经》之后十三个殖民地拥有读者量最多的书,每个律师都在自己的 公事包里备了一本。事实上,北美对《大宪章》的热情始终比英国人更 高(扬基佬在那时候就和现在一样,喜欢把《大宪章》这个词当做一个 特定名词)。
早在1687年,北美大陆就首次印行了《大宪章》副本。该副本收录 于威廉 ·佩恩(William Penn)所著的《论自由与财产权之优越性:作为生而自由的英国臣民的天赋权利》 (The Excellent Privilege of Liberty and Property:being the birth-right of the Free-Born Subjects of England)一书。威廉 ·佩恩是宾夕法尼亚殖民地的创始人,他毫不怀疑正是《大 宪章》将英语民族和世界上其他国家区别开来。
3马姆斯伯里的威廉(William of Malmesbury,约1080/1095—约1143),12世纪英国历史学家,在1120年前后创作了《盎格鲁国王史》,记载从449年到 1120年间,英国国王事迹或者英国人的国王的事迹。该书被认为是英格兰最重 要的历史著作之一,以有说服力的文档资料和清晰生动的写作风格而留名。
不妨看看平等派在他们的宣言《英格兰自由人民协议》 (An Agreement of the Free People of England) 中提出的主张: 国会无权制定法律限制或者阻碍任何人进行贸易或者交易….国会也无权 继续统配任何种类的食物及其他商品、货物。前述两种做法都是对贸易的极度 负担和压制…..我们一致同意并宣布:任何代表均无权改变一个人的等级,剥 夺人的财产权,或者做其他类似的事情。
1689年,不列颠面临的最迫切的事就是要有一部成文宪法,一部与 后来的北美继承者相似的权利法案。与《大宪章》不同,1689年英国《权利法案》 (the 1689 Bill of Rights)被普遍视为一个宪法性解决方案。并且,也与《大宪章》不同,《权利法案》所提供的议会主权的机 制远远超越了此前的御前咨商会。因此,我们有必要花点时间来重温一 下反对斯图亚特王朝的斗争——是它第一次把英语民族联合在了一起, 并且为我们留下了议会政体。
詹姆斯国王对王权绝对主义充满狂热。在他的政论集《自由君主制的真正法律》(The Trew Law of Free Monarchies,1598) 和《王权》(Basilikon Doron,1603)中,詹姆斯提出了“君权神授”理论。没有人敢质疑这位放言无忌的国王如此直陈自己的观点:“君主制国家是世界 上最高的事物。国王不仅是上帝在尘世的代理人,端坐于上帝的宝座, 而且他们本人就是被上帝亲口所称的上帝。”
接下来的冲突横扫了所有讲英语者居住的王国。在苏格兰,主教战 争让位于盟约派与保皇党之间的内战,后者得到了爱尔兰军队的支持。 而在爱尔兰,教派冲突更为激烈,演变为联合战争(有时又被称为十一 年战争)。这场战争终结于英格兰和苏格兰方面的两线入侵,以及至今 想来仍叫人不寒而栗的大屠杀。至于英格兰境内,则先后发生了两场以 恢复君主制为目的但以破产而告终的战争,第一场苏格兰人支持国会, 第二场却支持国王。很多历史学家喜欢将这系列交错的战乱称为三国之 战 (Wars of the Three Kingdoms,威尔士那时是英格兰的一部分),尽 管将它们视为第一次盎格鲁圈内战更为准确。
1689年2月,议会起草了《权利宣言》(Declaration of Right)。当 年晚些时候,这一宣言成为议会的正式立法,也就是我们现在所称的《英国权利法案》(English Bill of Rights)。以今人的眼光看,它的形 式和内容都非常接近于《独立宣言》和美国宪法的先声- 尽管法案的 起草者并不是在向前看,而恰恰是往回看,从17世纪40年代的各种请愿 书,最终回到《大宪章》上。
所有这些研究成果后来都凝结在菲利普斯1990年出版的《表亲战争:宗教、政治以及盎格鲁的胜利》 (The Cousins’Wars:Religion, Politics,and the Triumph of Anglo-America) 一书中。该书揭示的中心议 题是,英国内战、美国革命和美国内战是同一场持续冲突的三次爆发。 这一观点一经如此直截了当地说出来,总让人觉得有点不踏实。但菲利 普斯是做了很多功课的。他考察了三场战争中若干教会团体,甚至是个 人及家庭,发现了其中一以贯之的政治延续性。要知道,一个有说服力 的新观点的标志往往是:尽管最初看上去有点别扭,但最后会被证明是 显而易见的。一旦我们把美国革命理解为是一场内战,那么,很多问题都会水落石出、各归其位了。
殖民地流传最广的历史著作——纳撒尼尔 ·培根 (Nathaniel Bacon)的《统一的英格兰政府的历史讲稿》(Historical Discourse of the Uniformity of the Government of England)、亨利 ·卡尔 (Henry Care) 的《英国的自由》(English Liberties)、卡姆斯勋爵 (Lord Kames)的《古代英国》(British Antiquities)——讲述的都是同样的故事:1066 年,一个自由的民族因为大陆入侵者丧失了自由,其后就是为了恢复自 由而进行斗争的历史。甚至就在美国独立期间,有一些明知自己没有英 国祖先的美国人仍然热衷于为自己购得一个盎格鲁——撒克逊政治身份。
但是将盎格鲁圈视为扩大版的盎格鲁——撒克逊国家的最大问题,在 于印度就无处可放了。泛大不列颠的一些支持者公然断言印度永远不可 能加入,因为如克莱武所宣称,他们从根子里就是独裁、腐化和贪图享 受的。与集中保留了不列颠辉格党式民主文化的殖民地不同,印度被认为只适合威权统治。因此,正如历史学家J.R.西莱在他的《英格兰的扩 张》 (The Expansion of England)中所说:“当我们问泛大不列颠未来如 何时,我们必须更多地考虑我们的殖民地,而不是印度帝国。”
奥巴马从没见过他爷爷,但他后来了解到的家族史使他很受震撼。 尽管盎扬戈被英国当局拘捕,但他还是保留了一个帝国主义者的立场, 相信英国在肯尼亚的高层机构应有一席之地。盎扬戈常常提到,非洲人 太懒了,根本不可能争取到独立。为此,年轻的奥巴马感到很震惊。“我想象他是他的民族的一分子,反对白人的规则。”他在自传《我父亲的梦想》(Dreams from My Father) 中写道,“奶奶告诉我的故事完全颠覆了我过去的印象,那些丑陋的字眼在我的脑海不断闪现:汤姆 大叔,投敌者,顺从的黑奴”。
但是,且让我在此提醒读者,傅利曼可不是个简单的人物。他的正统利伯维尔场论述在多数领导企业的董事会中仍是主流,就连那些从美国政府手中赚进大量利润的公司也不例外──此外还有商学院,甚至是公立的商学院。至今美国商会(US Chamber of Commerce)仍奉傅利曼的正统学说为圭臬。因此,美国与其他自由经济的民主国家往往不会承认,我们和利伯维尔场思想在本质上是恐怖情人般的关系,我们以为利伯维尔场能创造财富与带来革新,但现实中却不断上演各种无止尽的循环:法规松绑、债务危机、破产、诈欺与市场崩溃,随之而来的是政府纾困、日益严重的垄断、财富不均与政治不稳定。于是,我们一次又一次地因为矛盾且自扯后腿的政策而回到原点。我们正步入关键新世纪,即将要面对各种经济挑战,为此我们必须去理解“利伯维尔场”这个词汇的意义、它的历史,它何时能顺利运作,以及何时无法。5
如果傅利曼是利伯维尔场的拥护者最喜爱的儿子,那么十八世纪的苏格兰哲学家亚当斯密(Adam Smith)就是这个传统的父亲。然而,将亚当斯密视作傅利曼式放松管制、不受约束的利伯维尔场之拥护者,这样的现代概念并不完全准确。斯密的论述早已被错误理解、错误引用,脱离了他著述的十八世纪背景脉络并沦为陈腔滥调,但他的著作仍提供了宝贵的经验,让我们理解如何看待经济学。在斯密于一七七六年撰写《国富论》(The Wealth of Nations )之前,从没有人把规模这么大又这么复杂的经济体与社会体,视为一个巨大的、自我调节的财富创造系统。不过,斯密也认为政府与其机构在市场中扮演了重要角色。在他看来,让市场以绝佳状态运作的状况,就是品德高尚的斯多噶领袖──他们通晓希腊与罗马哲学中透过自知与纪律追求幸福的理念──和富有的地主并肩合作,共同主导政治与市场,制定适当的指导、诱因与调查制度,维持经济体运行。
矛盾的是,解开利伯维尔场之谜的关键人物早在亚当斯密出生前四十年就已经过世了,他长久以来被经济学家视为站在斯密的对立面:法国国王路易十四的著名内政大臣尚─巴提斯特.柯尔贝(Jean-Baptiste Colbert),柯尔贝打从一六五○年代中期开始监督法国经济,直至一六八三年离世为止。法国皇家与公共财政的组织方式与管理良好、标准化的度量衡系统,以及法国道路、港口与运河的商业流通系统建造,全都要归功于柯尔贝。他一手创建了巴黎警察与工业检验单位,以至法国工业、法国海军与凡尔赛宫。他同时也是国家研究的主任,设立了皇家图书馆与档案馆,以及法国皇家科学院(French Royal Academy of Sciences)。柯尔贝认为这些努力对于一个能够顺利运作的流动市场来说是必要的,他是那个时代最成功的大规模市场建造者,使用关税、补贴、国家垄断与政治压迫来达成各种目标。
柯尔贝用国家的强硬手段介入市场建设,其最主要的目标是推动法国商业发展到足以和英格兰商业自由竞争。他相信他所谓的“商业自由”(liberty of commerce)源自于相互对称的市场与平衡的贸易条约。柯尔贝将国际贸易视为零和游戏,认为黄金和财富是有限的,同时他也确信把焦点放在商业与工业的社会能在经济上获得最大的成功。在他初掌权时,法国主要还是农业国家。他以推动经济发展为使命,比起农业更偏爱工业、创新与贸易;他相信这些事物能铺设一条道路,通往更自由、更顺畅的经济循环,使法国变成富裕且辉煌的国度。
1. Léon Walras, Elements of Pure Economics; or, the Theory of Social Wealth , trans. William Jaffe (London: Routledge, 1954), 153–155; Bernard Cornet, “Equilibrium Theory and Increasing Returns,” Journal of Mathematical Economics 17 (1988): 103–118; Knud Haakonssen, Natural Law and Moral Philosophy: From Grotius to the Scottish Enlightenment (Cambridge: Cambridge University Press, 1996), 25–30.
2. Milton Friedman, Capitalism and Freedom , 3rd ed. (Chicago: University of Chicago Press, 2002), 15; Milton Friedman, Free to Choose: A Personal Statement , 3rd ed. (New York: Harcourt, 1990), 20, 145.
3. Anat Admati, “Anat Admati on Milton Friedman and Justice,” Insights by Stanford Business, October 5, 2020, www.gsb.stanford.edu/insights/anat-admati-milton-friedman-justice ; Diane Coyle, Markets, State, and People: Economics for Public Policy (Princeton, NJ: Prince ton University Press, 2020), 98–101; Rebecca Henderson, Reimagining Capitalism in a World on Fire (New York: Public Affairs, 2020), 19, 67; Bonnie Kristian, “Republicans More Likely Than Democrats to Say the Free Market Is Bad for America,” Foundation for Economic Education, December 9, 2016, https://fee.org/articles/republicans-more-likely-than-democrats-to-say-the-free-market-is-bad-for-america ; Jonah Goldberg, “Will the Right Defend Economic Liberty?” National Review , May 2, 2019; Martin Wolf, “Why Rigged Capitalism Is Damaging Liberal Democracy,” Financial Times , September 17, 2019, www.ft.com/content/5a8ab27e-d470-11e9-8367-807ebd53ab77 ; Ben Riley-Smith, “The Drinks Are on Me, Declares Rishi Sunak in Budget Spending Spree,” The Telegraph , October 27, 2021; Inu Manak, “Are Republicans Still the Party of Free Trade?,” Cato Institute, May 16, 2019, www.cato.org/blog/are-republicans-still-party-free-trade ; Aritz Parra, “China’s Xi Defends Free Markets as Key to World Prosperity,” Associated Press, November 28, 2018.
4. Erik S. Reinert, How Rich Countries Got Rich, and Why Poor Countries Stay Poor (London: Public Affairs, 2007); Ciara Linnane, “China’s Middle Class Is Now Bigger Than America’s Middle Class,” MarketWatch, October 17, 2015, www.marketwatch.com/story/chinese-middle-class-is-now-bigger-than-the-us-middle-class-2015-10-15 ; Javier C. Hernández and Quoctrung Bui, “The American Dream Is Alive. In China,” New York Times , November 8, 2018; Karl Polanyi, The Great Transformation: The Political and Economic Origins of Our Time (Boston: Beacon Press, 1957), 267–268; Fred Block and Margaret R. Somers, The Power of Market Fundamentalism: Karl Polanyi’s Critique (Cambridge, MA: Harvard University Press, 2014), 2; David Sainsbury, Windows of Opportunity: How Nations Create Wealth (London: Profile Books, 2020).
5. Martin Wolf, “Milton Friedman Was Wrong on the Corporation,” Financial Times , December 8, 2020, www.ft.com/content/e969a756-922e-497b-8550-94bfb1302cdd .
6. Adam Smith, An Inquiry into the Nature and Causes of the Wealth of Nations , ed. Roy Harold Campbell and Andrew Skinner, 2 vols. (Indianapolis: Liberty Fund, 1981), vol. 1, bk. IV, chap. ii, para. 10; William J. Barber, A History of Economic Thought (London: Penguin, 1967), 17; Lars Magnusson, The Tradition of Free Trade (London: Routledge, 2004), 16.
7. Joseph A. Schumpeter, History of Economic Analysis (London: Allen and Unwin, 1954), 185.
8. Smith, Wealth of Nations , vol. 2, bk. IV, chap. ix, para. 3.
9. D. C. Coleman, ed. , Revisions in Mercantilism (London: Methuen, 1969), 91–117, at 97; William Letwin, The Origins of Scientific Economics: English Economic Thought, 1660–1776 (London: Methuen, 1963), 43; Lars Magnusson, Mercantilism: The Shaping of an Economic Language (London: Routledge, 1994); Philip J. Stern, The Company State: Corporate Sovereignty and Early Modern Foundations of the British Empire in India (Oxford: Oxford University Press, 2011), 5–6; Rupali Mishra, A Business of State: Commerce, Politics, and the Birth of the East India Company (Cambridge, MA: Harvard University Press, 2018); Philip J. Stern and Carl Wennerlind, eds. , Mercantilism Reimagined: Political Economy in Early Modern Britain and Its Empire (Oxford: Oxford University Press, 2014), 6; Schumpeter, History of Economic Analysis, 94; Eli F. Heckscher, Mercantilism , trans. Mendel Shapiro, 2 vols. (London: George Allen and Unwin, 1935); Steve Pincus, “Rethinking Mercantilism: Political Economy, the British Empire, and the Atlantic World in the Seventeenth and Eighteenth Centuries,” William and Mary Quarterly 69, no. 1 (2012): 3–34.
这种身分认同的中心是对于自然与农业的理解,而西塞罗也慎重其事地借鉴了一长串农业思想家的观点。对于他的愿景来说,不可缺少的人物是老加图(Cato the Elder),一名极端保守派的军人、史学家暨罗马父权制的捍卫者,他在公元前一六○年的著作《论农业》(On Farming )中阐述道,贵族财产依靠的是良好的农业管理。对于了解农耕的人来说,大自然的每一丝恩赐都与共和体制一样安定稳固。对于创新与贸易,老加图直接表达了鄙视。只有大规模的土地拥有制才是真正“良好”的,才能培养出具有道德良知的公民与士兵。3
凭借着与大自然的密切关系,并且为了延续贵族社会,地主阶级的成员自认有责任去研究他们所谓的大自然神圣法则。西塞罗在《论共和国》(On the Republic ,公元前五四至五一年)中指出,在“最好的人”用“合度的方式”进行统治时,就能透过和平与繁荣使“公民们享受到最大程度的幸福”。富裕的贵族阶级因为没有“任何烦恼或担忧”的负荷,能够专注于以纯粹的美德为基础来运作政府。西塞罗对于“最好的人”的概念,立基于自然并非平等地创造出每一个人类。而如果自然在创造人类时有所区别,那么人类也应该要效仿自然的区别。真正的政治自由与经济自由本就只属于少数地主。5
于是罗马贵族透过他们对国家的奉献达成这点,他们经由广大的小麦分配系统(annona civica)捐献面包给公民,这个系统是经济体制的支柱。罗马帝国的船队把小麦分送至地中海彼岸,当时罗马人将地中海称作“我们的海”(mare nostrum)。若说罗马是身体的话,地中海就像是身体里的器官──博物学家暨军事领袖老普林尼(Pliny the Elder)在他的著作《自然史》(Natural History )中,把地中海称作“肠海”(mare intestinum),因为地中海促进了罗马经济的自由流动。如此一来,财富──首先便是地主阶级的小麦收获──就会根据自我调节的自然法则,在罗马帝国中自然而然地流动。在看似永恒不坠的国家与元老院阶级的协助下,罗马透过四季的无形之手制造出商品并养活自己。罗马资助的不只有意大利与北非之间的交易与船运航道,也扩及了伊比利亚、希腊、安纳托利亚(Anatolia)与黑海。各种商品在幅员辽阔的罗马贸易区中自由地流通。9
如果说西塞罗在罗马攀升到权力顶峰是一件令人惊叹的事,那么他的逝世就更加戏剧化了,他的死亡肇因于他对罗马宪法、前述的良性交易规则,以及私有财产与自由贸易基本原则的捍卫。公元前六三年,年仅四十二岁的西塞罗成为了罗马的两位执政官之一,这是罗马政府最高阶的职位了。在他担任罗马执政官的期间发生了暴力叛乱,他很快就陷入和元老院议员喀提林(Catiline)之间的冲突,喀提林当时正在竞选执政官,他的改革主义聚焦在免除穷人债务与分配土地。西塞罗蔑视所有行事不符合贵族精神的人民改革家。他觉得提供土地给穷人不但破坏了市场规则,更破坏了现有的秩序本身。因此,西塞罗在元老院中,当着喀提林的面发表了那名留青史的演说。他花了好几天的时间痛斥喀提林目无法纪,也谴责喀提林的朋友亏欠债务,并质疑喀提林救济穷人的动机。最后,西塞罗成功要求当局处决了喀提林的几个同谋者。当西塞罗高呼:“喔,时代!喔,习俗!”(O tempora, o mores!)时,指的是喀提林对法律的彻底漠视,与他在金融上的腐败和贪婪。同时,西塞罗也是在捍卫他眼中的自然道德经济秩序。10
我们可以从西塞罗捍卫现状的戏剧化行为了解到,他如何把荣誉看作市场的必要条件。贿赂和诈欺不只是“不公正”的行为,更是一种“虚伪”。举例来说,西塞罗在公元前六三年通过了一项禁止用选票换取好处的法律,名为《图利亚贿选法》(Lex Tullia de ambitu )。我们必须在此指出,包括尤利乌斯.西泽在内的许多人都认为西塞罗本身也贪污,更多人相信他不过是善于营造自我形象──我们确实无法否定这一点。但西塞罗与西泽不同,他捍卫了严格的元老院法律,也从未试图推翻宪法。11
公元前四九年,尤利乌斯.西泽开始对罗马共和国行使终身独裁权。接着,在公元前四四年的三月十五日──也就是著名的日子“三月中”(Ides of March)──马库斯.尤尼乌斯.布鲁图斯(Marcus Junius Brutus)带领一群共和派的元老院议员暗杀了西泽。西塞罗本人没有参与暗杀行动,但他如今也希望能引导元老院回到共和政府。在罗马共和国殒落及罗马帝国崛起的暴力动荡中,西塞罗在命运处于最低谷的时刻写下他最为永垂不朽的著作《论责任》(公元前四四年)。他声称这本充满哲学性建议的著作是写给儿子的,但后来《论责任》变成了西方传统中影响力最广泛的书籍之一,也成了利伯维尔场思想的蓝图。12
西塞罗听闻这项判决后,逃到了位于乡间的一处宅邸,希望能在那里准备好光荣赴死。当士兵到来时,他请求他们干净利落地一刀斩断他的脖子。最后士兵却斩了三次才成功。除了砍下这名命运悲惨的哲学家的头颅之外,一名士兵还砍掉了他的一只手。彼时马克.安东尼的举动完全符合西塞罗生前所犀利指控的残暴粗俗形象,他下令把西塞罗的头和手钉在集会广场的主要讲台(rostra)上,面对着元老院。这就是罗马最伟大的雄辩家暨共和政体捍卫者最后遗留的东西,一个将在未来数千年回荡不止的象征。西塞罗的出现比拿撒勒的耶稣(Jesus of Nazareth)还更早,作为一个世俗的共和主义殉道者,他的政治与经济美德理念被赋予了一种接近基督教式的悲怆,也使得西塞罗成为了西方历史上最重要的人物之一。他实现了自己的理想,与暴政和贪腐交易的背德行为战斗。他试图维护自然秩序与经济道德,揭示了一条通往财富的有德之路。
1. Titus Livy, History of Rome , trans. John C. Yardley, Loeb Classical Library (Cambridge, MA: Harvard University Press, 2017), bk. 1, chap. 8. For an online version of Livy edited by Rev. Canon Roberts, see the Perseus Digital Library, Tufts University, gen. ed. Gregory R. Crane, www.perseus.tufts.edu/hopper/text?doc=urn:cts:latinLit:phi0914.phi0011.perseus-eng3:pr .
2. Livy, History of Rome , bk. 23, chap. 24; bk. 1, chap. 35; Ronald Syme, The Roman Revolution , rev. ed. (Oxford: Oxford University Press, 2002), 15.
3. Cato, On Agriculture , in Cato and Varro: On Agriculture , trans. W. D. Hooper and H. B. Ash, Loeb Classical Library (Cambridge, MA: Harvard University Press, 1935), bk. 1, paras. 1–2.
4. Cicero, De officiis , trans. Walter Miller, Loeb Classical Library (Cambridge, MA: Harvard University Press, 1913), bk. 1, sec. 13, para. 41.
5. Cicero, On the Republic , in Cicero, On the Republic, On the Laws , trans. Clinton W. Keyes, Loeb Classical Library (Cambridge, MA: Harvard University Press, 1928), bk. 1, sec. 34, paras. 52–53; bk. 1, sec. 5, para. 19; bk. 1, sec. 8–9, para. 24.
6. Dan Hanchey, “Cicero, Exchange, and the Epicureans,” Phoenix 67, no. 1–2 (2013): 119–134, at 129; Wood, Cicero’s Social and Political Thought , 55, 81–82, 112; Cicero, De officiis , bk. 3, sec. 6, para. 30; bk. 1, sec. 7, para. 22.
7. Cicero, On Ends , trans. H. Rackham, Loeb Classical Library (Cambridge, MA: Harvard University Press, 1914), bk. 2, sec. 26, para. 83; Hanchey, “Cicero, Exchange,” 23; Cicero, De officiis , bk. 1, sec. 13, para. 41; bk. 1, sec. 16, para. 50; bk. 1, sec. 17, paras. 53–54; Cicero, De amicitia , in On Old Age, On Friendship, On Divination, trans. W. A. Falconer, Loeb Classical Library (Cambridge, MA: Harvard University Press, 1923), sec. 6, para. 22; sec. 7, paras. 23–24; sec. 7, paras. 23–24; sec. 14, paras. 50–52.
8. Cicero, De officiis , bk. 14, sec. 5, paras. 21–22; bk. 3, sec. 5, para. 23.
9. Caesar, The Gallic War , trans. H. J. Edwards, Loeb Classical Library (Cambridge, MA: Harvard University Press, 1917), bk. 5, para. 1. 另见 “Internum Mare,” in William Smith, Dictionary of Greek and Roman Geography , 2 vols. (London: Walton and Maberly, 1856), 1:1084; Peter Brown, Through the Eye of the Needle: Wealth, the Fall of Rome, and the Making of Christianity in the West, 350–550 AD (Princeton, NJ: Princeton University Press, 2014), 69; Pliny, Natural History , trans. H. Rackham, 37 vols. , Loeb Classical Library (Cambridge, MA: Harvard University Press, 1942), bk. 3.
10. Wood, Cicero’s Social and Political Thought , 48; Cicero, In Catilinam, in Cicero, Orations: In Catilinam, I–IV, Pro Murena, Pro Sulla, Pro Flacco , trans. C. Macdonald, Loeb Classical Library (Cambridge, MA: Harvard University Press, 1977), bk. 2, para. 21.
11. Cicero, De officiis , bk. 1, sec. 13, para. 47; Hanchey, “Cicero, Exchange,” 129; Brown, Through the Eye of the Needle , 253.
12. A. E. Douglas, “Cicero the Philosopher,” in Cicero , ed. T. A. Dorey (New York: Basic Books, 1965), 135–171.
13. Douglas, “Cicero the Philosopher. ”
14. Cicero, De officiis , bk. 1, sec. 13, para. 41; bk. 1, sec. 7, para. 27.
15. Cicero, On Ends , bk. 1, sec. 9, para. 30; bk. 1, sec. 10, paras. 32–33.
16. Cicero, On Ends , bk. 1, sec. 19, para. 69; Cicero, On the Republic , bk. 6, sec. 24, paras. 26–28.
17. Emily Butterworth, “Defining Obscenity,” in Obscénités renaissantes , ed. Hugh Roberts, Guillaume Peureux, and Lise Wajeman, Travaux d’humanisme et Renaissance, no. 473 (Geneva: Droz, 2011), 31–37; Cicero, Orations: Philippics 1–6 , ed. and trans. D. R. Shackleton Bailey, rev. John T. Ramsey and Gesine Manuwald, Loeb Classical Library (Cambridge, MA: Harvard University Press, 2009), chap. 2, paras. 96–98.
第二章 神圣经济
施予面包就能抓住天堂。 ──约翰(Saint John Chrysostom),〈讲道集三:思考救济与十个童女〉(Homily 3: Concerning Almsgiving and the Ten Virgins),约公元三八六年
虽然当时基督教遍布罗马帝国,但古罗马的诸神信仰仍拥有十分强大的势力。尽管君士坦丁大帝在公元三一二年左右归信了基督教,但一直到四世纪末为止,西塞罗仍在学院课程中占据主要地位。在基督诞生后的数个世纪中,教会教父(Father of the Church,有圣德的特定基督徒,其著作与教导对基督教有很大的贡献 )主要都是罗马贵族出身,这代表了他们是在非基督教的帝国文化中长大的。他们很熟悉罗马法律,并且他们得依靠皇帝来确保生活稳定。有些教会教父努力和西塞罗的思想搏斗,希望用一种基督教版本的新道德愿景取代西塞罗的论述,包括米兰主教圣安博(Saint Ambrose),以及后来在西方基督教最有影响力的神学作家圣奥古斯丁。到了最后,他们对财富的态度变得比西塞罗所设想的更加个人主义,也更加民主。
在西塞罗笔下,欲望从本质上就是一种负面特质。基督徒则相信,如果他们的欲望是被救赎,那么这种欲望就是道德的──举例来说,当一个人藉由把钱施舍给穷人、放弃世俗的享乐来交换天堂的奖赏时,这个人就是在满足符合道德的欲望。他们以《马太福音》和《路加福音》为基础,不但把这种对于天堂财宝的欲望视为一种好事,甚至视为神圣的事。基督徒引述福音书与其他典籍,用利益、选择、意志、交易与奖赏等经济语言来建构基督教的救赎。事实上,基督被钉在十字架上的本质就是一笔交易,《希伯来书》(Book of Hebrews )的作者写道,如果“不流一滴血”,罪就不会被赦免。换句话说,基督偿还了人类的集体债务。1
福音传道士圣路加(Saint Luke the Evangelist)坚持基督徒应该要施舍穷人,藉此摆脱世俗财产,如此才能获得天堂的财富。耶稣在传福音时说:“你们要变卖所有的赒济人,为自己预备永不坏的钱囊,用不尽的财宝在天上,就是贼不能近、虫不能蛀的地方。”圣马太(Saint Matthew)原本是一名税吏,而后在耶稣的召唤下成为门徒,他也对此做出呼应。圣马太在《新约》中跟着马可和路加引用了一句耶稣曾提及的古老犹太谚语:富人上天堂的机率比骆驼穿过针眼的机率更渺茫。他也引述道,耶稣曾说过世俗财宝的本质是转瞬即逝的,并将世俗财宝描述为:“地上有虫子咬,能锈坏,也有贼挖窟窿来偷。”他呼吁信徒应该在心中寻找永恒的宝藏。马太的叙述和路加一样,他指出耶稣在描述救赎时其实是以贫困为前提的,那是一种交换的过程,一个人若想获得救赎就必须施舍穷人:“耶稣说:‘你若愿意作完全人,可去变卖你所有的,分给穷人,就必有财宝在天上;你还要来跟从我。’”2
这一点在早期教会教父的生活型态中表现得非常明显,他们的生活与罗马贵族的传统奢华生活形成了鲜明对比。基督教领导人实践的是自我克制的极端生活型态,这种自我克制承袭自悠久的禁欲主义传统。“亚历山大的革利免”(Clement of Alexandria)在《富人的救赎》(The Rich Man’s Salvation )中虽然承认了世俗财富必须存在,但他说明道,这些财富的使用有其规则,人们尤其应该遵循“供给”的虔诚实践,将财富施舍出去。若一名富人把所有财富都施予穷人与教会,并藉此过程把他的热忱倾注于耶稣,就能找到救赎。6
在公元前一世纪,禁欲主义的基本原则透过非基督教的希腊道德家塞克斯都(Sextus)的作品,流传至罗马帝国各处,塞克斯都协助创造了一种能够自我调节的灵性交易市场概念,他的行为准则和新基督教的道德规范是互通的。《塞克斯都语录》(The Sentences of Sextus )在论及人与上帝之间的关系还有死后生命时,描述了一种货币流通过程。塞克斯都写道,唯有“放弃肉体的事物,人才能自由地获得灵魂的事物”,并直言不讳地补充道:“富人难以获得救赎。”他阐述了柏拉图式的观点,认为一个人可以透过灵性研究与自我克制成为贴近上帝的“圣人”。透过“征服肉体”,圣人可以“把一切能给的全都施予穷人”。世俗的依附情感──甚至对于儿女的情感──都应该受到鄙夷。塞克斯都感叹道:“信仰虔诚的人会心怀感激地承受失去孩子的痛苦。”他警告道,世俗享乐的罪恶将会“被邪恶的恶魔追究,直到还清最后一分为止”。7
塞克斯都的行为准则很快就传遍了希腊的基督教社群。首屈一指的神学家们也欣然接受了这些准则──包括亚历山大学派的基督教学者欧利根(Origen),他在三世纪时惊叹地指出阅读塞克斯都作品的人“为数众多”。随后问世的一系列基督教作品也响应了这个概念:人们必须用天堂市场来取代世俗市场。原罪代表了人类不能真正享受世俗的快乐。例如,大约在公元九○年至一五○年间出现的《黑马牧人书》(The Shepherd of Hermas )就是以这个概念作为核心。书中包含了最早由圣马太写下的基本原则,也就是富人“在上主的事物方面”是贫乏的,并补充道,人类唯有透过贫困与谦卑才能享有上帝的赏赐。该书大加赞颂禁食与禁欲的生活,这是古典时代晚期的宗教文学中随处可见的主题。在《启示录》(公元九五年)中,拔摩岛的约翰(John of Patmos)描述了耶稣对安纳托利亚的七个城市的罪予以谴责。这七个城市──以弗所(Ephesus)、士每拿(Smyrna)、别迦摩(Pergamum)、推雅推喇(Thyatira)、撒狄(Sardis)、非拉铁非(Philadelphia)、老底嘉(Laodicea)──被视为世俗世界的隐喻,代表了《圣经》对于肉体和商业都市生活的不信任。大约在公元二○八年,神学家特土良(Tertullian)以同样戏剧化的方式痛斥罗马是浸染了殉道者鲜血的现代巴比伦。他也同样呼吁人们压抑性冲动,甚至反对人们在配偶逝世后再婚。他赞扬人们透过鳏寡生活与童贞将自己一心奉献给上帝的神圣行为。他坚持认为处女应该蒙上头巾,如此一来才更能全心全意仰望基督。蒙头可保护她们不受罪恶沾染,因而“值得进入天堂”。8
基督徒用这种极端的、自愿的性欲克制去换取救赎,这使得基督教从根本上来说比犹太教更具有交易的特质。钱财、色欲、享乐,甚至吃饭、说话和微笑──从基督教的观点来看,这些全都是坏事,都是原罪的产物,必须抛弃这些事物才能换取天堂作为报偿。在三世纪刚开始的数十年,欧利根撰写了一本讨论死后生命的奠基之作,他在书中主张唯有透过自我克制才能获得进入天堂的奖赏。欧利根将贞操能够换到救赎的观点推到极端,而阉割了自己。写下《罗马帝国衰亡史》(The Decline and Fall of the Roman Empire )的启蒙时代重要作家爱德华.吉朋(Edward Gibbon),曾就欧利根对《圣经》的字面解释做出著名的评论,说那是一个“不幸的”错误。9
神圣市场与它追求更高目标的模式,逐渐变成基督教生活的核心,其中强调的是选择、纪律、报偿和奖赏。古典时代晚期有许多人以戏剧化的形式自我牺牲,希望能藉此进行神圣交易,欧利根只是其中之一。男性守贞变成一种寻求上帝财富的自律形式而受到重视,而后成了神职人员与修道士守贞传统的基础。沙漠教父(Desert Father,指的是在三世纪、四世纪隐居于埃及沙漠的一群基督教徒 )为这种新兴的修道院主义与禁欲经济定下了基调。一代又一代的修道士进入了埃及的沙漠,只接受最微薄的捐献,他们活着的唯一目的就是和上帝交流。其中最有名的可能是柱顶修道士西蒙(Simeon the Stylite,约公元三九○至四五九年),他在叙利亚阿勒坡市(Aleppo)一根柱子上方的小平台生活了三十七年。10
西蒙是牧羊人之子,不过有许多淡泊名利的基督教领导人都来自富有的贵族。部分贵族依据罗马的公民义务理想,成为了主教和首屈一指的神学家。值得注意的例子包括教会领导人圣巴西略(Saint Basil,约三二九年至三七九年),和他的兄弟“尼撒的贵格利”(Gregory of Nyssa,约三三五年至三九五年)、圣金口约翰(约三四七年至四○七年)及圣安博(约三四○年至三九七年)。对他们来说,美德就是“祷告”与拒绝肉体。人与人之间的友谊也只应该以基督教团契为基础。贵格利拒绝了异教徒西塞罗对自然世界的崇拜,他写下了后来变成基督教格言的句子:“大自然是软弱的,并非永恒的。”是上帝创造了大自然,上帝才是永恒的,而所有自然系统都源自神。11
约翰利用恐惧和宗教狂热式的舞台展演来鼓动当地居民,他热中于对犹太人与同性恋者传道,并且警告基督徒,观赏君士坦丁堡的淫秽表演会使他们入地狱。他在以弗所城呼吁暴徒拆除古代世界七大奇迹之一的阿提密斯神庙(Temple of Artemis)。他在安提阿布道时,藉由听众的经济敏感度来号召:他在著作〈讲道集三:思考救济与十个童女〉(约公元三八六至三八七年)中提出了简短有力的请求,要人们把所有享乐与经济活动纳入神圣交易的逻辑中。
安博身上结合了帝国的官员职责与坚实的基督教信仰,因此成为了热心传教的现实主义者。他认为自己必须直面西塞罗,才能改变所谓职责的本质。因此我们也无需讶异,安博用他最重要的著作之一《论神职人员的责任》(On the Duties of the Clergy ,约公元三九一年)来抨击西塞罗的作品。他谴责西塞罗的修辞理论,坚信优雅与美丽并非存在于言语的艺术中,而是存在于上帝之中。真正的知识只可能出自神性的启示,而非出自世俗的科学。安博也直接攻击了私有财产:“我们认为一切都毫无意义,只有能帮助我们获得永生祝福的事物例外。”人类理所当然不可能拥有任何事物,因为上帝赐予人类的比人类能给予上帝的还要更多,使人类不可避免地“在救赎方面成为债务人”。15
奥古斯丁在离开意大利之前开始撰写《论意志的自由选择》(On Free Choice of the Will ),旨在理解善恶与预定论。这是一部了解恩典与救赎的道德市场逻辑的关键作品。奥古斯丁在书中解释道,若一个人想要从原罪中解脱与获得恩典,首先必须被上帝拣选。换句话说,人类必须经由神的意图才能做出正确的选择。当上帝能预见一切后果,他仍为人类保留了犯下极端错误的自由。奥古斯丁指出,交易市场中只有两种人,一是善用纪律的美德,二是成为“欲望的奴隶”,这样的主张透露出西塞罗的斯多噶主义带来的影响。
就像所有世间事物一样,这个新基督教的罗马也无法长久存在。西哥德王国(Visigoths)的国王阿拉里克(Alaric)在四一○年洗劫了罗马,整座城市就此沦陷。部分罗马菁英阶层为了逃离入侵的日耳曼军而一路逃到了奥古斯丁所在的希波,但那里理所当然地同样一片恐慌。希波没有任何军事资源能保护自己。不过,对奥古斯丁来说,教会面对的世俗挑战提供了一个机会,能让他推展他对救赎经济中之个人主义的所思所想。过去西塞罗在面对罗马共和崩溃的艰苦逆境时,展示了文学的力量。而现在,罗马的真正陷落则启发了奥古斯丁写下他的不朽著作《天主之城》(City of God ),他在书中阐释了尘世财富的必要性,与这些财富在神圣经济中的位置。22
1. Matthew, 13:44; Luke 12:33; Hebrews 9:22; Giacomo Todeschini, Les Marchands et le Temple: La société chrétienne et le cercle vertueux de la richesse du Moyen Âge à l’Époque Moderne (Paris: Albin Michel, 2017).
2. Luke 12:33; Matthew 6:19–21. 另见 Mark 10:25 and Luke 18:25.
3. Matthew 25:29. 投资与报偿的概念变成了 Robert K. Merton’s “Matthew Effect in Science: The Reward and Communication Systems of Science Are Reconsidered,” Science 159, no. 3810 (1968): 56–63 的基础。
4. Proverbs 19:17. See also Matthew 25:45.
5. Matthew 19:12.
6. Clement of Alexandria, The Rich Man’s Salvation , trans. G. W. Butterworth, rev. ed. , Loeb Classical Library (Cambridge, MA: Harvard University Press, 1919), 339; Todeschini, Les Marchands et le Temple , 28.
7. Walter T. Wilson, ed. and trans. , Sentences of Sextus (Atlanta: Society of Biblical Literature, 2012), 33–38, 74, 261–264.
8. Wilson, Sentences of Sextus, 2; The Shepherd of Hermas , trans. J. B. Lightfoot (New York: Macmillan, 1891), Parable 2, 1[51]:5, available at Early Christian Writings, www.earlychristianwritings.com/text/shepherd-lightfoot.html ; Tertullian, “On the Veiling of Virgins,” trans. S. Thelwall, in The Ante-Nicene Fathers , ed. Alexander Roberts, James Donaldson, and A. Cleveland Coxe, vol. 4, revised for New Advent by Kevin Knight (Buffalo, NY: Christian Literature Publishing, 1885).
9. Edward Gibbon, History of the Decline and Fall of the Roman Empire , 6 vols. (London: Strahan, 1776–1789), vol. 1, chap. 15, n. 96.
10. Richard Finn, Almsgiving in the Later Roman Empire: Christian Promotion and Practice, 313–450 (Oxford: Oxford University Press, 2006), 93.
11. Benedicta Ward, The Desert Fathers: Sayings of the Early Christian Monks (London: Penguin, 2005), 20–54; Gregory of Nyssa, On Virginity , ed. D. P. Curtin, trans. William Moore (Philadelphia: Dalcassian Publishing, 2018), 19.
12. John Chrysostom, “Homily 3: Concerning Almsgiving and the Ten Virgins,” in On Repentance and Almsgiving , trans. Gus George Christo (Washington, DC: Catholic University of America Press, 1998), 28–42, at 29–31.
13. Chrysostom, “Homily 3,” 32.
14. Ambrose, On the Duties of the Clergy , trans. A. M. Overett (Savage, MN: Lighthouse Publishing, 2013), 55, 89, 205–206; Ambrose, De Nabuthae , ed. and trans. Martin R. P. McGuire (Washington, DC: Catholic University of America Press, 1927), 49.
15. Ambrose, On the Duties of the Clergy , 55, 78, 83.
16. Ambrose, On the Duties of the Clergy , 122–124.
17. Ambrose, “The Sacraments of the Incarnation of the Lord,” in Theological and Dogmatic Works , trans. Roy J. Deferrari (Washington, DC: Catholic University of America Press, 1963), 217–264, at 240.
18. Peter Brown, Augustine of Hippo: A Biography (Berkeley: University of California Press, 2000), 169.
19. Augustine, On the Free Choice of the Will, On Grace and Free Choice, and Other Writings , ed. and trans. Peter King (Cambridge: Cambridge University Press, 2010), 1; Peter Brown, “Enjoying the Saints in Late Antiquity,” Early Medieval Europe 9, no. 1 (2000): 1–24, at 17.
20. Brown, Augustine of Hippo , 218–221.
21. Augustine, “Sermon 350,” in Sermons , ed. John E. Rotelle, trans. Edmund Hill, 10 vols. (Hyde Park, NY: New City Press, 1995), 3:107–108, available at https://wesleyscholar.com/wp-content/uploads/2019/04/Augustine-Sermons-341-400.pdf ; Peter Brown, Through the Eye of a Needle: Wealth, the Fall of Rome, and the Making of Christianity in the West, 350–550 AD (Princeton, NJ: Princeton University Press, 2014), 355; Augustine, Letters , vol. 2 (83–130), trans. Wilfrid Parsons (Washington, DC: Catholic University of America Press, 1953), 42–48; Brown, Augustine of Hippo , 198.
22. Brown, Augustine of Hippo , 299.
23. Augustine, City of God , trans. Henry Bettenson (London: Penguin, 1984), bk. 1, chap. 8; bk. 1, chap. 10.
24. Augustine, City of God , bk. 12, chap. 23; Augustine, Divine Providence and the Problem of Evil: A Translation of St. Augustine’s de Ordine , trans. Robert P. Russell (Whitefish, MT: Kessinger, 2010), 27–31.
25. Augustine, “Exposition of the Psalms,” ed. Philip Schaff, trans. J. E. Tweed, in Nicene and Post-Nicene Fathers , First Series, vol. 8 (Buffalo, NY: Christian Literature Publishing, 1888), revised for New Advent by Kevin Knight, www.newadvent.org/fathers/1801.htm .
第三章 中世纪市场机制中的神
事实上,正是因为某些事物非常稀少或难以寻获,这些事物才变得更加被需要。根据这样的准则,相较于足以满足所有人的小麦丰收期,小麦在短缺时期的价值更高。 ──彼得.约翰.奥利维(Peter John Olivi),《合约论》(Treatise on Contracts ),一二九三年
中世纪的城市之所以会难以理解自由贸易,是因为当时的商业自由最初是以明显的垄断形式出现的:教会和国家都把自由贸易的特权授予城市与城市里的行会,也只把特权限制于此。这种结合带来了经济发展与市场扩张。一一二七年,在法国北部法兰德斯郡(County of Flanders)的圣奥梅尔(Saint-Omer),威廉.克利托伯爵(William Clito)授予特权给市区居民──也就是圣奥梅尔的城市公民,允许他们无论犯了什么罪,都可以在自己的城市法庭中受审。此外,他也免除了他们在法兰德斯服兵役、缴交通行费与缴纳多项税款的义务。大致上来说,这些市民摆脱了封建的束缚,不需要缴纳日耳曼的汉萨税(hansa tax),也不需要支付安全过路费给神圣罗马帝国的皇帝,或通行费给法国王室。他们也可以随心所欲地维持地方垄断,伯爵保证所有在城市内签署的合约都必定会履行。在一份海关文件中,伯爵列出了他与各国统治者达成的协议,以保护当地居民的免税权利。此外,伯爵也保证会对市镇提供军事保护。8
神学家往往对商人抱持戒心。这是因为商人为了谋取利润而汲汲营营,他们不耕作土地,被视为在精神上甚至比真正的穷人还要更贫穷。十世纪,“维洛纳的瑞提尔”(Rathier of Verona)把商人归类成“流浪者和贫民”。但到了十一世纪,神学家对于商业的看法有了转变。从意大利主教暨法律神学家格拉提安(Gratian)到神学家“克莱尔沃的伯纳德”(Bernard of Clairvaux),这些首屈一指的思想家都以正向态度看待虔诚的商人。本笃会修道士暨教会改革者伯多禄.达弥盎(Peter Damian)指出,一个优秀的主教应该要像优秀的商人一样管理自己的教区。如果商人能把财富奉献给慈善事业,那么商人当然就是好的。教会藉由这种方式清楚区分哪些人是自然经济的一部分,哪些人不是:举例来说,“不信基督者”和“犹太人”被视为侵占基督教合理财富的有罪者,他们是“坏”商人,不得与任何有道德的当权者交易。但在多数情况下,教会并不想要抨击商人的财富,他们只希望商人分享财富。因此,教会开始利用强大的影响力去控制正在成长的经济,同时在市场中坚持基督教的道德观。11
虽然教会没有权力控制商业生态,但会指导行会设下有道德的价格,这些价格同时反映着市场价值公平公正的交易原则,其中也包括了对利润的限制。基督教自行定义了他们的道德商业社群与新市场规则,只要遵循基督教的方法,基督徒就可以自由交易。这里出现了与西塞罗相互呼应的观点:正如弗兰伯勒的罗伯特牧师(Robert of Flamborough)在《忏悔书》(Penitential ,约一二○八年至一二一三年)中写下的,建立在基督教式关系的“文明友谊”上而执行的交易,就是一种美德。12
从许多方面来说,中世纪经济思想的故事都始于方济各会(Franciscan Order)的创办者“亚西西的圣方济各”(Saint Francis of Assisi)的人生。他在一一八一年出生于意大利翁布里亚(Umbria),原名为约翰.伯铎.伯纳戴德(Giovanni di Pietro di Bernardone),他的父亲是丝绸商人,母亲是普罗旺斯贵族。他的家族属于富有商人这个新阶级,居住在拉丁地中海地区──大约是从意大利与法国南部延伸到巴塞罗那的区域。这个社会经济阶级在往后被方济各拒之门外。一二○五年,他所目睹的异象引领他舍弃了世俗的财富。他声明放弃继承遗产,而为了展现自己将以基督之名献身于绝对的贫困,他惊世骇俗地当众脱去自己的衣物,这使他的父亲惊恐不已而和他断绝关系。从那时候开始,他只穿农民的粗布衣,成为了一名托钵修士,居住生活皆与穷人为伍,只靠着捐献过活。他是欧洲文化传统中第一位真正关注自然的生态学家,将动物视为有灵性的存在,并向牠们传道。他认为他的教堂没有墙壁,他的教堂就是自然本身,而从本质上拒绝富裕的修道院生活。当时宗教机构已经成了整个西欧的财富核心,而方济各的追随者、方济各会以及他们向绝对贫困立下的誓言对这些机构来说是莫大的威胁。
放弃财富会带来的深刻哲学反思,除了审视财富究竟为何,也审视了价格是如何由道德力量与市场力量创造出来。方济各经院派(Franciscan Scholastic)的神学家──他们接受过使用辩证法与演绎推理来解决哲学问题的训练──以巴黎大学(University of Paris)为中心,汲取柏拉图、亚里士多德和西塞罗的论点,去理解市场的运作要如何才能符合基督教的道德观。他们将亚里士多德的平衡观念与罗马的自然法结合起来,正如中世纪的法律典范著作,格拉提安的《教令集》(Decretals ,一一四○年)中描述的一样。《教令集》是一部中世纪罗马教会法的创始性汇编与典范之书,书中声明道,每一次不公平的损失──也就是教会认为对交易双方来说价值不相等的协议,或者诈欺──都必须用价值完全对等的事物来“恢复”。此一概念来自亚里士多德的《尼各马可伦理学》(Nicomachean Ethics )与“公平交换”(equal for equal)的原则。《尼各马可伦理学》更描述了人们要如何以私人财产、合约和许可为基础进行交易。这是公平价格理论的基础,此一理论指出,所有价格都应该反映出交易的公正平衡性,参与交易的人应该要平等获利。13
道明会修士暨意大利经院派思想家圣多马斯.阿奎那(Saint Thomas Aquinas)在他的著作《神学大全》(Summa Theologica ,一二六五年至一二七四年)中,也同意方济各会的说法,认为商人必须具备道德并使用“公正”的价格。然而,阿奎那不认同方济各为绝对贫困立下的誓言。他主张贫困不应该是一种要求或规则,而应该是个人选择或志向。事实上,他认为完全的贫困是不可能做到的事,这是因为所有人都必定拥有某些东西,他认为方济各会的誓言会带来犯下大罪与下地狱的风险,毕竟违背对上帝的誓言是非常严重的。这或许只是一个为了自身方便而提出的观点,鉴于道明会十分富有,拥有面积广袤的封建土地,在阿奎那看来,以道德方法取得的财富不会使他产生任何疑虑:他觉得教会需要变得富有。这样的观点影响了他对市场自然运作方式的理解。14
凑巧的是,方济各会士往往来自受过良好教育的经商背景,这也就代表了其中有些人对于商业与定价的运作方式具有较深入的认识。方济各会的领导人与信奉者逐渐开始认为,若想要确实遵守贫困誓言,就应该要更仔细地编订誓言内容。方济各会神学家圣文德(Saint Bonaventure)的《纳波内教会法规》(Constitutions of Narbonne ,一二六○年)对富裕与贫困进行了详细分析,目的是制定出严格的规范帮助方济各会士维持誓言。章程中最重要的主题之一是服装,在意大利,服装是最明显的财富象征,因此处的蓬勃经济核心正是布料生产。圣方济各认为服装对于保持贫困来说是一种物质阻碍,也是富裕的象征。举例来说,《纳波内教会法规》因此规范每位弟兄都只能拥有一件外衣,甚至特别阐明了修道士在外衣损坏或者需要用其他布料修补外衣时该怎么做。19
一二八六年,方济各会开始探讨他们是否不该把书籍(当时的书籍是昂贵的羊皮纸手稿)视为一种有价值的物品,而看成一种单纯的学习工具。依照方济各会士的看法,如果在使用昂贵的书籍时能恪守灵性实用目的,那么在方济各会的严格经济规范中,书籍就不算是奢侈品。据此,一般信徒可以把书籍当作礼物来赠送给修道士或修道院,但是必须由宗教机构的领导人或托管者来决定谁能使用这些书籍。一二九七年,波隆那的巴塞洛缪修士(Brother Bartholomeus of Bologna)从另一位修道士那里收到两本书。而后他把这两本书遗赠给了吴高利诺修士(Brother Hugolinus)。我们可以肯定的是,他们的行为符合灵性实用原则。这些修道士们谨慎地记录这些物品,明确写下自己的使用方式,如此一来他们才能用属世与属灵的标准算出这些物品的价值。20
教宗尼阁三世(Pope Nicholas III,在位期间一二七七年至一二八○年)支持方济各会的誓言,他认为有许多虔诚的方济各会士都证明了这个誓言是可以遵守的。他在一二七九年颁布了主题为“方济各会规范之确认”的教宗诏书《撒种的出去撒种 》(Exiit qui seminat ),并在其中提出了一项实现贫困誓言的革命性方法。教宗尼阁三世认为,方济各会士是不可能违背贫困誓言的,因为方济各会名下所有财产的实际拥有人其实是教宗;也就是说,方济各会士从来没有实际“拥有”任何事物。不只如此,尼阁还进一步用市场价值观念来解释道,就算方济各会士手上拥有任何货品与地产,这些财产的价值也不是固定的,而是取决于这些修道士在哪里、为了什么、用什么方式使用这些财产。每一件事物的价值都会依据它的实际用途与灵性用途而改变。尼阁强调,放弃财产“并不表示修道士在任何情况下都必须放弃使用物品”。他解释道,物品的价值来自“地点与时节”,而且也和特定的责任有关。他指出““科学是需要研究的”,如果没有““使用书籍”,修道士不可能执行这种研究。尼阁认为,宗教当局可以监督定价的过程,这么做不只能确保方济各会士只拥有必要的事物,也能减轻他们对于违背誓言的恐惧。为了解决教堂内部的冲突,教宗尼阁藉由这次的教宗诏书传达了他全心接受市场机制的观点。21
在同一年,法国方济各会士彼得.约翰.奥利维写下了《简约使用商品论》(De usu paupere ),此著作说明了发下贫困誓言者在使用商品时有何限制。奥利维在其中针对要如何在遵守誓言的同时拥有世俗物品的问题加以阐释。他创造了一些最早期、最创新的自我调节市场机制的特定概念。他出生于法国蒙彼利埃(Montpellier),曾在意大利佛罗伦萨生活过一段时间,也曾住在普罗旺斯一个有三万人口的城市──纳波内市(Narbonne)。他因此身处于地中海商业世界的核心,这里的方济各会士往往是商人的告解对象。奥利维曾在尼阁三世的教宗管理系统中工作,他试着为方济各会士的誓言辩护,并因此提出了第一个边际效用递减法则的理论,根据该理论的描述,在商品的可取得数量与消费量增加时,该商品的价值也会随之减少。奥利维指出,如果人们“普遍地”或“惯常地”使用某些物品的话,这些物品的价值就会受到影响。愈容易取得的事物,价值就愈低。举例来说,像是油和蔬菜这类为大众大量生产、又能“轻易”获得的原物料,价值就比稀有商品要低。22
方济各会的思想,将会在杰出的经院哲学家暨英国方济各会士“奥坎的威廉”(William of Ockham)的研究中出现革命性转变,奥坎把焦点转向市场上的个体与主观选择,趋近于现代观念。和奥利维一样,奥坎在一三二○年代为完美与绝对贫困的概念辩护,但他捍卫贫困誓言使用的是全新方法。奥坎认为,没有法律能强迫任何人违背自己的意愿去拥有任何事物,他开始宣扬“宽容式”法律的必要性,比如让人有权利拒绝私有财产。拥有个人选择,代表的是方济各会可以拒绝拥有财产,就像他们可以拥有财产一样毫无疑问。28
1. Michael McCormick, Origins of the European Economy: Communications and Commerce AD 300–900 (Cambridge: Cambridge University Press, 2001), 37, 87.
2. Georges Duby, The Early Growth of the European Economy: Warriors and Peasants from the Seventh to the Twelfth Century , trans. Howard B. Clarke (Ithaca, NY: Cornell University Press, 1974), 29; J. W. Hanson, S. G. Ortman, and J. Lobo, “Urbanism and the Division of Labour in the Roman Empire,” Journal of the Royal Society Interface 14, no. 136 (2017), Interface 14, 20170367; Rosamond McKitterick, ed. , The Early Middle Ages (Oxford: Oxford University Press, 2001), 100.
3. McCormick, Origins of the European Economy , 38, 40–41, 87, 101; Procopius, The Wars of Justinian , trans. H. B. Dewing, rev. Anthony Kaldellis (Indianapolis: Hackett Publishing, 2014), bk. 2, chaps. 22–33; Guy Bois, La mutation de l’an mil . Lournand, village mâconnais de l’antiquité au féodalisme (Paris: Fayard, 1989), 31.
4. Valentina Tonneato, Les banquiers du seigneur (Rennes, France: Presses Universitaires de Rennes, 2012), 291.
5. Tonneato, Les banquiers du seigneur , 315; Giacomo Todeschini, Les Marchands et le Temple: La société chrétienne et le cercle vertueux de la richesse du Moyen Âge à l’Époque Moderne (Paris: Albin Michel, 2017), 37.
6. Tonneato, Les banquiers du seigneur , 160; Alisdair Dobie, Accounting at the Durham Cathedral Priory: Management and Control of a Major Ecclesiastical Corporation, 1083–1539 (London: Palgrave Macmillan, 2015), 145–146.
7. McKitterick, Early Middle Ages , 104.
8. “Customs of Saint-Omer (ca. 1100),” in Medieval Europe , ed. Julius Kirshner and Karl F. Morrison (Chicago: University of Chicago Press, 1986), 87–95.
9. Alan Harding, “Political Liberty in the Middle Ages,” Speculum 55, no. 3 (1980): 423–443, at 442.
10. “Customs of Saint-Omer,” 87.
11. Giacomo Todeschini, Franciscan Wealth: From Voluntary Poverty to Market Society , trans. Donatella Melucci (Saint Bonaventure, NY: Saint Bonaventure University, 2009), 14; Todeschini, Les Marchands du Temple , 70.
12. Henry Haskins, The Renaissance of the Twelfth Century (Cambridge, MA: Harvard University Press, 1933), 344–350; D. E. Luscumbe and G. R. Evans, “The Twelfth-Century Renaissance,” in The Cambridge History of Medieval Political Thought , c. 350–c. 1450, ed. J. H. Burns (Cambridge: Cambridge University Press, 1988), 306–338, at 306; F. Van Steenberghen, Aristotle in the West: The Origins of Latin Aristotelianism , trans. L. Johnston (Leuven, Belgium: E. Nauwelaerts, 1955), 30–33.
13. Odd Langholm, Price and Value in the Aristotelian Tradition: A Study in Scholastic Economic Sources (Bergen, Norway: Universitetsforlaget, 1979), 29; Gratian, The Treatise on Laws (Decretum DD. 1–20 ), trans. Augustine Thompson (Washington, DC: Catholic University of America Press, 1993), 25; Brian Tierney, The Idea of Natural Rights: Studies on Natural Rights, Natural Law, and Church Law, 1150–1625 (Atlanta: Emory University, 1997), 56.
14. David Burr, “The Correctorium Controversy and the Origins of the Usus Pauper Controversy,” Speculum 60, no. 2 (1985): 331–342, at 338.
15. Saint Thomas Aquinas, Summa Theologica , vol. 53, Question 77, Articles 1, 3; Raymond de Roover, “The Story of the Alberti Company of Florence, 1302–1348, as Revealed in Its Account Books,” Business History Review 32, no. 1 (1958): 14–59.
16. W. M. Speelman, “The Franciscan Usus Pauper : Using Poverty to Put Life in the Perspective of Plenitude,” Palgrave Communications 4, no. 77 (2018), open access: https://doi.org/10.1057/s41599-018-0134-4 ; Saint Bonaventure, The Life of St. Francis of Assisi , ed. Cardinal Manning (Charlotte, NC: TAN Books, 2010), 54–55.
17. Norman Cohn, Pursuit of the Millennium: Revolutionary Millenarians and Mystical Anarchists of the Middle Ages (Oxford: Oxford University Press, 1970), 148–156.
18. John Duns Scotus, Political and Economic Philosophy , ed. and trans. Allan B. Wolter (Saint Bonaventure, NY: Franciscan Institute Publications, 2000), 27.
19. Lawrence Landini, The Causes of the Clericalization of the Order of Friars Minor, 1209–1260 in the Light of Early Franciscan Sources (Rome: Pontifica Universitas, 1968); David Burr, Olivi and Franciscan Poverty: The Origins of the Usus Pauper Controversy (Philadelphia: University of Pennsylvania Press, 1989), 5, 9.
20. Burr, Olivi and Franciscan Poverty , 11–12.
21. Nicholas III, Exiit qui seminat (Confirmation of the Rule of the Friars Minor ), 1279, Papal Encyclicals Online, www.papalencyclicals.net/nichol03/exiit-e.htm .
22. Piron Sylvain, “Marchands et confesseurs: Le Traité des contrats d’Olivi dans son contexte (Narbonne, fin XIIIe–début XIVe siècle),” in Actes des congrès de la Société des historiens médiévistes de l’enseignement supérieur public, 28e congrès 28 (1997): 289–308; Pierre Jean Olivi, De usu paupere: The quaestio and the tractatus , ed. David Burr (Florence: Olschki, 1992), 47–48.
23. Olivi, De usu paupere , 48.
24. Sylvain Piron, “Censures et condemnation de Pierre de Jean Olivi: Enqûete dans les marges du Vatican,” Mélanges de l’École française de Rome—Moyen Âge 118, no. 2 (2006): 313–373.
25. Pierre Jean Olivi, Traité sur les contrats , ed. and trans. Sylvain Piron (Paris: Les Belles Lettres, 2012), 103–115.
26. Peter John Olivi, “On Usury and Credit (ca. 1290),” in University of Chicago Readings in Western Civilization , ed. Julius Kirshner and Karl F. Morrison (Chicago: University of Chicago Press, 1987), 318–325, at 318; Langholm, Price and Value , 29, 52.
27. Langholm, Price and Value , 119, 137.
28. Tierney, Idea of Natural Rights , 33; William of Ockham, On the Power of Emperors and Popes , ed. and trans. Annabel S. Brett (Bristol: Theommes Press, 1998).
29. Tierney, Idea of Natural Rights , 101.
30. Tierney, Idea of Natural Rights , 35; Ockham, On the Power of Emperors and Popes , 35–37, 97.
31. Ockham, On the Power of Emperors and Popes , 15, 76, 79, 96.
32. Harry A. Miskimin, The Economy of Later Renaissance Europe, 1460–1600 (Cambridge: Cambridge University Press, 1977), 11.
第四章 佛罗伦萨的财富与马基维利的市场
秩序良好的共和国必须保持公众的富裕,但同时保持公民的贫困。 ──马基维利,《利瓦伊论》(Discourses on Livy ,一五一七年)
到了一二○○年代,锡耶纳的托斯卡纳(Tuscan)城邦已经变成欧洲金融业的领导者,这是因为该城邦许多公民都擅长金融,各国对于此共和国的银行机构充满信心。锡耶纳的政府官员意识到,若想让借债人和投资人在他们的城市里存款与进行金融交易,就必须先让借债人和投资人认为,这里的市场会按照他们的预期运作。从一二八七年至一三五五年,锡耶纳社群与人民的九位总督与辩护者(Nine Governors and Defenders of the Commune and the People of Siena)把焦点放在维护良好金融管理的法律规范与声誉上。政府监管的不只是高度组织化的税收系统,还有稳定的信用网络。2 良好政府与商业美德的价值观弥漫在社会中。在锡耶纳的著名中世纪公共机关建筑“锡耶纳市政厅”(Palazzo Pubblico)中,画家安布罗乔.洛兰采蒂(Ambrogio Lorenzetti)创作了一组三连幅的湿壁画,《好政府与坏政府的预言》(The Allegory of Good and Bad Government ,一三三八年至一三三九年),画中传达出守法的商人能维护良好的政府。这些壁画显然是参考了西塞罗与罗马哲学家塞内卡(Seneca,公元四年至六五年)的思想,描绘了正义、智慧、和平、坚韧、谨慎、宽容与节制等斯多噶美德围绕在好政府周围。洛兰采蒂把斯多噶主义和良好的商业行为划上等号。他将锡耶纳描绘成一个充满富裕公民、商店、商人和工匠的城市。他传达了很明确的道德与经济讯息:在法律规范的支持下,优秀的菁英共和政府可以为创造财富的交易打造出所需的环境条件。健康的市场也会相应地支持共和国的发展。另一幅画则重述了西塞罗派的古老讯息:政治的暴君将会直接导致贪腐,暴君破坏的不只是信任与和平,也会破坏市场本身与市场本应创造的财富。3
佩脱拉克希望能找到一种足以吸引菁英执行公民义务的哲学。他在西塞罗的“派代亚”(paideia)公民教育思想中找到此一哲学,希望能藉此带动罗马美德在佛罗伦萨的复兴。佩脱拉克解释道,托斯卡纳的菁英必须要付出努力,研读古代的伦理、修辞与法律来学习何谓优秀的治理方式,如此才能实践西塞罗所谓的公民“首要之善”(summum bonum)。他在《统治者应该如何治理他的国家》(How a Ruler Ought to Govern His State ,一三七三年)此一专著中,使用了西塞罗的作品来描述自己理想中具备道德正义的统治者。这些统治者付出努力是出于共和国的爱,也是出于“大众”的共同利益。佩脱拉克认为成功国家的基础不是军事武器,而是财富与优秀的公民。他追随西塞罗的观点,指出领导人应该是清廉且高效率的管理者。5
佛罗伦萨的商人在信件、账本和正式的商业与家族回忆录中写下了这些崭新观点,这些回忆录(ricordi)可以视为商业艺术之书。多数时候,经济史学家认为上述文字内容充其量只是实用文件,不会把它们纳入经济思想的政治历史中。然而,若经过仔细检视,我们会发现这些文件揭示了商人对于商业与其美德的激进新观点。佛罗伦萨商人乔瓦尼.迪.帕戈洛.莫雷利(Giovanni di Pagolo Morelli)在他的《回忆录》(Ricordi ,一三九三年至一四一一年)中大力赞扬市场,并夸耀“托斯卡纳的市场”之“富饶”,使得佛罗伦萨与他自己的家族都变得富有。他对于祖先赚得的财产非常骄傲,甚至为他们“富有地死去”而感到自豪──他认为这是一种殊荣。然而,以无关公民美德、无关共和国公民义务的方式累积个人财富,这样的追求有待商榷。一四二八年,佛罗伦萨的人文主义者暨历史学家马泰奥.帕尔米耶里(Matteo Palmieri)明确指出,追求利润的行为必须对国家利益有直接的贡献。帕尔米耶里引用了西塞罗的话,坚称商人必须把“口才”与“美德”结合,避免贪图小利,聚焦于把对财富的欲望导向“有用的商业艺术”,这样的行为对于“共和国政府”的参与者有“很大的效益”。7
在这些著作中,涵盖范围最广且最杰出之作是班尼迪托.科特鲁利(Benedetto Cotrugli)的《贸易艺术之书》(The Book of the Art of Trade ,写于一四五八年,但直到一世纪后的一五七三年才付梓出版)。来自威尼斯贸易城市拉古沙(Ragusa,如今的杜布罗夫尼克〔Dubrovnik〕)的商人科特鲁利(Cotrugli,现代克罗地亚语拼法为Kotrulj)十分钦慕佛罗伦萨的价值观,并加以仿效。他比同年代的其他人更进一步建立了如下观点:良好的西塞罗派伦理与得体的行为,能创造出市场运作所需的信任与政治稳定性。这是很核心的论点。科特鲁利观察到,贪婪和必需性无处不在,就算是最贫困的地区也一样有市场,但并不是所有市场都会创造出财富或宏伟的城市。他清楚表明,若要使商业与投资蓬勃发展,市场终究需要制度支持、信心与合作,少了这些事物,交易是无法妥善运作的。8
马基维利认为羊毛工人暴动(Revolt of the Ciompi,一三七八年至一三八二年)这场发生在佛罗伦萨的劳动阶级起义,能为众人带来经济自由方面的教训。在他献给第二任梅迪奇教宗克勉七世(Clement VII)的《佛罗伦萨历史》(Florentine Histories ,一五二五年)中,他主张寡头垄断是很危险的,会阻碍稳定的贸易与财富。他说,是寡头政治与经济不平等为佛罗伦萨带来了内战。共和国与其市场必须拥有一定程度的经济公平性才能正常运作。他利用西塞罗的说法批判那些“靠着诈骗或武力”获得财富的商人,他把这种赚钱方式称为“丑陋的收购”。马基维利不赞同佛罗伦萨的上层阶级限制了行会中只有哪些人能成为羊毛工人的代表,他相信正是这样的限制导致了充满杀戮与不稳定的激进政治。《君王论》指出,唯有在共和国解体后,才会轮到禽兽般的法律治理这个社会。唯有稳定的国家能抵御“狐狸”和“狮子”做出的危险野蛮行为,藉此维护美德,保护良好的贸易与市场。18
1. Raymond de Roover, “The Story of the Alberti Company of Florence, 1302–1348, as Revealed in Its Account Books,” Business History Review 32, no. 1 (1958): 14–59, at 46; Marcia L. Colish, “Cicero’s De officiis and Machiavelli’s Prince ,” Sixteenth Century Journal 9, no. 4 (1978): 80–93, at 82; N. E. Nelson, “Cicero’s De officiis in Christian Thought, 300–1300,” in Essays and Studies in English and Comparative Literature , University of Michigan Publications in Language and Literature, vol. 10 (Ann Arbor: University of Michigan Press, 1933), 59–160; Albert O. Hirschman, The Passions and the Interests: Political Arguments for Capitalism Before Its Triumph (Princeton, NJ: Princeton University Press, 1977), 10.
2. William M. Bowsky, The Finance of the Commune of Siena, 1287–1355 (Oxford: Clarendon Press, 1970), 1, 209.
3. Nicolai Rubenstein, “Political Ideas in Sienese Art: The Frescoes by Ambrogio Lorenzetti and Taddeo di Bartolo in the Palazzo Pubblico,” Journal of the Warburg and Courtauld Institutes 21, no. 3/4 (1958): 179–207; Quentin Skinner, “Ambrogio Lorenzetti’s Buon Governo Frescoes: Two Old Questions, Two New Answers,” Journal of the Warburg and Courtauld Institutes 62, no. 1 (1999): 1–28, at 6.
4. Arpad Steiner, “Petrarch’s Optimus Princeps ,” Romanic Review 23 (1934): 99–111; Christian Bec, Les marchands écrivains: Affaires et humanismé à Florence, 1375–1434 (Paris: École Pratique des Hautes Études, 1967), 49–51; Francesco Petrarca, “How a Ruler Ought to Govern His State,” in The Earthly Republic: Italian Humanists on Government and Society , ed. Benjamin G. Kohl and Ronald G. Witt (Philadelphia: University of Pennsylvania Press, 1978), 35–92, at 37.
5. James Hankins, Virtue Politics: Soulcraft and Statecraft in Renaissance Italy (Cambridge, MA: Belknap Press of Harvard University Press, 2019), 2, 42, 46; Steiner, “Petrarch’s Optimus Princeps ,” 104.
6. Raymond de Roover, “The Concept of the Just Price: Theory and Economic Policy,” Journal of Economic History 18, no. 4 (1958): 418–434, at 425; Cicero, De officiis , trans. Walter Miller, Loeb Classical Library (Cambridge, MA: Harvard University Press, 1913), bk. 1, sec. 13–14, paras. 43–45.
7. Gertrude Randalph Bramlette Richards, Florentine Merchants in the Age of the Medici: Letters and Documents from the Selfridge Collection of Medici Manuscripts (Cambridge, MA: Harvard University Press, 1932), 5; Armando Sapori, La crisi delle compagnie mercantili dei Bardi dei Peruzzi (Florence: Olschki, 1926); Robert S. Lopez, The Commercial Revo lution of the Middle Ages, 950–1350 (Cambridge: Cambridge University Press, 1976), 27–36; Gino Luzzato, Breve storia economica dell’Italia medieval (Turin: Einaudi, 1982); Giovanni di Pagolo Morelli, Ricordi , ed. V. Branca (Florence: F. Le Monnier, 1956), 100–101; Matteo Palmieri, Dell’ Ottimo Cittadino: Massime tolte dal Trattato della Vita Civile (Venice: Dalla Tipografia di Alvisopoli, 1829), 20, 66, 167–168.
8. Benedetto Cotrugli, The Book of the Art of Trade , ed. Carlo Carraro and Giovanni Favero, trans. John Francis Phillimore (Cham, Switzerland: Palgrave Macmillan, 2017).
9. Cotrugli, Book of the Art of Trade , 4.
10. Cotrugli, Book of the Art of Trade , 112–115.
11. Cotrugli, Book of the Art of Trade , 25, 30, 33.
12. Cotrugli, Book of the Art of Trade , 46–49, 62, 86, 112–113.
13. Felix Gilbert, Machiavelli and Guicciardini: Politics and History in Sixteenth-Century Florence (Princeton, NJ: Princeton University Press, 1965), 160–161.
14. Hirschman, The Passions and the Interests , 33; Niccolò Machiavelli, The Prince , ed. and trans. William J. Connell (Boston: Bedford/St. Martin’s, 2005), 61–62; Colish, “Cicero’s De officiis and Machiavelli’s Prince ,” 92.
15. Jacob Soll, Publishing The Prince: History, Reading, and the Birth of Political Criticism (Ann Arbor: University of Michigan Press, 2005), 23; Niccolò Machiavelli, The Discourses , ed. Bernard Crick, trans. Leslie J. Walker, rev. Brian Richardson (London: Penguin, 1970), 37–39, 201.
16. Machiavelli, The Discourses , 39; John McCormick, Machiavellian Democracy (Cambridge: Cambridge University Press, 2011), 55, 201; Gilbert, Machiavelli and Guicciardini, 184–185; Machiavelli, The Prince , 61–62.
17. Machiavelli, The Prince , 55; Jérémie Bartas, L’argent n’est pas le nerf de la guerre: Essai sur une prétendue erreur de Machiavel (Rome: École Française de Rome, 2011), 32–36; McCormick, Machiavellian Democracy , 87; Machiavelli, The Discourses , 201–203.
18. McCormick, Machiavellian Democracy , 26; Charles Tilly, “Reflection on the History of European State-Making,” in The Formation of National States in Western Europe , ed. Charles Tilly (Princeton, NJ: Princeton University Press, 1975), 3–83, at 52–56; Margaret Levy, Of Rule and Revenue (Berkeley: University of California Press, 1988), 202; Niccolò Machiavelli, Florentine Histories , trans. Laura F. Banfield and Harvey K. Mansfield Jr. (Princeton, NJ: Princeton University Press, 1988), 121–123.
19. Machiavelli, Florentine Histories , 159.
第五章 以国家为手段的英格兰自由贸易
贸易欣欣向荣时,国王的收入会增加,土地和租金会上涨,航海技术会发展,穷人会受到雇用。但如果贸易衰败,这一切也会随之衰退。 ──爱德华.米塞尔顿(Edward Misselden),《自由贸易,又名,使贸易蓬勃发展的方法》(Free Trade, or, the Means to Make Trade Flourish ),一六二二年
十六世纪之初,欧洲出现了剧烈的变化。一五一七年,也就是马基维利写下《利瓦伊论》的那一年,日耳曼的新教创始人马丁.路德(Martin Luther)将他执笔的《九十五条论纲》(Ninety-five Theses )钉在威登堡大教堂(Wittenberg Cathedral)的门上,启动了未来将导致基督教分裂的第一步。首批新教徒如同马基维利一样,对于人类本性无比悲观,他们认为人类是堕落的,会按照自身的兽性行事。但是,他们也如同马基维利一样相信个人选择与利己有其力量。只要做出适当的个人选择,人类就能形塑自己的命运。1 在同一时期,西班牙探险家胡安.庞塞.莱昂(Juan Ponce de Léon)发现了佛罗里达,并进一步探索该地。欧洲人感到美洲的自然资源远比他们所能想象的更加富饶。哲学家开始把科学与探索视为获得这些资源财富的关键。而崭新的世界探索任务也为人们带来了新的体认:国家必须扮演主导角色,资助与保护探险家进行长途海上交易,并与其他帝国交涉,这些探索对于个人与公司来说太过昂贵也太过复杂了,他们无法靠自己做到。十六与十七世纪的经济思想家一再强调,财富生产需要国家投资与个人冒险精神彼此结合。 当时欧洲站在科学革命的临界点,这场革命将会迎来对各种自然法则的发现,从行星运动到血液循环皆尽有之,因此,我们也无需意外十六世纪的经济思想见证了全新的自然市场机制运作理论如雨后春笋般涌现。其中,最引人注目的就是利伯维尔场的相关概念了,诸如货币数量理论、报酬递减法则、“进入壁垒”的概念、通货膨胀、劳动生产力和企业家精神──当时的先驱经济思想家认为,这些概念全都得依赖某种形式的国家干涉。
到了一五三○年代,欧洲遍地都是来自日耳曼与波希米亚矿坑的黄金,还有些黄金来自葡萄牙与西班牙帝国。西班牙船队从新世界带回了堆积如山的贵金属,这些贵金属从塞维利亚(Seville)的瓜达几维海岸(Guadalquivir)与安特卫普(Antwerp)的法兰德斯港口(Flemish port)等地上岸。尽管更多的黄金能带来财富,但这些黄金同时也导致了通货膨胀,甚至货币短缺,破坏了从波希米亚到马德里、巴黎与伦敦的经济稳定性。2 突如其来的不稳定状态使得哲学家开始研究货币,以及是什么为货币赋予了价值。他们开始意识到市场力量在其中扮演了关键角色。正如早期的经院哲学家认为个人行为会创造出定价与价值的市场机制,晚期的经院哲学家──尤其是西班牙的经院哲学家认为,王室法令与国家其实无法完全控制货币的价值。一个新的法律思想流派出现在西班牙的萨拉曼卡大学(University of Salamanca)与葡萄牙的埃武拉大学(University of Evora),他们把焦点放在理解市场机制上。一五五○年代,西班牙巴斯克(Basque)的神学家马丁.阿兹匹区塔(Martín de Azpilcueta)提出了一种货币数量理论,指出货币的价值同时来自流通的货币多寡(铸币数量上升会抑制货币价值,而这种通膨又会反过来导致货币短缺)以及人们对货币能买到什么的认知。3
支持卡尔文主义的日耳曼新教改革者马丁.布塞珥(Martin Bucer)以最强烈的力道为有息放贷辩护,他挑战的不只是天主教对于高利贷的禁令,也挑战了“货币的本质是不结果实的”背后的基础概念。4 当时有愈来愈多神学家认为,只要以纯粹的基督教脉络行事,那经商就是正向的事,布塞珥也是其中之一,他帮助当时的人们解除对于货币的偏见(不过他并没有帮助人们解除对于犹太人的偏见,而希望能将犹太人逐出公民生活与商业生活)。布塞珥在一五四七年因为宗教冲突而向英格兰新教寻求庇护,国王亨利八世在宫廷里接见了他。一五四九年,他成为剑桥大学的钦定教授,写下了《论基督的王国》(On the Kingdom of Christ ),在其中勾勒出他的愿景,他认为若借贷双方都同意一个并非“滥用”的利率,那么借贷就是对经济有益的行为。布塞珥引用了西塞罗和圣安博的话来正当化基督教社群中的商品获利,指这些利润可以“用来为上帝的子民购买和平”。他专注于透过商业支持公民生活,这代表了基督教思想正逐渐向世俗世界靠拢。“金钱同样是上帝的恩赐,上帝要我们以正确的方式使用金钱。”他在《论高利贷》(Treatise on Usury )中如此写道。如果金钱能帮助基督徒好好生活,还能支持西塞罗过去提出的公民稳定性的“首要之善”观点,那么金钱也就未必是“不结果实的”。5
卡尔文派的新教主义在法国产生了重大的影响,法国是当时西欧人口最多的国家,也可能是最富有的国家。然而,从一五六二年开始的法国宗教战争(French Wars of Religion)延续了超过三十五年,天主教极端分子攻击了新教教徒,甚至也攻击了天主教的温和派,使法国面临攸关存亡的威胁。城市与富有的工业产业纷纷解体。有些法国思想家希望能找到一个理论来停止宗教冲突并重建社会,于是他们全心接纳了马基维利的观点,认为若想要稳定国家与社会并创造有利的市场条件,马基维利的理论至关重要。
其中一位思想家是法国法学家、历史学家暨自然哲学家尚.布丹(Jean Bodin)。他在宗教战争最高峰期间写下许多政治理论,为专制君主制辩护,他认为这种制度不仅能维持政治和平,还能发展法国经济。他的理论是他对圣巴托罗缪大屠杀(Saint Bartholomew’s Day Massacre,一五七二年)做出的反馈,在这场大屠杀中,天主教狂热分子于巴黎杀害了数百名新教的高阶贵族,且在法国各地共杀害了数千人。这场史无前例的暴力事件对法国造成重挫,那些暴徒摧毁了各个城市与商业财富,使法国一夕之间变得动荡不安。布丹对于宗教派系斗争与内乱所做出的响应就是“专制主义”。布丹认为,如果经济是透过自然程序运作的,那么国家就必须稳定社会并重建市场。布丹采用了马基维利的观点来为国家的稳定性与权力辩护,但他的主张中更加明确地指出,国家能促进财富,并使市场得以自然系统的状态运作。别忘了,布丹和马基维利的地位截然不同──布丹是一名在各国都受人尊敬的学者、律师暨国王顾问,因此能够直言不讳地表达意见。
布丹在《国家六论》(Six Books of the Republic ,一五七六年)中解释道,在面对消耗着政治实体的“热情”时,专制君主制是唯一的答案。虽然布丹不同意马基维利为不道德行为提出的辩护,但他认为马基维利优先关注政治稳定性是正确的。仇恨与狂热的宗教信仰会打破政治实体的和谐,摧毁商业与财富。布丹和过去的无数市场理论家一样,也向西塞罗借鉴,他指出,有权制定法律且有道德的君主会实行斯多噶式的“节制”,把自然平衡带回经济中。6
我们可以在布丹的身上看到十六世纪经济思想的复杂性:他在稳定经济与确保市场条件方面为国家所扮演的角色做了辩护,但他同时也是那个时代首屈一指的货币理论学家,对市场机制进行了突破性的观察分析。一五六八年,布丹在职涯早期写下《响应马列斯妥先生》(Response to the Paradoxes of Monsieur de Malestroit )作为对欧洲通膨问题的响应,并用此作品为货币数量理论进行强而有力的辩护,指出钱币的流通数量会影响货币价值。8
马基维利、经院哲学家与布丹启发了乔凡尼.博泰罗(Giovanni Botero)对于经济与政治的思想,他是一名耶稣会神职人员、哲学家暨外交官。博泰罗最重要的构想之一,是为城市培育出工业并刺激市场。有别于农业,这些构想把核心放在探索、创新与制造,再加上透过大量累积资产,来开启一个持续创造出财富的动态过程。这意谓着各国必须把焦点放在管理和投资城市上。博泰罗赞同马基维利的观点,认为国家应该要为自身的存续与繁荣做出艰难的决定,博泰罗是第一个将此概念称作“国家理性”(reason of state,或国家利益)的人。经济史学家将这个后来在法文中写作“raison d’état”的概念与现代的重商主义概念连结在一起,根据此概念,君主或领导人必须在能力所及内尽自己的一切努力去增强国家经济,无论是囤积黄金还是补贴工商业。不过,博泰罗并不认为单靠国家就可以管控经济;国家必须和商人合作,才能创造出使生产最大化的恰当环境条件。12
拿坡里哲学家安东尼奥.塞拉(Antonio Serra)也利用市场分析来支持工业胜过农业的观点。他在一六一三年的著作《国家贫富短论》(Short Treatise on the Wealth and Poverty of Nations )中详细阐述了农业产品是如何导致收益递减,而收益递减会导致生产成本提高,充其量也只能带来有限的盈余。农业根本无法为大规模投资创造出足够的财富。唯有制造才能“利用产品的倍增来使收入倍增”,并产出不会迅速贬值的耐久货品。塞拉解释道,随着生产量增加,成本将会下降,这使得工业有机会同时提高薪水并压低价格。这就是能够使收益增加的机制。因此具竞争性的工业市场具有很大的潜力,至少在塞拉描述的这种收益增加导致了后来所谓的“进入壁垒”之前都是如此──进入壁垒是一种创造出寡头与垄断的机制。15
伴随着贸易、信任与贷款的蓬勃发展而出现的,是一波重要的英格兰经济著作。由英格兰议员、剑桥学者暨先驱市场思想家汤姆士.史密斯爵士(Thomas Smith)撰写的《论英格兰共同体》(A Discourse on the Common Weal of This Realm of England ,约一五四九年)指出,政府必须给予农业市场自由,同时严密管控工业以推动城市制造业。史密斯主张,议会干预人们在过去的公有农业土地上进行圈地,这样的行为削减了作物产量,并回过头来削减了城市的财富。史密斯不但赞成建立一个工业供需的国际市场体制,他也对于国家要如何帮助具企业家精神的工匠有一套看法。虽然他相信富裕的市场本身就具有自我扩张的力量,但他也引用西塞罗的话,主张国家必须利用“奖励”(rewardes)来帮助、甚至“强迫”城市工业发展,并利用“痛苦”(paine)来进行监管。史密斯认为,虽然农业需要的是自由,但工业需要的是国家的监督,也需要国家协助往国际市场发展。扩张的工业为整个国家创造出一道财富之流,藉此,“城镇与都市将会重新充满各种工匠;不只是如今我们视为日常的布匠,还有帽匠、手套匠、造纸匠、玻璃匠、指标工、金匠、铁匠与各种金属的锻造工、床罩制造商、针匠和针头匠。”所有这些交易和行业彼此扶持,创造出能带来经济成长的市场体制。18
英格兰政府支持的不只是国内工业,他们也支持英格兰市场往殖民世界扩张。一五七九年,英国女王伊丽莎白一世资助了弗朗西斯.德瑞克(Francis Drake)环绕世界航行的计划。她也特别准许华特.雷利(Walter Raleigh)带领探险队在一五九五年前往奥利诺科河(Orinoco River),这条河位于如今的委内瑞拉,此前克里斯多福.哥伦布也是在委内瑞拉找到了他心目中通往天堂的道路。比哥伦布晚一百多年出生的雷利,在一本名为《发现广阔、富裕又美丽的圭亚那帝国,以及伟大的黄金之城马诺亚,西班牙人称之为黄金国》(The Discovery of the Large, Rich, and Beautiful Empire of Guiana, with a Relation of the Great and Golden City of Manoa Which the Spaniards Call El Dorado ,一五九六年)的书中描述了他的旅行,并声称自己找到了无尽的财富,找到了“黄金之母”。19
虽然许多英格兰人都认为国家必须参与商业帝国的打造,但他们同时也在试着了解他们眼中推动市场持续生产的自然法则。盎格鲁─法兰商人暨德斯贸易商杰拉德.马林斯(Gerard de Malynes)在他的著作《商人法》(Lex Mercatoria ,一六二二年)中,以极为精深的观点看待规章制度与自由在商业建立中扮演的角色。他援引了《圣经》、斯巴达、克里特、迦太基和西塞罗的法律,也引用了尚.布丹的研究,坚称国家必须带有策略地支持贸易。20
马林斯并不是唯一一个这么认为的人。多数英格兰经济中的领导人都赞同这个观点:国家可以在创造自由贸易条件的方面发挥作用。在这些人之中,最具有影响力的是东印度公司(East India Company)的董事托玛斯.孟恩(Thomas Mun)和商人爱德华.米塞尔顿。对于孟恩与米塞尔顿来说,国家执行保护主义会推动贸易自由的这个概念没有任何矛盾之处。因此,虽然经济史学家一直以来都因为他们两人坚持要王室透过关税来保护英格兰船运与制造业,而认为他们是重商主义的理论家,但我们也必须把他们视为利伯维尔场思想的先驱。
《航海法》除了保护国家工业外,也限制了只有英格兰的船只能进入国内。此法律使英格兰与荷兰的竞争进入白热化。英格兰内战才刚结束,第一次英荷战争就在一六五二年展开,但这场为期两年的战争并没有为英格兰带来决定性的胜利。虽然英格兰在一六五三年的席凡宁根战役(Battle of Scheveningen)成为胜利者,却没能击败荷兰船队,也无法封锁英格兰海岸。荷兰继续维持着优势商业国家的地位,于是英格兰政府的决策者采纳了孟恩和米塞尔顿的建议,打造了关税体制以扶植国家工业。他们也请求国家协助他们挑战荷兰在印度、非洲直至北美洲的全球贸易优势地位,尤其是奴隶贸易这一部分。
1. Quentin Skinner, The Foundations of Modern Political Thought , 2 vols. (Cambridge: Cambridge University Press, 1978), 2:5, 284.
2. Harry A. Miskimin, The Economy of Later Renaissance Europe, 1460–1600 (Cambridge: Cambridge University Press, 1977), 36.
3. Skinner, Foundations of Modern Political Thought , 2:139; Francisco de Vitoria, Political Writings , ed. Anthony Pagden and Jeremy Lawrence (Cambridge: Cambridge University Press, 1991), xv–xix; Martín de Azpilcueta, Commentary on the Resolution of Money (1556) , in Sourcebook in Late-Scholastic Monetary Theory: The Contributions of Martín de Azpilcueta, Luis de Molina, S. J. , and Juan de Mariana, S. J. , ed. Stephen J. Grabill (Lanham, MD: Lexington Books, 2007), 1–107, at 79; Martín de Azpilcueta, On Exchange , trans. Jeannine Emery (Grand Rapids, MI: Acton Institute, 2014), 127. 另见 Alejandro Chafuen, Faith and Liberty: The Economic Thought of the Late Scholastics (Lanham, MD: Lexington Books, 2003), 54; Marjorie Grice-Hutchinson, The School of Salamanca: Readings in Spanish Monetary Theory, 1544–1605 (Oxford: Clarendon Press, 1952), 48.
4. Raymond de Roover, Money, Banking and Credit in Medieval Bruges (Cambridge, MA: Medieval Academy of America, 1948), 17; Mark Koyama, “Evading the ‘Taint of Usury’: The Usury Prohibition as a Barrier to Entry,” Explorations in Economic History 47, no. 4 (2010): 420–442, at 428.
5. Martin Bucer, De Regno Christi , in Melancthon and Bucer , ed. Wilhelm Pauk (Philadelphia: Westminster Press, 1969), 155–394, at 304; Steven Rowan, “Luther, Bucer, Eck on the Jews,” Sixteenth Century Journal 16, no. 1 (1985): 79–90, at 85; Bucer, Regno Christi , 302; Constantin Hopf, Martin Bucer and the English Reformation (London: Blackwell, 1946), 124–125; Martin Greschat, Martin Bucer: A Reformer and His Times , trans. Stephen E. Buckwalter (Louisville, KY: Westminster John Knox Press, 2004), 236–237.
6. Jacob Soll, “Healing the Body Politic: French Royal Doctors, History and the Birth of a Nation, 1560–1634,” Renaissance Quarterly 55, no. 4 (2002): 1259–1286.
7. Jean Bodin, Les six livres de la République , ed. Gérard Mairet (Paris: Livre de Poche, 1993), 428–429, 431, 485, 487, 500.
8. Louis Baeck, “Spanish Economic Thought: The School of Salamanca and the Arbitristas,” History of Political Economy 20, no. 3 (1988): 394.
9. Henri Hauser, ed. , La vie chère au XVIe siècle: La Réponse de Jean Bodin à M. de Malestroit 1568 (Paris: Armand Colin, 1932), xxxii; J. H. Elliott, “Self-Perception and Decline in Early Seventeenth-Century Spain,” Past and Present 74 (1977): 49–50.
10. Hauser, La vie chère , lviii.
11. Hauser, La vie chère , 499–500.
12. David Sainsbury, Windows of Opportunity: How Nations Create Wealth (London: Profile Books, 2020), 11.
13. Giovanni Botero, The Reason of State (Cambridge: Cambridge University Press, 2017), 4; Giovanni Botero, On the Causes of the Greatness and Magnificence of Cities , ed. and trans. Geoffrey Symcox (Toronto: University of Toronto Press, 2012), xxxiii, 39–45.
14. Botero, On the Causes of the Greatness and Magnificence of Cities , 43–44; Sophus A. Reinert, Translating Empire: Emulation and the Origins of Political Economy (Cambridge, MA: Harvard University Press, 2011), 117; Erik S. Reinert, “Giovanni Botero (1588) and Antonio Serra (1613): Italy and the Birth of Development Economics,” in The Oxford Handbook of Industrial Policy , ed. Arkebe Oqubay, Christopher Cramer, Ha-Joon Chang, and Richard Kozul-Wright (Oxford: Oxford University Press, 2020), 3–41.
15. Antonio Serra, A Short Treatise on the Wealth and Poverty of Nations (1613) , ed. Sophus A. Reinert, trans. Jonathan Hunt (New York: Anthem, 2011), 121; Jamie Trace, Giovanni Botero and English Political Thought (doctoral thesis, University of Cambridge, 2018).
16. Craig Muldrew, The Economy of Obligation (New York: Palgrave, 1998), 53.
17. Muldrew, Economy of Obligation , 97, 109, 138, 151; Nicolas Grimalde, Marcus Tullius Ciceroes Thre Bokes of Duties, to Marcus His Sonne, Turned Oute of Latine into English , ed. Gerald O’Gorman (Washington, DC: Folger Books, 1990), 207.
18. Joyce Oldham Appleby, Economic Thought and Ideology in Seventeenth-Century England (Princeton, NJ: Princeton University Press, 1978), 34. 另见 Elizabeth Lamond, ed. , A Discourse of the Common Weal of This Realm of England. First Printed in 1581 and Commonly Attributed to W. S. (Cambridge: Cambridge University Press, 1929), 15, 59, 93; Mary Dewar, “The Authorship of the ‘Discourse of the Commonweal,’ ” Economic History Review 19, no. 2 (1966): 388–400.
19. Sir Walter Raleigh, The Discovery of the Large, Rich, and Beautiful Empire of Guiana, with a Relation of the Great and Golden City of Manoa Which the Spaniards Call El Dorado , ed. Robert H. Schomburgk (New York: Burt Franklin, 1848), lxxix.
20. Gerard de Malynes, Lex Mercatoria (Memphis: General Books, 2012), 5.
21. Malynes, Lex Mercatoria , 27; William Eamon, Science and the Secrets of Nature: Books and Secrets in Medieval and Early Modern Culture (Princeton, NJ: Princeton University Press, 1994); Claire Lesage, “La Littérature des secrets et I Secreti d’Isabella Cortese,” Chroniques italiennes 36 (1993): 145–178; Carl Wennerlind, Casualties of Credit: The English Financial Revolution, 1620–1720 (Cambridge, MA: Harvard University Press, 2011), 48.
22. Wennerlind, Casualties of Credit , 79, 114, 211; Gerard de Malynes, The Maintenance of Free Trade (New York: Augustus Kelley, 1971), 47.
23. Malynes, Maintenance of Free Trade , 83, 105.
24. Appleby, Economic Thought and Ideology , 37; Thomas Mun, The Complete Works: Economics and Trade , ed. Gavin John Adams (San Bernardino, CA: Newton Page, 2013), 145.
25. Edward Misselden, Free Trade, or, The Meanes to Make Trade Florish (London: John Legatt, 1622), 20, 80, 84.
26. Lawrence A. Harper, The English Navigation Laws: A Seventeenth-Century Experiment in Social Engineering (New York: Octagon Books, 1960), 40.
27. Charles Henry Wilson, England’s Apprenticeship, 1603–1763 (London: Longmans, 1965), 65; Jean-Baptiste Colbert, “Mémoire touchant le commerce avec l’Angleterre, 1651,” in Lettres, instructions, et mémoires de Colbert , ed. Pierre Clément, 10 vols. (Paris: Imprimerie Impériale, 1861–1873), vol. 2, pt. 2, pp. 405–409; Harper, English Navigation Laws , 16; Moritz Isenmann, “Égalité, réciprocité, souvraineté: The Role of Commercial Treaties in Colbert’s Economic Policy,” in The Politics of Commercial Treaties in the Eighteenth Century: Balance of Power, Balance of Trade , ed. Antonella Alimento and Koen Stapelbroek (London: Palgrave Macmillan, 2017), 77–104.
第六章 荷兰共和国的自由与财富
上帝创造了人的αὐτεξούσιον,意即“自由与法权”,所以每个人的行为以及对自身财产的使用,都应该出于自己的意志,而不是出于他人的意志……因此,俗话说:“每个人在论及与自身财产相关的事物时,都是自己的统治者与仲裁者。” ──雨果.格劳秀斯(Hugo Grotius),《论捕获法》(De Iure Praedae Commentarius ),一六○三年
就算此时英格兰也有条不紊地建立起商业实力,荷兰仍继续主导着欧洲经济。后人所谓的荷兰黄金时代(Dutch Golden Age)培养出了许多关于经济学的复杂概念,其中以利伯维尔场的观点特别值得一提。无论从后见之明来看,这个利伯维尔场的概念有多超前,其实它就和英国与法国的经济思想一样,是以政府大量干涉经济作为前提。政治与帝国的经济现实并不总是完全符合荷兰共和国的思想家所拥护的自由理想。正如历史中的许多其他时期,荷兰的利伯维尔场理想也同样与更加复杂的国家干预现实并存。
荷兰的一位杰出人文学家西蒙.斯蒂文(Simon Stevin)在荷兰共和国成立时从布鲁日市(Bruges)搬到了莱顿市(Leiden)。他出生于一个普通的商人家庭,在莱顿念大学时认识了纳绍伯爵,伯爵后来成为奥兰治亲王的“奥兰治的莫里斯”(Maurice of Orange, Count of Nassau)。身为沉默者威廉一世(William I the Silent)的儿子,莫里斯在一五八五年成为荷兰共和国的省总督,他选择了斯蒂文来担任他的首席顾问与导师。莫里斯担任省总督直到他在一六二五年逝世。在任职期间,他指定斯蒂文负责处理最重要的供水系统──运河、堤防、水坝和挡海的水闸,又让斯蒂文成为军队的军需官,并帮助他成立了莱顿的工学院。斯蒂文是个博学的人,他写了一本影响力深远的会计手册《亲王会计》(Accounting for Princes ,一六○四年),主张政府必须由熟悉商业之道的人来治理。1
斯蒂文和其他荷兰领导人都认为,在激发市场信心与吸引外国人进入荷兰共和国的过程中,容忍政策会扮演很重要的角色。许多卡尔文教派的纺织品制造商在又称为八十年战争(Eighty Years’ War)的荷兰独立战争(Dutch War of Independence,一五六八年至一六四八年)期间,逃到了荷兰共和国北方的城市寻求庇护。到了一六○九年,阿姆斯特丹的卡尔文主义者和天主教徒数量已经持平了,另外也有许多犹太人与路德教徒。这些人全都有权可以投资与建立公司。容忍与信心,再加上金融素养、透明度和效率,这些因素迭加起来,推动着一个仍在不断成长的丰富市场文化。3
荷兰商人在西班牙与葡萄牙帝国内设立了贸易站,藉此侵吞更多贸易量,他们成为欧洲赚进最多钱的一群人。一五九九年,雅各布.哥尼拉斯.范尼克(Jacob Cornelius van Neck)在东印度群岛的香料探索获得了高达百分之三百九十九的利润。新成立的公司在荷兰各地大量涌现,使得人们开始担忧荷兰内部的过多竞争可能会导致贸易受损。荷兰最重要的其中一位领导人,类似于首相的“土地倡导者”(land’s advocate)约翰.奥登巴那维(Johan van Oldenbarnevelt)坚持认为,荷兰七个省的所有公司应该要联合起来,组成一间共同对外贸易的联盟公司。因此,他在一六○二年协助成立了荷兰东印度公司(United Dutch East India Company,荷兰文为Vereenigde Oost Indische Compagnie,简称VOC)。公司的章程说明了私人资本与国家利益的连结方式,奥登巴那维认为这对荷兰共和国是最有利的营运制度。荷兰东印度公司的任务不只是发展出贸易垄断,还得维护国家利益。就像英国东印度公司一样,荷兰东印度公司是一间由国家建立的私人企业,在成立时就获得了国家赋予的各种独有特权;举例来说,他们有权编组属于公司的海军和陆军。根据公司内部文件指出,立法机关对荷兰东印度公司与其他公司的监督和管制,在一六二○年代形成的商业奴隶贸易政策中扮演重大的角色。荷兰政府也参与了东印度公司的决策,并与公司共享档案与情资,帮助公司拟定策略。于是,就像英国与法国一样,荷兰的帝国企业以及史上首批大规模跨国公司的建立,全都源自于国家和私营部门的合作。9
在荷兰东印度公司成立不久后,荷兰政府与公司股东在一六○二年一起执行了一个大型的市场建设计划。在荷兰东印度公司的帮助下,奥登巴那维与荷兰当局在阿姆斯特丹设立了第一间真正的股票交易所,藉此推动该公司的股票交易。荷兰东印度公司是史上第一间上市公司,其股份在欧洲各国皆有销售。这个具开创性的成熟、先进市场并不是凭空出现的。一六○九年,阿姆斯特丹的领导阶层在市政厅成立了交易银行(Exchange Bank),又称为阿姆斯特丹银行(Bank of Amsterdam),政府监督此银行的运作,希望能藉此建立信心;并保证了贵金属货币与存款的价值,以便支付帐款给荷兰东印度公司。10
荷兰共和国在一五八一年成功脱离西班牙哈布斯堡王朝(Hapsburg Spain)并宣布独立后,开始试着进入原本向他们紧闭大门的西班牙与葡萄牙市场与贸易站。东印度公司的计划是控制亚洲贸易。在荷兰攻击与窃取伊比利亚人的财富与贸易的过程中,海盗行为发挥了重要作用。一六○三年二月,荷兰船长雅各布.希姆斯科(Jacob van Heemskerck)在新加坡海岸以东袭击并俘虏了葡萄牙船只圣卡特琳娜号(Santa Catarina)。荷兰海军部门先前已经直接命令希姆斯科不得涉入战争一类的行为。然而这艘船上的财富比荷兰法令更有说服力。圣卡特琳娜号抵达阿姆斯特丹时,船上载着一千两百捆的稀有中国丝绸和数百盎司的麝香,价值超过三百万荷兰盾──约三十万英镑。希姆斯科当然没有合法权力可以接管这艘船。虽然荷兰海事法庭最终裁定这些来自船上的战利品是合法取得的,仍有一些荷兰东印度公司的股东认为这种完全就是窃盗的行为并不道德,这使得正积极进军新帝国市场的荷兰东印度公司面临了挑战。15
荷兰共和国渴望能进入伊比利亚帝国贸易的大门,这样的想望催生了该时期最具影响力的一些利伯维尔场哲学。当圣卡特琳娜号的丑闻持续延烧,荷兰东印度公司找来了希姆斯科刚满二十岁的表亲,著名的人文主义法学天才雨果.格劳秀斯,请他撰写一篇文章来捍卫公司的利益。他们希望格劳秀斯能主张在抢攻西班牙与葡萄牙帝国市场的过程中,东印度公司拥有采用海盗行为的道德权利。格劳秀斯是著名的学者暨政治家的儿子,在十一岁时就被著名的莱顿大学(University of Leiden)录取。大学时期的他沉浸在经典典籍中,特别喜欢西塞罗的作品。而格劳秀斯接下来的人生就和这位著名的罗马法学家一样多彩多姿。他将会从卢夫斯泰因堡(Loevestein Castle)的囚牢逃脱,藏匿在一只本应该装满了书的箱子前往巴黎(这个箱子至今仍展示在该城堡),他将会在一场船难中幸存,并成为一名大政治家。他会运用具人文主义的渊博知识,成为那个时代最重要的法学理论家与卡尔文派神学家。
格劳秀斯的《论捕获法》(Commentary on the Law of Prize and Booty ,一六○四年)是一部对利伯维尔场思想产生了深远影响的著作,开启了格劳秀斯作为现代自然权利理论奠基者的法学作者生涯。《论捕获法》运用了普遍自然法的逻辑,为荷兰攻击甚至入侵葡萄牙帝国领土的行为进行辩护。这部充满专业术语的长篇著作很可能不是荷兰东印度公司原本想要的政治宣传文稿。无论如何,《论捕获法》为格劳秀斯的未来作品奠定了框架。格劳秀斯借用了西塞罗的观点,指出道德与自然的法则是举世通用的,任何个人都可以透过理性判断来厘清这些法则是什么。“背信弃义又残暴”的葡萄牙人想要控制全世界海洋的行为,已经造成了道德损害。此外,葡萄牙人拒绝荷兰进入帝国领土和原住民贸易,剥夺了荷兰人的自然权利,根据格劳秀斯的说法,这也是一种罪行。因而荷兰人对葡萄牙船只的俘获是合理的战利品,这样的行为是具有“诚实信用”(good faith)的。由于主权是一项自然权利,而非基督教专属,所以西班牙帝国的原住民也同样有选择和荷兰成为贸易盟友的权利与自由。考虑到荷兰大炮与堡垒的规模,这个针对伊比利亚提出的“原住民自由选择论”也就显得很有说服力了。16
一六○九年,格劳秀斯匿名出版了这本书的第十二章〈海洋自由论〉(The Free Sea),他这么做不只是为了东印度公司,也是为了发表他身为法律学者的第一篇公开著作。这篇文章在哲学与政治宣传两方面都带来了意想不到的成功。格劳秀斯针对自然、海洋与个人自由的本质提出了他的观点,这些观点为后来十七世纪的塞缪尔.普芬道夫(Samuel von Pufendorf)、约翰.洛克(John Locke)与之后其他关注自然权利与人类权利的欧洲思想家打下了基础。
格劳秀斯并且再次引用西塞罗的话,主张任何干涉自由的国家都是在招致一场正义的战争。此论点将会成为格劳秀斯在国际法方面的巨作《战争与和平的权利》(The Rights of War and Peace ,一六二五年)之核心。在阐述国家间互动应遵守的规则时,格劳秀斯坚持认为,个人应该有自然权利能选择自己的行为。“国际法律”(law of nations)和自然法则是相互独立的,国际法律清楚表明,只要以不伤害他人为前提,个人就拥有积极自由,可以去做他们选择的事。而这同样也是私有财产所有权的基础论点。任何国家都不能占有大自然中“不会耗竭”的广大资源;个人与国家只能拥有明确位于国界内部的有限事物,例如“湖泊、池塘和河流”。18
不过,跨国经济力量的现实状况并没有引起荷兰经济思想家的太多关注。在十七世纪中叶,荷兰的商业霸权正处于颠峰,这段时期的荷兰经济理论中最重要的著作是身为新教徒的布料制造商、经济学家暨利伯维尔场与共和国理论家彼得.寇特(Pieter de la Court)所撰写的《荷兰共和国的真正利益与政治准则》(The True Interest and Political Maxims of the Republic of Holland ,一六六二年)。这部作品是当时最精密成熟的利伯维尔场理论之一,寇特在其中主张,政治自由与自由贸易胜过了君主制的权柄。在荷兰大议长的支持下,掌握实权的首相约翰.维特(Johan De Witt)写道,寇特的作品是针对君主制的一记致命攻击,并指出这部作品详细描绘出了政治自由与宗教自由、自由贸易与自由竞争、制造业与船运都是自我调节的经济体制的一部分。寇特直接引用了英荷商人作家杰拉德.马林斯与其著作《商人法》(一六二二年)来主张商人的地位凌驾于君主之上。22 寇特主张的观点很单纯:君主制度对经济成长有害,荷兰的居民“在他们的政治体系中遭受的最大祸害,莫过于受到君主和最高领主的统治”。“伯爵”追求权力的野心会使政治变得不稳定,而“阿谀奉承的臣子”则会破坏那些使国家富裕的东西:“航海、制造业与商业”。23
在经历了无与伦比的经济成功之后,荷兰共和国于一六七二年遇上了史上恶名昭彰的灾难年 (Rampjaar),当时维特为了控制整个共和国,试图镇压国内权势最大的荷兰贵族,奥兰治的威廉三世亲王(Prince William III of Orange)。那一年,尽管在好战的法国国王路易十四入侵了荷兰共和国的境况下,威廉仍试图主张自己统治荷兰的权力。威廉自称为终身军队总司令,此举引起了法国打算让他担任国王的传言。荷兰共和国屈服后,威廉在七月九日成为总督,并公开挑战维特与寇特的影响力。七月二十三日,多德雷赫市(Dordrecht)的奥兰治派支持者抓到了维特的兄弟柯奈尔(Cornelis),对他用刑,并指控他意图谋反对抗威廉。威廉下令要约翰.维特支付巨额罚款换取释放柯奈尔。在约翰抵达多德雷赫市时,他原本以为自己可以使愤怒的奥兰治派群众冷静下来,却遭到了攻击与刺杀。群众谋杀了这对兄弟,斩下他们的头颅,吊起他们的身体,吃掉他们的肉──而威廉没有否认这些暴力行为。27
1. M. F. Bywater and B. S. Yamey, Historic Accounting Literature: A Companion Guide (London: Scholar Press, 1982), 87.
2. Jacob Soll, The Reckoning: Financial Accountability and the Rise and Fall of Nations (New York: Basic Books, 2014), 77.
3. Maarten Prak, The Dutch Republic in the Seventeenth Century (Cambridge: Cambridge University Press, 2005), 29.
4. Prak, Dutch Republic , 102.
5. Prak, Dutch Republic , 91.
6. Koen Stapelbroek, “Reinventing the Dutch Republic: Franco-Dutch Commercial Treaties from Ryswick to Vienna,” in The Politics of Commercial Treaties in the Eighteenth Century: Balance of Power, Balance of Trade , ed. Antonella Alimento and Koen Stapelbroek (Cham, Switzerland: Palgrave Macmillan, 2017), 195–215, at 199.
7. Prak, Dutch Republic , 105.
8. Prak, Dutch Republic , 96; Margaret Schotte, Sailing School: Navigating Science and Skill, 1550–1800 (Baltimore: Johns Hopkins University Press, 2019), 42, 53.
9. J. M. de Jongh, “Shareholder Activism at the Dutch East India Company, 1622–1625,” January 10, 2010, Palgrave Macmillan 2011, available at SSRN,https://ssrn.com/abstract=1496871 ; Jonathan Koppell, ed. , Origins of Shareholder Activism (London: Palgrave, 2011); Alexander Bick, Minutes of Empire: The Dutch West India Company and Mercantile Strategy, 1618–1648 (Oxford: Oxford University Press, forthcoming); Theodore K. Rabb, Enterprise and Empire: Merchant and Gentry Investment in the Expansion of England, 1575–1630 (Cambridge, MA: Harvard University Press, 2014), 38–41.
10. Lodewijk J. Wagenaar, “Les mécanismes de la prospérité,” in Amsterdam XVIIe siècle: Marchands et philosophes . Les bénéfices de la tolérance, ed. Henri Méchoulan (Paris: Editions Autrement, 1993), 59–81.
11. “A Translation of the Charter of the Dutch East India Company (1602),” ed. Rupert Gerritsen, trans. Peter Reynders (Canberra: Australasian Hydrographic Society, 2011), 4.
12. De Jongh, “Shareholder Activism,” 39.
13. Soll, Reckoning , 80; Kristof Glamann, Dutch Asiatic Trade, 1620–1740 (The Hague: Martinus Nijhoff, 1981), 245.
14. Soll, Reckoning , 81.
15. Hugo Grotius, Commentary on the Law of Prize and Booty , ed. Martine Julia van Ittersum (Indianapolis: Liberty Fund, 2006), xiii.
16. Grotius, Commentary , 10, 27; Hugo Grotius, The Free Sea , ed. David Armitage (Indianapolis: Liberty Fund, 2004), xiv, 7, 18.
17. Grotius, Free Sea , 5, 24–25, 32.
18. Grotius, Free Sea , 57; Hugo Grotius, The Rights of War and Peace , ed. Richard Tuck, 3 vols. (Indianapolis: Liberty Fund, 2005), 3:1750, 2:430–431.
19. Grotius, Rights of War and Peace , 2:556–557; Brett Rushforth, Bonds of Alliance: Indigenous and Atlantic Slaveries in New France (Chapel Hill: University of North Carolina Press, 2012), 90.
22. On new attitudes of merchant virtue, see J. G. A. Pocock, The Machiavellian Moment: Florentine Political Thought and the Atlantic Republican Tradition (Princeton, NJ: Princeton University Press, 1975), 478.
23. Pieter de La Court, The True Interest and Political Maxims of the Republick of Holland and West-Friesland (London: 1702), vi, 4–6, 9.
24. De La Court, True Interest and Political Maxims , 24–35.
25. De La Court, True Interest and Political Maxims , 63, 51, 55.
26. De La Court, True Interest and Political Maxims , 45, 51, 55, 312, 315.
27. Prak, Dutch Republic , 51, 53.
28. Prak, Dutch Republic , 59.
第七章 尚─巴提斯特.柯尔贝与国家市场
在重建商业的过程中,有两个必要条件:确定性和自由。 ──尚─巴提斯特.柯尔贝,《英格兰商业备忘录》(Mémoire Concerning Commerce with England ),一六五一年
荷兰是柯尔贝最大的担忧,因为尽管彼得.寇特针对利伯维尔场发表了许多高尚的言词,但真实状况就是荷兰的国家主义贸易政策非常具有侵略性,还拥有一支傲视其他国家的海军。对于“法国商业的糟糕处境”与法国高达四百万英镑的贸易逆差,柯尔贝始终充满怨言,他认为这是荷兰制定的条约导致的直接结果,该条约以牺牲竞争对手为代价来换取荷兰的贸易自由。柯尔贝认为荷兰对法国的种种侵犯,特别是他们对法国各种出口货品的劫持──举例来说,荷兰控制了法国在波罗的海这个富裕市场的酒类贸易──侵害了法国的自然权利。此外,荷兰也禁止那些可能在国内市场真正具有竞争力的法国商人与工匠进入荷兰境内。柯尔贝知道法国还太弱小了,还没有做好竞争的准备。如果他直接关闭与荷兰的贸易边界,只会对法国的发展造成损害。因而他追求的并不是贸易壁垒,而是设计良好的贸易条约,至少实现两国互惠。为此,柯尔贝认为政府应该招募经验丰富的商人来管理与撰写商业条约和法律。9 柯尔贝在打造法国工业时采用的策略,有一部分是基于他对一六五一年的英格兰《航海法》的理解,他(以及后来的亚当斯密)认为这项法令是英格兰获得发展优势的关键。同时,柯尔贝也主张荷兰人制定关税是为了要扼杀法国的贸易与制造业。一六七○年,在法国与荷兰进行了长时间的协商后,柯尔贝仍持续抱怨荷兰不但把所有法国商品排除在荷兰市场之外,同时还将矛头指向里尔市,想要扼杀该处的工业。此外,荷兰还致力于控制法属西印度群岛的贸易,迫使法属群岛购买荷兰商品。10 由于荷兰将一些法国边境城市、甚至法属殖民地的法国贸易商排除在交易对象之外,所以柯尔贝认为法国的保护主义关税是很公正合理的。因此,他想要追求的是巩固法国在自身领土内的贸易自由。他提议安地列斯群岛的居民靠着武装自己来抵御荷兰的干涉,如此一来他们才能以“完全自由”的状态来做生意。手段残酷的尚─查尔斯.巴斯(Jean-Charles de Baas)是法属安地列斯群岛的奴隶殖民地总督,柯尔贝在他寄给巴斯的信中写道,“商业的自由”不只是为了让法属西印度公司进行垄断而已。为了柯尔贝声称的“共同利益”,这种自由必须延伸至所有法国商人身上才行。他仍抱持着中世纪的概念,也就是经济自由是国家授予的特权。自由不会延伸到农奴、契约劳工、罪犯或奴隶的身上。自由仅限于贵族,以及那些持有国王通行证的法国商人和具有人身自由的定居者身上。经济自由不是一种普遍的自然权利,而是国家给予的特权。不过,无论这种想法有多局限,都一样建构出某种自由贸易的愿景。11
他为此颁布了一套商业的法律与标准,任何违反的人都会遭到重罚。柯尔贝手下的警察局长加布里埃尔.尼古拉斯.莱尼(Gabriel-Nicolas de La Reynie)是个聪明而无情的人,他负责监督巴黎的市场与街道──肉店、裁缝店、性工作者、街道照明与印刷业──并管理贸易行会,确保行会成员都遵守规定。他制裁了外国印花布料的非法流通,当时这些违禁布料在法国处处可见,而对法国工业造成了损害。意大利人、荷兰人和英格兰人长久以来一直利用法国宽松的商业监管措施来占便宜。作为响应,柯尔贝打造了一套印章系统来标示法国布料的质量,这使外国市场对法国布料充满信心。当英格兰人找到方法伪造法国皇家印章时,莱尼没收了数千令(ream)的外国布料。他帮助法国确保国内的羊毛业能够对英格兰羊毛业构成高度的商业威胁。13
对柯尔贝来说,在建立商业贸易与外国殖民地贸易的过程中,建立人们对法国声誉的信心就和法规以及保护主义同样重要。因此,在他建立法国商业市场的计划中,宣传(也就是如今所谓的广告)是一个关键。他定期邀请备受尊敬的学者担任代言人,藉此提高法国作为知识、文化与科技创新中心的声誉。一六六三年,柯尔贝正在成立法国东印度公司(French East India Company)时,邀请了院士暨学者法朗索瓦.夏邦提耶(François Charpentier)针对东印度贸易的历史与实用性撰写一篇文章。这篇文章的目的不只是刺激法国商业,同时也是在向外国竞争对手做宣传。夏邦提耶遵循柯尔贝的路线,主张“危险的自由放任主义”已经占据了法国,因此使得这个王国的繁荣发展受到战争和动荡的侵害。商业“就像博雅教育(liberal arts)一样”──是可以透过聚焦与专注来“培育”的。于是,夏邦提耶向读者提出挑战,要他们航向崭新的海洋,透过发现新“财富”。他说,“创新者”会创造出富裕。14
同时柯尔贝也雇用了耶稣会学者皮耶.丹尼尔.辉特(Pierre-Daniel Huet),他是阿夫杭士市(Avranches)的主教,也是一位博学的法兰西学术院(Académie Française)成员。柯尔贝令他负责撰写商业历史,将路易十四统治的法国与罗马帝国的荣光相比拟。在他的著作《商业与古代航海之历史》(History of Commerce and of the Navigation of the Ancients ,一七六三年)的序言中,辉特解释了柯尔贝如何利用法国的“优点”展示出商业对国家的重要。法国人们若想要与他国进行商业竞争,就必须开始重视航海与帝国建设。他解释说,罗马帝国的成功源自于贸易与帝国制度;如今法国也应该要跟随这种模式,成为国际商业界的新罗马。15
柯尔贝在一六六三年写下了〈为历史而写的法国金融事务备忘录〉(Memoirs on France’s Financial Affairs to Serve History),这篇文章循着马基维利、布丹和博泰罗的观点,认为一个国家唯有在“其方法得到妥善管理”时才能生存下去。换句话说,内政大臣必须运用财政能力来管理国家、有效征税,并妥善管理收入、支出、资产与负债。这种良好的管理将会创造出信心,使贸易之轮转动得更顺畅,并且如同柯尔贝反复提起的那样,创造出“商业自由”。柯尔贝动用了所有他能使用的经济模型与工具──从马基维利的国家愿景,到荷兰对会计的聚焦,再到英格兰的发展保护主义──去为市场带来信心。17
为接触法国的广大读者,柯尔贝赞助出版了他认为能够在法国公民身上培养商业知识与信心的一系列书籍。举例来说,他委托数学家暨会计大师法兰索瓦.巴雷姆(François Barrême)撰写复式记账会计的手册与关于货币兑换的书籍。会计学校采用了他撰写的实用数学手册《巴雷姆的算数》(The Arithmetic of Sir Barrême ,一六七二年)。巴雷姆在序言中指出了法国在财务素养方面的缺乏,就算在国家的最高层也一样:“柯尔贝先生一直希望国王管辖之下的所有业务都能使用复式记账,但他找不到足够多的熟悉复式记账的人才,使得财务监察机构的老旧做法迟迟无法革新。”巴雷姆的著作大获成功,后来成为了《巴雷姆通用手册》(Barrême Universel ),这本会计手册一直到十九世纪仍持续出版。18
一六六三年,设计了罗浮宫东面的著名院士暨建筑师克劳德.佩罗(Claude Perrault)开始和柯尔贝合作执行一项建造皇家科学院(Royal Academy of Sciences)的计划。佩罗写信给柯尔贝,说皇家科学院不只能光耀路易十四,更能宣传法国科学可信度,“出版科学发现,使这些发现为人所知”,并让法国“在全世界声名远播”。关于此计划的最初摘要显示,化学、解剖学、几何学、天文学和代数等研究领域具有实用性,且可以应用在法国的商业与金融事业中。他们的目标是使皇家科学院成为实验与公共教学的中心,把科学权威交到王室手中,接着再向全世界广为宣传。23
海更斯说服了柯尔贝:皇家科学院最重要的其中一个活动是出版自然历史著作,使用“共通”且容易理解的语言来解释科学实验,让社会大众也能了解。一六六五年,柯尔贝开始赞助丹尼斯.萨罗(Denis de Sallo)的计划,创办由国家控管的科学期刊《科学家周刊》(Journal des sçavans ),这份期刊使得法国成为了受信任的科学权威来源。《科学家周刊》主张他们会刊登“学术共和国(Republic of Letters)中的新事物”,也就是全球学界中的新事物。发行人表示,此期刊会聚焦在“有用”的事物上,人们将会在这里找到“每年的重大事件”。甚至到后来路易十四统治的法国进入了战争与政治、宗教压迫的最高峰时,欧洲各地的学者仍视此期刊为科学、数学、力学、哲学与最重要的“艺术与工艺”(也就是工程学)之重要权威。就连战争时期,法国仍因为《科学家周刊》而享有国际信誉。25
这些科学出版品使法国获得了工业与商业领导者的声誉──这样的声誉甚至有些言过其实。这项策略十分成功,在一六七○年代,英格兰人开始把法国视为比荷兰更大的商业强国──这在一六六一年还是无法想象的事。柯尔贝的弟弟是克鲁瓦西侯爵查尔斯.柯尔贝(Charles Colbert, marquis de Croissy),柯尔贝在一六六八年派查尔斯到伦敦担任大使,查尔斯让英国人留下绝佳的印象,成功说服了当时的英国国王查理二世私下支持法国对抗荷兰的行动,以换取每年二十三万英镑的个人报偿。尚─巴提斯特.柯尔贝在短短的数年内,使法国成为其他国家的真正商业竞争对手,甚至成为国际间的领导强国──至少表面上看起来是如此。27 著名的英国日记作者暨海军部秘书山缪.皮普斯(Samuel Pepys)对于这位“来自克鲁瓦西的柯尔贝”印象深刻,就皮普斯与其他人的了解,查尔斯是在哥哥的命令下来到英国监视英国工业与海军计划的。这使得尚─巴提斯特.柯尔贝显得更加令人生畏。皮普斯也热中阅读柯尔贝为商业宣传出版的作品。一六六九年一月三十日,皮普斯在日记中写道,他“认真阅读了一本法国的专书”,他担心这篇关于航海的书籍会使得人们觉得法国的海军与贸易能力就快要超越英国了。那本书正是法朗索瓦.夏邦提耶为东印度公司的成立所写的宣传著作,而这样的手法显然奏效了,使得皮普斯感到法国已经转变为成功的贸易大国,是英国最重要的竞争对手。法国的科技专长也同样使各国感到钦佩。皮普斯在一六九○年代的“海军会议纪录”(Naval Minutes)中记载道,法国拥有最精良的造船技术、船舰、港口和水手,并引用了柯尔贝在一六七一年制定的造船规范和一六七三年的战舰规范。皮普斯认为,从这些书籍就可以看出法国的海军能力远比英国更优越,他感叹道:“我国海军中的每一条优秀规范,有哪个不是法国早就设立好的规范呢?”柯尔贝的政策与宣传正中要害。28
在尚─巴提斯特.柯尔贝于一六八三年逝世时,他已经成功为法国打开了英国市场。法国甚至取得了对英国的贸易顺差。这对于英国商人来说是一场危机,他们认为法国占了上风,必须立刻予以阻止。在十七世纪,由于每个国家都在抢夺竞争优势,所以自由贸易条约的进步十分缓慢。29 不过,当时已有迹象显示,柯尔贝试图把法国转变成商业国家让太阳王很不满意。路易十四鄙视商人,认为他们是庸俗的暴发户,因而撤回了柯尔贝的许多改革政策。路易十四非但没有努力促进法国与最大贸易伙伴英国的自由贸易,反而想要发动战争。他不顾柯尔贝的意见,在一六七二年入侵荷兰。 光是向外侵略还不能让路易十四满足,他甚至在国内也走上了公民暴力的路线。一六八五年,也就是柯尔贝逝世两年后,路易十四废除了《南特诏令》(Edict of Nantes ),此法令原本旨在保护法国的新教徒少数族群。有超过二十万名法国新教徒遭受酷刑、被迫改信天主教,及受到镇压、监禁和驱逐。路易十四很清楚柯尔贝因为对贸易不利而反对宗教压迫,残暴成性的路易十四派了柯尔贝的儿子,也就是塞涅来侯爵(marquis de Seignelay)负责强迫新教徒转信天主教。法国新教徒的流亡目的地从荷兰、丹麦与英格兰,扩散到了日耳曼与美洲殖民地的多个地点。这对法国商业造成了严重打击。新教的胡格诺派(Huguenot)商人和工匠离开时,也带走了柯尔贝当初砸重金发展的专业技能;欧洲各国的君主都因为玻璃工匠、银匠、橱柜工匠和各种商人具有的优秀技术而乐于迎接他们的到来。事实上,正是《南特诏令》的废除使得法国今日没有制表的优良传统,法国的新教钟表匠全都逃到了卡尔文派的瑞士日内瓦(Geneva),那里至今仍是全球钟表贸易的中心。 与经济史学家一直以来所认知不同的是,大幅削弱柯尔贝主义与扩张市场自由可能性的,正是路易十四。作为在辉煌的贵族宫廷中心统治一整个王朝的国王,路易十四从不认为自己是普通商人的国王。目光短浅的路易十四更停止了对海军的经费支持,对殖民地的关注也下降了。现在,他的目光转向了战争。一六八八年,他开启了九年战争(Nine Years’ War),美洲将之称作威廉王之战(King William’s War),路易十四在这场战事中越过了莱茵河,积极地把法国的边界与领土向外扩张。为了对抗路易十四的侵略,英格兰、荷兰共和国、奥地利哈布斯堡神圣罗马帝国(Austrian Hapsburg Holy Roman Empire)、西班牙、葡萄牙与萨伏依(Savoy)结成了同盟。此外再加诸那些公开反对路易十四的胡格诺派教徒带来的影响,新教君主开始将太阳王视为巨大的威胁。长期的战争与饥馑,消灭了自由贸易的所有可能性。 一六九三年,法国北部的作物收成欠佳。在战争税与食物短缺造成的压力下,饥荒恶化成了伤寒疫情,此外还有类似沙门氏菌的细菌引起的腐热(putrid fever)与瘟疫腹热(pestilent abdominal fever)。一六九三年至一六九四年的大饥荒(Great Famine),扣掉正常死亡率后大约导致了一百三十万人死亡。士兵纷纷感染伤寒,不得不抱病作战。法国的财政陷入混乱,人民被大规模死亡的阴影尾随,整个国家都活在路易十四造成的无常战争与其灾难性影响的威胁之下。当路易十四发现自己无法入侵荷兰共和国与英格兰之后,便开始骚扰他们分布在世界各地的商人,威胁到了从西印度群岛至印度的英格兰殖民地和贸易路线。等到九年战争终于在一六九七年结束时,法国在所有层面上都元气大伤。威廉三世现在随时保持着英格兰与法国间的备战状态,英国商人也将法国视为军事与商业上的威胁。 这一切和柯尔贝过去的希望背道而驰。柯尔贝的梦想是以平等贸易的条约和互利作为基础,实现平衡的自由贸易,如今这个梦想已被暴力战争与大规模死亡取代。改革者为了与过去切割,便把路易十四毫无道理的破坏行为归咎到柯尔贝身上。那些推动法国改革与利伯维尔场的人,开始把柯尔贝这位逝世已久的内政大臣拿来作为法国需要改变之事物的象征。柯尔贝主义和柯尔贝在经济史上的地位遭到扭曲,并因为路易十四晚期的灾难性统治而蒙上污点。法国的利伯维尔场思想发展之所以窒碍难行,不是因为柯尔贝执行的经济政策,而是因为路易十四好战又专制的愚行扭曲了这位内政大臣的余荫。
1. Pierre Deyon, “Variations de la production textile aux XVIe et XVIIe siècles: Sources et premiers résultats,” Annales. Histoire, sciences sociales 18, no. 5 (1963): 939–955, at 949.
2. Daniel Dessert and Jean-Louis Journet, “Le lobby Colbert,” Annales 30, no. 6 (1975): 1303–1329; Georg Bernhard Depping, Correspondance administrative sous le règne de Louis XIV , 3 vols. (Paris: Imprimerie Nationale, 1852), 3:428; Philippe Minard, “The Market Economy and the French State: Myths and Legends Around Colbertism,” L’Économie politique 1, no. 37 (2008): 77–94; Jean-Baptiste Colbert, “Mémoire sur le commerce: Prémier Conseil de Commerce Tenu par le Roy, dimanche, 3 aoust 1664,” in Lettres, instructions, et mémoires de Colbert , ed. Pierre Clément, 10 vols. (Paris: Imprimerie Impériale, 1861–1873), vol. 2, pt. 1, p. cclxvi; Jean-Baptiste Colbert, “Mémoire touchant le commerce avec l’Angleterre,” in Lettres , vol. 2, pt. 2, p. 407.
3. Colbert, “Mémoire touchant le commerce avec l’Angleterre,” vol. 2, pt. 2, pp. cclxviii, 48, 407; D’Maris Coffman, Excise Taxations and the Origins of Public Debt (London: Palgrave Macmillan, 2013).
4. Colbert, “Mémoire sur le commerce, 1664,” vol. 2, pt. 1, pp. cclxii–cclxxii, at cclxviii, cclxix; Jean-Baptiste Colbert, “Aux maires, échevins, et jurats des villes maritimes de l’océan, aoust 1669,” in Lettres , vol. 2, pt. 2, p. 487; Colbert to M. Barillon, intendant at Amiens, mars 1670, in Lettres , vol. 2, pt. 2, pp. 520–521; Colbert to M. Bouchu, intentant at Dijon, juillet 1671, in Lettres , vol. 2, pt. 2, p. 627.
5. Gustav von Schmoller, The Mercantile System and Its Historical Significance (New York: Macmillan, 1897); Erik Grimmer-Solem, The Rise of Historical Economics and Social Reform in Germany, 1864–1894 (Oxford: Oxford University Press, 2003). 有关发展经济,参见 Erik S. Reinert, “The Role of the State in Economic Growth,” Journal of Economic Studies 26, no. 4/5 (1999): 268–326.
6. Deyon, “Variations de la production textile,” 949, 951–953; François Crouzet, “Angleterre et France au XVIIIe siècle: Essaie d’analyse comparé de deux croissances économiques,” Annales. Économies, sociétés, civilisations 21, no. 2 (1966): 254–291, at 267.
7. Crouzet, “Angleterre et France au XVIIIe siècle,” 266, 268; Eli F. Heckscher, Mercantilism , trans. Mendel Shapiro, 2 vols. (London: George Allen and Unwin, 1935), 1:82; Stewart L. Mims, Colbert’s West India Policy (New Haven, CT: Yale University Press, 1912); Charles Woolsey Cole, Colbert and a Century of French Mercantilism , 2 vols. (New York: Columbia University Press, 1939), 1:356–532; Charles Woolsey Cole, French Mercantilism, 1683–1700 (New York: Octagon Books, 1971); Glenn J. Ames, Colbert, Mercantilism, and the French Quest for Asian Trade (DeKalb: Northern Illinois University Press, 1996); Philippe Minard, La fortune du colbertisme: État et industrie dans la France des Lumières (Paris: Fayard, 1998).
8. Colbert, Lettres , vol. 2, pt. 2, p. 457.
9. Colbert, “Mémoire sur le commerce, 1664,” vol. 2, pt. 1, pp. cclxii–cclxxii, at cclxviii; Colbert, “Mémoire touchant le commerce avec l’Angleterre,” 405–409; Georg Bernhard Depping, Correspondance administrative sous le règne de Louis XIV , vol. 3 (Paris: Imprimerie Nationale, 1852), 90, 428, 498, 524, 570; Moritz Isenmann, “Égalité, réciprocité, souvraineté: The Role of Commercial Treaties in Colbert’s Economic Policy,” in The Politics of Commercial Treaties in the Eighteenth Century: Balance of Power, Balance of Trade , ed. Antonella Alimento and Koen Stapelbroek (London: Palgrave Macmillan, 2017), 79.
10. Colbert, “Mémoire touchant le commerce avec l’Angleterre,” 405–409, 496, 523, 570; Lawrence A. Harper, The English Navigation Laws: A Seventeenth-Century Experiment in Social Engineering (New York: Octagon Books, 1964), 16; John U. Nef, Industry and Government in France and England, 1540–1640 (repr. , Ithaca, NY: Cornell University Press, 1957 [1940]), 13, 27.
11. Colbert, “Mémoire touchant le commerce avec l’Angleterre,” 487; Colbert to M. du Lion, September 6, 1673, in Lettres , vol. 2, pt. 1, p. 57; Colbert to M. de Baas, April 9, 1670, in Lettres, vol. 2, pt. 2, p. 479.
12. Ames, Colbert, Mercantilism , 189; Mims, Colbert’s West India Policy , 232; Mireille Zarb, Les pivilèges de la Ville de Marseille du Xe siècle à la Révolution (Paris: Éditions A. et J. Picard, 1961), 163, 329; Jean-Baptiste Colbert, “Mémoire touchant le commerce avec l’Angleterre,” 407.
13. Jacques Saint-Germain, La Reynie et la police au Grand Siècle: D’après de nombreux documents inédits (Paris: Hachette, 1962), 238, 240.
14. François Charpentier, Discours d’un fidèle sujet du roy touchant l’establissement d’une Compagnie Françoise pour le commerce des Indes Orientales; Adressé à tous les François (Paris: 1764), 4, 8; Paul Pellisson, Histoire de l’Académie François e, 2 vols. (Paris: Coignard, 1753), 1:364.
15. Urban-Victor Chatelain, Nicolas Foucquet, protecteur des lettres, des arts, et des sciences (Paris: Librarie Académique Didier, 1905), 120; Pierre-Daniel Huet, Histoire du commerce et de la navigation des anciens (Lyon: Benoit Duplein, 1763), 1–2.
16. Huet, Histoire du commerce et de la navigation , cclxxii.
17. Heckscher, Mercantilism , 1:81–82; Jean-Baptiste Colbert, “Mémoires sur les affaires de finances de France pour servir à leur histoire, 1663,” in Lettres , vol. 2, pt. 2, pp. 17–68; J. Schaeper, The French Council of Commerce, 1700–1715: A Study of Mercantilism After Colbert (Columbus: Ohio State University Press, 1983); Colbert, “Mémoire sur le commerce,” 44–45.
18. François Barrême, Le livre nécessaire pour les comptables, avocats, notaires, procureurs, négociants, et généralement à toute sorte de conditions (Paris: D. Thierry, 1694), 3; François Barrême, Nouveau Barrême universel: Manuel complet de tous les comptes faits (Paris: C. Lavocat, 1837).
19. Ordonnance du commerce du mois de mars 1673; et ordonnance de la marine, du mois d’août 1681 (Bordeaux, France: Audibert et Burkel, an VIII), 5, Art. 4.
20. Jacques Savary, Le parfait négociant; ou, Instruction générale pour ce qui regarde le commerce des Marchandises de France, & des Païs Estrangers , 8th ed. , ed. Jacques Savary Desbruslons, 2 vols. (Amsterdam: Jansons à Waesberge, 1726), 1:25; Adam Smith, An Inquiry into the Nature and Causes of the Wealth of Nations , ed. Roy Harold Campbell and Andrew Skinner, 2 vols. (Indianapolis: Liberty Fund, 1981), vol. 2, bk. IV, chap. vii, pt. 2, para. 53.
21. Peter Burke, The Fabrication of Louis XIV (New Haven, CT: Yale University Press, 1994); Colbert, “Mémoire sur le Commerce,” vol. 2, pt. 1, p. cclxiii; Alice Stroup, A Company of Scientists: Botany, Patronage, and Community in the Seventeenth-Century Parisian Royal Academy of Sciences (Berkeley: University of California Press, 1990), 30.
22. Colbert, Lettres , vol. 2, pt. 2, p. 62; vol. 5, pp. 241–242; Charles Perrault, “Autre note à Colbert sur l’établissement de l’Académie des Beaux-Arts et de l’Académie des Sciences,” 1666, in Colbert, Lettres , 5:513–514. Also see Roger Hahn, The Anatomy of a Scientific Institution: The Paris Academy of Sciences, 1666–1803 (Berkeley: University of California Press, 1971), 15; Lorraine Daston, “Baconian Facts, Academic Civility, and the Prehistory of Objectivity,” Annals of Scholarship 8 (1991): 337–363; Steven Shapin, A Social History of Truth: Civility and Science in Seventeenth-Century England (Chicago: University of Chicago Press, 1995), 291; Michael Hunter, Science and Society in Restoration England (Cambridge: Cambridge University Press, 1981), 48; Anthony Grafton, The Footnote: A Curious History (Cambridge, MA: Harvard University Press, 1997), 202–205; Jean-Baptiste Say, A Treatise on Political Economy , 2 vols. (Boston: Wells and Lilly, 1821), 1:32–33; Margaret C. Jacob, Scientific Culture and the Making of the Industrial West (Oxford: Oxford University Press, 1997), chap. 8.
23. Perrault, “Autre note à Colbert,” 5:514; Charles Perrault, “Note de Charles Perrault à Colbert pour l’établissement d’une Académie Générale, 1664,” in Colbert, Lettres , 5:512–513.
24. Christiaan Huygens, Oeuvres completes, 22 vols. (The Hague: Martinus Nijhoff, 1891), 19:255–256. 中括号内的批注来自麦可.马奥尼(Michael Mahoney)的翻译,在此采用:“[Memorandum from Christiaan Huygens to Minister Colbert Regarding the Work of the New Académie Royale des Sciences],” Princeton University, www.princeton.edu/~hos/h591/acadsci.huy.html .
25. Huygens, “Note from Huygens to Colbert, with the Observations of Colbert, 1670,” in Colbert, Lettres , 5:524; James E. King, Science and Rationalism in the Government of Louis XIV, 1661–1683 (Baltimore: Johns Hopkins University Press, 1949), 292; Joseph Klaits, Printed Propaganda Under Louis XIV: Absolute Monarchy and Public Opinion (Princeton, NJ: Princeton University Press, 1976), 74; Denis de Sallo, “To the Reader,” Journal des sçavans (January 5, 1665): 5; Jacqueline de la Harpe, Le Journal des Savants en Angleterre, 1702–1789 (Berkeley: University of California Press, 1941), 6, 8; Arnaud Orain and Sylvain Laubé, “Scholars Versus Practitioners? Anchor Proof Testing and the Birth of a Mixed Culture in Eighteenth-Century France,” Technology and Culture 58, no. 1 (2017): 1–34.
26. Liliane Hilaire-Pérez, Fabien Simon, and Marie Thébaud-Sorger, L’Europe des sciences et des techniques: Un dialogue des savoirs, xve–xviiie siècle (Rennes, France: Presses Universitaires de Rennes, 2016); John R. Pannabecker, “Diderot, the Mechanical Arts, and the Encyclopédie in Search of the Heritage of Technology Education,” Journal of Technology Education 6, no. 1 (1994); Cynthia J. Koepp, “Advocating for Artisans: The Abbé Pluche’s Spectacle de la Nature (1731–1751),” in The Idea of Work in Europe from Antiquity to Modern Times , ed. Josef Ehmer and Catherina Lis (Farnham, VT: Ashgate, 2009), 245–273. 有关柯尔贝艺术协会(Colbertist Société des Arts)转变成重农主义的转变过程,参见 Hahn, Anatomy of a Scientific Institution , 108–110; Robert Darnton, The Business of Enlightenment: A Publishing History of the Encyclopédie, 1775–1800 (Cambridge, MA: Belknap Press of Harvard University Press, 1979); Kathleen Hardesty, The Supplément to the Encyclopédie (The Hague: Nijhoff, 1977); John Lough, Essays on the “Encyclopédie” of Diderot and d’Alembert (London: Oxford University Press, 1968); Dan Edelstein, The Enlightenment: A Genealogy (Chicago: University of Chicago Press, 2010); Jacob Soll, The Information Master: Jean-Baptiste Colbert’s Secret State Information System (Ann Arbor: University of Michigan Press, 2009), 161; Robert Darnton, “Philosophers Trim the Tree of Knowledge: The Epistemological Strategy of the Encyclopédie,” in The Great Cat Massacre and Other Episodes in French Cultural History (New York: Vintage, 1984), chap. 5; Colbert, 1619–1683 (Paris: Ministère de la Culture, 1983), 168; Paola Bertucci, Artisanal Enlightenment: Science and the Mechanical Arts in Old Regime France (New Haven, CT: Yale University Press, 2017), 214. 另见 Linn Holmberg, The Maurist’s Unfinished Encyclopedia (Oxford: Voltaire Foundation, 2017), 175.
27. Colbert, “Mémoire touchant le commerce avec l’Angleterre,” vol. 2, pt. 2, p. 405.
28. Samuel Pepys, Naval Minutes , ed. J. R. Tanner (London: Navy Records Society, 1926), 352–356, at 356; King, Science and Rationalism , 272.
29. D. G. E. Hall, “Anglo-French Trade Relations Under Charles II,” History 7, no. 25 (1922): 17–30, at 23; Jacob Soll, “For a New Economic History of Early Modern Empire: Anglo-French Imperial Codevelopment Beyond Mercantilism and Laissez-Faire,” William and Mary Quarterly 77, no. 4 (2020): 525–550.
第八章 太阳王的噩梦和利伯维尔场的美梦
我们的美德往往是经过伪装的恶行。 ──拉侯谢傅科公爵(Duc de La Rochefoucauld),《格言录》(Maxims ),一六六五年
等到九年战争(一六八八年至一六九七年)结束时,法国和欧洲各国一样都疲惫不堪,他们经历的是二十多年间几乎未曾止歇的冲突。路易十四恐吓西属尼德兰,并利用他的影响力追捕与迫害各个邻国的法国新教难民。他的战争大臣,个性极为残忍的卢瓦侯爵(marquis de Louvois)在欧洲与世界各地推行暴力统治。为了应付战争的开支,法国征收了额外税金,使广大法国人民陷入悲惨的生活,多数人只能不断挨饿。
十七世纪最重要的其中一位探讨利己的哲学家,是著名的法国贵族法朗索瓦(François),即拉侯谢傅科公爵(Duc de La Rochefoucauld)。他的著作推动了人们相信个人机会主义能推动商业社会与市场,对利伯维尔场思想造成了重大的影响。拉侯谢傅科公爵质疑西塞罗那套“爱与友谊推动交易”的说法,他承袭圣奥古斯丁与霍布斯的观点,认为人类的行为并非出自仁慈,而是出自对于自身的关注。因此,他希望能了解欲望,也就是他所谓的“自爱”(self-love,法文为amour propre),会如何影响人类的所有行为。他相信在更好的环境条件下,人类确实可以透过斯多噶派的纪律找到美德。但当统治者是专制且道德破产的帝王时,这种道德自由是不可能的事。拉侯谢傅科公爵尤其反对路易十四用君主专制主义剥夺贵族的古老农业美德,他将凡尔赛宫的皇室比做交易荣誉和特权的“股票交易所”,而贵族们正试图从中获利。他谴责道,在路易十四的世界中,所有行为与友谊都“只以利己为基础”。3
对于路易十四压迫性的天主教主义,最主要的批判来自杨森主义天主教徒(Jansenist Catholics)。他们和拉侯谢傅科公爵一样,希望能找出一套系统来运用利己,将之转变成好的事物。法国的杨森主义信徒受到十七世纪初法兰德斯的伊珀尔主教(bishop of Ypres)康涅留斯.杨森(Cornelius Jansen)的启发,追求的不只是灵性上的完善,还要寻找一套能够减轻原罪与改善世俗生活的体系。杨森主义者是圣奥古斯丁的忠实深度读者,他们相信上帝创造出了一个完美的世界,人类的罪行却扰乱了这个世界。杨森主义者因为路易十四的贪婪与自恋而感到疲惫,认为自给自足的商业市场最可能让人类有机会把原罪与欲望转换成美德。他们相信奇迹的时代已经结束了,“上帝已经隐藏了”。除一小群被选中的人能透过上帝的恩典获得救赎之外,其他人类不会得到上帝的解救,只能赤身裸体地留在孤独之中,成为自身罪恶本质的猎物。包括著名的法京剧作家尚.拉辛(Jean Racine)在内,些许法国思想家因为杨森主义者的观点深受感动,从世俗中完全抽身并独自住在小房间里,追求奥古斯丁式的自我克制和虔诚美德。但是这种纯粹主义缺乏广泛的吸引力。广大人类中的绝大多数不可能在社会中生活的同时完全避免罪恶与利己。事实上在路易十四统治下的法国,若不参与他的政权就无法完全正常地生活。于是,有些人开始寻找新方法,希望至少能用这个方法来应付受到人类的贪婪与利己所主宰的世界。5
尚.多马(Jean Domat)是一位信奉杨森主义的著名罗马法学专家,他塑造了基督徒版本的旧佛罗伦萨理想,把商业视为能够使国家富强的一种公民货品。多马仔细研究市场机制如何疏导、甚至消除罪恶,为利伯维尔场思想设计了一套基督徒观点的框架,对后世产生长远的影响。他的著作《公民法之自然法则》(The Civil Law in Its Natural Order ,一六八九年至一六九四年)是一部国际知名的罗马法摘要集,清楚描述了市场如何自由地对人类的渴望与情绪做出回应。多马承袭了西塞罗的看法,认为人类可以在自然之中辨认出永恒不变的法则,一旦我们允许这些法则自然运作,就能启动一种动态的市场系统,控制住人类唯利是图的倾向。
若说拉侯谢傅科公爵和多马这一类的哲学家在寻找的,是一个把个人罪恶转变成公共美德的公式,那么其他更直接参与路易十四国家事务的哲学家,在寻找的就是能够治疗法国痼疾的解药。来自鲁昂的杨森主义税吏暨利伯维尔场与经济均衡的先驱理论家,布阿吉尔贝尔男爵皮耶.皮森特(Pierre Le Pesant, sieur de Boisguilbert)甚至直接向路易十四的财政大臣提出了利伯维尔场作为解决方案,其他提案参与者中,也包括柯尔贝的外甥和他在专业知识方面的继承人尼古拉斯.德马雷兹(Nicolas Desmaretz)。
布阿吉尔贝尔在柯尔贝最成功的其中一个商业区担任警方督察(intendant of police):拥有羊毛加工业的繁荣城镇鲁昂。运用他在自己的贵族领地与行政辖区实施收税的经验,为国家政策的实际应用发展出了第一个自我延续市场的现代观念。他认为法国的经济困境源自人类的错误判断,于是开始撰写一本说明经济能如何自我驱动的著作。他在一六九五年出版的《详述法国》(Detail of France )是史上第一本专门讨论自我延续市场机制之经济思想的详尽书籍。他在书中指责,虽然有货币在法国境内流通,但它们并没有在创造财富,这些货币若非只对富人的利益有帮助,就是被税收侵蚀掉。针对农民的税收制度既不公平又具有惩罚性,此一制度瘫痪了消费、破坏了农业、使货币的价值与流通性下降,还阻碍了能带来财富的生产与市场本身。7
在柯尔贝的直系继任者们所制定的政策中,利伯维尔场哲学发挥作用的例子并非只有这次。事实上,在十七世纪末,柯尔贝家族已站在利伯维尔场思想的先锋位置。德马雷兹并不是家族中唯一一个和其他人连手进行利伯维尔场改革的人。柯尔贝的女婿和康佩(Cambrai)主教法朗索瓦.萨利尼克.莫斯─芬乃伦(François de Salignac de la Mothe-Fénelon)密切合作,芬乃伦是一位狂热的自由放任主义理论家,也是当时影响力最大的作家之一。 芬乃伦在一六八九年至一六九七年担任路易十四的推定继承人勃艮第公爵(duc de Bourgogne)的导师,因而成为皇室家庭的成员,能定期接触到国王、他的家人和他的大臣。芬乃伦不但是一位才华洋溢的宗教演说家,后来也成为了提出自由放任主义愿景的十七世纪作者中,拥有最广大阅读群众的一位。芬乃伦的老师是路易十四的首席神学家雅克─贝尼涅.波苏维(Jacques-Bénigne Bossuet),负责在凡尔赛宫的皇家礼拜堂里布道的波苏维不仅支持宗教绝对主义的政治理论,也提倡宗教不宽容。在一六八五年的《南特诏令》废除后,路易十四派出波苏维和芬乃伦执行国家任务,到法国西南大西洋沿岸的拉荷歇尔(La Rochelle)周边改变新教徒的信仰。在拉荷歇尔的这段期间,芬乃伦对他们以暴力军事手段改变宗教信仰一事感到心灰意冷,也对路易十四的政治和经济政策感到失望。 芬乃伦在宫廷中的人脉很广,与柯尔贝的女婿第二代圣艾尼昂公爵保罗.波维利尔(Paul de Beauvilliers, 2nd duc de Saint-Aignan)过从甚密,并在其他人的引见下和德马雷兹变得关系密切。波维利尔的另一位密友是在宫廷中声势逐渐崛起的吕纳公爵(duc de Luynes)查尔斯.奥诺雷.达贝尔(Charles-Honoré d’Albert),他是柯尔贝的另一个女婿,一般对他的称呼来自另一个家族头衔谢夫勒斯公爵(duc de Chevreuse)。如今柯尔贝的女婿波维利尔和谢夫勒斯在宫廷中掌权,德马雷兹进入财政部,柯尔贝的侄子托尔西侯爵尚─巴提斯特.柯尔贝(Jean-Baptiste Colbert, marquis de Torcy,又称作托尔西的柯尔贝〔Colbert de Torcy〕)则在一六九六年被任命为外交事务大臣,于是柯尔贝家族集团得以在路易十四的宫廷与政府高层中呼风唤雨。我们可以从他们的通信中得知,他们是以家族为单位在运作,持续累积他们的财富,就连在支持芬乃伦的构想时也一样。在波维利尔和德马雷兹的带领下,这个强大的集团一起制定战略,希望能找回柯尔贝的优秀政府管理,建立更加自由的市场。13
波维利尔同时也是皇室未成年子女的监护人,因此在皇室中拥有绝大的影响力。路易十四知道他们是一个集团,所以在召开正式会议时,只会召集柯尔贝政府集团里的领导成员:托尔西的柯尔贝、波维利尔和德马雷兹。他让柯尔贝集团任命芬乃伦担任路易十四的七岁孙子的家教老师,这个孙子就是最终继承了王位的勃艮第公爵。波维利尔和芬乃伦相信,这名年幼的君主是通往改革的道路,更是能让他们获得更多权力的途径。他们打算以柯尔贝的治理方法为基础为这位年轻公爵制定学习计划。一六九七年,波维利尔和芬乃伦开始执行这项勃艮第公爵计划,使用一套庞大的统计书籍《绍讷列表》(The Tables of Chaulnes ),希望让这位继承人了解,要如何透过一套能带来经济自由的治理改革,来扩张法国的人口与商业规模。其内容聚焦于透过柯尔贝当年的统计法去计算、测量与在地图上标示法国的所有重要财富与管辖区。此外,计划的另一个目的是创造更好的税收制度:每一种形式的应税财产都要确实记录下来。14
一六九九年,柯尔贝家族密切支持芬乃伦撰写小说《忒勒马科斯的冒险》(The Adventures of Telemachus ),供勃艮第公爵的教育所用。《忒勒马科斯的冒险》是那个时代最明确、影响力也最大的农业利伯维尔场思想著作,也是十八世纪的畅销书,启发了从莫扎特到亚当斯密等多位重要人物。芬乃伦的小说填补了荷马的著作《奥德赛》(Odyssey)中缺漏的情节,描述了奥德修斯的儿子忒勒马科斯在冒险中学习的故事。故事中,有一位睿智的老师一直陪在忒勒马科斯身边,芬乃伦透露,这位老师其实是伪装过后的智慧女神密涅瓦(Minerva)。15
想当然耳,路易十四既没有听从芬乃伦的建议,也没有理会柯尔贝家族中的其他成员。芬乃伦提出的利伯维尔场改革方案全都没有问世。不如说,我们可以认为路易十四后来的统治彻底摧毁了柯尔贝与其后继者真正追求的目标。路易十四对于芬乃伦的批判怒火中烧,在一六九九年将他逐出宫廷,继续进行西班牙王位继承战争(War of Spanish Succession,一七○一年至一七一四年)。这正是芬乃伦曾提出警告的那种噩梦。路易十四的战争使得法国开始对抗英格兰大同盟(Grand Alliance of England),包括荷兰共和国、奥地利大公国以及后来的西班牙和萨伏依。根据军事史学家的估计,交战中的死亡人数大约落在七十万至一百二十万之间──且法国在之前一六九三年至一六九四年间的大饥荒已经死了一百二十万人。一七○九年,太阳黑子引起的气温骤降导致了大霜冻(Great Frost),法国在这段期间又死了六十万人。在虚弱、饥饿与绝望中,法国人口共减少了数百万之多。
路易十四践踏了柯尔贝留下的功绩,也抹煞了可能随之而来的商业自由与经济成长。不过,在这些惨烈的失败中,柯尔贝最重要的其中一些改革存活了下来。虽然法国仍是农业社会,受到贵族与专制君主的统治,但法国工业仍有持续产出,在全球商业的舞台上和英格兰继续竞争。法国非但仍是全世界的两大科学强国之一,而且还成为了欧洲启蒙运动的摇篮。启蒙运动是一场错综复杂的科学与思想进步的运动,事实将证明此运动是现代利伯维尔场思想哲学的核心。法国经济思想家将会透过哲学家查理.路易.德.色贡达(Charles-Louis de Secondat),也就是孟德斯鸠男爵(baron de Montesquieu)所谓的“温和”商业,以贸易的互利性取代自爱的战争本能,寻找通往和平与繁荣的永久道路。换句话说,自由贸易就是嫉妒、战争与贫困的解药。法国将会在这方面对英国经济哲学造成深远的影响。在这两个国家中,人们此刻还坚持认为,只要人类能靠着解放农业市场来妥善利用大自然,那么市场就能在和平之中创造奇迹,制造无穷尽的财富。21
1. Albert O. Hirschman, The Passions and the Interests: Political Arguments for Capitalism Before Its Triumph (Princeton, NJ: Princeton University Press, 1977), 16.
2. Thomas Hobbes, Leviathan , ed. Richard Tuck (Cambridge: Cambridge University Press, 1997), pt. 1, chaps. 13–14.
3. La Rochefoucauld, Maxims , trans. Leonard Tancock (London: Penguin, 1959), maxims 48, 85, 112, 563; Pierre Force, Self-Interest Before Adam Smith: A Genealogy of Economic Science (Cambridge: Cambridge University Press, 2003), 146, 176; Norbert Elias, The Court Society (New York: Pantheon Books, 1983), 105.
4. La Rochefoucauld, Maxims , 66, 77, 223, 305.
5. David A. Bell, The Cult of the Nation in France: Inventing Nationalism, 1680–1800 (Cambridge, MA: Harvard University Press, 2003), 28; Dan Edelstein, On the Spirit of Rights (Chicago: University of Chicago Press, 2019), 120; Pierre Nicole, “De la grandeur,” in Essais de morale , 3 vols. (Paris: Desprez, 1701), 2:186; Dale van Kley and Pierre Nicole, “Jansenism, and the Morality of Self-Interest,” in Anticipations of the Enlightenment in England, France, and Germany , ed. Alan C. Kors and Paul J. Korshin (Philadelphia: University of Pennsylvania Press, 1987), 69–85; Gilbert Faccarello, Aux origins de l’économie politique libérale: Pierre de Boisguilbert (Paris: Éditions Anthropos, 1985), 99.
6. Jean Domat, The Civil Law in Its Order Together with the Publick Law , 2 vols. (London: William Strahan, 1722), vol. 1, chap. 2, sec. 2; vol. 1, chap. 5, sec. 7; vol. 2, bk. 1, title 5; Faccarello, Aux origins de l’économie politique libérale , 146; Edelstein, On the Spirit of Rights , 120; David Grewal, “The Political Theology of Laissez-Faire : From Philia to Self-Love in Commercial Society,” Political Theology 17, no. 5 (2016): 417–433, at 419.
7. Pierre Le Pesant de Boisguilbert, Détail de la France (Geneva: Institut Coppet, 2014), 18, 61–63.
8. Boisguilbert, Détail de la France , 77, 89, 99.
9. Faccarello, Aux origins de l’économie politique libérale , 115, 119.
10. Gary B. McCollim, Louis XIV’s Assault on Privilege: Nicolas Desmaretz and the Tax on Wealth (Rochester, NY: University of Rochester Press, 2012), 106, 149; A. -M. de Boislisle, Correspondance des contrôleurs généraux des finances , 3 vols. (Paris: Imprimerie Nationale, 1883), 2:530.
11. Boisguilbert to Desmaretz, July 1–22, 1704, Archives Nationales de France, G7 721; Boislisle, 2:207, 543–547, 559.
12. Boislisle, Correspondance des contrôleurs généraux , 2:544.
13. Georges Lizerand, Le duc de Beauvillier (Paris: Société d’ÉditionLes Belles Lettres, 1933), 43, 153.
14. Lionel Rothkrug, Opposition to Louis XIV: The Political and Social Origins of the French Enlightenment (Princeton, NJ: Princeton University Press, 1965), 263–269, 286–287; Louis Trénard, Les Mémoires des intendants pour l’instruction du duc de Bourgogne (Paris: Bibliothèque Nationale, 1975), 70–82; David Bell, The First Total War: Napoleon’s Europe and the Birth of Warfare as We Know It (New York: Houghton Mifflin, 2007), 62; Lizerand, Le duc de Beauvillier , 46–77; marquis de Vogüé, Le duc de Bourgogne et le duc de Beauvillier: Lettres inédites, 1700–1708 (Paris: Plon, 1900), 11–23; Jean-Baptiste Colbert, marquis de Torcy, Journal Inédit , ed. Frédéric Masson (Paris: Plon, Nourrit et Cie, 1884), 57; Louis de Rouvroy, duc de Saint-Simon, Projets de gouvernement du duc de Bourgogne , ed. P. Mesnard (Paris: Librarie de L. Hachette et Cie, 1860), xxxix, 13; Edmond Esmonin, “Les Mémoires des intendants pour l’instruction du duc de Bourgogne,” in Études sur la France des XVIIe et XVIIIe siècles (Paris: Presses Universitaires de France, 1964), 113–130, at 117–119; Boislisle, Correspondance des contrôleurs généraux, 2:ii.
15. Georges Weulersse, Le movement physiocratique en France de 1756 à 1770 , 2 vols. (Paris: Félix Alcan, 1910), 2, 302; François Fénelon, Telemachus , ed. and trans. Patrick Riley (Cambridge: Cambridge University Press, 1994), 60, 195, 325.
21. Montesquieu, De l’Esprit des lois , ed. Victor Goldschmidt, 2 vols. (Paris: Garnier-Flammarion, 1979), vol. 2, bk. 20, chap. 1.
第九章 行星运动与英国自由贸易的新世界
贸易的本质是自由的,它会找到自己的渠道,决定最好的路线:所有针对贸易制定的规则、引导、限制和约束,往往都是对特定个人有利的法律,鲜少对公众有利。 ──查尔斯.达凡南特(Charles Davenant),《论东印度贸易》(An Essay on the East India Trade ),一六九六年
在十七世纪的前数十年,佛罗伦萨仕绅暨天文学家伽利略.伽利莱(Galileo Galilei)延续了哥白尼的研究,坚持认为基础物理可以透过严谨且客观的数学定律,应用在行星上。伽利略试着透过惯性的力量来了解行星运动,惯性力量会使行星能抗拒方向的变化,藉此维持绕行太阳的轨迹。伽利略的发现在该世纪早期带来了巨大的影响,但他并不是唯一一个致力于动力学的杰出科学家。一六二八年,英国医师威廉.哈维(William Harvey)发表了《论心脏与血液之运动》(Anatomical Account of the Motion of the Heart and Blood ),指出心脏会推动血液流往全身,形成自我延续的回路;人体像是一个能够运输与流动的有机器械,反映了星辰的运动方式。伽利略和哈维的作品启发了法国哲学家勒内.笛卡儿(René Descartes)写下《世界》(The World ,一六三三年),此著作描述了物质是如何遵循自身的自然轨迹运行,推动这种运行的并不是神秘学性质的力量,而是物质之间的相互作用力。他认为运动的动力并非来自上帝,而是来自较小的物体,也就是微粒(corpuscule)之间的机械式相互作用力。2 英国自然哲学家、数学家暨天文学家艾萨克.牛顿主张,大自然会按照物理的自我延续法则,以可预测的方式运作。牛顿因此建立了一套对于上帝神圣行动的崭新观点,认为上帝是大自然运行的监督者,而不是直接执行者。举例来说,上帝并没有创造闪电与暴风雨当作惩罚,彗星也不是预兆;这些只是大自然这个巨大机械中的零件在移动罢了。牛顿认为,自然现象所遵循的恒定物理定律,是人类可以藉由数学去理解的。更有甚者,他认为行星的运行定律也可以套用在社会与市场上。如果人类能了解社会与市场的运作机制的话,那么人类也将能预测社会与市场。3 牛顿相信,如果人类能理解大自然的运作流程,就可以揭露无限量创造黄金与白银的秘密方法。他遵循悠久且神秘的炼金术传统,推测地球是透过“植物精神”(vegetable spirit)的力量运作,此外,地球本身就是一种“巨大的动物”,会呼吸、寻求“更新”并维持自身的生命。牛顿确信地球内部有一种秘密能量,源自硫磺与水银组成的“贤者之石”(philosopher’s stone)。这其实并不只是幻想而已。牛顿在一六八七年写下的典范之作《数学原理》(Principia mathematica )中描述了行星的引力运动与日心说的数学原理,希望能让无神论者别再主张宇宙的混乱代表了这个世界上没有所谓的神圣计划。牛顿认为,从根本上来说,这个世界的系统是以明确规律为基础在运行的机械式系统,而他相信这种规律让我们看见了上帝之手的创造痕迹。4 和牛顿同一时代的日耳曼新教哲学家戈特弗里德.威廉.莱布尼兹(Gottfried Wilhelm von Leibniz)也同样在寻找宇宙的驱动力。莱布尼兹是一名博学之士,他发明了微积分和现代物理学,认为是上帝创造了人类的生命和大自然,使这两者像精密的时钟一样运作,并且拥有无限种运动的可能性。他指出,手表中的平衡摆轮的德文是“Unruhe “,同时也有“不安”和“骚动”的意思。莱布尼兹认为,这种骚动不安就是制造出运动的源头。这个宇宙是所有事物在一个“预先建立的和谐系统”中不断流通的无限总和。他以辨给的口才指出,理解这种无休止运动的困难之处就像要理解“一座由连续体(continuum)构成的迷宫”。5
政治理论家约翰.洛克认为,人类社会是依据各种理性原则自行组织而成的,这些原则反映了牛顿的运动力学理论和佩第的观点,也就是个人可以透过自由选择创造出经济效率。洛克强烈反对政治专制主义,成为那个时代在宪政与个人权利方面影响力最高的理论家。洛克正是因为极端厌恶斯图亚特和波旁(Bourbon)的专制军权与践踏个人权利的行为,才写下了《政府论两篇》(Two Treatises on Government ,一六八九年)。他的灵感同时来自西塞罗和基督教,解释说私有财产是政治自由与有效运作市场的重要关键。伊甸园的所有事物都是共享的,而在亚当从伊甸园坠落至俗世时,也就创造出了我们对私有财产与人类劳动的需求。10
洛克和达凡南特的想法十分符合当时的科学与政治观点。事实上,在一六八八年的英国光荣革命(Glorious Revolution)中,奥兰治的威廉与他的英格兰妻子玛丽推翻了她的父亲,也就是倾向专制的詹姆士二世;威廉实施了《权利法案》(bill of rights )与君主立宪制,带领英格兰迈入真正的全球商业时代。英法之间的全球经济霸权争夺战又再进一步升温。讽刺的是,这两个国家为了经济主导地位而进行的斗争,将会催化新的政治经济思想运动。英法愈是在商业与工业相互竞争,哲学家们就愈渴望把西塞罗对农业与和平的信念,结合到永恒运动和财富创造的概念中,藉此达成他们理想中的自由贸易。18
1. Ludwig Wittgenstein, Culture and Value , ed. Georg Henrik Wright, Heikki Nyman, and Alois Pichler, trans. Peter Winch (London: Blackwell, 1998), 18; Richard J. Blackwell, “Descartes’ Laws of Motion,” Isis 52, no. 2 (1966): 220–234, at 220.
2. Vincenzo Ferrone, “The Epistemological Roots of the New Political Economy: Modern Science and Economy in the First Half of the Eighteenth Century,” paper presented at the conference “Mobility and Modernity: Religion, Science and Commerce in the Seventeenth and Eighteenth Centuries,” University of California, Los Angeles, William Andrews Clark Memorial Library, April 13–14, 2018.
3. Margaret C. Jacob, The Newtonians and the English Revolution, 1689–1720 (Ithaca, NY: Cornell University Press, 1976), 174; Rob Iliffe, The Priest of Nature: The Religious Worlds of Isaac Newton (Oxford: Oxford University Press, 2017), 6.
4. Betty Jo Teeter Dobbs and Margaret C. Jacob, Newton and the Culture of Newtonianism (Amherst, NY: Humanity Books, 1990), 26, 100; William R. Newman, Newton the Alchemist: Science, Enigma, and the Quest for Nature’s “Secret Fire” (Princeton, NJ: Princeton University Press, 2019), 64, 70.
5. Dobbs and Jacob, Newton and the Culture of Newtonianism , 42; Gottfried Wilhelm Leibniz, Theodicy , ed. Austen Farrer, trans. E. M. Huggard (Charleston, SC: BiblioBazaar, 2007), 43, 158; G. W. Leibniz, “Note on Foucher’s Objection (1695),” in G. W. Leibniz, Philosophical Essays , ed. and trans. Roger Ariew and Daniel Garber (Indianapolis: Hackett, 1989), 146; G. W. Leibniz, The Labyrinth of the Continuum: Writings on the Continuum Problem, 1672–1686 , trans. Richard T. W. Arthur (New Haven, CT: Yale University Press, 2001), 566.
6. William Letwin, The Origins of Scientific Economics: English Economic Thought, 1660–1776 (London: Methuen, 1963), 128.
7. François Crouzet, “Angleterre et France au XVIIIe siècle: Essaie d’analyse comparé de deux croissances économiques,” Annales. Économies, sociétés, civilisations 21, no. 2 (1966): 254–291, at 268; T. S. Ashton, An Economic History of England: The Eighteenth Century (London: Methuen, 1955), 104; François Crouzet, Britain Ascendant: Comparative Studies in Franco-British Economic History (Cambridge: Cambridge University Press, 1991), 17–23, 73.
8. William Petty, “A Treatise of Taxes and Contributions,” in William Petty, Tracts Chiefly Relating to Ireland (Dublin: Boulter Grierson, 1769), 1–92, at 23–26, 32.
9. William Petty, “The Political Anatomy of Ireland, 1672,” in Petty, Tracts , 299–444, at 341.
10. John Locke, Two Treatises of Government , ed. Peter Laslett (Cambridge: Cambridge University Press, 1960), 171; John F. Henry, “John Locke, Property Rights, and Economic Theory,” Journal of Economic Issues 33, no. 3 (1999): 609–624, at 615.
11. Locke, Two Treatises , 291, 384.
12. John O. Hancey, “John Locke and the Law of Nature,” Political Theory 4, no. 4 (1976): 439–454, at 219, 439.
13. Holly Brewer, “Slavery, Sovereignty, and ‘Inheritable Blood’: Reconsidering John Locke and the Origins of American Slavery,” American Historical Review 122, no. 4 (2017): 1038–1078; Mark Goldie, “Locke and America,” in A Companion to Locke , ed. Matthew Stuart (Chichester: Wiley-Blackwell, 2015), 546–563; Letwin, Origins of Scientific Economics , 163–165; David Armitage, “John Locke, Carolina, and The Two Treatises of Government,” Political Theory 32, no. 5 (2004): 602–627, at 616; J. G. A. Pocock, The Machiavellian Moment: Florentine Political Thought and the Atlantic Republican Tradition (Princeton, NJ: Princeton University Press, 1975), 283–285, 339.
14. Charles Davenant, An Essay on the East India Trade (London, 1696), 25.
15. Pocock, Machiavellian Moment , 437, 443.
16. Pocock, Machiavellian Moment , 446; Charles Davenant, Reflections upon the Constitution and Management of the Trade to Africa (London: John Morphew, 1709), 25, 28.
17. Davenant, Reflections , 27, 36, 48, 50, 58.
18. Steven Pincus, 1688: The First Modern Revolution (New Haven, CT: Yale University Press, 2009), 308.
第十章 英国与法国:贸易战、赤字与找到天堂的美梦
因此,尽管每一个角落都充满了罪恶,但整体来说这里却是天堂。 ──伯纳德.曼德维尔,《蜜蜂的寓言》(The Fable of the Bees ),一七一四年
此时的英国正处于金融革命(Financial Revolution)之中。一六九四年,威廉三世的政府需要更好的信用条件才能在英格兰与法国的战争中继续坚持,而英格兰银行(Bank of England,通称英国央行)的成立对政府带来了很大的帮助,英格兰银行不但以合理的利率借钱给政府,让政府能管理债务,同时也在信贷市场中建立了信心,并资助创业计划。正如约翰.洛克的主张,社会需要信心与达成共识的体制,才能建立对市场的信任。但是债务仍然不断成长,从一六八八年的一百万英镑增加到一六九七年的一千九百万英镑,这些债务是个大杂烩,包括利率百分之七的年金、浮动债务、抽签公债(lottery loan),以及来自英格兰银行和南海与东印度公司的贷款。就算有了这间新银行,国家债务仍是一个棘手的问题。2
除此之外,英格兰也处于政治动荡之中。一七○七年,英格兰和苏格兰合并成为大不列颠(Great Britain)。威廉与玛丽的女儿安妮女王(Queen Anne)于一七一四年在没有继承人的情况下过世,这推动了宪制的《光荣革命嗣位法令》(Act of Settlement of the Glorious Revolution )的制定,明确规定王位由女王关系最近且仍旧存活的新教徒亲戚来继承,当时的王位正好落在日耳曼血统的汉诺威选帝侯(imperial elector of Hanover),布伦瑞克─吕讷堡公爵乔治.路易(George Louis, Duke of Brunswick-Lüneburg)的身上,也就是后来的大不列颠国王乔治一世(George I of Great Britain)。他在一七一四年八月一日登基,同时也继承了国家的债务。3
这些想法很快就引起了社会大众的注意。一七○七年,伦敦出现了一本标题非常精彩的匿名小册子:《论有效应对方法;又名,图隆等式:改善美洲西南部贸易的友好认购提案,每年为东印度贸易和王室收入增加三百万黄金与白银,若得到鼓励则将会产生相应的结果》(An Account of What Will DO; or, an Equivalent for Thoulon: In a Proposal for an Amicable Subscription for Improving TRADE in the South-West Part of AMERICA, and Increasing BULLION to About Three Millions per Annum, Both for the East India Trade and the Revenue of the Crown, Which by Consequence Will Be Produced if This Is Encouraged )。这本小册子主张,美洲是“所有黄金与白银的唯一泉源”,任何占领了美洲的国家就能拥有“这个世界上的所有物质财富 “,并控制“全天下的贸易”,并坚持英格兰应该要比法国先一步统治西印度群岛。英格兰应该要帮助“计划者”──也就是冒险家暨企业家──占领美洲,在必要时使用强烈手段,以便英国能控制美洲的所有财富。如此一来,英国就能打造一支胜过所有国家的海军,建立起一个全球帝国。5
在这样的氛围中,英荷讽刺作家、医师暨经济哲学家伯纳德.曼德维尔写下了《蜜蜂的寓言:又名,个人恶行,公众利益》(The Fable of the Bees: or, Private Vices, Public Benefits ,一七一四年),这是早期利伯维尔场哲学中最清楚好懂、也是引起最多争议且最知名的著作之一。《蜜蜂的寓言》为英国的商业社会总结出一个同时充满批判与希望的愿景。曼德维尔遵循马基维利、霍布斯、拉侯谢傅科描述人类本质时采取的愤世嫉俗观点,描述了一种充斥着恶行的商业文化,在这个宛如蜂巢的国家中,律师、商人、神职人员和乡绅都无异于“骗子、寄生虫、皮条客、赌徒、扒手、伪币制造者、江湖医师〔和〕占卜师”,全都对于“诈骗、奢侈品和傲慢”轻微上瘾。事实上,他还以押韵的文体指出:“所有交易和每个角落都必定有欺骗存在/没有任何志愿能免于诈欺的残害。”他相信是“自私”在推动人类的行为。6
法国就和英国一样,想要为他们的债务与不断衰退的经济系统找到神奇解方。法国被饥荒压垮了,现在已濒临破产。一七一四年,柯尔贝的外甥,也就是财政总监督尼古拉斯.德马雷兹正绞尽脑汁,希望能解决法国实际上已经面临的破产问题。所有改革都停滞不前,他仍在努力试着从法国饱受摧残的人民手中榨取每一分税收。法国没有国家银行,税收基础薄弱,这是因为法国贵族不需要定期缴税。德马雷兹已经无路可退。他曾听闻著名的苏格兰经济理论学家暨赌博玩家约翰.劳(John Law,在法语中,他的姓氏〔l’as〕念起来像是“王牌”〔the ace〕)提出一个计划,要在苏格兰建立国家银行并印制纸钞。一七○五年,劳出版了一本非同寻常的小册子《货币与贸易的思考》(Money and Trade Considered ),指出一个国家拥有愈多货币,就能进行愈大量的贸易。他的点子就是印制货币,这并不是在制造财富,而是制造一种推动财富创造的催化剂。8
这位苏格兰人与法国摄政王在法国的上层阶级赌场碰面。劳是一名赌徒,既会研究赚钱的机率方法,同时也对风险上了瘾。这样的个性着实不像是成为未来法国财政大臣的最佳人选。一七一六年,奥尔良公爵批准劳建立私人资助的通用银行(Banque Générale),可以依据法国的黄金储备量发行纸钞。法国政府接受人民用这些纸钞来缴税。一七一八年,劳创办的通用银行变成了皇家银行(Royal Bank)。这间银行承办存款与借贷业务,也进行有利可图的国家垄断,营运殖民地的烟草贸易与销售。劳在同一年新成立了西部公司(Company of the West,为密西西比公司〔Mississippi Company〕的前身),接着和几间在塞内加尔与几内亚进行奴隶贸易的公司合并。一七一九年,劳的公司并购了法属东印度公司与中国公司,成为全球金融集团“永存印度公司”(Perpetual India Company),靠着包括奴隶买卖在内的殖民贸易获利。摄政王希望劳成立的垄断公司能为国家管理财政,并带来他们急需的资金。11
乍看之下,所谓的“劳氏体制”(Law’s System)似乎和利伯维尔场没有半点关系。然而,劳的货币理论和创新构想──也就是可以靠着一间公司来处理整个国家的债务──至少被视为与被宣传为一种以市场为基础的因应方式。身为赌徒的劳深知在推动信贷与驱动市场的过程中,想象力将扮演重要的角色,因此他发起了一场大规模的宣传活动,宣扬美国有多少潜在财富,希望能说服社会大众投资他的银行和公司股份。密西西比河谷(Mississippi Valley)就是劳的黄金国与法国版的美国梦。劳引用了拉萨勒男爵勒内.罗伯特.卡维利耶(René-Robert Cavelier, sieur de La Salle)对密西西比探险经历的描述,又出版了制图师纪尧姆.迪莱尔(Guillaume Delisle)为路易斯安那州的广阔未开垦领地绘制的杰出地图,并聘请皇家学院的成员撰写书籍,颂扬法国新世界的自然财富。12
劳所描绘的愿景为:路易斯安那州是财富的奇迹,而对此最关键的一篇宣传就是法国的尚.特拉松神父(Jean Terrasson)撰写的《无限创造论》(The Treatise on the Creation of Infinity ,约一六九五年至一七一五年)。这篇文章声称地球具有“无限可能”,对于那些前往美洲的人来说,美洲的丰富资源也充满“无限可能”,这本书在巴黎风行一时,广受欢迎。特拉松断定国家经济不需要专家、金融管理人员和会计师的指导。只要有信心的驱使,经济就会逐渐进入一个能够自我调节的系统。皇家银行将会提供贷款给所有想要投资劳的公司的人,进而把“整个国家转变成一个商人主体”。这项国家投资计划将会得到永存印度公司的担保和纸钞产生的经济燃料作为支持。如此一来,财富就会普遍化,社会中的所有成员将公平地共享财富。这样的财富没有任何风险,“开明”且拥有无上权力的君主,也就是摄政王本人,将会克服所有困难。13
1. Guy Rowlands, The Financial Decline of a Great Power: War, Influence, and Money in Louis XIV’s France (Oxford: Oxford University Press, 2012), 2; Richard Dale, The First Crash: Lessons from the South Sea Bubble (Princeton, NJ: Princeton University Press, 2004), 77.
2. Carl Wennerlind, Casualties of Credit: The English Financial Revolution, 1620–1720 (Cambridge, MA: Harvard University Press, 2011), 68, 89; Stephen Quinn, “The Glorious Revolution’s Effect on English Private Finance: A Microhistory, 1680–1705,” Journal of Economic History 61, no. 3 (2001): 593–615, at 593; Julian Hoppit, Britain’s Political Economies: Parliament and Economic Life, 1660–1800 (Cambridge: Cambridge University Press, 2017), 149; P. G. M. Dickson, The Financial Revolution in England: A Study in the Development of Public Credit, 1688–1756 (New York: Macmillan, 1967), 80.
3. John Brewer, The Sinews of Power: War, Money and the English State, 1688–1783 (New York: Alfred A. Knopf, 1989), 116–117.
4. Wennerlind, Casualties of Credit , 10; Ian Hacking, The Emergence of Probability: A Philosophical Study of Early Ideas About Probability, Induction and Statistical Inference (Cambridge: Cambridge University Press, 1975); Lorrain Daston, Classical Probability in the Enlightenment (Princeton, NJ: Princeton University Press, 1988), 164.
5. An Account of What Will DO; or, an Equivalent for Thoulon: In a Proposal for an Amicable Subscription for Improving TRADE in the South-West Part of AMERICA, and Increasing BULLION to About Three Millions per Annum, Both for the East India Trade and the Revenue of the Crown, Which by Consequence Will Be Produced if This Is Encouraged (London: Mary Edwards, 1707), 3.
6. Bernard Mandeville, The Fable of the Bees , ed. Philip Harth (London: Penguin, 1970), 64.
7. Mandeville, Fable of the Bees , 67–68.
8. Antoin E. Murphy, John Law: Economic Theorist and Policy-Maker (Oxford: Oxford University Press, 1997), 94–95.
9. John Law, Money and Trade Considered (Glasgow: A. Foulis, 1750), 167.
10. Arnaud Orain, La politique du merveilleux: Une autre histoire du Système de Law (1695–1795) (Paris: Fayard, 2018), 10; Charly Coleman, The Spirit of French Capitalism: Economic Theology in the Age of Enlightenment (Stanford, CA: Stanford University Press, 2021), 119.
11. Coleman, Spirit of French Capitalism , 119.
12. Coleman, Spirit of French Capitalism , 20, 81.
13. Jean Terrasson, Lettres sur le nouveau Système des Finances , 1720, 2–5, 29, 32, 33; Jean Terrasson, Traité de l’infini créé , ed. Antonella Del Prete (Paris: Honoré Champion, 2007), 225–227.
14. Orain, La politique du merveilleux , 13.
15. Claude Pâris La Montagne, “Traité des Administrations des Recettes et des Dépenses du Royaume,” 1733, Archives Nationales, 1005, II: 3–8, 48–49, 55.
16. Norris Arthur Brisco, The Economic Policy of Robert Walpole (NewYork: Columbia University Press, 1907), 43–45; Richard Dale, The First Crash: Lessons from the South Sea Bubble (Princeton, NJ: Princeton University Press, 2004), 74.
17. Cited by Dickson, Financial Revolution in England , 83.
18. Jacob Soll, The Reckoning: Financial Accountability and the Rise and Fall of Nations (New York: Basic Books, 2014), 101–116.
第十一章 法国的自然崇拜与启蒙经济学的发明
所有能够制造出财富的泉源与物质,都来自土地。 ──理查德.卡丁伦(Richard Cantillon),《贸易本质概论》(Essay on the Nature of Trade in General ),约一七三○年
支持西塞罗与牛顿的自然崇拜学说的人们在法国组成了一个势力庞大的利伯维尔场游说团体。一七三○年代早期,爱尔兰裔的法国利伯维尔场经济学家理查德.卡丁伦写下了奠基性的农业经济著作《贸易本质概论》,该著作以手稿的形式流通,在一七五五年于作者逝世后正式出版。卡丁伦的著作拥护的是一个过度简化又机械式的观点:不受税制与法规约束的农业将会产生资本,并转化成经济成长。十九及二十世纪的两位经济学家威廉.史坦利.杰文斯(William Stanley Jevons)和约瑟夫.熊彼得(Joseph Schumpeter)一致将卡丁伦誉为比亚当斯密更早出现的第一位“系统性的”经济思想家。对他们来说,所谓系统性经济学意思就是所有听起来像是经济均衡理论的事物。事实上,许多思想家都对创新与工业蕴含的财富创造潜力有所误解,卡丁伦只是其中之一,他们都认为解放农业是创造富裕社会的唯一途径。3
其他思想家寻求的则是更通用的经济计划,能像万有引力定律和行星运动定律一样适用于所有时空。法国哲学家孟德斯鸠在影响力深远的著作《法的精神》(On the Spirit of Laws ,一七四八年)中指出,繁荣来自和平,社会与国家必须用和谐的方式自我管理。他进一步断言,“和平是商业自然而然带来的结果”。各国可以透过贸易合作分享共同的利益,使他们“温和”地对待彼此。11
一七五二年,在启蒙哲学和经济思想大量萌发的期间,法国商业总督雅克─克劳德─马里.文森.古尔奈(Jacques-Claude-Marie Vincent de Gournay)决定他要建立一个经济思想家的“圈子”,藉此处理法国面对的商业挑战,并发展出不同的方法来打造市场机制。古尔奈出生于法国圣马洛(Saint-Malo),曾在家族位于西班牙的公司中从事国际贸易产业工作。除了商业方面的实务经验外,他也因为柯尔贝的国家总督传统而接受过商业法规管理训练。他同样认为若想管理法国商业,就应该采用具有连贯性的国家经济政策。古尔奈很清楚法国需要改革,包括在政治与经济方面都需要更高的自由,他为此邀请了许多年轻的经济思想家加入他的团队。12
虽然古尔奈不支持某些政府干预,但他的格言是“放任作为,放任通行”(Laissez-faire, laissez-passer),也就是让商业随心所欲地自行发展。赫赫有名的哲学家暨经济思想家,也是利摩日(Limoges)总督与未来的财政大臣奥尼男爵安.罗伯特.雅克.杜尔哥(Anne-Robert-Jacques Turgot, baron de l’Aulne)写道,古尔奈的观点可以用两个词来表达:“自由与保护,但自由才是最重要的。”古尔奈也打造了官僚主义(bureaucratie)一词作为一个讽刺笑话,这意思是用办公桌来管理政府。虽然他大加批判法国的严格法规和保密机制,并希望公众的意见与喜好能协助推动市场,但他仍然在柯尔贝式发展和自由放任主义之间选边站。13
古尔奈的圈子是一群致力于研究经济思想的哲学家。法朗索瓦.维隆.福尔博纳(François Véron de Forbonnais)是来自布商家族的金融家,而后攀升至铸币监察长的高位,在古尔奈的团体中是主要成员,他不同意农业致富理论。福尔博纳是柯尔贝的崇拜者,支持自由开放版本的国内经济监督。他相信商业自由,认为国家不应该在没有具体目标的情况下帮助工业发展并干预经济。他的著作《商业要素》(Elements of Commerce ,一七五四年)是针对卡丁伦提出的谨慎批判。福尔博纳指出,虽然财富同时来自农业与制造业,但他不偏不倚地坚持,制造业和商业才是能创造财富的真正泉源。他和柯尔贝一样,认为一旦达到了特定的贸易平等水平,市场就可以自由化。14
魁奈在凡尔赛宫居住与工作,他撰写了卷帙浩繁的著作来描述放血这种致命的医疗技术在治疗病人上具有何种医学优势。他的医学背景让他相信,经济的运作原理就像血液循环一样。他是路易十五才华洋溢的情妇暨哲学家赞助者──庞巴杜夫人(Madame de Pompadour)─的医师,随后因此被封为贵族,这令他欣喜万分。他们两人都是新晋贵族,且都在路易十四的旧权力殿堂中爬升至具有重要影响力的职位。事实上,庞巴杜夫人后来还资助魁奈推广他的经济哲学。她与生俱来的聪慧、财富与远近驰名的谈吐技巧,使她成为巴黎文学沙龙中光彩夺目的人物。她主动去吸引路易十五的目光,在一七四五年成为正式情妇,为这位国王带来严重丑闻。路易十五为表达他对这位平民的爱,赐予了贵族头衔和土地,又替她买下巴黎最好的城市宫殿艾佛宅邸(Hôtel d’Évreux),这栋建筑如今被称作艾丽榭宫(Elysée Palace),是法国总统的居所。 在庞巴杜夫人权力窜起的一年之前,魁奈搬进了凡尔赛宫地下室的住所。这位即将领导早期最强大的利伯维尔场思想家运动的人,就在国王的宫殿中开始构思他的哲学观。利伯维尔场思想就这样在非常专制、非常亲工业的国家内部逐渐发展起来,许多利伯维尔场主义者都想用他们的哲学来抗衡这样的国家。但魁奈并没有因这种矛盾而感到困扰。他是“法治专制主义”这个巨大矛盾修辞的信奉者。他受到哲学家皮耶─保罗.卢梅希.利瓦伊耶赫(Pierre-Paul Lemercier de la Rivière)的启发,相信自然系统会透过君主的意志进行自我表达。魁奈说,只有国王才有能力解放谷物市场,为地主创造更多财富。18 魁奈时而前往庞巴杜夫人位于巴黎的宫殿,在那里举办晚宴招待当时的重要哲学家们。他邀请的客人包括畅销著作《百科全书》(Encyclopédie ,一七五一年至一七七二年)的主要作者丹尼斯·狄德罗(Denis Diderot)与尚·瑞恩·达朗贝尔(Jean le Rond d’Alembert);无神论者、平等主义哲学家暨路易十五的虔诚波兰皇后玛丽.莱什琴斯卡(Marie Leszczyńska)的医师克劳德─安德林·艾尔维修(Claude-Adrien Hélvetius);著名的自然学家与皇家植物园(Jardin des Plantes)管理者布丰伯爵乔治─路易.勒克莱尔(Georges-Louis Leclerc, comte de Buffon);以及杰出的放任主义经济学家杜尔哥。庞巴杜夫人身为皇室的情妇,既不能正式邀请这些人参加餐宴,也不能自行举办沙龙,所以她会不时参加魁奈的聚会,这些宾客在优雅的环境中讨论有关形上学与经济学的新哲学。除了在关于农业放任主义的哲学对话中尽情畅谈,魁奈的高贵客人也能享受惊人的奢侈品、王室厨房提供的精致美食,此外还能透过庞巴杜夫人把话直接传进国王的耳中。19
重农主义者在巴黎沙龙滔滔不绝地主张人们应该重视农业财富胜过工业时,海峡的另一边出现了截然不同的景象。英国的第一次工业革命已然展开,大力驱动着英国经济。蒸气引擎登场了。英国人托马斯.萨维里(Thomas Savery)在一六九八年打造了无活塞引擎,托马斯.纽科门(Thomas Newcomen)在一七一二年制造了一种可以产生连续能量与运动的蒸气泵引擎。除了蒸气动力,到了一七○○年代,机械纺纱也出现了。一七三三年,约翰.凯(John Kay)发明了一种可以自动配线给线轴的飞梭,加快了手工编织的速度。一七三八年,刘易斯.保罗(Lewis Paul)和约翰.怀亚特(John Wyatt)则打造了能生产羊毛布和棉布的纺纱架。到了一七五○年代与六○年代,魁奈和他的重农学派追随者开始写作的当下,英国制造业已经开始在大规模工厂中广泛使用水力磨坊了。整个一七五○年,英国的手工纺织业共制造了两百五十万磅的原棉。到了一七八○年代末,英国织布机曾加工过的棉花总计已经有两千两百万磅。这对于欧洲和贵族地主的农业社会秩序造成了威胁。随着工业蒸蒸日上,法国这个仍然实施封建制度、农业挂帅的社会中展开了一场商业地位争夺战。利伯维尔场思想家努力想找回农业的优势。他们认为针对谷物的自由放任改革将能彻底激发大自然的潜能,届时农业将会气势如虹地返回经济主导地位。20 一七五六年,北美爆发了七年战争。战事从欧洲席卷至北美与南美,再蔓延到印度与非洲,这是史上第一场全球冲突,法国与英国陷入国际贸易控制权的争夺战,同时也把其他欧洲强权给牵扯了进来。这场战争像是法国利伯维尔场思想的催化剂,因其清楚显示出农业社会正在让位给一套新的商业秩序。出于显而易见的原因,保守派的法国贵族统治阶级不愿意顺从地坐视商人接手他们的位置;有些人甚至建议,贵族应该要掌控制造业的生产方法,把这些方法从工业阶级手中夺走。一七五六年,法国神职人员暨亲工业经济思想家盖比尔.法朗索瓦.科耶(Gabriel François Coyer)写下了一部颠覆性作品《商业贵族阶级》(The Commercial Nobility ),在其中大力抨击贵族农业社会秩序。科耶是古尔奈的圈子里的一员,他呼吁贵族对担任士兵与牧师的天职放手,别再被动地生活在他们的土地上,只想靠着农业榨取财富。他警告说,法国正承受着经济竞争和战争的压力,需要利用贸易与工业制造财富。科耶不认为坐拥土地的贵族是经济的驱动力,反而将他们视为寄生虫。科耶指控道,由于法国的封建法禁止这些贵族参与贸易,所以这些贵族在经济方面“一无是处”。21 科耶认为,相较于商业和制造业,农业和相关封建体系的生产力极为低落。科耶要求法国改变贵族的地位。根据他的计算,如果法国贵族能成为商人并去工作的话,法国会变得富有得多,像英格兰就让贵族的第二个儿子从事贸易。他这是在实质上呼吁要推翻法国的封建宪法。科耶的作品大受欢迎,被收录在广泛流通的期刊《法国信使》(Mercure de France )中,而他的书也获得了无数次的再版与翻译。22
这部作品的回响来得很快。身为贵族的亚克骑士(chevalier d’Arcq)菲利普─奥古斯特.圣富瓦(Philippe-Auguste de Sainte-Foix)发表了《反对商业贵族的军事贵族,又名,法国爱国者》(The Military Nobility Opposed to the Commercial Nobility, or The French Patriot ,一七五六年)作为响应,捍卫传统秩序。一场文字论战随之而来,接着政府禁止了所有追随科耶并呼吁修法改变贵族地位的著作。不过作为商业与工业的信徒,古尔奈和福尔博纳继续公开支持科耶。23 科耶和他的追随者想要实现经济自由,但他们也希望透过工业化和商业来实现广泛的社会改革。地主必须对这种日益增长的威胁做出回应,而他们的响应则是更彻底的利伯维尔场农业主义。
魁奈开始寻求追随者,来将重农主义转变成一场日益壮大的意识形态运动。一七五七年,他邀请年轻的米拉波侯爵维克多.里克提(Victor de Riqueti, marquis de Mirabeau)到他位于凡尔赛宫地下室的住所,和他讨论农业经济学奠基者理查德.卡丁伦的著作。小米拉波(Mirabeau the Younger)出身贵族家庭(他的父亲是恶名昭彰的米拉波伯爵,将会成为法国大革命的领导人之一),是孟德斯鸠的朋友。他在《人类之友,又名,族群论》(The Friend of Mankind, or Treatise on Population ,一七五六年)中为贵族的财产权与免税权辩护,反对政府侵犯这些权利。魁奈请年轻的米拉波帮助他完成他的新计划《经济表》(Tableau économique ),这本书试图证明卡丁伦的理论,而他的理论是用伪科学方式主张财富来自土地。这本书后来成为重农主义与十八世纪利伯维尔场思想的《圣经》。26
魁奈大肆宣扬地主应该拥有市场自由的同时,他也相信只有强而有力的国家才能创造并维持这些市场自由。重农主义者希望国王能成为完整掌权的专制统治者,可以独断独行,并保证地主阶级获得经济自由。魁奈的典范就是中国。在他的著作《中国专制主义》(Despotism in China ,一七六七年)中,他指出皇帝能维护自然的父权制与农业秩序,经由训练他的子民聚焦在“种养”技能,让社会集中关注纪律严明的农业活动。魁奈认为,中国皇帝的绝对权力,代表他永远都不会违法,也不会做出任何违背普遍利益的事,因为他就代表了普遍利益。所以,魁奈相信中国皇帝的子民享有纯粹的自由,可以无拘无束地耕作养畜。30
对于重农主义者来说,所有批评都无关紧要,即使这些批评来自古尔奈的圈子里备受尊敬的成员、即使人们对魁奈的统计数据提出了具体质疑,都没有差别。福尔博纳直言不讳地批评了魁奈在数字方面的错误。他提出数据,指出法国的农业产量比魁奈声称的更高,且许多《经济表》中的数字都不准确。他无法理解为什么魁奈会认为农民有生产力,而商人却没有,他在魁奈对国家生产净值的计算中找到严重错误,货品与货币流通的部分也谬误百出。对福尔博纳而言,最后一个重大分歧点是魁奈认为经济可以一种用他在《经济表》中提出的“超然经济真理”来理解。福尔博纳不认同有一种普遍的经济模型能适用于任何时空,并断定魁奈的虚假统计数据不能证明经济能透过自由放任主义自动运作的理论。32 尽管面对种种批评,魁奈和他的信徒仍不知疲倦地捍卫与宣扬他们对农业与王室专制的愿景。在魁奈的追随者中,最成功的其中一位是皮耶─山缪.杜邦.内穆赫(Pierre-Samuel du Pont de Nemours),他是一名充满热忱的重农主义者、法国革命支持者,也是奴隶制度的批评者。杜邦.内穆赫是一个新教徒钟表匠的儿子,但他为了追求抱负而离家前往巴黎,加入米拉波成为重农主义教的信徒。一七六五年,杜邦.内穆赫针对“自然权利”撰写了一系列文章,这些文章奠定了他后来最著名的著作《重农主义》(Physiocracy ,一七六八年)。他透过这些文章为劳工与财产的积极自然权利辩护,自然权利代表人类有权拥有土地,也有权靠着在土地上的劳动赚进财富。杜邦重申了洛克的观点,认为个人享有自我保护的自由,且只要不去侵犯他人的财产或“所有权”,他们就应该有致富的自由。政府的作用是为民众确保个人自由与私有财产权。这种个人权利的观点使杜邦反对奴隶制,他认为此制度违反了全人类与生俱来的自由。在此要留意的是,杜邦和魁奈一样,都支持贵族封建主义原则。事实上,他热切地接受了路易十五赐予的贵族头衔。33 魁奈和杜邦联手合作,坚称自由的国际谷物贸易对农业有利,并能够建立起一套系统:各国透过天然的相对优势,和谐地只进口自己所需的农产品。对魁奈来说,自由贸易的重点不是竞争,而是和谐。大自然给予每个国家不同的在地农业资源。因此,他们不需要任何规则:国家只会进出口他们需要的货品,从而避免了直接竞争。当时英国在工业发展方面突飞猛进,而七年战争却已经使法国陷入更严重的贫困、债务与破产之中,这使得魁奈的讯息显得充满希望又容易理解。34
1. Charles M. Andrews, “Anglo-French Commercial Rivalry, 1700–1750: The Western Phase, I,” American Historical Review 20, no. 3 (1915): 539–556, at 547; David Hume, Selected Essays , ed. Stephen Copley and Andrew Edgar (Oxford: Oxford University Press, 1996), 189, 214.
2. Georges Weulersse, Le mouvement physiocratique en France (de 1756 à 1770) , 2 vols. (Paris: Félix Alcan, 1910), 1:23; Montesquieu, De l’Esprit des lois , ed. Victor Goldschmidt, 2 vols. (Paris: Garnier-Flammarion, 1979), vol. 2, bk. 20, chap. 2; David Hume, An Inquiry Concerning Human Understanding, with a Supplement: An Abstract of a Treatise on Human Nature , ed. Charles W. Hendel (Indianapolis: Liberal Arts Press, 1955), 173.
3. Robert B. Ekelund Jr. and Robert F. Hébert, A History of Economic Theory and Method , 6th ed. (Longrove, IL: Waveland Press, 2014), 70.
4. Tony Brewer, Richard Cantillon: Pioneer of Economic Theory (London: Routledge, 1992), 8.
5. Richard Cantillon, Essai sur la nature du commerce en général , ed. and trans. Henry Higgs (London: Macmillan, 1931), 58.
6. Cantillon, Essai sur la nature du commerce , 97, 123; Marian Bowley, Studies in the History of Economic Theory Before 1870 (London: Macmillan, 1973), 95.
7. Cantillon, Essai sur la nature du commerce , 51–55, 85; Bowley, Studies in the History of Economic Theory , 96.
8. Jean-François Melon, Essaie politique sur le commerce , in Eugène Daire, Économistes financiers du XVIIIe siècle (Paris: Guillaumin, 1851), 659–777, at 671, 666.
9. Melon, Essaie politique sur le commerce , 673, 708.
10. Melon, Essaie politique sur le commerce , 683, 746, 765.
11. Paul Cheney, Revolutionary Commerce: Globalization and the French Monarchy (Cambridge, MA: Harvard University Press, 2010), 22; Montesquieu, De l’esprit des lois , bk. 20, chaps. 1–2.
12. David Kammerling-Smith, “Le discours économique du Bureau du commerce, 1700–1750,” in Le Cercle de Vincent de Gournay: Savoirs économiques et pratiques administratives en France au milieu du XVIIIe siècle , ed. Loïc Charles, Frédéric Lefebvre, and Christine Théré (Paris: INED, 2011), 31–62, at 34.
13. R. L. Meek, The Economics of Physiocracy (London: Allen and Unwin, 1963), xiii.
14. François Véron de Forbonnais, Éléments du commerce , 3 vols. (Paris: Chaignieau, 1793–1794), 1:62.
15. Forbonnais, Éléments du commerce , 1:67–68, 75–76.
16. Forbonnais, Éléments du commerce , 1:3, 38, 45.
17. Steven L. Kaplan, Bread, Politics, and Political Economy in the Reign of Louis XV , 2nd ed. (New York: Anthem Press, 2012), 108; Gérard Klotz, Philippe Minard, and Arnaud Orain, eds. , Les voies de la richesse? La physiocratie en question (1760–1850) (Rennes, France: Presses Universitaires de Rennes, 2017), 11; Gustav Schachter, “François Quesnay: Interpreters and Critics Revisited,” American Journal of Economics and Sociology 50, no. 3 (1991): 313–322; Paul Samuelson, “Quesnay’s ‘Tableau Économique’ as a Theorist Would Formulate It Today,” in Paul Samuelson on the History of Economic Analysis: Selected Essays , ed. Steven J. Medema and Anthony M. C. Waterman (Cambridge: Cambridge University Press, 2015), 59–86, at 60.
18. Pierre-Paul Mercier de la Rivière, L’ordre naturel et essentiel des sociétés politiques , 2 vols. (London: Jean Nourse, 1767).
19. Liana Vardi, The Physiocrats and the World of the Enlightenment (Cambridge: Cambridge University Press, 2012), 42.
20. Vardi, Physiocrats , 84; David S. Landes, Unbound Prometheus: Technological Change and Industrial Development in Western Europe from 1750 to the Present (Cambridge: Cambridge University Press, 1969), 82.
21. Steven Pincus, The Global British Empire to 1784 , unpublished manuscript; Gabriel François Coyer, La noblesse commerçante (London: Fletcher Gyles, 1756), 33–34, 45, 72.
22. Simone Meyssonnier, La balance et l’horloge: La genèse de la pensée libérale en France au XVIIIe siècle (Paris: Les Éditions de la Passion, 1989), 264.
23. Meyssonnier, La balance et l’horloge , 265.
24. Meyssonnier, La balance et l’horloge , 249.
25. Meyssonnier, La balance et l’horloge , 80–81; Coyer, La noblesse commerçante , 33–34, 279.
26. Le marquis de Mirabeau, L’ami des hommes, ou traité de la population , 2 vols. (Avignon: 1756); Meek, Economics of Physiocracy , 15.
27. Meek, Economics of Physiocracy , 18.
28. Meek, Economics of Physiocracy , 23; E. P. Thompson, The Making of the English Working Class (New York: Vintage, 1966), 218; Boaz Moselle, “Allotments, Enclosure, and Proletarianization in Early Nineteenth-Century Southern England,” English Economic History Review 48, no. 3 (1995): 482–500.
29. Meek, Economics of Physiocracy , 109–114, 136.
30. François Quesnay, Despotism in China , trans. Lewis A. Maverick, in Lewis A. Maverick, China: A Model for Europe , 2 vols. (San Antonio: Paul Anderson and Company, 1946), 1:216; W. W. Davis, “China, the Confucian Ideal, and the European Age of Enlightenment,” Journal of the History of Ideas 44, no. 4 (1983): 523–548; Stefan Gaarsmand Jacobsen, “Against the Chinese Model: The Debate on Cultural Facts and Physiocratic Epistemology,” in The Economic Turn: Recasting Political Economy in Enlightenment Europe , ed. Steven L. Kaplan and Sophus A. Reinert (London: Anthem Press, 2019), 89–115; Cheney, Revolutionary Commerce , 203; Pernille Røge, Economists and the Reinvention of Empire: France in the Americas and Africa, c. 1750–1802 (Cambridge: Cambridge University Press, 2019), 10.
31. Quesnay, Despotism in China , 11; Røge, Economists and the Reinvention of Empire , 88.
32. Loïc Charles and Arnaud Orain, “François Véron de Forbonnais and the Invention of Antiphysiocracy,” in Kaplan and Reinert, Economic Turn , 139–168.
33. Meek, Economics of Physiocracy , 46–50.
34. Meek, Economics of Physiocracy , 70.
35. Jean Ehrard, Lumières et esclavage: L’esclavage colonial et l’opinion publique en France au XVIIIe siècle (Brussels: André Versaille, 2008); Røge, Economists and the Reinvention of Empire , 176; David Allen Harvey, “Slavery on the Balance Sheet: Pierre-Samuel Dupont de Nemours and the Physiocratic Case for Free Labor,” Journal of the Western Society for French History 42 (2014): 75–87, at 76.
第十二章 利伯维尔场与自然
人虽生而自由,却无处不在枷锁之中。 ──鲁索(Rousseau),《社会契约论》(The Social Contract ),一七六二年
在制造业蒸蒸日上、海外帝国扩张且国际贸易蓬勃发展的年代,重农主义可算不上受欢迎的经济理论。尽管重农主义哲学家的著作受到现代利伯维尔场思想家的热烈赞赏,但这些作品在他们那个年代并不畅销。事实上,十八世纪最畅销的那些经济学书籍都在批评“经济完全可以自我调节”的观点。处于经济成长前线的人都在寻找方法推动工业与利伯维尔场的发展。这意谓着除了自由放任的要素外,还必须让国家扮演具有建设性的经济角色。 于是无须讶异,接下来亲工业改革运动出现在意大利这个欧洲资本主义与贸易的起源地。意大利哲学家寻求的是更加贴近柯尔贝主义的道路,透过新的法律体系与开明的政府机构来建立市场。博学多闻的卢多维科.安东尼奥.穆拉多利(Ludovico Antonio Muratori)是神职人员、历史学家,也是米兰宏伟的安布罗西亚那图书馆(Ambrosiana Library)的图书馆员,他的著作《论公共幸福》(On Public Happiness ,一七四九年)受到柯尔贝和孟德斯鸠的启发。穆拉多利的文章解释了人类要如何透过政府改革与立法来改善安全、教育、健康与宗教生活,使这个世界变成一个“更幸福”的所在。包括奥地利女皇玛丽亚.特蕾莎(Maria Theresa)在内的几位专制君主都遵循他的建议,支持自然科学与宗教宽容,并透过宪政主义扩张个人与市场的自由──尽管是有限的自由。意大利和奥地利的启蒙运动思想家与巴黎、伦敦和苏格兰的思想家密切合作,致力于打造出更公正的社会,一些意大利人把这种概念称作“社会主义”,也就是透过现代化的法院与法典、学校和基础设施等国家机构来打造社会与市场的一套计划。(历史学家伊斯凡.洪特〔István Hont〕将此时社会主义“socialism”的追随者称作“society-ists”。)此一社会运动后来也影响了斯密。1
在意大利的国家市场建造者中,最重要的一位就是拿坡里的政治经济学家安东尼奥.杰诺维齐(Antonio Genovesi),他可以说是亚当斯密的前辈,认为经济是一系列能够自我延续的市场机制。身为一名有远见的市场思想家,他认为政府必须打造适合市场的条件。他不赞成劳动力本身就能创建价格的观点,而认为驱动价格的是无形的社会条件与劳动条件。在他广受赞誉的《商业课,又名,论公民经济》(Lessons on Commerce, or On Civil Economics ,一七六五年)中,他指出效用性、个人关系与公共信任决定了劳动与货品的价值。虽然国家必须给予市场自由,但同时也要小心翼翼地扶植市场。举例来说,政府必须修建道路,并保护道路不受盗匪侵扰。杰诺维齐引述了梅隆、休谟和孟德斯鸠,认为财富是有效率的农业与工业之间的互相作用。他和福尔博纳一样,认为消除商业上的障碍通常是好事,但商人仍然必须遵守法规与支付一定的关税。因此,利伯维尔场是国家与商人之间持续且小心地互相退让的成果。并不存在一种通用法则,反之,需要具备的是一种务实的意识:信任与商业自由必须根据当地环境去协商、建造与维持。2
在众多意大利经济思想家中,重农主义的头号敌人是一名翻译了洛克著作的拿坡里人,修道院长费迪南多.加利亚尼(Ferdinando Galiani)。一七五九年,拿坡里国王查理四世派遣这位杰出的经济学家到巴黎的拿坡里大使馆担任秘书。他成为巴黎社交场合与时尚沙龙的常客,和狄德罗交上朋友,并向狄德罗介绍了经济学研究。加利亚尼曾在拿坡里执行过货币改革,并因此和重农主义者有过密切往来,他向来没有耐心应对那些魁奈信徒无知的农业乐观主义。他相信社会必须和大自然彼此合作,而非只是追随自然。加利亚尼在《谷物商业对话》(Dialogues on the Commerce of Grains ,一七七○年)中坚称,只有国家才有足够的外界信用,能够在歉收、饥荒与战争的处境下处理食物短缺的问题。4 他同意自然与社会都是以系统的形式在运作的。他也认为制造业需仰赖农业。然而,他同时坚持农业仍然太不可靠,不能让农业完全控制市场体系。在歉收的时期,不只有农业,相关产业也会跟着停滞不前,接着社会就会陷入经济与财政灾难之中。若国家没有储备与管理粮食供应,农民很容易会“失去所有资金”而无法重新开始种植。换句话说,加利亚尼认为成功的农业系统既不能完全依赖自然,也不能完全依赖市场。他坚称大自然带来的灾难规模只有国家才能应对。5
虽然杜尔哥是利伯维尔场的支持者,但他在一七五七年出版的《百科全书》中的〈市集与市场〉(Fairs and Markets)一文中,表达得比魁奈反复强调重农主义观点的文章还要更加隐晦。杜尔哥主张,大型的中世纪市集──著名的现代法国历史学家费尔南.布劳岱尔(Fernand Braudel)后来把这些市集连结到资本主义的崛起──是一种压迫性垄断。中世纪的博览会往往坐落在各个国家或各个地区之间的主要贸易路线交会点,例如法国香槟区。每年都有数周的时间,农民、工匠、商人和银行家会带着他们的商品和技能来到这里,创建一个推动中世纪经济的巨大商业区。杜尔哥说,“方便性”使博览会地点不会变动;这也使得博览会成为控制价格的垄断场所。博览会有一群固定的参加者,因此限制了竞争与交易总量。固定地点的博览会也使国家得以简化和控制货品税收。他说这种做法“不理性”,让博览会只有利于税收,而不利于财富创造。7
在杜尔哥眼中,市场不是由拥有财产的个体驱动的,而是由农村的劳动者驱动的。杜尔哥和杜邦.内穆赫合作撰写了《对财富的形成与分配之反思》(Reflections on the Formation and Distribution of Wealth ,一七六六年),杜尔哥在书中透过效益主义劳动的概念,为封建贵族进行了革命性的现代辩护,即地主没有生产力,但地主是合乎情理的闲置者。他在他对贵族财产的辩护中,主张物业拥有者对经济制度来说具有社会必要性,他写道:“仅仅是因为人类习俗以及公民法律,耕种者需要物业拥有者。”杜尔哥的看法呼应了西塞罗、洛克和孟德斯鸠的论点,他认为虽然地主本身是闲置的,但对整个制度的平衡来说至关重要,这些地主产生了一个菁英阶层,他们具备道德能力,因此得以精通法律、博雅教育和科学,也能领导社会与农业耕种。9
一七七四年,杜尔哥有了机会可以更大范围地尝试他的政策,他接掌了曾经属于柯尔贝的、手握大权的财政总监督一职。杜尔哥上任后采取的第一步非常成功。他坚持中止国家借款,并设法降低了利率。然而,杜尔哥想要使谷物贸易自由化的尝试却一败涂地。他取消了价格控制与政府补贴,废除了法国境内复杂而古老的面粉与面包分配系统,接着他们马上遇到了歉收。食物短缺、混乱、投机买卖、价格上涨和饥荒酿成了一七七五年四月与五月的一系列抗议行动,史称面粉战争(Flour Wars)。加利亚尼利用这个机会重申了他的观点,也就是在自然灾害发生时,政府必须介入提供帮助。在法规松绑的同时若没有对穷人提供援助,将会导致一场大灾难。杜尔哥已经忘却他当初的市场发展原则了。13 在面粉战争的高峰期,贾克.内克(Jacques Necker)出版了《论立法与谷物商业》(On the Legislation and the Commerce of Grain ,一七七五年),抨击杜尔哥和重农主义。内克是一位非常成功的瑞士新教银行家、金融家暨哲学家,他住在巴黎,而且借了一大笔钱给法国。身为一名经济思想家,他同意自由比监管更好,而且一般来说,贸易自由都是好的。他主张人们应该有权利能依照自己想要的方式,来运用自己的金钱、劳力与产业。内克追随柯尔贝的观点,坚持认为国家立法者必须制定“禁制性法律”,如此一来,谷物贸易中才不会出现“对自由的滥用”而导致饥荒。他同意加利亚尼的想法,认为人们不能只是把谷物留给市场力量操作──自然太过反复无常,社会又太过脆弱。他就像加利亚尼一样,认为易受影响的食物供应需要政府提供护栏。因此,内克提出了古老的论点:虽然市场自由很重要,但这种自由比较适合非必需品。14 尽管受到了这样的批评,杜尔哥仍铁了心要进行他的自由化改革。他希望能打破封建制度中的强制性农民劳动与行会特权。他在这过程中成功与所有人为敌──从农民、商人到贵族。杜尔哥的改革和宫廷中的角力斗争导致所有政府派系都和他作对。一七七六年五月,国王路易十六令他辞职。他在农业自由放任方面进行的大型自由主义实验,被人们视为一次无比壮观的失败。在这场颜面尽失的惨败所带来的混乱中,他的许多其他现代化改革也化为泡影了。15
对于“利伯维尔场无需政府干预就能自动运作”这一观点的反对,因为杜尔哥的失败而更加牢不可破。有些基进派的哲学家认为封建社会与文化需要的不是改善,而是革命性的转变。政府首长在君主制度下未能取得成果,哲学家们于是又重新回到拉侯谢傅科公爵与曼德维尔的观点,也就是情绪感受是市场的主要驱动力。他们试着去理解这些人类情感能如何创造出更加公正的市场社会。 关于人类情感与经济之间的关系,出生于瑞士的哲学家尚─贾克.鲁索(Jean-Jacques Rousseau)提出了其中一些最有力的观点。尽管他也相信农业在经济上占首要地位,和杜尔哥不同的是,鲁索反对由贵族地主支配的社会制度。他设想的是一个民主而平等的农村社会,此社会以原始状态的自然为基础,人们共同管理财产,也共享地球上的果实。鲁索回过头去研究拉侯谢傅科公爵对市场运作方式的看法。他不相信大自然会自发性地打造出健康或和谐的社会与经济秩序。相反地,“自然”和农业创造出了社会阶级,导致贫困、不公正与不平等。他认为贵族拒绝纳税是法国经济问题的根源。鲁索对于法国社会的严重不平等感到怒火中烧,这启发他写下了基进立场的《论人类不平等的起源与基础》(Discourse on Inequality ,一七五五年)。这本书划下了一条清楚的战线,区分了菁英式的自由放任主义哲学,以及基进的共和式民主的呼吁,这种民主以马基维利和霍布斯的政治思想为基础,要求制衡市场与向富人征税。鲁索指出,很显然地多数派政府必须要严格监管财富、商业和地主掌握的权力。在他看来,西塞罗一派对自然状态的尊崇,以及效法大自然永恒法则的社会,都导致了不公正。民主政治必须介入并打破这种“自然”阶级制度,打造更加公正的世界。16 鲁索将会成为那个年代最负盛名的作家以及伟大的基进派领袖,他的思想将会启发托马斯.潘恩(Thomas Paine)和其他大西洋两岸的革命者。他的政治手册《社会契约论》(一七六二年)将会动摇欧洲体制的根基,为国家地位和民主奠定了框架。正是在这本着作中,鲁索写下了这句名言:“人虽生而自由,却无处不在枷锁之中。”与霍布斯以及洛克相反,鲁索并不认为社会能使人类变善良;相反地,他认为社会破坏了人类最原初的善良状态,从而堕落。真正的原罪就是社会与财产本身。对鲁索来说,不平等是自爱(self-love)与骄傲的产物,透过自爱与骄傲,个人只藉由与他人比较来定义自己。人会为了满足自己的骄傲,而创造出不自然的“常规”与“特权”,藉此在阶级制度中区分自己和歌颂自己。反洛克和反重农主义的思想在此昭然若揭。人类的枷锁就是私有财产和菁英阶级,是少数决的政治和经济规则。17
1. Erik S. Reinert and Fernanda A. Reinert, “33 Economic Bestsellers Published Before 1750,” European Journal of the History of Economic Thought 25, no. 6 (2018): 1206–1263; Derek Beales, Enlightenment and Reform in Eighteenth Century Europe (London: I. B. Tauris, 2005), 64; Istvan Hont, Jealousy of Trade: International Competition and the Nation-State in Historical Perspective (Cambridge, MA: Harvard University Press, 2005), 45, 134; Sophus A. Reinert, The Academy of Fisticuffs: Political Economy and Commercial Society in Enlightenment Italy (Cambridge, MA: Harvard University Press, 2018), 7; John Robertson, The Case for Enlightenment: Scotland and Naples, 1680–1760 (Cambridge: Cambridge University Press, 2005), 22; Koen Stapelbroek, “Commerce and Morality in Eighteenth-Century Italy,” History of European Ideas 32, no. 4 (2006): 361–366, at 364; Antonio Muratori, Della pubblica felicità: Oggetto de’buoni principi (Lucca, 1749), p. 3 of “To the Reader. ”
2. Eric Cochrane, Florence in the Forgotten Centuries, 1527–1800 (Chicago: University of Chicago Press, 1973), 461; Reinert, Academy of Fisticuffs , 299; Antonio Genovesi, Delle lezioni di commercio, o s’ia d’economia civile , 2 vols. (Naples: Fratelli di Simone, 1767), 2:77, 133; Robertson, Case for Enlightenment , 356–357.
3. Steven L. Kaplan and Sophus A. Reinert, eds. , The Economic Turn: Recasting Political Economy in Enlightenment Europe (London: Anthem Press, 2019), 3–13; Pietro Verri, Meditazioni sulla economia politica (Venice: Giambatista Pasquale, 1771), 18, 33–34.
4. Ferdinando Galiani, Dialogues sur le commerce des blés , ed. Philip Stewart (Paris: SFEDS, 2018), 59.
5. Galiani, Dialogues, 115–116; Franco Venturi, “Galiani tra enciclopedisti e fisiocrati,” Rivista storica italiana 72, no. 3 (1960): 45–64, at 53.
6. Jean-Claude Perrault, Une histoire intellectuelle de l’économie politique (XVII–XVIIIe siècles) (Paris: Éditions de l’EHESS, 1992), 238.
7. Perrault, Une histoire intellectuelle , 16–17.
8. Perrault, Une histoire intellectuelle , 19.
9. Meek, The Economics of Physiocracy (London: Allen and Unwin, 1963), 47–49.
10. Meek, Economics of Physiocracy , 51; Madeleine Dobie, Trading Places: Colonization and Slavery in Eighteenth-Century French Culture (Ithaca, NY: Cornell University Press, 2010), 14–15.
11. Benoit Malbranque, Le libéralisme à l’essaie. Turgot intendant du Limousin (1761–1774) (Paris: Institut Coppet, 2015), 44.
12. Emma Rothschild, Economic Sentiments: Adam Smith, Condorcet, and the Enlightenment (Cambridge, MA: Harvard University Press, 2001), 79; Malbranque, Le libéralisme à l’essaie , 58.
13. Cynthia A. Bouton, The Flour War: Gender, Class, and Community in Late Ancien Régime French Society (University Park: Penn State University Press, 1993), 81; Gilbert Foccarello, “Galiani, Necker, and Turgot: A Debate on Economic Reform and Policy in 18th Century France,” European Journal of the History of Economic Thought 1, no. 3 (1994): 519–550.
14. Jacob Soll, “From Virtue to Surplus: Jacques Necker’s Compte Rendu (1781) and the Origins of Modern Political Discourse,” Representations 134, no. 1 (2016): 29–63; Jacques Necker, Sur la législation et le commerce des grains (Paris: Chez Pissot, 1775), 50–52.
15. Steven L. Kaplan, Bread, Politics, and Political Economy in the Reign of Louis XV , 2nd ed. (New York: Anthem Press, 2012), 589–595.
16. Kaplan, Bread, Politics , 247; Istvan Hont, Politics in Commercial Society: Jean-Jacques Rousseau and Adam Smith , ed. Béla Kapossy and Michael Sonensher (Cambridge, MA: Harvard University Press, 2015), 18–19.
17. Antoine Lilti, The Invention of Celebrity (Cambridge, UK: Polity, 2017), 117; Jean-Jacques Rousseau, Du contrat social , ed. Pierre Burgelin (Paris: Garnier-Flammarion, 1966), 41; Jean-Jacques Rousseau, A Discourse on Inequality , ed. Maurice Cranston (London: Penguin, 1984), 77.
18. Rousseau, Discourse on Inequality , 101, 109, 127, 137.
第十三章 亚当斯密和良性自由贸易社会
他们〔商人与制造商〕正是凭借着对自身利益拥有较多知识,因此经常强迫利用他〔乡绅〕的慷慨,并说服他放弃自己的利益与公众的利益,出于非常简单且正直的信念:他们的利益才是公众的利益,而他的利益则不是。然而,无论在贸易或制造业的任何一个分支,商人的利益总是会在某些方面和公众利益有所分歧,甚至相反。 ──亚当斯密,《国富论》(The Wealth of Nations ),一七七六年
亚当斯密和鲁索一样不欣赏贪婪。并且他也同样有些担心曼德维尔在《蜜蜂的寓言》中表达的愤世嫉俗。斯密是在格拉斯哥大学(University of Glasgow)研究斯多噶道德哲学的教授,他不认为恶行会是美德。美德是一种艰苦的努力,而他的工作就是教导何谓美德。斯密不同意鲁索对于纯粹天生的人类情绪的看法,无论是贪婪还是怜悯都一样,他也不同意鲁索认为社会的本质是罪恶的论点。西塞罗的斯多噶哲学教导我们,个人可以学习自律和道德,进而使社会变得更美好,斯密相信这一点。如果要从斯密的经济作品中提炼出一个明确的概念,那这个概念就是:道德是市场运作的必备要素。我们可以从《国富论》(一七七六年)清楚看出,斯密不是现代所谓的经济自由主义者,更不用说自由意志主义者(libertarian)了。他认为只有道德农业社会搭配上强大的统治菁英阶级,才能够创造与维持利伯维尔场。 现代经济学家对斯密的看法多半不是这样。人们往往觉得他是个为贪婪与商业利益辩护的人。但就和柯尔贝一样,现代经济学家用讽刺的手法将他扭曲成一种截然不同的样貌。举例来说,一九四四年,弗里德里希.奥古斯特.海耶克(Friedrich August von Hayek)将斯密描绘成一个反对所有政府干预,并且聚焦于经济效率的思想家。米尔顿.傅利曼也依循同样的脉络,把斯密在《国富论》中提及看不见的手的段落,解读为呼吁社会将政府从经济生活之中完全移除。傅利曼主张,斯密的“关键见解”是经济合作应该维持“严格自愿”,必须“没有外力、没有胁迫、没有对自由的侵犯”。然而,海耶克和傅利曼引用的段落都经过精心挑选,在过程中把斯密从一位道德哲学家──不信任商人和企业,相信强大的菁英政府、殖民规范、奴隶制度、公共教育和针对性关税──转变成了一位现代企业的自由意志主义辩护者。1 不过老实说,要阅读斯密那本将近一千页的《国富论》确实是件苦差事,而且他引述的许多语句都使得他像是在提倡完全的自由放任主义。他提出警告,政府“试着指示人民要以何种方式应用他们的资本”是一种愚行。他也批判政府不该干预个人的直接经济决策:“在人类社会这个巨大的棋盘上,每一枚棋子都有自身的移动原则,与立法机关可能选择强迫采用的原则完全不同。”此外,尽管他在未来成为了关税部长,但他也对税收带来的痛苦有所深思:“一个政府向另一个政府学习经验时,学得最快的就是从人民的口袋里搜刮钱财的艺术。”斯密认为,生产和消费必须免受政府的任何阻碍:“消费行为是所有生产行为的唯一终点和目的;生产者的利益只应在促进消费者利益的必要范围内予以关注。”斯密的部分文章段落使他看起来像是彻头彻尾的利伯维尔场支持者:“〔在没有贸易限制的状况下,〕自然自由(natural liberty)这个理所当然又单纯的系统会自行建立起来。每个人……都可以全然自由地以自己的方式追逐自己的利益。”2 然而,如果我们按照当时的历史脉络去解读斯密针对市场自由所写的这些引述内容,就会清楚看到他的愿景和现代利伯维尔场思想家相去甚远。《国富论》是一部充满雄心壮志的作品,旨在调和当时实际存在的农业寡头和愿景中的自我调节的市场,同时应对商业与帝国的崛起。斯密认为,贸易只会在农业主导的社会中蓬勃发展,在这样的社会中,拥有大量土地的统治阶级菁英能够限制商人的利益、推广学习与提倡斯多噶美德。斯密是罗马道德哲学教授,这个身分很适合协助引导这种西塞罗式的道德复兴。
英国与法国之间的持续冲突,打碎了重农主义者对于农业、利伯维尔场与国际和平能卷土重来的希望。这两个国家都采取了保护性策略,藉此发展国内产业,相互争夺全球市场的主导地位。十八世纪上半叶,英国的经济景气衰退。法国的布料制造业正在蚕食英国经济。法国紧密控制地中海市场,阻碍了英国与土耳其以及西班牙的贸易。法国也主宰着糖业市场,他们的国家出口总糖量和英国持平,甚或略胜一筹。到了一七四○年代,法国的海外贸易成长速度是英国的三倍。在一七二○至一七五○年代间,法国的出口以每年百分之三至五的速度成长,英国的出口成长率则是百分之一点五。奥地利王位继承战争(War of Austrian Succession,一七四○年至一七四八年)是英法的全球代理战争,将这两大强权的对抗置于帝国的舞台上,而七年战争(一七五六年至一七六三年)则成为一场更大规模的全球商业与帝国霸权斗争。战事从欧洲扩及美洲、印度和西非。人们需要达成某种协议来平息纷乱,而许多经济思想家认为利伯维尔场就是能带来和平的解决方案。3 斯密是一名学者,他认为国际学术互动证明了自由交流是一种互惠的模式。在法国与英国军事上互相对抗的期间,两国在知识与科学方面的合作仍十分自由。英法两国的杰出思想家时常进行跨海峡的研究工作,这是源远流长的传统,他们在冲突、友谊与学习中共同发展。托马斯.霍布斯在一六三○年代于法国接受教育,一六四○年代再次为了躲避英国内战初期的政治冲突而逃到法国,并在这里写下了《利维坦》(一六五一年)。这样的交流是双向的。法国哲学家伏尔泰流亡至伦敦,写下了有关英国哲学、政治与生活的作品。到了十八世纪中叶,全欧洲与美洲的知识分子都涌入了巴黎的沙龙,哲学家在那里谈论科学、政治、无止尽全球冲突的可能解决方案,以及如何面对市场带来的挑战。英法知识交流的悠久传统对于斯密的利伯维尔场理论来说至关重要。4 此外,斯密在社交与知识两种层面上也很依赖他的导师,苏格兰哲学家戴维.休谟;休谟的法国知识渊源和关于利伯维尔场思想的文章,为斯密铺设了一条通往《国富论》的道路。休谟的作品是斯密的作品蓝图。自小就是神童的休谟出生在贫困的贵族家庭,拥有爱丁堡大学(University of Edinburgh)的学位,他到法国继续接受教育以“增进”他的“文学才能”。一七三四年至一七三九年,休谟在罗亚尔河谷(Loire Valley)的安朱(Anjou)就读弗莱彻耶稣会学院(Jesuit college of La Flèche),该学校以笛卡儿曾就读过而闻名。许多当地的耶稣会士曾是传教士,他们向年轻的休谟讲述他们旅行至亚洲与南美洲的故事,听得津津有味的休谟因此对于各个社会与民族之间的对比深感着迷。他充分利用了学校图书馆中有关希腊哲学、欧陆哲学、法国历史、道德与经济思想的广泛藏书。5
休谟在弗莱彻学院写下了开创性的著作《人类理解论》(Essay on Human Understanding ),而后在一七三八年返回伦敦后发表此作。休谟的书是启蒙认识论的基础──认识论是研究人类如何学习与认识事物的一种学科。休谟认为,人类可以透过对伦理的了解,建立道德的经济制度与社会。他描述了斯多噶学派与伊比鸠鲁学派的希腊哲学家如何对自然运动与行为建立历久不衰的原则,并将这些原则拿去和托勒密(Ptolemy)以及哥白尼如何发展出他们对行星运动的理解进行比较。他相信若能把斯多噶主义和天文学结合起来,就能更深入了解人类行为与经济。这个方法后来对斯密的经济思想产生了深刻的影响。6
休谟和斯密写作的时间都是在一七○七年《合并法案》(Act of Union )签订之后的那段期间,英格兰与苏格兰根据此法案合并为大不列颠。苏格兰因为《合并法案》而进入了英格兰市场与殖民市场。爱丁堡与格拉斯哥(Glasgow)成为富裕的帝国贸易城市,取得筹码可以进行有利的条款与契约协商。休谟与斯密都见证了当时的经济扩张,也都因此受益。一七四七年,格拉斯哥市经交涉后签署了一项从法国殖民地进口烟草的垄断协议。克莱德河(Clyde)变成了烟草与制造业商品的贸易枢纽,苏格兰商人在此处的贸易圈交易奴隶,这对五十年前的格拉斯哥人来说是作梦也想不到的。烟草、奴隶、棉花、糖和兰姆酒使苏格兰商人发家致富,使学院和优秀的大学蓬勃发展。苏格兰人终于品尝到了财富的滋味,那滋味令人陶醉又充满诱惑力。很显然的,正是这种帝国自由贸易带来的确凿承诺与随之而来的富饶,使得戴维.休谟与其门生亚当斯密支持《合并法案》,也支持自由贸易和帝国的广阔愿景。10
亚当斯密就是在这么一个充满冲突、经济扩张和知识野心的时代下步入成年。他于一七二三年出生于苏格兰的古老商业制造城镇克尔卡迪(Kirkaldy),隔着福斯湾(Firth of Forth)与爱丁堡遥遥相望。他的父亲(在他两个月大时去世)是一名律师与海关首长。他的母亲来自拥有土地的乡绅家族,而斯密就读的是镇上一所出色的自治学校,他在那里接受丰富的古典教育,打下扎实的拉丁语基础。斯密从小聪颖过人,十四岁就进入格拉斯哥大学就读,他的老师是杰出的道德哲学家弗朗西斯.哈奇森(Francis Hutcheson)。在哈奇森充满感召力的鼓励下,斯密开始对当时的启蒙运动风潮产生了兴趣,启蒙运动重视罗马伦理、科学、言论自由与洛克的自由思想。一七四○年,斯密获得了奖学金,成为牛津大学贝里欧学院(Balliol College)的研究生。斯密痛恨这个地方,觉得这里既堕落又缺乏智识上的挑战。他靠自己大量广泛地阅读,但却受神经颤抖所苦。他在奖学金耗尽之前,于一七四六年离开了牛津。一七四八年,他开始在爱丁堡大学(University of Edinburgh)授课,一七五○年,他成为格拉斯哥大学的教授,教学内容包括古典修辞学、道德哲学、法律与纯文学。
一七五九年,斯密出版了《道德情感论》(Theory of Moral Sentiments ),在书中提出了他的核心思想:人可以透过斯多噶式的道德哲学建立道德的社会。在霍布斯和鲁索的描述中,情绪的根源是与生俱来且野蛮的,斯密则不同,他依循的是斯多噶派的理想,认为道德情绪是可以培养的,而我们可以藉此创造美好的社会。斯密认为:“悲痛与憎恨带来的情绪是苦涩且疼痛的,更加需要同情的治疗与安慰。”他撰写此书的背景是一七五○年代末的英法冲突期间,他希望能找到一种哲学方法以摆脱战争的控制,在他看来,战争是人类在道德方面失败后制造出来的产物。12
虽然斯密的行文带有一种基督教的口吻,但他的作品没有提及过《圣经》。他使用的语言是绝对的自然神论。他将神描述成“自然的全智创作者”,这个作者创造了人类当作“他在人间的代理人,监督他的弟兄的所作所为”。斯密也把神称作“宇宙监督者”。但这位神祇并不是道德判官。取而代之的是,人类必须成为彼此行为举止的道德判官。斯密希望人类可以透过道德、透过牛顿式的因果概念,建立一个自我规范的社会。而后,他在一七七三年的著作《天文学历史》(The History of Astronomy )中写道:“一连串看不见的对象,链接着两个按照全世界都很熟悉的顺序发生的事件。”在牛顿提出的“系统”中,是一只“看不见的手”设置了一种理性的、发条式的平衡状态。14 在斯密看来,人类的道德行为、爱与合作都是杠杆,共同维持社会机制的平衡与恒动。他认为在劳动分工的机制中,自由、合乎道德、以农业为重点的贸易是必不可少的一个零件。这种分工机制能有效率地分配具有差异且相互协作的制造业活动与贸易活动,使人们能够共同努力,和平地创造出财富。斯密把论述导向西塞罗,并写道,商业“应当是联系国与国、人与人的一种友谊团结的纽带”。斯密的杰出见解是,如果人类和国家能在经济上彼此合作,就能为所有人创造财富。15 然而,斯密理想中那个仁慈、合作且自我规范的社会是无法单靠自己实现的;这个社会需要领导人与立法者,而对斯密来说,这些人只能是受过教育的富裕贵族地主。斯密很早以前就注意到,鲜少有人能真正理解治理的法律原则,就连瑕不掩瑜的都很少见。用一种带有亚里士多德和西塞罗色彩的观点,他把理想的立法者描述成受过良好教育、礼貌、仁慈并且只会对法律偏心的人。只有这种人才能实践公民法律所需的自我约束和“科学精神”。16 具有道德良知的贵族政府,将会为国家带来著名的路易十四批评家芬乃伦在小说《忒勒马科斯的冒险》中所描述的那种自由与富裕。斯密主张,法国也许比英国有钱,但法国缺乏成为商业领导国家的道德社会特质,原因在于法国没有自由的议会政府能维持“我国公民享有的安全、体面且幸福的境况”。法国的君主制专制且不容异己,在这种缺乏政治与社会美德的国家中,社会无法实现真正的仁慈。斯密相信,英国从一六八八年的光荣革命后开始实施的菁英代议制政府,是唯一能够避免“国际战争与国内派系斗争”并打造一个幸福、阔绰国家的途径。这也是唯一能成就利伯维尔场的方法。值得注意的是,斯密的理论未能解释英国为什么会和法国交战将近一个世纪,而且仍然没有通过利伯维尔场法规。但是,他似乎十分乐观,觉得英国有道德基础能做到他热切相信的这些进步。17
我们在检视亚当斯密的哲学时,绝不能忽略他的个人生活与物质环境,正是他的所处环境使他的第一本书《道德情感论》大获成功。在休谟的帮助下,斯密悉心建立了有权有势的朋友网络,藉此累积财富与推广他的作品。《道德情感论》在一七五九年首次出版时,休谟和斯密在《爱丁堡评论》的朋友联络了斯密的出版商安德鲁.米勒(Andrew Millar),确保他将其中几本书寄给拥有权力与影响力的几位著名苏格兰贵族:王室宠儿暨首相比特伯爵(Earl of Bute)、阿盖尔公爵(Duke of Argyll)、曼斯菲德勋爵(Lord Mansfield)、塞尔伯尔尼伯爵(Earl of Shelburne)与查尔斯.汤森(Charles Townshend),也就是巴克勒公爵(Duke of Buccleuch)的继父。经由休谟优越的人脉关系,《道德情感论》“送到了所有受欢迎人物的手中”。这些权贵之手能够形塑斯密的职业生涯与社会大众对其作品的接受度。18 一七五九年的夏天,斯密成为了第一代塞尔伯尔尼伯爵(Earl of Shelbourne)的小儿子托马斯.费兹莫里斯(Thomas Fitzmaurice)的老师。对斯密来说,这是一段激动人心的时期,他开始教授许多伟大苏格兰贵族的儿子。他引导这些晚辈认识古代哲学、法律与罗马贵族美德。作为一个长年单身的学者,斯密喜欢奢侈品,也渐渐喜欢上昂贵的服装。他生活在所谓的英国“寡头时代”(Age of Oligarchy),当时主导社会的是“独立的乡村仕绅”,他们往往是托利党员(Tories)或保守派的辉格党员(Whigs),一手掌控着下议院。这些世袭的贵族族长在议会掌握的权力几乎达到了有史以来的最高峰。尽管斯密曾批评过专断的社会阶级制度,但他成功爬上苏格兰地主社会的顶端,对此感到称心如意。如果他的经济愿景看起来像是为他的赞助人量身打造的,或许并非偶然。19
如往常一般,休谟为这位门生铺平了道路,并确保他会在成功之后与老师共享。一七六三年,赫特福德伯爵(Earl of Hertford)招揽休谟担任英国驻巴黎大使馆的秘书,这是一个有利的职位。休谟写信给斯密,表示这项工作邀约“伴随着绝佳的前景与期望”。法国在七年战争败北后陷入经济萧条。尽管如此,休谟的巴黎社交生活还是非常丰富,他几乎连“翻开书”的时间都没有,忙着和其他的知名哲学家往来。斯密在汤森的重金资助下,于一七六四年跟随休谟的脚步前往欧陆。他曾提及他利用这个机会开始“撰写一本小书来打发时间”。一般认为这本书就是《国富论》。21
英国社会的看不见的手,得负责将英国的文明力量带到殖民地,这意谓着要教育殖民地的人口,他们因为距离大都市很遥远,需要花时间才能发展为成熟的商业社会。斯密以美洲为例,说明商人之所以不适合执政,是因为他们在决策过程中只会考虑自身利益。斯密并没有提到是约翰.洛克自己创造出马里兰州的烟草垄断的,只是抱怨商人“出于怪异的荒谬想法”,认为“君主的特质”只不过是贸易与商人利益的“附属品”,一心只想要排除竞争对手。对于先进商业社会尚未完全形成的地方,一个洛克的菁英式开明政府,必须先透过文明的影响力介入,将自然之手引导向适当的位置。斯密写作的时候正值美国独立战争(American War of Independence,一七七五年至一七八三年),虽然他反对美国殖民地脱离大英帝国,但若这件事真的发生了,他希望两国能结成自由贸易联盟。但新生的美利坚合众国做的决定却正好相反,美国在一七八三年对所有外国商品征收关税,以保护正在发展中的脆弱经济。30
1. Friedrich Hayek, The Road to Serfdom , ed. Bruce Caldwell (Chicago: University of Chicago Press, 2007), 88, 100; Milton Friedman, Free to Choose: A Personal Statement, 3rd ed. (New York: Harcourt, 1990), 1–2.
2. Adam Smith, An Inquiry into the Nature and Causes of the Wealth of Nations , ed. Roy Harold Campbell and Andrew Skinner, 2 vols. (Indianapolis: Liberty Fund, 1981), vol. 1, bk. I, chap. vii, para. 12; vol. 2, bk. V, chap. iih, para. 12; vol. 2, bk. IV, chap. viii, para. 49; vol. 2, bk. IV, chap. 9, para. 3; Adam Smith, The Theory of Moral Sentiments , ed. D. D. Raphael and A. L. Macfie (Indianapolis: Liberty Fund, 1984), pt. 6, sec. 2, chap. 2, para. 17.
3. Steven Pincus, The Global British Empire to 1784 , unpublished manuscript; Paul Butel, “France, the Antilles, and Europe in the Seventeenth and Eighteenth Centuries: Renewals of Foreign Trade,” in The Rise of Merchant Empires , ed. James D. Tracy (Cambridge: Cambridge University Press, 1990), 168–172; T. S. Ashton, An Economic History of England: The Eighteenth Century (London: Methuen, 1955), 104; François Crouzet, “Angleterre et France au XVIIIe siècle: Essaie d’analyse comparé de deux croissances économiques,” Annales. Économies, sociétés, civilisations 21, no. 2 (1966): 254–291, at 268; Ralph Davis, “English Foreign Trade, 1700–1774,” Economic History Review , n. s. , 15, no. 2 (1962): 285–303, at 286; François Crouzet, La guerre économique franco-anglaise au XVIIIe siècle (Paris: Fayard, 2008), 367–370; Paul Cheney, Revolutionary Commerce: Globalization and the French Monarchy (Cambridge, MA: Harvard University Press, 2010), 101; François Crouzet, Britain Ascendant: Comparative Studies in Franco-British Economic History , trans. Martin Thom (Cambridge: Cambridge University Press, 1990), 216.
4. Dan Edelstein, The Enlightenment: A Genealogy (Chicago: University of Chicago Press, 2010), 9.
5. David Hume, An Inquiry Concerning Human Understanding , ed. Charles W. Hendel (Indianapolis: Library of the Liberal Arts, 1955), 1–11, 17; Dario Perinetti, “Hume at La Flèche: Skepticism and the French Connection,” Journal of the History of Philosophy 56, no. 1 (2018): 45–74, at 57–58; Margaret Schabas and Carl Wennerlind, A Philosopher’s Economist: Hume and the Rise of Capitalism (Chicago: University of Chicago Press, 2020), 33; Pedro Faria, “David Hume, the Académie des Inscriptions, and the Nature of Historical Evidence in the Eighteenth Century,” Modern Intellectual History 18, no. 2 (2020): 288–322.
6. Perinetti, “Hume at La Flèche,” 54; Hume, Concerning Human Understanding , 168.
7. Hume, Concerning Human Understanding , 172–173; James A. Harris, Hume: An Intellectual Biography (Cambridge: Cambridge University Press, 2015), 97.
8. Carl L. Becker, The Heavenly City of the Eighteenth-Century Philosophers (New Haven, CT: Yale University Press, 1932), 85, 102; Anthony Grafton, The Footnote: A Curious History (Cambridge, MA: Harvard University Press, 1997), 103; David Hume, Selected Essays , ed. Stephen Copley and Andrew Edgar (Oxford: Oxford University Press, 1998), xiii, 56, 58, 61.
9. Hume, Selected Essays , 188–189, 193, 194.
10. Jesse Norman, Adam Smith: The Father of Economics (New York: Basic Books, 2018), 194.
11. Smith, Theory of Moral Sentiments , sec. 1, chap. 1, para. 1; sec. 3, chap. 2, para. 9; Adam Smith, “Letter to the Edinburgh Review ,” 1755, in Smith, Essays on Philosophical Subjects , with Dugald Stewart’s “Account of Adam Smith,” ed. W. P. D. Wightman, J. C. Bryce, and I. S. Ross (Indianapolis: Liberty Fund, 1982), 253.
12. Smith, Theory of Moral Sentiments , pt. 1, sec. 1, chap. 2, para. 5.
13. Epictetus, The Discourses, The Handbook, Fragments , ed. J. M. Dent (London: Orion Books, 1995), 42, 44, 58; Smith, Theory of Moral Sentiments , pt. 1, chap. 1, para. 5.
14. Smith, Theory of Moral Sentiments , pt. 3, chap. 5, paras. 6–7; pt. 7, sec. 2, chap. 1, para. 39; Adam Smith, Essays on Philosophical Subjects , ed. W. P. D. Wightman and J. C. Bryce (Indianapolis: Liberty Fund, 1980), 45, 49, 104; Emma Rothschild, “Adam Smith and the Invisible Hand,” American Economic Review 84, no. 2 (1994): 319–322, at 319.
15. Smith, Wealth of Nations , vol. 1, bk. IV, chap. iiic, pt. 2, para. 9.
16. Smith, Theory of Moral Sentiments , sec. 2, chap. 3, para. 1; sec. 5, chap. 2, paras. 10–13; sec. 7, chap. 4, paras. 36–37; Donald Winch, Riches and Poverty: An Intellectual History of Political Economy in Britain, 1750–1834 (Cambridge: Cambridge University Press 1996), 98–99; Fonna Forman-Barzilai, Adam Smith and the Circles of Sympathy: Cosmopolitanism and Moral Theory (Cambridge: Cambridge University Press, 2010), 226.
17. Smith, Theory of Moral Sentiments , pt. 6, sec. 2, chap. 2, para. 13.
18. Nicholas Phillipson, Adam Smith: An Enlightened Life (New Haven, CT: Yale University Press, 2010), 159–166.
19. Phillipson, Adam Smith , 166; Geoffrey Holmes and Daniel Szechi, The Age of Oligarchy: Pre-Industrial Britain, 1722–1783 (London: Longman, 1993), 282.
20. Phillipson, Adam Smith , 182.
21. Harris, Hume , 409–415; Phillipson, Adam Smith , 188.
22. Phillipson, Adam Smith , 193.
23. Smith, Wealth of Nations , vol. 2, bk. IV, chap. ix, para. 38; vol. 1, bk. II, chap. v, para. 12.
24. Smith, Wealth of Nations , vol. 1, bk. I, chap. viii, paras. 15–22; vol. 1, bk. I, chap. x, paras. 19, 31.
25. Smith, Wealth of Nations , vol. 2, bk. IV, chap. ix, paras. 11–14, vol. 2, bk. IV, chap. ii, para. 9; vol. 1, bk. I, chap. viii, para. 35; vol. 1, bk. IV, chap. ii, para. 9; vol. 2, bk. IV, chap. ix, para. 9; vol. 2, bk. V, chap. iik, para. 7.
26. Smith, Wealth of Nations , vol. 1, bk. I, chap. ii, paras. 1–2.
27. Emma Rothschild, Economic Sentiments: Adam Smith, Condorcet, and the Enlightenmen t (Cambridge, MA: Harvard University Press, 2001), 127.
28. Smith, Wealth of Nations , vol. 1, bk. IV, chap. ii, para. 38; vol. 2, bk. IV, chap. ix, paras. 1–3; vol. 1, bk. IV, chap. ii, para. 30.
29. E. P. Thompson, “Eighteenth-Century English Society: Class Struggle Without Class?,” Social History 3, no. 2 (1978): 133–165, at 135; Frank McLynne, Crime and Punishment in Eighteenth-Century England (London: Routledge, 1989); Smith, Wealth of Nations , vol. 1, bk. I, chap. xic, para. 7.
30. Smith, Wealth of Nations , vol. 2, bk. IV, chap. viib, para. 20; vol. 2, bk. IV, chap. viic, para. 103.
31. Smith, Wealth of Nations , vol. 1, “Introduction and Plan of the Work,” para. 4; vol. 2, bk. IV, chap. viib, para. 54.
32. John Rae, Life of Adam Smith: 1895 , ed. Jacob Viner (New York: Augustus M. Kelley Publishers, 1977), 71–72.
33. Rothschild, Economic Sentiments , 133; Dugald Stewart, Account of the Life and Writings of Adam Smith , in Works, ed. Dugald Stewart, 7 vols. (Cambridge, MA: Hilliard and Brown, 1829), 7:1–75, at 67.
34. Smith, Wealth of Nations , vol. 1, bk. III, chap. iv, para. 20.
35. Smith, Wealth of Nations , vol. 2, bk. IV, chap. ii, paras. 10–20.
36. Smith, Wealth of Nations , vol. 1, bk. IV, chap. iiic, paras. 9, 13.
37. Rothschild, Economic Sentiments , 133–136; Voltaire, Candide , ed. Philip Littell (New York: Boni and Liveright, 1918), 168; Jacob Soll, The Reckoning: Financial Accountability and the Rise and Fall of Nations (New York: Basic Books, 2014), 129–130.
第十四章 利伯维尔场帝国
你们认为保护政策如何能增加一个国家的财富?你们能否透过立法使国家的财富增加任何一文?你们或许可以透过立法,在一夜之间摧毁一世纪的劳动带来的成果和累积;但在我看来,你们不可能透过本院的立法,为国家财富增加任何一文。财富来自勤奋与智慧,你们无法找到比任其自行发展更好的方法。 ──理查德·科布登(Richard Cobden),《下议院演讲》(Speech to the House of Commons ),一八四六年
十九世纪初,李嘉图形塑与捍卫着斯密遗留下来的建树,坚持认为财富来自农业。不过他跟斯密不同的地方在于,他认为财富是有限的。在《论政治经济与赋税原则》(On the Principles of Political Economy and Taxation ,一八○九年)一书中,他发展出了地租法则(Law of Rent),此法则的基础概念是土壤的肥沃决定了劳动的价值。他认为定价与薪水会随着土地的生产能力而起伏,而需求不会带来任何影响。李嘉图在马尔萨斯的影响下,发展出了工资铁律(Iron Law of Wages),根据该定律的描述,穷人的收入总是会持续下降到可维生的最低水平。一旦农场工人得到报酬,他们就会生下更多孩子,这只会使他们变得更加贫困,抵销任何工资增长。唯一能够大幅提升工资的方式就是解放国际谷物市场以创造竞争,如此一来,英国的土地拥有者就会投资农场,推高生产率与工资,也可能一并提高生活水平。然而,李嘉图警告如果土地拥有者是靠着固定的总资本来支付工人高薪,他们以后就没有钱重新投资农场了,这将会再次压低工资。6
到了十九世纪初,英国无庸置疑成为了世界工厂──在工业与殖民方面首屈一指的国家。同时英国也是谷物的主要生产国。李嘉图身为议员的伟大计划就是支持自由贸易。他支持废除谷物法,也就是一八一五年拿破仑战争结束时设立的保护主义谷类关税,当时设立关税的目的是保护英国地主不受定价更便宜的外国谷物影响。李嘉图借鉴了斯密对于自由贸易自我调节本质的牛顿式信念,主张土地拥有者只不过是利用关税来创造国家对谷物的垄断,并推高价格。尽管李嘉图没来得及亲眼目睹,但后来在实业家理查德.科布登的带领之下,反谷物法联盟(Anti-Corn Law League)的自由放任提倡者施加压力,使英国的谷物法于一八四六年遭到废除,科布登是来自制造业中心──曼彻斯特的企业家与国会议员,他代表了历史学家称作“自由贸易国度”的英国时代之起始。9
即使在世界市场占据了主导地位,英国仍必须面对贫困与财富不均的棘手问题。正如马尔萨斯所警告的那样,任由市场自生自灭是无法解决这些问题的。经济与政治哲学家约翰.史都华.弥尔(John Stuart Mill)认为,自由贸易是一把双面刃,我们在欢庆自由贸易的自由面时,也必须承认它并没有为穷人带来更好的生活水平。从许多方面来说,弥尔都是最能代表十九世纪早期利伯维尔场思想内部矛盾的思想家──他相信利伯维尔场的生产能力,同时也承认国家需要为了打造出更公正的经济系统而进行社会改革,并在两者间达到平衡。
弥尔在一八六九年写下了《论社会主义诸篇》(Chapters on Socialism ),距离查尔斯.达尔文出版《物种起源》(The Origin of Species ,一八五九年)正好十年。达尔文透过商业的视角思考生物学,他的演化理论将会对利伯维尔场思想留下深远影响。根据他的理论,演化看起来就像是把斯密的理想主义进步观点结合马尔萨斯认为自然会剔除弱者的想法,形成了某种积极的、超出道德范畴的演化方式。虽然达尔文在《人类的由来及性选择》(The Descent of Man, and Selection in Relation to Sex ,一八七一年)引用了马尔萨斯“令人永远难忘”的著作,但达尔文与马尔萨斯的基督教道德观完全切割。达尔文不再受《旧约圣经》的创世纪故事所限制,他眼中的大自然只会按照自然本身的无情逻辑运作。在自然选择(natural selection,又称天择或物竞天择)中,既没有高尚的西塞罗观点,也没有基督教伦理的存在,只有适者才能生存与繁衍。15
哈密尔顿坚信,共和体制必须由强大的政府来建立。他认为国家应该要由多位握有重权的首长来管理,“就像法国的那些首长一样”──正如他后来在《联邦党人文集》(Federalist Papers )第三十五篇中坚持的──这些人应该各自专精不同的领域,像是金融。一七九一年,哈密尔顿在“致国会之制造业报告”(Report to the Congress on the Subject of Manufactures)中坚称,处于起步阶段的国家政府必须把焦点放在发展工业上,而非农业。虽然农业是生活中不可或缺的,但农业其实不如重农主义者、休谟和斯密所说的是创造财富的基础。事实上,哈密尔顿深深认为这个概念必须在公众面前接受挑战,并由此明确声明,真正使得英国获得“大幅进步”的是工业的“棉花纺织厂”,而不是农耕。19
德国经济学家佛瑞德里克.李斯特(Friedrich List)也将会从哈密尔顿和克莱提出的美国体制中获得灵感。李斯特在一八二五年移居宾州,因为美国内部受到外部关税保护的自由贸易区而获得启发,主张要建立德国关税同盟(Zollverein ),将德国各州都纳入经济同盟的各个方面。李斯特在《政治经济学的国家体系》(National System of Political Economy ,一八二七年)中,解释了德国各州之间为何需要贸易条约来支持德国国内工业。关税将会在他们遇到国外竞争力时保护他们,如此一来,德国才能顺利发展,养成国际竞争力。李斯特的想法在法国也很受欢迎。这些观点反映了内部自由贸易的有效性,并且可以由内部关税同盟来促进,此外,策略性保护主义可以刺激德国在面对英国工业巨头时蓬勃发展。
值得注意的是,就在实施保护主义的经济大国:美国、德国和日本在经济成长方面赶上了英国时,剑桥大学哲学家阿尔弗雷德.马歇尔(Alfred Marshall)则在继续挥舞着教条式的自由贸易旗帜。就好像剑桥与世隔绝一样。马歇尔的《经济学原理》(Principles of Economics ,一八九○年)取代了弥尔的《论政治经济与赋税原则》,成为英国最重要的经济学教科书,马歇尔也成为了剑桥大学最举足轻重的经济思想家。他不但继续发展杰文斯提出的边际效用等概念,也提出了新的构想,诸如价格弹性、需求与定价的关系,以及部分均衡理论,这些构想对往后的经济学思想来说至关重要。他深入研究单一市场(例如羊毛)的供需流动,针对特定经济领域的运作提出细部分析,而不是提出他对整体经济的综合看法。马歇尔认为供需的运作就像机械一样,能创造出经济活动的“连续链”,他指出正是这具机械决定了价格。这具机械能为市场带来“均衡”,使市场能够靠自身运作,创造恒定的回报。30 马歇尔和斯密一样,是一名道德哲学教授。虽然他把焦点放在总量与边际效用价值等,但他仍在大自然中寻求经济“法则”,他认为这套法则能使得经济学变得类似于天文学等自然科学。因此,马歇尔盼望能靠着与天文学和物理学的模拟,去理解斯密所说的普遍驱动经济系统。他希望经济学的“个别学生”能够变得有资格“使用他的科学权威发话”。对马歇尔来说,在理解创造财富与经济活动时,必须结合工业生产价格、数量、效率,以及“需求层次”和竞争一起理解,这些要素彼此连结在一起后才创造出了成长。31 尽管马歇尔对于一直持续存在着的贫困感到有些不知所措,但他相信,只要靠着市场就能解决经济问题,工资终究会上涨,生活水平终究会提高。他没注意到的是,他这具巨大的经济机械已经快解体了。他在一九二四年逝世,五年后发生了一九二九年的华尔街大崩盘,美国开始步入经济大萧条。马歇尔不断寻找新的市场机制,而从没想过市场会崩盘。有一些二十世纪利伯维尔场思想家一心追随马歇尔的思想──他们就像《白鲸记》中的船长亚哈(Captain Ahab)一样,站在对市场的固定立场,愈来愈执着于传统观念:市场会自行运作,政府对经济事务几乎没有影响。
1. William J. Baumol, Economic Dynamics: An Introduction (New York: Macmillan, 1951); D. M. Nachane, “In the Tradition of ‘Magnificent Dynamics,’ ” Economic and Political Weekly , June 9, 2007.
2. Jeremy Bentham, The Principles of Morals and Legislation (Amherst, NY: Prometheus Books, 1988), 1–3, 29, 40.
3. Jeremy Bentham, “Bentham on Population and Government,”Population and Development Review 21, no. 2 (1995): 399–404.
4. Thomas Malthus, An Essay on the Principle of Population and Other Writings , ed. Robert J. Mayhew (London: Penguin, 2015), 19; Adam Smith, An Inquiry into the Nature and Causes of the Wealth of Nations , ed. Roy Harold Campbell and Andrew Skinner, 2 vols. (Indianapolis: Liberty Fund, 1981), vol. 1, bk. I, chap. viii, para. 36.
5. Malthus, Essay on the Principle of Population , 40, 65, 74, 155–163.
6. David Ricardo, Works , ed. John Ramsay McCulloch (London: John Murray, 1846), 50–55; Paul Samuelson, “The Canonical Classical Model of Political Economy,” in Paul Samuelson on the History of Economic Analysis: Selected Essays , ed. Steven J. Medema and Anthony M. C. Waterman (Cambridge: Cambridge University Press, 2015), 89–116, at 102–105.
7. Ricardo, Works , 55.
8. Smith, Wealth of Nations , vol. 1, bk. I, chap. viii, para. 37; Joan Robinson, “What Are the Questions?” Journal of Economic Literature 15, no. 4 (1977): 1318–1339, at 1334; Andre Gunder Frank, Dependent Accumulation and Underdevelopment (New York: Monthly Review Press, 1979); Henk Ligthart, “Portugal’s Semi-Peripheral Middleman Role in Its Relations with England, 1640–1760,” Political Geography Quarterly 7, no. 4 (1988): 353–362, at 360–361; Matthew Watson, “Historicising Ricardo’s Comparative Advantage Theory, Challenging the Normative Foundations of Liberal International Political Economy,” New Political Economy 22, no. 3 (2017): 257–272, at 259; John Gallagher and Ronald Robinson, “The Imperialism of Free Trade,” Economic History Review 6, no. 1 (1953): 1–15, at 5; D. C. M. Platt, “The Imperialism of Free Trade: Some Reservations,” Economic History Review 21, no. 2 (1968): 296–306; Joan Robinson, Contributions to Modern Economics (New York: Academic Press, 1978), 213; Joan Robinson, The Economics of Imperfect Competition , 2nd ed. (London: Palgrave Macmillan, 1969).
9. Frank Trentmann, Free Trade Nation: Commerce, Consumption, and Civil Society in Modern Britain (Oxford: Oxford University Press, 2008), 1–8.
10. Anthony Howe, Free Trade and Liberal England, 1846–1946 (Oxford: Oxford University Press, 1998), 4, 113; Eileen P. Sullivan, “J. S. Mill’s Defense of the British Empire,” Journal of the History of Ideas 44, no. 4 (1983): 599–617, at 606; John Stuart Mill, Principles of Political Economy and Chapters on Socialism , ed. Jonathan Riley (Oxford: Oxford University Press, 1994), xxxix, 112–113.
11. Mill, Principles of Political Economy , 113.
12. John Stuart Mill, Considerations on Representative Government (Ontario: Batoche Books, 2001), 46; Gary Remer, “The Classical Orator as Political Representative: Cicero and the Modern Concept of Representation,” Journal of Politics 72, no. 4 (2010): 1063–1082, at 1064; Mill, Principles of Political Economy , 86.
13. Mill, Principles of Political Economy , 124–125, 377.
14. Mill, Principles of Political Economy , 381.
15. Charles Darwin, The Life and Letters of Charles Darwin , ed. Francis Darwin, 3 vols. (London: John Murray, 1887), 3:178–179; Charles Darwin, The Origin of Species by Means of Natural Selection, or, The Preservation of Favoured Races in the Struggle for Life (New York: Signet Classics, 2003), 5; Charles Darwin, The Descent of Man, and Selection in Relation to Sex (New York: Appleton and Company, 1889), 44.
16. Geoffrey Martin Hodgson, Economics in the Shadows of Darwin and Marx: Essays on Institutional and Evolutionary Themes (Cheltenham, UK: Edward Elgar, 2006), 12; Karl Marx, “The Production Process of Capital: Theories of Surplus Value,” in Karl Marx and Friedrich Engels, Collected Works , vol. 31, Marx, 1861–1863 (London: Lawrence and Wishart, 1989), 551; Gareth Stedman-Jones, Karl Marx: Greatness and Illusion (Cambridge, MA: Belknap Press of Harvard University Press, 2016), 174–175, 382–383; Karl Marx, Capital , ed. Ernest Mandel, trans. David Fernbach, 3 vols. (London: Penguin, 1992), 2:218; Bela A. Balassa, “Karl Marx and John Stuart Mill,” Weltwirtschaftsliches Archiv 83 (1959): 147–165, at 150.
17. Michael Hudson, America’s Protectionist Takeoff, 1815–1914: The Neglected American School of Political Economy (New York: Garland, 1975).
18. Hudson, America’s Protectionist Takeoff , 54.
19. Jack Rackove, Original Meanings: Politics and Ideas in the Making of the Constitution (New York: Vintage, 1997), 236; Alexander Hamilton, Report on the Subject of Manufactures (Philadelphia: William Brown, 1827), 20.
20. Maurice G. Baxter, Henry Clay and the American System (Lexington: University of Kentucky Press, 1995), 27–28; Brian Reinbold and Yi Wen, “Historical U. S. Trade Deficits,” Economic Research, Federal Reserve Bank, 2019, no. 13, https://research.stlouisfed.org/publications/economic-synopses/2019/05/17/historical-u-s-trade-deficits .
21. Cheryl Shonhardt-Bailey, From the Corn Laws to Free Trade: Interests, Ideas, and Institutions in Historical Perspective (Cambridge, MA: MIT Press, 2006), 285; Francis Wrigley Hirst, Free Trade and Other Fundamental Doctrines of the Manchester School (London: Harper and Brothers, 1903).
22. Richard Cobden, “Repeal of the Corn Laws,” May 15, 1843, in Hirst, Free Trade , 143–190, at 190; Richard Cobden, “Free Trade and the Reduction of Armaments,” December 18, 1849, in Hirst, Free Trade, 239–257, at 252.
23. Richard Cobden, “Armaments, Retrenchment, and Financial Reform,” January 10, 1849, in Hirst, Free Trade , 291–308, at 305; David Todd, Free Trade and Its Enemies in France, 1814–1851 (Cambridge: Cambridge University Press, 2015), 201.
24. Boyd Hilton, The Age of Atonement: The Influence of Evangelicalism on Social and Economic Thought, 1785–1865 (Oxford: Clarendon Press, 1986), 7, 261.
25. William Stanley Jevons, “Brief Account of a General Mathematical Theory of Political Economy,” Journal of the Royal Statistical Society, London 29 (June 1866): 282–287; William Stanley Jevons, Political Economy (New York: Appleton and Company, 1878), 7; Eric Hobsbawm, Industry and Empire: The Birth of the Industrial Revolution (London: Penguin, 1999), 17, 211.
26. Hobsbawm, Industry and Empire , 31–38.
27. Jevons, Political Economy , 62, 76, 77, 79, 81; Donald Winch, “The Problematic Status of the Consumer in Orthodox Economic Thought,” in The Making of the Consumer: Knowledge, Power, and Identity in the Modern World , ed. Frank Trentmann (Oxford: Berg, 2006), 31–52.
28. William Stanley Jevons, The Coal Question (London: Macmillan,1865).
29. Jennifer Siegel, For Peace and Money: French and British Finance in the Service of the Tsars and Commissars (Oxford: Oxford University Press, 2014).
30. Alfred Marshall, Principles of Economics (New York: Cosimo, 2006), 233.
31. Marshall, Principles of Economics , 30–31, 68–69, 273.
一九○五年,阿尔弗雷德.马歇尔在剑桥的同事威廉.康宁汉(William Cunningham)发表了《自由贸易运动的兴衰》(The Rise and Decline of the Free Trade Movement ),表达他对正统利伯维尔场思想的控诉。康宁汉在这篇针对英国正统经济观念的抨击文章中指出,传统观念源自杜尔哥和斯密的观点,在这些观点中,“经济学把社会视为一种机械”,提供了“宝贵的真理,至少就目前状况来说是如此;但问题在于这并不是完整的真相”。康宁汉主张,如果经济学想要被视为科学的话,就必须承认,经济学中的许多人类活动根本和机械运作截然不同。他使用了达尔文的说法,说社会应该是一种“在面对环境时具有自我适应能力的有机体”。因此,市场只是整具机械的一部分,而且还常常故障。为了让机械保持运转,必须“一遍又一遍地测试”,即便如此,这种利伯维尔场思想的伟大机械真理仍有可能根本行不通。1 康宁汉认为,经济学只不过是一种“沉闷的阅读材料”,人们可以利用供需原则等简明扼要的原理来代替整段沉闷的经济学阅读。他明白“自由贸易原则”,根据该原则所述,货品与服务的交换是没有限制的,而消费者可以依照此原则自由选择货品,追求舒适与效率。康宁汉用讽刺又强而有力的言词指出,他“打从心底完全支持自由贸易倡导者所假设的目标”,但如果他到富裕又实施保护主义的美国去,询问一个住在纽约的美国人,想必会发现这个人对自由贸易学说抱持着截然不同的态度。2 一九○○年,英国仍是一个实施自由贸易的国家,自由贸易的理念几乎就像是邪教一样:消费者就是国王,人们把自由贸易的圣战士理查德.科布登视为国家英雄,建立雕像与纪念碑来荣耀他。然而康宁汉主张这种意识形态已经破产。从剑桥大学这块阴暗、舒适且与世隔绝的区域深处,他所发出的批判开始萌芽。康宁汉提出警告,欧洲和羽翼未丰的美国提出的“柯尔贝派”改革计划将会成为英国最大的敌人。他指出,佛瑞德里克·李斯特的发展模型在欧洲与美国奏效了,这是各国能顺利通往自由贸易先进国家的唯一可行路径。除此之外,科布登对和平与裁军的盼望一直都没有实现。康宁汉预测,军国主义在欧洲与美国已逐渐发展起来,作为优势帝国的英国将会继续仰赖国家的海军和其他军事的压制力量。帝国竞争仍在持续引发殖民冲突,一八九九年在南非爆发的波耳战争(Boer War)就是一例。3
在两次世界大战期间,阿尔弗雷德.马歇尔的学生开始攻击市场系统能完全自我调节的概念。剑桥经济学家约翰.梅纳德.凯因斯(John Maynard Keynes)支持的是利伯维尔场──他在一九二○年代警告,共产主义与个人自由放任主义将会交战,而自由放任主义必须获胜。但凯因斯认为,利伯维尔场主义是有漏洞的,并且为了生存和对抗共产主义,而必须去理解自己的弱点。凯因斯指出,他和导师马歇尔的不同之处在于他认为利伯维尔场需要保护,凯因斯相信放任市场自行运作是不行的。他在《就业、利息和货币的一般理论》(General Theory of Employment, Interest, and Money ,一九三六年)中提出了一项根本性的经济新发现,他认为薪资并不是透过市场机制自然调节而出现的。凯因斯主张,在经济大萧条期间,只有透过政府、公司与劳工之间进行的“谈判”,才能让市场创造出充分就业的结果。经济大萧条让我们看到的是,如果经济体的支出──也就是“总需求”──出现了急剧下降,就像一九二九年的股市崩盘与接踵而至的经济大萧条那样,那么就业率也会下降,这将会再次使总需求随之下降,造成恶性循环。更糟的是,边际价值理论可能反过来损害市场,将之吞噬。如果不能实现资本的边际效率(也就是由于投资回报大于利息,使得投资在通货膨胀的状态下仍然能长期获得利润),那么市场就不会提供投资的动机,进一步削弱成长与就业的希望。消费者无法只靠自己维持总需求,正如美国总统赫伯特.胡佛(Herbert Hoover)发现他放任市场的做法只让经济大萧条变得更糟那样。8 这也就代表了,如果政府不愿透过支出与推动市场流动来帮助提高总需求的话,经济危机将会愈滚愈大,让更多人失去他们的工作和财富。以经济大萧条这种情况来说,光靠有钱人是没办法把总支出的水平提高到足以停止经济危机恶性循环的程度。唯有国家才有资源透过总支出来催化整体的就业与经济机能。简而言之,在大规模的金融或经济危机中,必须由政府这只可见的手来增加总需求。任何无形的市场力量都无法做到这一点。国家必须承担“直接参与和规划投资的更重大责任”。凯因斯在批判的是提倡利伯维尔场的“古典经济学”和马歇尔认为供给与需求可以自我调节的构想。9 马歇尔的另一位知名学生琼.罗宾逊(Joan Robinson)和凯因斯一起加入论战,并告诉我们所有所谓的自我调节市场系统都可能失败的原因。罗宾逊是剑桥大学的教授,也是最早的重要女经济学家之一,至今人们仍无法理解,她为什么会在中国共产党主席毛泽东执行了可怕且造成经济灾难的文化大革命期间(一九六六年至一九七六年)支持毛泽东。无论是否受到误导,她之所以会支持毛泽东对社会与经济方面的暴力国家干预,都是基于她的此一信念:贫困国家无法在经济上和富裕国家竞争,需要冲击式的刺激。罗宾逊成为发展经济学的创始人,激发人们对马克思研究产生了新一波的兴趣。发展经济学旨在为没有大规模商业与工业基础的国家寻求致富的途径。此经济学可溯源至十七世纪所谓的重商主义著作,以及柯尔贝和亚历山大.汉米尔顿的政策。发展经济学在二十世纪的出现与经济未开发国家(所谓的第三世界)有关,这类国家没有能力进行必要的结构性经济改革,因此无法实现现代化并建立具有竞争力的商业与工业基础。
罗宾逊带头指出,经济未开发的国家在实质上无法与经济已开发的国家竞争,那些属于弱势群体的人们也无法与根基稳固的外国公司或个人竞争。她的著作《不完全竞争经济学》(Economics of Imperfect Competition ,一九三三年)创造出了“买方垄断”(monopsony,又称独买)的概念,指的是具有强大权力的单一买家控制了商品出售给其他买家的定价,因此市场价格会被一种买家对薪资的垄断所扭曲──就像是在一个“公司市镇”(company town,指大部分居民受雇于同一家公司的城镇)中,所有薪资与经济生活都由单一公司所控制的状况。买方垄断破坏了边际效用的逻辑。买方垄断的基础并不是市场力量,而仅仅是少数买家的决定或偏见,他们可以把薪资压低到低于边际价值的水平。买方垄断也解释了为什么女性的薪资比男性低,和少数族群的薪资比其他族群低。举例来说,如果一名雇主单纯出于偏见而决定要降低所有女性的薪资,那么这就会协助确立一个既定的市场价值;其他公司也可能效法此一趋势,而女性薪资就会受到整体削弱。10
一九五六年,罗宾逊出版了《资本的累积》(The Accumulation of Capital ),延续了凯因斯的传统,指出在一些未发展的经济体中,存在的只有资本家和劳工。劳工的薪资只能勉强维持生活,资本家在这个原始生产经济体中的消费很少,把钱都拿去买外国商品,损害了能够创造财富的当地消费者社会的发展。她提出的模式批判了由供需驱动的经济模型在较贫困国家的适用性。在较贫困国家中,不仅资本成长极低,而且资本会被拉向经济发展较高的市场,近一步削弱国内经济发展。11
剑桥曾是福音派利伯维尔场经济学的发源地,但后来成为了凯因斯主义的中心。如果说注重均衡的利伯维尔场思想在英国失去了优势,那么此种思想将会在奥地利找到最有力的新追随者。现代自由意志主义经济传统正是在奥地利出现,而在之后流传到了美国,在二次世界大战期间造成了巨大的影响。律师、记者暨奥地利经济学派创始人卡尔.门格尔(Carl Menger)大力抨击斯密的劳动价值理论,并用边际效用理论取而代之,根据后者所述,驱动经济的是互利的交易。他的自由主义思想,是斯密和边沁提出的“透过实现由市场驱动的人类需求来实现人类进步”之概念的简化版本。一八七一年,也就是杰文斯出版《政治经济学》的那一年,门格尔出版了《经济学原理》(Principles of Economics )。门格尔清楚地认识到,斯密和李嘉图的劳动价值理论是行不通的。他带我们回到曼德维尔的《蜜蜂的寓言》,宣称能够推动经济发展的只有一件事:对商品的渴望。与曼德维尔不同的是,门格尔不认为恶行能创造出美德,他描绘了一个简陋而单纯的经济系统,单单只由“渴望”造成的“因果关系”来驱动,并且是这些因果关系建构了社会关系与经济关系。他认为社会主义者──无论是民主的或其他形式的──是不能去计划经济关系的。人类渴望各种事物,这种需求会创造供给,在这个不断循环的循环中持续发展成更加复杂的商业与工业社会。12
备受尊敬的经济学家暨学者路德维希.冯.米塞斯(Ludwig von Mises)是名犹太裔的利伯维尔场思想家,住在国际化且学术思想丰富的奥地利城市维也纳,他改信基督教的行为十分符合自身的经济意识形态。利伯维尔场思想已经远离了原本的自然神论源头,变得更加贴近基督教运动。冯.米塞斯和科布登一样,反对政府干预经济,他谴责战争,也谴责战争使个人屈从于一个虚无目标的可怕行为。一九二○年,冯.米塞斯根据他的信念,以惊人的先见之明痛斥了“社会主义国家联合体”中的国家中央经济计划。他认为当时苏联的中央计划方式在预测商品价值时,其准确度与效率都比不上供给与需求的自然定价过程。早在苏联出现惊人的经济崩溃之前,冯.米塞斯就看出了社会主义的中央计划经济无法有效地选出应该重视哪些产业,只有利伯维尔场能做到这一点。13
傅利曼和许多利伯维尔场思想家一样,生活在矛盾之中。他的事业始于富兰克林.罗斯福(Franklin Roosevelt)的罗斯福新政(New Deal),协助政府进行预算研究,接着进入国家经济研究局(National Bureau of Economic Research)工作。他后来指出,虽然政府的创造就业计划并不完美,但在遭遇经济大萧条时,这种计划是必要的。不过,傅利曼认为罗斯福新政的其余部分都在以马克思主义的方式“控制”个体的经济生活。傅利曼在回顾罗斯福的改革时,避开了尖锐的党派偏见,称赞总统怀抱着“崇高的意图”,但同时也十分遗憾地指出,他认为社会安全保险、国家福利、公共住宅与其他政府计划全都彻底失败了。斯密同样曾警告过,亲商的经济政策只会对特殊利益有利。傅利曼坚持认为社会政策也是一样的,他指出政府的援助破坏了“上帝面前人人平等”的原则。22
傅利曼对经济学的重要贡献始于一九五六年,他在那年发表了对于货币主义的研究,利用此理论与方法指出,控制货币供应量是稳定经济的主要方法。他在著名文章〈货币数量理论:重述〉(Quantity of Money Theory: A Restatement)中主张,经济体在逐年成长的过程中会创造出稳定的货币需求。他的看法与早期的货币数量理论学家互相呼应,认为货币的价值与经济体中的货币数量互有关联,但是他比早期的理论学家更像是柯尔贝,原因在于他担心经济体若没有定期提供货币,就会使经济交易的速度变慢、数量减少。他感兴趣的并非货币的价值,而是经济体如何创造出了必定出现又必须被满足的货币需求。这也就代表了政府必须每年都提供货币,而供给量应该相当于经济体的平均成长值。他回到了约翰.劳提出纸币理论时的中心思想,也就是政府必须稳定供应才能打造出信心,而傅利曼将这套观点称为经济行为者的“理性期待”。23
傅利曼的货币数量理论批判了凯因斯的“政府能靠支出刺激经济”的观点。傅利曼认为,除了军队和警察之外,所有国家支出都是错误,所有涉及联准会(Federal Reserve)的事情都很危险。事实上,他认为美国应该完全废除联准会,直接根据统计出来的预期成长数字来发行货币。他和共同作者安娜.舒瓦兹(Anna Schwartz)一起写下的巨著《美国货币史》(Monetary History of the United States ,一九六三年)指出,美国的货币存量正随着时间推移而不断成长。然而在经济大萧条期间,联准会限制了货币供给,希望能藉此抑制通膨。根据傅利曼所述,这些行为加剧且延长了经济大萧条的“大收缩”(great contraction)。他和舒瓦兹做出结论,认为联准会能够为国家的成长与扩张做出贡献的方式只有两种,一是什么都不做,二是拿出更多钱。24
当保护公司免受政府干预的运动在美国展开,希望能阻止罗斯福新政在社会、教育与社会福利方面的计划,杜邦兄弟也在行列之中。当时有许多亲利伯维尔场的团体都获得了工业家的支持,杜邦兄弟支持的是美国自由联盟(American Liberty League),他们与该联盟同心协力,试图撤销罗斯福的政策。若想达成目标,他们就需要一套意识形态。到了一九四○年代后期,另一个保守的基督教团体也开始反对罗斯福新政,这些福音派信徒认为罗斯福新政正在把人民的信仰从基督教转移到世俗国家。30
如今,当来自各方的批评者开始抨击傅利曼的利伯维尔场思想时,我们不禁要问:哪些版本的利伯维尔场思想是到了现今仍然有用的?正如我们在中国、新加坡乃至所有经济已开发国家中看到的,没有一种经济模式能占据主导地位。从以前到现在,从来没有任何一个。我们总是根据环境状况而不断变化。但我们能确定一件事:在没有政府的地方,例如南苏丹这类充满极端暴力的“边境经济体”,正统的自由意志主义利伯维尔场模式并不存在,也从未存在过。大多数已开发工业经济体都会遵循一种相对类似的配方,即自由社会民主制度,搭配上普遍的利伯维尔场机制,以及政府对于经济体的广泛监督和参与。多数私营公司会根据供给与需求的市场机制来生产和销售商品及服务,但也有些公司的根据来自私人国家垄断(如波音公司〔Boeing〕和空中巴士〔Airbus〕),有些则依据政府合约(如IBM和微软〔Microsoft〕)、或者依据国家补贴公司和社会福利的计划来获得可观的国家援助(请回想一下亚马逊〔Amazon〕早期使用美国邮政署〔United States Postal Service〕,或者沃尔玛和麦当劳靠着国家医疗补助〔Medicaid〕作为低工资战略的一部分)。34 每个国家都会依据环境的不同,在发展的过程中采用极独特的方法与途径,这些发展往往违背了纯粹的经济模式。因此,我们不可能把新加坡拿去和中国、德国或美国相提并论,中美德皆拥有庞大且多样化的国内市场。虽然全球规模最大的公司大多都位于美国,但目前看来,亚洲的公司成长率比美国高得多。它们全都具有不同的优势与策略。把美国拿去和中国比较,就像是在一七○○年把英国与法国拿来比较一样。双方需要的是彼此不同的一系列经济政策,藉此发展经济状况并进行有效的竞争。35
1. William Cunningham, The Rise and Decline of the Free Trade Movement (Cambridge: Cambridge University Press, 1905), 5–9.
2. Cunningham, Rise and Decline ; Frank Trentmann, Free Trade Nation: Commerce, Consumption, and Civil Society in Modern Britain (Oxford: Oxford University Press, 2008), 91–98, 243.
3. Cunningham, Rise and Decline , 37, 85.
4. Cunningham, Rise and Decline , 97.
5. Cunningham, Rise and Decline , 119, 121–123, 158, 160.
6. Cunningham, Rise and Decline , 191–194, 197–198.
7. Cunningham, Rise and Decline , 200, 210.
8. John Maynard Keynes, Laissez-Faire and Communism (New York: New Republic, 1926), 65.
9. Keynes, Laissez-Faire , 31, 164.
10. Joan Robinson, The Economics of Imperfect Competition , 2nd ed. (London: Palgrave Macmillan, 1969), 211–228.
11. Joan Robinson, The Accumulation of Capital (New York: Palgrave Macmillan, 2013), 248, 330.
12. Carl Menger, Principles of Economics , trans. James Dingwall and Bert F. Hoselitz (Auburn, AL: Ludwig von Mises Institute, 2007), 51, 72–73; Janek Wasserman, The Marginal Revolutionaries: How Austrian Economists Fought the War of Ideas (New Haven, CT: Yale University Press, 2019), 33; Wasserman, Marginal Revolutionaries, 73.
13. Ludwig von Mises, Economic Calculation in the Socialist Commonwealth , trans. S. Alder (Auburn, AL: Ludwig von Mises Institute, 1990), 1–10.
16. Stephan A. Marglin and Juliet B. Schor, eds. , The Golden Age of Capitalism: Reinterpreting the Postwar Experience , 2nd ed. (Oxford: Oxford University Press, 2007), 41.
17. Henry Ashby Turner Jr. , “Big Business and the Rise of Hitler,” American Historical Review 75, no. 1 (1969): 56–70.
18. Friedrich Hayek, The Road to Serfdom , ed. Bruce Caldwell (Chicago: University of Chicago Press, 2007), 35, 76, 89, 100, 110.
19. Elisabetta Galeotti, “Individualism, Social Rules, Tradition: The Case of Friedrich A. Hayek,” Political Theory 15, no. 2 (1987): 163–181, at 169.
20. David Levy, “Interview with Milton Friedman,” Federal Re serve Bank of Minneapolis, June 1, 1992, www.minneapolisfed.org/article/1992/interview-with-milton-friedman .
21. Milton Friedman, “Market Mechanisms and Central Economic Planning,” in Milton Friedman, Sidney Hook, Rose Friedman, and Roger Freeman, Market Mechanisms and Central Economic Planning (Washington, DC: American Enterprise Institute, 1981), 1–19, at 9.
22. Milton Friedman, Free to Choose: A Personal Statement , 3rd ed. (New York: Harcourt, 1990), 94–97, 129.
23. Milton Friedman, “Quantity of Money Theory: A Restatement,” in Milton Friedman, ed. , Studies in the Quantity Theory of Money (Chicago: University of Chicago Press, 1956), 3–21, at 12.
24. Milton Friedman and Anna Jacobson Schwartz, A Monetary History of the United States, 1867–1960 (Princeton, NJ: Princeton University Press, 1963), 7, 11.
25. Milton Friedman, “The Demand for Money: Some Theoretical and Empirical Results,” National Bureau of Economic Research, Occasional Paper 68, 1959, www.nber.org/system/files/chapters/c5857/c5857.pdf , 1–25, at 2.
26. Milton Friedman, Capitalism and Freedom , 3rd ed. (Chicago: University of Chicago Press, 2002), 137.
27. Milton Friedman, An Economist’s Protest: Columns in Political Economy (Sun Lakes, AZ: Thomas Horon and Daughter, 1972), 6; Milton Friedman, “Say ‘No’ to Intolerance,” Liberty Magazine 4, no. 6 (1991): 17–20.
28. Kim Phillips-Fein, Invisible Hands: The Businessmen’s Crusade Against the New Deal (New York: Norton, 2009), 3.
29. Phillips-Fein, Invisible Hands, 4, 61 (du Pont quotation p. 4); Kevin M. Kruse, One Nation Under God: How Corporate America Invented Christian America (New York: Basic Books, 2015), 25.
30. Kruse, One Nation Under God , 61.
31. Kruse, One Nation Under God , 35; Phillips-Fein, Invisible Hands , 69, 77; Barry Goldwater, The Conscience of a Conservative (Shepherdsville, KY: Victor Publishing, 1960), 53.
32. Phillips-Fein, Invisible Hands , 228.
33. Jennifer Burns, “Godless Capitalism: Ayn Rand and the Conser vative Movement,” Modern Intellectual History 1, no. 3 (2004): 359–385; Brian Doherty, Radicals for Capitalism: A Freewheeling History of the Modern Libertarian Movement (New York: Public Affairs, 2008), 11.
34. Doug Bandow, “The West Fails to Social Engineer South Sudan,” American Conservative , September 19, 2019, www.cato.org/commentary/west-fails-social-engineer-south-sudan .
35. Richard H. K. Vietor, How Countries Compete: Strategy, Structure, and Government in the Global Economy (Boston: Harvard Business School Press, 2007), 18.
1. Isabella M. Weber, “The (Im-)Possibility of Rational Socialism: Mises in China’s Market Reform Debate,” 2021, University of Massachusetts, Amherst, Economics Department Working Paper Series, no. 2021-19, available at ScholarWorks@UMassAmherst, https://scholarworks.umass.edu/econ_workingpaper/316 ; Isabella M. Weber, How China Escaped Shock Therapy: The Market Reform Debate (Abingdon, Oxon, UK: Routledge, 2021); Steven Mark Cohn, Competing Economic Paradigms in China: The Co-Evolution of Economic Events, Economic Theory and Economics Education, 1976–2016 (Abingdon, Oxon, UK: Routledge, 2016), 26; Milton Friedman, Friedman in China (Hong Kong: Chinese University Press, 1990), 74; Milton Friedman, Capitalism and Freedom , 3rd ed. (Chicago: University of Chicago Press, 2002), 3–4; Milton Friedman, Free to Choose: A Personal Statement , 3rd ed. (New York: Harcourt, 1990), 57.
2. Cited in Weber, “The (Im-)Possibility of Rational Socialism. ”
3. Isabella Weber, “Origins of China’s Contested Relation with Neoliberalism: Economics, the World Bank, and Milton Friedman at the Dawn of Reform,” Global Perspectives 1, no 1 (2020): 1–14, at 7; Milton Friedman, “Market Mechanisms and Central Economic Planning,” in Milton Friedman, Sidney Hook, Rose Friedman, and Roger Freeman, Market Mechanisms and Central Economic Planning (Washington, DC: American Enterprise Institute, 1981), 3; Weber, “The (Im-)Possibility of Rational Socialism. ”
4. Keith Bradsher and Li Yuan, “China’s Economy Became No. 2 by Defying No. 1,” New York Times , November 25, 2018.
5. Justin Yifu Lin, Economic Development and Transition: Thought, Strategy, and Viability (Cambridge: Cambridge University Press, 2009); Barry Naughton, The Chinese Economy, Adaptation and Growth (Cambridge, MA: MIT Press, 2018); Pankaj Mishra, “The Rise of China and the Fall of the ‘Free Trade’ Myth,” New York Times , February 7, 2018; Keith Bradsher and Li Yuan, “The Chinese Thought They Had Little to Learn from Conventional Wisdom. Now It’s the West That’s Taking Notes,” New York Times , November 25, 2018.
6. Jason Brennan, Against Democracy (Princeton, NJ: Princeton University Press, 2016), 192–193.
7. Karl Polanyi, The Great Transformation: The Political and Economic Origins of Our Time (Boston: Beacon Press, 1957).
8. Ellen Frankel Paul, “W. Stanley Jevons: Economic Revolutionary, Political Utilitarian,” Journal of the History of Ideas 40, no. 2 (1979): 263–283, at 279.
根据2009年至2017年美国社区调查(Integrated Public Use Microdata Series,IPUMS)的人口加权平均年薪数据,23岁时工程和计算机科学毕业生起薪超过4万美元,而社科毕业生只有不到3万美元。但到40岁,双方的年薪都来到了10万美元上下,其后也没有再拉开差距,尽管工程和计算机科学类的工资一直要高一些。
1.Muse, W. B., & Muse, I. (2024). College Selectivity, Choice of Major, and Post-College Earnings. Journal of Economic Analysis, 3(2), 33-51. 2.Weiss, D. M., Spitzer, M. L., Cronin, C., & Chin, N. (2024). Why college majors and selectivity matter: Major groupings, occupation specificity, and job skills. Contemporary Economic Policy, 42(2), 278-304. 3.Deming, D. J., & Noray, K. (2020). Earnings dynamics, changing job skills, and STEM careers. The Quarterly Journal of Economics, 135(4), 1965-2005. 4.Yao, M., & Han, S. (2024). Who earns the iron rice bowl? Major marketability and state sector jobs among college-educated workers in urban China. Chinese Journal of Sociology, 10(2), 167-191. 5.何书瑶,连俊翔,熊程心子(2023).不同专业考公“上岸”难度数据揭秘,这些专业机会为何较多. 上观新闻 6.海南省2024年度定向选调应届优秀大学毕业生公告. (2024, April 22).
第三,就宏观层面的国家治理而言,数据汇集机制也可能对央地关系产生结构性影响。例如,美国学者罗伯特?米科斯(Robert A. Mikos)指出,州政府向联邦政府汇集数据,这对联邦与州的关系产生了很大冲击,带来了很高的政治成本。联邦政府借助数据汇集机制将原属于联邦政府的数据处理成本转嫁给地方政府,违背了原本的财政分权架构。同时,数据汇集机制实际上要求州变相地贯彻联邦的政策而非州的政策,这将冲击州的自主权,也可能导致问责对象的模糊化。而且,向联邦汇集数据超出了被收集信息的主体的预期。州根据自身的权限收集数据之后,超出原有目的向上汇集,将会削弱公民对州的信任。布里奇特?法黑(Bridget A. Fahey)指出,这种“数据联邦主义”(Data Federalism)理念下联邦与州政府之间的数据合作,面临法治与民主的双重拷问。州与联邦之间成立了大量协调机构以推进数据共享,但对这些机构的控制机制存在缺位;虽然数据本身是非竞争性的,但数据汇集制度存在一定的竞争性,将会与既有行政管理体系产生冲突,改变原有的权力配置关系。
在这样一个“推演性的表意文字”的天才构想的推动下,莱布尼兹对于中文表示出极大兴趣,感到未来的世界语言应走这种表意的路子。但中文符号系统是否含有推演的结构于其中呢?他渴望知道。因此,在他关于中国的通信中,就中文性质的问题一再向有关的传教士或有可能回答他的人们发问。比如,在1679年6月24日/7月4日致埃尔斯霍茨(Johann S. Elsholz)的信中,他写道:“第二,众所周知,由于中国的文字不是表示话语[口语],而是表示‘东西’、‘事物’的,因此我想知道,‘汉字’是否总是按照事物的性质创造的。第三,是否所有文字都可以回溯到一些确定的元素或基本的字母,是否从组合中还能形成其他的汉字。第四,人们是否把不可见的事物借助于同有形的、可见的事物的比较带到某种确定的形式之中。..十一,人们是否能够以及在多大程度上从汉字[本身]学习到它的含义”。[53] 所以,当他后来于1689年和1697年分别遇见了来华的传教士闵明我(Claudio F. Grimaldi,1638-1712)和白晋(Joachim Bouvet,1656-1730)时,这种热情就一次次地显露了出来。
莱布尼兹和白晋在讲到《易》卦象时,总将它们归为伏羲,并相信伏羲“是中国古代的君主,世界知名的哲学者,并且是中华帝国的东方科学的创造者”。[62] 这一方面是由于中国解《易》传统中“伏羲画卦”的说法,另一方面则与白晋所属的索隐象征派(Figuralism)的学说有关。按这一派,比如巴斯卡(Pascal),《旧约》对《新约》中发生的事情有预表或预示,后来主要在法国传教士中形成了《旧约》对中国文化经典有预表的看法。[63] 著名天文学家开普勒和莱布尼兹也都受到这种思想影响,假定在上帝“变乱人类语言”(见《旧约·创世纪》11章)之前,人类有共同的文化与文字来源。伏羲就属于那样一个共同起源的时代,是一位伟大的世界性人物。我现在还不确知莱布尼兹在开始构思他的普遍表意文字时是否受到了这种学说的影响,但很明显,他和白晋都倾向于在伏羲画的卦象或在他们看来是二进制数学的成果中看到中文的起源。莱布尼兹写道:“我与白晋神父两人已发现了中国创始人伏羲所造的符号的明白无误的原本意义。这类符号,只是由断线〔阴爻〕与不断线〔阳爻〕组合的,并算是中国最古的、最简单的文字(the most ancient writing of China in its simplest form)”。[64] 在1702年给白晋的信中,他已直接讲到这个问题:“我想伏羲当时是把六十四的数再加一倍[因‘方位图’中有64卦按‘方’与‘圆’的方式的两种排列],为百二十八,加以他所认为最基本的名辞,而对名辞又与以最适当的文字。这文字就是表示卦的数和卦的阶段。由单纯的而重要的名辞,再加以字画,作成他的文字。..历代的君主和哲人,是以改良为目的,对于文字加以种种的变更,但并不是基于同一的文法和语原之法则。这样,文字起源的意义完全消失,而伏羲造卦的起源,亦失其本来的意义。我很想知道各卦的中国文字的意义”。[65]
第二,在这种数理中,“从无产生有”是一个自发的、简捷的、具有内在和谐和直观美的过程,而这些都是这个过程的原本性的证据。按照莱布尼兹,这个过程是:在数符的右边第一栏或最后一栏处交错地写下0,1,0,1,等,即两个基数中的任何一个出现一次后就改变到对方;在右数第二栏中交错写下0,0,1,1,0,0,1,1,等,也就是每个数出现二次后就变到对方;而在右数第三栏中,0与1则各自每出现四次就变到对方;第四栏中它们每出现八次就变。这也就是说,每向左一栏,数的循环期就加一倍。如此而可以一直有序而交错地写下去,得到一个从0到任意大的数的序数表。这就是莱布尼兹所说的“我们不经计算,不须记忆,即可写出我们要的数字..[从中]可看出和谐的序列与美”的意思。于是我们“看出”:神从无(零)创造一个越来越丰富、多样的世界所依据的数理结构或数象(IMAGO,IMAGE)结构,它显得极端简捷、自然与和谐。“由此我们也可以演绎到一种道理,即是人似在神的手工中看到的无序只是表面上如此而已;当我们如同通过望远镜一般地从正确的观点观物时,自然会看到左右相称的美。这一切使我们更称扬、更敬爱身为众善、众美之源的至善的智慧与善美”。[69] 因此,莱布尼兹要在这纪念币的一面刻上:“G. W. 莱布尼兹所发现的创造之象”,以及一句画龙点睛的铭文:“[为了]从无中产生一切,壹就足够了”。[70] 这里的“壹”既指二进制数字中的1,又像毕达哥拉斯学派那样地指本原的纯存在,也就是从神那里来的光明。莱布尼兹欣喜自得之余,希望闵明我将此“造化之象”的道理告诉康熙,以“显现出基督教信仰的优越”。[71]
尽管古人在鹿角、骨头和洞壁上创作过很多出色的艺术作品,但在早至35,000年前(同样,这一时间也存有争议)猎人们精彩地描绘出的那些动物当中,我们却并未看到他们的自画像。事实上,我们只是在一些极其罕见的情况下一睹了古人的身影,比如从法国西南部发掘出的一尊大约有25,000 年历史、用象牙雕制的头像,人称“布拉桑普伊的妇人”(Lady of Brassempouy)。这个妇人头像(尽管它的模样更像是一个小姑娘,甚至像是一个男孩),是欧洲已知最古老的、对人脸进行真实再现的艺术作品。至于头像有什么意义,人们一直争论不休;头像上还覆盖着一种角度倾斜、垂在肩膀上的图案,人们对此的解释也各不相同,有人说是假发,有人说是头巾。其实更有可能的情况是,这一图案不过是此人紧紧编成了辫子的头发而已。这种发型并不令人觉得惊讶,因为目前的遗传证据表明,当时欧洲的智人有着卷发和黑色/深色的皮肤;这就明明白白地提醒世人,我们拥有非洲血统。
[1] John F. Hoffecker, A Prehistory of the North (New Brunswick, NJ: Rutgers University Press, 2005).
[2] Brian Fagan, ed., The Complete Ice Age (London and New York: Thames & Hudson, 2009),这本文集收录了专业人士撰写的通俗文章。至于大冰期的气温,参见Jessica Tierney et al., “Glacial Cooling and Climate Sensitivity Revisited,” Nature 584 (2020): 569–573. doi: 10.1038/s41586-020-2617-x。
[3] Brian Fagan, Cro-Magnon: How the Ice Age Gave Birth to the First Modern Humans (New York: Bloomsbury Press, 2010).
[4] Ian Gilligan, Climate, Clothing, and Agriculture in Prehistory: Linking Evidence, Causes, and Effects (Cambridge: Cambridge
University Press, 2018),对这一主题进行了明确而缜密的分析。
[5] Charles Darwin, Charles Darwin’s“Beagle” Diary, ed. Richard Darwin Keynes (Cambridge: Cambridge University Press, 1988), 134.
[6] Paul H. Barrett and R. B. Freeman, Journal of Researches: The Works of Charles Darwin (New York: New York University Press, 1987), pt. 3, 2:120.
大约 13,000 年前,北美洲出现了分布广泛的克洛维斯人,他们以制作出了独具特色、带有薄底座的石制枪头而闻名。克洛维斯人全都是技术高超的猎手,能捕杀各种大小的猎物,但他们也曾广泛采集各种植物性食物。与先辈们一样,他们的流动性极强,能够长途追踪野牛和体形较小的猎物。克洛维斯人还曾从遥远的地方获得纹理细密、用于制造工具的石头。例如,在相距1,770千米之远的密苏里州圣路易斯附近,人们竟然发现了用来自北达科他州一些采石场的“刀河燧石”(Knife River Flint)制作而成的克洛维斯燧石矛尖。这些流动性强、多才多艺的克洛维斯部落适应了各种具有挑战性的环境,从“大平原”上的草地直到西部的沙漠之地,以及从寒冷的北方到炎热的沙漠这样的极端气温。
[1] 据说,古希腊哲学家西诺帕的第欧根尼(前386—前354)曾经从今坦桑尼亚的拉普塔镇往内陆而去,游历了25天。他将鲁文佐里山命名为“月亮山”,并且认为那里就是尼罗河的源头。地理学家提尔的马利纳斯(Marinus of Tyre,约 70—130)记录了第欧根尼的历次旅行,为托勒密的《地理学指南》一书奠定了基础。遗憾的是,马利纳斯的地理专著已经佚失。后来的阿拉伯旅行者,则恰如其分地把这些传说中的山峰称为“吉贝尔厄尔库姆里”(Jibbel el Kumri,即阿拉伯语中的“月亮山”)。 1889年,以“我想您就是利文斯通博士?”这句话而出名的探险家亨利·莫顿·斯坦利最终在地图上确定了这条山脉的位置。此前的欧洲旅行者从未见过这条山脉,因为它们通常都笼罩在云层之下。
[2] Margaret S. Jackson et al., “High-Latitude Warming
Initiated the Onset of the Fast Deglaciation in the Tropics,”
[10] 埃及古物学家詹姆士·亨利·布雷斯特德(James Henry Breasted)在一个世纪前的通俗读物中创造了“肥沃新月”一词。它所指的范围呈一个巨大的半圆形,朝南敞开,从地中海的东南角向北隆起,穿过叙利亚、土耳其部分地区以及伊朗高地,然后往南至波斯湾。布雷斯特德把这里比作一个“沙漠海湾”。“肥沃新月”纯属一个便于使用的标签,并无严格的定义,却经受住了时间的检验。
[11] Klaus Schmidt, G.bekli Tepe: A Stone Age Sanctuary in South-eastern Turkey (London: ArchaeNova, 2012).
[12] Andrew T. Moore et al., Village on the Euphrates (New York: Oxford University Press, 2000).
[13] 以任何标准来看,加泰土丘都是一个由国际发掘工作者和研究人员组成的团队实施的真正非凡的长期性考古项目。这方面的文献资料,正在迅速增加。对于一般读者来说,最好从下述文献资料开始:Ian Hodder, The Leopard’ s Tale (London and New York: Thames & Hudson, 2011)。从更专业的层面来看,同一作者编著的Religion in the Emergence of Civilization: .atalh.yük as a Case Study (Cambridge: Cambridge University Press, 2010)一书引人入胜,可以让您对非物质考古一探究竟。
但在南方,人们却把气候变化的责任归咎于神灵,并且用诗歌或者“城市挽歌”表达了出来。《苏美尔与乌里姆之挽歌》(“The Lament for Sumer and Urim”),就是最早用神灵的行为来解释气候变化的书面史料之一。从中我们得知,恩利勒、恩奇和其他神灵曾经决定毁掉一座城市。“风雨集焉,若洪水之袭……竟至栏中之牛不得站立,圈中之羊不得繁衍;河中之水皆咸。”[18] 他们还曾下令让底格里斯河与幼发拉底河沿岸长满“邪恶之杂草”,并将城市变成“废墟”。庄稼无法种植,乡村将会干涸;“底格里斯河与幼发拉底河之水,恩利勒壅塞之”。
是不是一系列血腥的内战与叛乱,动摇了统治者的权威?还是说,残酷的战争与军事失利,削弱了一个过度扩张的帝国的基础?无疑,这两个方面都在其中扮演了重要的角色。亚述的统治与早期那些君主制国家的统治一样,向来都很脆弱,永远都变化无常,完全不像埃及历代法老那样,有精心形成的先例可循。然而,我们如今已经明白,还有一个大家都很熟悉的因素,也参与了帝国的崩溃过程,那就是气候变化。来自伊朗北部的库纳巴洞穴(Kuna Ba Cave)里一份分辨率高、断代精确的气候变化洞穴沉积物记录,就说明了问题。[21] 这些洞穴沉积物表明,新亚述帝国是在气候异常湿润的两个世纪里崛起的。对于成千上万的农民来说,充沛的降水就是上天的恩赐;他们不但要为城市提供粮食,也要为四处征伐、靠国家精心分配的口粮维持生计的军队提供粮食。此后,公元前7世纪早期到中期出现了一系列特大干旱,且每次干旱都持续了数十年之久;这种情况,似乎导致亚述帝国的农业生产力开始下滑,继而又导致了帝国在政治和经济上的最终崩溃。最后,整个新亚述帝国终于在艰苦的征战中土崩瓦解,只留下了一个早已为干旱所削弱的民族。
[12] Marc Van De Mieroop, A History of the Ancient Near East ca. 3000–323 BC, 2nd ed. (New York: Blackwell, 2006). See also Foster, The Age of Agade.
[13] 这一段在很大程度上参考了哈维·韦斯对气候变化与阿卡德王国崩溃进行的出色论述,事实上整章都是如此。参见Harvey Weiss,“4.2 ka BP Megadrought and the Akkadian Collapse,” in Megadrought and Collapse: From Early Agriculture to Angkor, ed. Harvey Weiss (New York: Oxford University Press, 2017),93–159。关于干旱及其成因的文献资料也越来越多。参见Heidi M. Cullen et al., “Impact of the North Atlantic Oscillation on Middle Eastern Climate and Streamflow,” Climatic Change 55(2002): 315–338。亦请参见Martin H. Visbeck et al., “The North Atlantic Oscillation: Past, Present, and Future,”Proceedings of the National Academy of Sciences 98, no. 23(2001): 12876–12877。
[14] Weiss, “4.2 ka BP Megadrought and the Akkadian Collapse,” 135–159,这篇文章列举了古气候学替代指标的遗址并附上了参考资料,因而价值非凡。
[15] M. Charles, H. Pessin, and M. M. Hald, “Tolerating Change at Late Chalcolithic Tell Brak: Responses of an Early Urban Society to an Uncertain Climate,” Environmental
Archaeology 15, no. 2 (2010): 183–198.
[16] Charles, Pessin, and Hald, “Tolerating Change at Late Chalcolithic Tell Brak,” 183–198.
[17] W. Sallaberger, “Die Amurriter-Mauer in Mesopotamien: der .lteste historische Grenzwall gegen Nomaden vor 4000 Jahren,” in Mauern als Grenzen, ed. A. Nunn (Mainz: Phillipp von Zabern, 2009), 27–38.
[18] J. A. Black et al., The Literature of Ancient Sumer (New York: Oxford University Press, 2004), 128–131.
[19] 卡尔胡的一处王室碑文上描绘了这场盛宴的情形。Van De Mieroop, A History of the Ancient Near East, 234.
[20] 尼努尔塔(Ninurta),美索不达米亚神话中的战争与农业灌溉之神。——译者注
[21] Kuna Ba: Ashish Sinha et al., “Role of Climate in the Rise and Fall of the Neo-Assyrian Empire,” Science Advances 5, no. 11 (2019). doi: 10.1126/sciadv.aax6656.
[22] Nathan J. Wright et al., “Woodland Modification in Bronze and Iron Age Central Anatolia: An Anthracological Signature for the Hittite State?” Journal of Archaeological Science 55 (2015): 219–230.
[23] Touraj Daryaee, Sasanian Persia: The Rise and Fall of an Empire. Rpt. ed. (New York: I. B. Tauris, 2013). See also Eberhard Sauer, ed., Sasanian Persia: Between Rome and the Steppes of Eurasia (Edinburgh: Edinburgh University Press, 2019).
[1] Herodotus, The Histories, trans. Robin Waterfield (Oxford: Oxford University Press, 1998), bk. 2, line 111, 136. [2] J. Donald Hughes, “Sustainable Agriculture in Ancient Egypt,” Agricultural History 66, no. 2 (1992): 13. [3] Barry Kemp, Ancient Egypt: The Anatomy of a Civilization, 3rd ed. (Abingdon, UK: Routledge, 2018),这是一部了解古埃及文明的出色指南。 [4] I. E. S. Edwards, The Pyramids of Egypt (Baltimore: Pelican, 1985), 12. [5] Mark Lehner, The Complete Pyramids (London: Thames & Hudson, 1997). See also Miroslav Verner, The Pyramids. Rev. ed. (Cairo: American University in Cairo Press, 2021). [6] 佩皮二世的在位时间存有争议,有可能短至64年;但按照法老的标准来看,这仍然是一段令人印象深刻的漫长统治时期。 [7] 在埃及学当中,气候变化在古王国的没落过程中所起的作用仍是一个具有争议的问题。有一篇论文对各种观点进行了有益的总结:Ellen Morris, “Ancient Egyptian Exceptionalism: Fragility,Flexibility and the Art of Not Collapsing,” in The Evolutionof Fragility: Setting the Terms, ed. Norman Yoffee (Cambridge,UK: McDonald Institute for Archaeological Research, 2019), 61–88。 [8] 人们认为《伊普味陈辞》(The Admonitions of Ipuwer)的创作时间可以追溯至中王国时期,这是一部不完整的文学作品,保存在大约公元前1250 年的一份纸莎草纸上,但其正文源自更早的时代。这是世人已知最早的一部政治伦理学专著。伊普味认为,贤明的法老应当约束其手下官吏,并且执行众神的意志。引自 Barbara Bell,“Climate and the History of Egypt: The Middle Kingdom,”American Journal of Archaeology 79 (1975): 261。 [9] Barbara Bell, “The Dark Ages in Ancient History, I: The
First Dark Age in Egypt,” American Journal of Archaeology
75 (1971): 9.
[10] 对印度河文明的概述之作:Andrew Robinson, The Indus: Lost
Civilizations (London: Reaktion, 2021)。亦请参见 Robin
Coningham and Ruth Young, From the Indus to Ashoka:
Archaeologies of South Asia (Cambridge: Cambridge University
Press, 2015)。
[11] Ashish Sinha et al, “Trends and Oscillations in the
Indian Summer Monsoon Rainfall over the Past Two Millennia,”
Nature Communications 6, no. 6309 (2015); Peter B. deMenocal,
“Cultural Responses to Climate Change During the Late
Holocene,” Science 292, no. 5517 (1976): 667–673. See also
Alena Giesche et al., “Indian Winter and Summer Monsoon
Strength over the 4.2 ka BP Event in Foraminifer Isotope
Records from the Indus River Delta in the Arabian Sea,”
Climate of the Past 15, no. 1 (2019): 73. doi: 10.5194/cp
15-73-2019.
[12] Gayatri Kathayat et al., “The Indian Monsoon
Variability and Civilization Changes in the Indian
[13] Mortimer Wheeler, The Indus Civilization, 3rd ed.
(Cambridge: Cambridge University Press, 1968), 44.
[14] 基本资料:Cameron A. Petrie, “Diversity, Variability,
Adaptation, and ‘Fragility’ in the Indus Civilization,”
in Yoffee, Evolution of Fragility, 109–134。
[15] C. A. Petrie and J. Bates, “ ‘Multi-cropping’, Intercropping and Adaptation to Variable Environments in Indus South Asia,” Journal of World Prehistory 30 (2017): 81–130,这是一篇全面论述印度河农业的论文。
[1] 由于我们两位作者都不是研究古罗马的专业人士,故本章在很大程度上参考了凯尔·哈珀(Kyle Harper)一部经过了严密论证的综合性著作:《罗马的命运:气候、疾病和帝国的终结》(The Fate of Rome: Climate, Disease, and the End of an Empire, Princeton, NJ: Princeton University Press, 2017)。哈珀汇集了广博的资料,讨论了气候变化与流行病在帝国漫长的崩溃过程中的核心作用。这是一部非凡的作品,有时会引发争论,有时又引人深思,可以引领读者巧妙掌握这一主题的纷繁难懂之处。当然,在这里进行简要总结的时候,我们忽略了其中的许多争议与意见不一的地方。哈珀的作品当中,还含有一份全面的参考书目。亦请参见Rebecca Storey and Glenn R. Storey, Rome and the Classic Maya (Abingdon, UK: Routledge, 2017)。
[2] 对于古罗马气候的概述,请参见Kyle Harper and M. McCormick, “Reconstructing the Roman Climate,” in The Science of Roman History, ed. W. Scheidel (Princeton, NJ: Princeton University Press, in preparation)。还有一份重要的综合性资料:Michael McCormick et al., “Climate Change During and After the Roman Empire: Reconstructing the Past from Scientific and Historical Evidence,” Journal of Interdisciplinary History 43, no. 2 (2012): 169–220。关于“奥克莫克二号”火山喷发的资料:Joseph R. McConnell et al., “Extreme Climate After Massive Eruption of Alaska’ s Okmok Volcano in 43 BCE and Effects on the Late Roman Republic and Ptolomaic Kingdom,”Proceedings of the National Academy of Sciences 117, no. 27(July 7, 2020): 15443–15449. doi: 10.1073/pnas.2002722117。 [3] 老普林尼(Pliny the Elder,23—79),古罗马时期一位百科全书式的作家兼博物学家,代表作是《自然史》(Natural History )。其拉丁语全名为盖乌斯·普林尼·塞孔都斯(Gaius Plinius Secundus),因其养子也叫普林尼,故冠以“老”“小”来加以区别。——译者注
[7] 关于西格韦尔斯(Sigwells):Richard Tabor, Cadbury Castle: The Hillfort and Landscapes (Stroud, UK: History Press, 2008), 130–142。关于卡茨戈尔(Catsgore): R. Leech, Excavations at Catsgore, 1970–1973 (Bristol, UK: Western Archaeological Trust, 1982)。
[8] Harper, Fate of Rome, 57.
[9] Harper, Fate of Rome, 57–58.
[10] 1 斗相当于1配克(peck),或者约合9升的干量货物。
[11] 这几段以哈珀的《罗马的命运》第92页至98页论述为基础。对于印度洋上的海运与贸易进行的总结,参见Brian Fagan, Beyond the Blue Horizon: How the Earliest Mariners Unlocked the Secrets of the Oceans (New York: Bloomsbury Press, 2012), chaps. 7 to 9。
[12] Hui-Yuan Yeh et al., “Early Evidence for Travel with
Infectious Diseases Along the Silk Road: Intestinal Parasites
from 2000-Year-Old Personal Hygiene Sticks in a Latrine at
[13] William H. McNeill, Plagues and Peoples (New York: Doubleday, 1976), and Harper, Fate of Rome, chap. 3,都论及了“安东尼瘟疫”。
[14] 西普里安(约200—258)虽有柏柏尔人的血统,但后来成了迦太基主教,他同时也是一位著名的早期基督教作家。他描述的那场瘟疫,后来就以他的名字命名。引自Harper, Fate of Rome, 130。
[15] 整体概述请参见 Lucy Grig and Gavin Kelly, eds., Two Romes: Rome and Con-stantinople in Late Antiquity (Oxford: Oxford University Press, 2012)。
[16] Harper, Fate of Rome, 185. [17] M. Finné et al., “Climate in the Eastern Mediterranean, and Adjacent Regions During the Past 6000 Years — a Review,”Journal of Archaeological Science 38 (2011): 3153–3173.
[18] E. Cook, “Megadroughts, ENSO, and the Invasion of Late Roman Europe by the Huns and Avars,” in The Ancient Mediterranean Environment Between Science and History, ed. William Harris (Leiden: Brill, 2013), 89–102. See also Q Bin Zhang et al., “A 2,326-Year Tree-ring Record of Climate Variability on the Northeastern Qinghai-Tibetan Plateau,”Geophysical Research Letters 30, no. 14 (2003). doi: 10.1029/2003GL017425.
[19] 引自Harper, Fate of Rome, 192。阿米亚努斯·马凯林努斯(Ammianus Marcellinus,约 330—约395)既是一名战士,也是古罗马最后一位了不起的历史学家。他的主要作品是《大事编年史》(Res gestae),这是一部从塔西佗结束之处写起的31卷本历史巨著,前13卷现已佚失。
[20] Described by Harper, Fate of Rome, 199–200.
[21] 在概述“查士丁尼瘟疫”时,我们主要参考了哈珀的《罗马的命运》第6章。然而,关于这场瘟疫的地方性影响和随之而来的死亡率,以及鼠疫杆菌的历史,我们还需要了解更多的信息。亦请参见William Rosen, Justinian’ s Flea (New York: Penguin Books, 2008)。
[23] 以弗所的约翰(约507—588)曾是叙利亚正教会的领袖兼历史学家。他的《教会史》(Ecclesiastical History)中的第三部分论及了“查士丁尼瘟疫”,其中的内容都是他目睹的第一手资料。他认为那是神之震怒的征兆。引自Harper, Fate of Rome, 227。
[24] Stuart J. Borsch, “Environment and Population: The Collapse of Large Irrigation Systems Reconsidered,” Comparative Studies in Society and History 46, no. 3 (2004):451–468,以及该作者的其他论文。
[26] 爱德华·吉本(1737—1794)是一位历史学家兼下院议员,著有不朽之作《罗马帝国衰亡史》。此书出版于1776年至1788年间,总计6卷。Edward Gibbon and David P. Womersley, History of the Decline and Fall of the Roman Empire, 3 vols. (London: Penguin Press, 1994).
II and Jeremy A. Sabloff, “Classic Period Collapse of the
Central Maya Lowlands: Insights About Human-Environment
Relationships for Sustainability,” Proceedings of the
National Academy of Sciences 109, no. 35 (2012): 13908-13914。
[4] 对古典玛雅文明进行通俗论述的经典作品:Michael Coe and
Stephen Houston, The Maya, 9th ed. (London and New York:
Thames & Hudson, 2015)。Linda Schele and David Freidel’ s A
Forest of Kings (New York, William Morrow, 1990),生动而通俗地描绘了玛雅的王权情况,只是如今有点过时了。
[5] Richard R. Wilk, “Dry-Season Agriculture Among the Kekchi Maya and Its Implications for Prehistory,” in Prehistoric Lowland Maya Environment and Subsistence Economy, ed. Mary Pohl (Cambridge, MA: Peabody Museum of Archaeology and Ethnology, Harvard University, 1985), 47–57. See also Richard R. Wilk, Household Ecology: Economic Change and Domestic Life Among the Kekchi Maya of Belize. Arizona Studies in Human Ecology (Tucson: University of Arizona Press, 1991).
[6] B. L. Turner II, “The Rise and Fall of Maya Population and Agriculture: The Malthusian Perspective Reconsidered,” in Hunger and History: Food Shortages, Poverty, and Deprivation, ed. L. Newman (Cambridge: Cambridge University Press, 1990), 178–211.
[7] Robert J. Oglesby et al., “Collapse of the Maya: Could Deforestation Have Contributed?” Papers in the Earth and Atmospheric Sciences 469 http://digitalcommons.unl.edu/geosciencefacpub/469. (2010).
[8] 论述古典玛雅文明崩溃的文献非常多。一般性的概述之作,请参见 T. Patrick Culbert, ed., The Classic Maya Collapse (Albuquerque: University of New Mexico Press, 1973),但如今此作有点过时了;另外可见D. Webster, The Fall of the Ancient Maya (London and New York: Thames & Hudson, 2002)。在此,我们很大程度上参考了一部有用的分析之作:Turner and Sabloff,“Classic Period Collapse of the Central Maya Lowlands”。
[9] David Hodell, M. Brenner, and J. H. Curtis, “Terminal Classic Drought in the Northern Maya Lowlands Inferred from Multiple Sediment Cores in Lake Chichancanab (Mexico),”Quaternary Science Reviews 24 (2005): 1413–1427.
[10] Douglas Kennett and David A. Hodell, “AD 750–100
Climate Change and Critical Transitions in Classic Maya
Sociopolitical Networks,” in Megadrought and Collapse: From
Early Agriculture to Angkor, ed. Harvey Weiss (New York:
Oxford University Press, 2017), 204–230. See also Douglas
Kennett et al., “Development and Disintegration of Maya
Political Systems in Response to Climate Change,” Science
338 (2012): 788–791.
[11] Copán: William L. Fash and Ricardo Agurcia Fasquelle,
“Contributions and Controversies in the Archaeology and
History of Copán,” in Copán: The History of an Ancient
Maya Kingdom, ed. E. Wyllys Andrews and William L. Fash
(Santa Fe, NM: School of American Research Press, 2005), 3
32. See also William L. Fash, E. Wyllys Andrews, and T. Kam
and the Early Postclassic in the Urban Center of Copán,
Honduras,” in The Terminal Classic in the Maya Lowlands:
Collapse, Transition, and Transformation, ed. Arthur A.
Demarest, Prudence M. Rice, and Don S. Rice (Boulder:
University Press of Colorado, 2005), 260–287.
[12] Arthur Demarest, Ancient Maya: Rise and Fall of a Rainforest Civilization (Cambridge: Cambridge University Press, 2004).
[13] Jeremy A. Sabloff, “It Depends on How You Look at Things: New Perspectives on the Postclassic Period in the Northern Maya Lowlands,” Proceedings of the American Philosophical Society 109 (2007): 11–25. See also Marilyn A. Masson, “Maya Collapse Cycles,” Proceedings of the National Academy of Sciences 109, no. 45 (2012): 18237-18238.
[14] Marilyn A. Masson and Carlos Peraza Lope, Kukulkan’ s Realm: Urban Life at Mayapan (Boulder: University of Colorado Press, 2014), 5.
那些武士祭司都很清楚,强大的厄尔尼诺现象会带来什么样的影响。他们的应对之法,就是派百姓重修灌溉系统,并且以人献祭。在考察研究莫切河谷中“月亮金字塔”(Huaca de la Luna)旁边一座隐蔽的广场时,考古学家史蒂夫·博格特(Steve Bourget)发现了一些描绘着海鸟与海洋生物、令人眼花缭乱的壁画,它们都与近海温暖的“恩索”洋流有关;可在这次轰动一时的艺术发掘当中,他还找到了大约70位被杀害武士的遗骸。他认为,在面对灾难时,莫切统治者曾经用活人献祭和复杂的仪式,来巩固他们的权威。接着,又一次强大的厄尔尼诺现象袭击了这个河谷。由河流冲积物形成的巨大沙丘被冲上海滩,掩埋了数百公顷的农田,淹没了莫切王国的都城。于是,莫切河谷里的君主和同一时期生活在兰巴耶克河谷中的人,都迁往了上游地区。
[1] L. G. Thompson et al., “A 1500-Year Record of Climate Variability Recorded in Ice Cores from the Tropical Quelccaya Ice Cap,” Science 229 (1985): 971–973.
[2] Michael Moseley, The Inca and Their Ancestors, 2nd ed.(London and New York: Thames & Hudson, 2001),这是一部旁征博引的综合性作品。
[3] Ruth Shady and Christopher Kleihege, Caral: First Civilization in the Americas. Bilingual ed. (Chicago: CK Photo, 2010).
[4] 关于莫切人:除了Moseley, The Inca and Their Ancestors,
请参见Jeffrey Quilter, The Ancient Central Andes (Abingdon,
UK: Routledge, 2013)。
[5] Walter Alva and Christopher Donnan, Royal Tombs of Sipán
(Los Angeles: Fowler Museum of Cultural History, 1989). 更
新之作:Nadia Durrani, “Gold Fever: The Tombs of the Lords
of Sipan,” Current World Archaeology 35 (2009): 18–30。
[6] L. G. Thompson et al., “Annually Resolved Ice Core
Records of Tropical Climate Variability over the Past 1800
Years,” Science 229 (2013): 945–950.
[7] Brian Fagan, Floods, Famines, and Emperors: El Ni.o and
the Fate of Civilizations. Rev. ed. (New York: Basic Books,
2009), chap. 7,其中为普通读者进行了描述。
[8] Michael Moseley and Kent C. Day, eds., Chan Chan: Andean Desert City (Albuquerque: University of New Mexico Press, 1982).
[9] Brian Fagan, The Great Warming (New York: BloomsburyPress, 2008), chap. 9,其中进行了大致的描述。 [10] Charles R. Ortloff, “Canal Builders of Pre-Inca Peru,” Scientific American 359, no. 6 (1988): 100–107.
[11] Tom D. Dillehay and Alan L. Kolata, “Long-Term Human Response to Uncertain Environmental Conditions in the Andes,” Proceedings of the National Academy of Sciences 101, no. 2:4325–4330.
[12] Alan L. Kolata, The Tiwanaku: Portrait of an Andean
[14] Charles Stanish et al., “Tiwanaku Trade Patterns in Southern Peru,” Journal of Anthropological Archaeology 29(2010): 524–532.
[15] 这一节在很大程度上参考了Lonnie G. Thompson and Alan L. Kolata, “Twelfth Century A.D.: Climate, Environment, and the Tiwanaku State,” in Megadrought and Collapse: From Early Agriculture to Angkor, ed. Harvey Weiss (New York: Oxford University Press, 2017), 231–246。
[16] R. A. Covey, “Multiregional Perspectives on the Archaeology of the Andes During the Late Intermediate Period (c. A.D. 1000–1400),” Journal of Archaeological Research 16 (2008): 287–338.
[17] E. Arkush, Hillforts of the Ancient Andes: Colla Warfare,
Society, and Landscape (Gainesville: University Press of
Florida, 2011). See also E. Arkush and T. Tung, “Patterns
of War in the Andes from the Archaic to the Late Horizon:
Insights from Settlement Patterns and Cranial Trauma,”
Journal of Archaeological Research 219, no. 4 (2013): 307-369; Alan L. Kolata, C. Stanish, and O. Rivera, eds., The Technology and Organization of Agricultural Production in the Tiwanaku State (Pittsburgh, PA: Pittsburgh Foundation, 1987).
[18] Clark L. Erickson, “Applications of Prehistoric Andean Technology: Experiments in Raised Field Agriculture, Huatta, Lake Titicaca, 1981–2,” in Prehistoric Intensive Agriculture in the Tropics, ed. I. S. Farrington. International Series 232 (Oxford: British Archaeological Reports, 1985), 209–232. 还有一篇论述这个地区传统农业的宝贵论文:Clark Erickson, “Neo-environmental Determinism and Agrarian ‘Collapse’ in Andean Prehistory,” Antiquity 73(1999): 634–642。
[1] Brian Fagan, Before California: An Archaeologist Looks
at Our Earliest Inhabitants (Lanham, MD: Rowman & Littlefield,
2003); Jeanne Arnold and Michael Walsh, California’ s
Ancient Past: From the Pacific to the Range of Light
(Washington, DC: Society for American Archaeology, 2011).
[2] Lynn H. Gamble, First Coastal Californians (Santa Fe, NM:
School for Advanced Research, 2015),这是一部供普通读者阅读
的佳作。
[3] Douglas J. Kennett and James P. Kennett, “Competitive and Cooperative Responses to Climatic Instability in Coastal Southern California,” American Antiquity 65 (2000): 379 395. See also Douglas J. Kennett, The Island Chumash: Behavioral Ecology of a Maritime Society (Berkeley: University of California Press, 2005).
[4] Lynn H. Gamble, The Chumash World at European Contact(Berkeley: University of California Press, 2011).
[5] Frances Joan Mathien, Culture and Ecology of Chaco Canyon and the San Juan Basin (Santa Fe, NM: National Park Service, 2005). See also Gwinn Vivian, Chacoan Prehistory of the San Juan Basin (New York: Academic Press, 1990).
[6] 描述查科供普通读者阅读的作品:Brian Fagan, Chaco Canyon: Archaeologists Explore the Lives of an Ancient Society (New York: Oxford University Press, 2005)。关于该峡谷的近期研究成果的论文:Jeffrey J. Clark and Barbara J. Mills, eds., “Chacoan Archaeology at the 21st Century,” Archaeology Southwest 32, nos. 2–3 (2018)。
[7] Jill E. Neitzel, Pueblo Bonito: Center of the Chacoan World (Washington, DC: Smithsonian Books, 2003). See also Timothy R. Pauketat, “Fragile Cahokian and Chacoan Orders and Infrastructures,” in The Evolution of Fragility: Setting the Terms, ed. Norman Yoffee (Cambridge, UK: McDonald Institute for Archaeological Research, 2019), 89–108. [8] Vernon Scarborough et al., “Water Uncertainty, Ritual Predictability and Agricultural Canals at Chaco Canyon, New Mexico,” Antiquity 92, no. 364 (August 2018): 870–889.
[9] Douglas L. Kennett et al., “Archaeogenomic Evidence Reveals Prehistoric Patrilineal Dynasty,” Nature Communications 8, no. 14115 (2017). doi: 10.1038/ncomms14115.
[10] 这一节参考的文献:David W. Stahle et al., “Thirteenth Century A.D.: Implications of Seasonal and Annual Moisture Reconstructions for Mesa Verde, Colorado,” in Weiss, Megadrought and Collapse, 246–274。亦请参见Mark Varien et al., “Historical Ecology in the Mesa Verde Region: Results from the Village Ecodynamics Project,” American Antiquity 72 (2007): 273–299。
[11] 关于卡霍基亚的文献资料极多。参见 Timothy R. Pauketat,
Cahokia: Ancient America’s Great City on the Mississippi
(New York: Viking Penguin, 2009),以及同一作者的 Ancient
Cahokia and the Mississippians (Cambridge: Cambridge
University Press, 2004)。亦请参见 Timothy R. Pauketat and Susan Alt, eds., Medieval Mississippians: The Cahokian World (Santa Fe, NM: School of Advanced Research, 2015);Pauketat, “Fragile Cahokian and Chacoan Orders and Infrastructures,”89–108。
[12] A. J. White et al., “Fecal Stanols Show Simultaneous
Flooding and Seasonal Precipitation Change Correlate with
Cahokia’s Population Decline,” Proceedings of the National
Academy of Sciences 116, no. 12 (2019): 5461–5466.
[13] Samuel E. Munoz et al., “Cahokia’s Emergence and
Decline Coincided with Shifts of Flood Frequency on the
Mississippi River,” Proceedings of the National Academy of
Sciences 112, no. 20 (2015): 6319–6327. See also Timothy R.
Pauketat, “When the Rains Stopped: Evapotranspiration and
Ontology at Ancient Cahokia,” Journal of Anthropological
Research 76, no. 4 (2020): 410–438.
[14] 汗屋(sweat house),美洲印第安人用于与祖先进行精神沟通、
净化身心和洗涤灵魂的地方,其大小不等,多用柳条编制,呈圆形或
者椭圆形,上面用水牛皮或者其他兽皮覆盖,从而围成一个黑暗、密
封的屋子。举行汗屋仪式时,人们会在屋里击鼓、唱歌、祈祷,并按
顺时针方向轮流为自己和家人祈福。——译者注
[15] A. J. White et al., “After Cahokia: Indigenous Repopulation and Depopulation of the Horseshoe Lake Watershed AD 1400–1900,” American Antiquity 85, no. 2 (April 2020): 263–278.
[1] 要想了解高棉文明的概况,请参见 Charles Higham, TheCivilization of Angkor (London: Cassel, 2002),或者 Michael D. Coe, Angkor and the Khmer Civilization (London and New York: Thames & Hudson, 2005)。亦请参见Roland Fletcher et al., “Angkor Wat: An Introduction,” Antiquity 89, no. 348 (2015):1388–1401。 [2] 对最新研究的通俗论述,请参见Brian Fagan and Nadia Durrani, “The Secrets of Angkor Wat,” Current World Archaeology 7, no. 5 (2016):14–21。
“Uncovering Archaeological Landscapes at Angkor Using
Lidar,” Proceedings of the National Academy of Sciences 110
(2013): 12595–12600。
[5] 东巴莱湖与西巴莱湖(East and West Barays),亦译“东大人工湖”与“西大人工湖”,或者“东池”与“西池”。——译者注
[6] Roland Fletcher et al., “The Water Management Network of Angkor, Cambodia,” Antiquity 82 (2008): 658–670.
[7] 本章的其余部分主要参考的文献是:Roland Fletcher et al., “Fourteenth to Sixteenth Centuries AD: The Case of Angkor and Monsoon Extremes in Mainland Southeast Asia,” in Megadrought and Collapse: From Early Agriculture to Angkor, ed. Harvey Weiss (New York: Oxford University Press, 2017), 275–313;此处引自其中的第279页。
[8] P. D. Clift and R. A. Plumb, The Asian Monsoon: Causes,
History, and Effects (Cambridge: Cambridge University Press,
2008).
[9] 对这种复杂的恶化过程的概述,见于Fletcher, “Fourteenth
to Sixteenth Centuries AD,” 292–304。
[10] B. M. Buckley et al., “Climate as a Contributing Factor
in the Demise of Angkor, Cambodia,” Proceedings of the
National Academy of Sciences 107 (2010): 6748–6752. See also
B. M. Buckley et al., “Central Vietnam Climate over the Past
Five Centuries from Cypress Tree Rings,” Climate Dynamics
Heidelberg 48, nos. 11–12 (2017): 3707–3708.
[11] 关于丹达克洞穴(Dandak Cave):A. Sinha et al., “A Global
Context for Mega-droughts in Monsoon Asia During the Past
商船水手们在印度洋水域航行,从阿拉伯半岛和美索不达米亚地区一路来到印度,至少已有5,000年的历史了。他们习得了在季风中航行的本领,因而能够掌控海上的贸易路线。几个世纪以来,他们都严守着关于印度洋季风的知识,只是父子相传。到了公元前118年至前116年左右,一名遭遇海难的水手从红海抵达了亚历山大港,在协助一位名叫“库齐库斯的欧多克索斯”(Eudoxus of Cyzicus)的希腊人两度前往印度之后,这些知识才传到了更广阔的外界。不久之后,另一位希腊兼亚历山大港的船长希帕卢斯(Hippalus)想出了一个比沿着海岸航行要快得多的办法,那就是利用8月份猛烈的西南季风,开辟一条能在12个月内返回的从红海近海的索科特拉岛直达印度的海上航线。远洋航行中的这一重大突破,将使人们接触到非洲几十个地处内陆且远离印度洋的社会。如此一来,全球天气模式就对数以百万计的非洲自给农民以及努力统治着他们的部落酋长产生了影响。
到了公元前1千纪末期,形势出现了一些变化。商人们开始更加频繁地出入红海,尽管我们从斯特拉波和阿伽撒尔基德斯(Agartharchides)这些古典作家那里了解到,这仍然是一段艰难的航程,因为一路上既有遍布暗礁的水域,还有汹涌的巨浪,且没有锚泊之地。阿伽撒尔基德斯在公元前2 世纪记述这些情况时,偶尔会发挥一点儿想象力,称有条河流流经那片土地,带来了大量的金沙,而继续往南的一座座金矿,则出产天然金块。我们认为,当时这条航线仍是一个秘密。一个世纪过后,知道这条航线的人就多得多了,连那些原本可以依靠广泛采用的航向去航行的外来者也知道了。公元1世纪的《红海环航》(Periplus of the Erythraean Sea )一书最为著名。此书的佚名作者可能是一位熟悉这个地区的航海者,用朴实无华的希腊文描述了进一步往南的非洲沿海的情况;当时,那里称为阿扎尼亚,一直延伸到了遥远的南方。[5]
[1] Mike Davis, Late Victorian Holocausts: El Ni.o Famines and the Making of the Third World (Brooklyn, NY: Verso Books, 2001), 201.
[2] Davis, Late Victorian Holocausts, 201.
[3] Brian Fagan, Floods, Famines, and Emperors: El Ni.o and the Fate of Civilizations. Rev. ed. (New York: Basic Books, 2009), 16. 阿布·扎伊德·艾尔赛拉菲(Abu Zayd al-Sirafi)是一名航海者。公元916年前后,他撰写了Accounts of China and India, trans. Tim Macintosh-Smith (New York: New York University Press, 2017)。
[4] Matthew Fontaine Maury, Explanations and Sailing
Directions to Accompany the Wind and Current Charts (New York:
Andesite Press, 2015),初版于1854年。
[5] Lionel Casson, The Periplus Maris Erythraei: Text with
Introduction, Translation, and Commentary (Princeton, NJ:
Princeton University Press, 1989). 关于古代红海航线的更多内
容,请参见Nadia Durrani, The Tihamah Coastal Plain of South
West Arabia in Its Regional Context c.6000 BC–AD 600. BAR
International Series (Oxford: Archaeopress, 2005)。
[6] 文献资料浩如烟海,并且在迅速增加。优秀的概述,请参见
Timothy Insoll, The Archaeology of Islam in Sub-Saharan
Africa (Cambridge: Cambridge University Press, 2003), 172
177。
[7] Roger Summers, Ancient Mining in Rhodesia and Adjacent
Areas (Salisbury: National Museums of Rhodesia, 1969), 218.
[8] David W. Phillipson, African Archaeology, 3rd ed.
(Cambridge: Cambridge University Press, 2010).
[9] T. N. Huffman, “Archaeological Evidence for Climatic Change During the Last 2000 Years in Southern Africa,” Quaternary International 33 (1996): 55–60.
[10] 后续各段主要参考的是P. D. Tyson et al., “The Little
Ice Age and Medieval Warming in South Africa,” South African
Journal of Science 96, no. 3 (2000): 121–125。
[11] Peter Robertshaw, “Fragile States in Sub-Saharan
Africa,” in The Evolution of Fragility: Setting the Terms,
ed. Norman Yoffee (Cambridge, UK: McDonald Institute for
Archaeological Research, 2019), 135–160,对本节涉及的问题进
行了讨论。亦请参见 Matthew Hannaford and David J. Nash,
“Climate, History, Society over the Last Millennium in
[12] Graham Connah, African Civilizations, 3rd ed. (Cambridge: Cambridge University Press, 2015),这是一部权威的概述之作。T. N. Huffman, “Mapungubwe and the Origins of the Zimbabwe Culture,” South African Archaeological Society Goodwin Series 8 (2000): 14–29,从这篇文章开始了解相关问题会很有帮助;Robertshaw, “Fragile States in Sub-Saharan Africa”和Tyson et al., “The Little Ice Age and Medieval Warming in South Africa”两篇论文则提供了最新的信息。
[13] Peter S. Garlake, Great Zimbabwe (London: Thames & Hudson, 1973),此书尽管有点过时,但仍属基础文献。Robertshaw, “Fragile States in Sub-Saharan Africa”一文参考了许多最近的研究。
[14] 相关讨论见 Tyson et al., “The Little Ice Age and Medieval Warming in South Africa”。
火山爆发能够对气候产生重大影响。大规模的爆发,有可能令大量的火山气体、火山灰和其他物质喷射到大气的平流层中。像二氧化硫之类的火山气体,可以导致全球气温下降。二氧化硫变成硫酸之后,硫酸会在平流层里迅速凝集,形成硫酸盐气溶胶。这些东西会提高大气对太阳辐射的反射量,将阳光反射回太空,从而导致地球的低层大气降温。1991年6月菲律宾的皮纳图博火山大爆发,曾令大约2,000万吨二氧化硫喷向高度达32千米的大气中。这一事件,使得地表温度的最大下降幅度超过了 1℃。过去一些规模更大的火山爆发,比如 19 世纪时的坦博拉火山爆发和喀拉喀托火山爆发[3] ,曾经让气温的下降持续数年之久。虽然没人会说公元1 千纪末期似乎频繁出现的火山爆发事件摧毁了一个又一个王国,但它们对这两个世纪的气候造成了强大的冲击,既影响了作物收成,也对动物和人类产生了影响。在那段艰难岁月里,人口下降现象严重,粮食供应方面也出现了经济倒退。从更广阔的历史范围来看,经历了快速气候变化的法兰克国王查理曼(742—814)相对来说还算幸运,因为他的臣民挺过了公元763年至764年那个可怕的冬季,以及公元792年至793年间的饥荒。然而,他的儿子“虔诚者”路易(Louis the Pious,778—840)却忧心忡忡,固执地相信公元821年至822年间那个同样可怕的冬天与上帝的震怒之间存在一种似是而非的联系,故他还在公元822年8月,为自己和父亲的罪孽进行了公开忏悔。可就算是忏悔,也无济于事,因为一年之后又是一个严冬,他的帝国陷入了酷寒之中。
“中世纪气候异常期”(约公元950年至1200 年)
就在4个多世纪之后的公元1244年,方济各会修士“英国人”巴塞洛缪(Bartholomew the Englishman)宣称,欧洲占据了已知世界的三分之一,从“北大洋”一直延伸到了西班牙南部。[4] 当时的学者,都在凝望着一片广袤的陆地。东边的尽头,是似乎无边无际的欧洲平原,并在遥远的天际融入了亚洲大草原。那里人口稀少,主要是经常四处奔波的游牧民族,他们受到没有规律的干旱周期与更加充沛的降雨所驱使,不断地迁徙。那里的半干旱草原宛如一个个吞吐呼吸着的巨肺,雨水降临时引来动物与人类,而到了干旱时节,又将其赶往周边水源条件较好的地方。所以,中世纪的欧洲人以为他们被一个危险的人类—自然世界包围着,并不让人感到奇怪。东面有伊斯兰教步步进逼,西面的大西洋则形成了一道屏障。来自东方平原上的游牧部落,则在欧亚大陆的边缘徘徊。
[13] 参考的是Hubert Lamb, Climate, History and the Modern
World (London: Methuen, 1982), 169–170。
[14] William Chester Jordan, The Great Famine (Princeton, NJ:
Princeton University Press, 1996),对那场饥荒进行了最权威的
描述,我们在这里也主要参考了这部作品。亦请参见William Rosen,
The Third Horseman: Climate Change and the Great Famine of
the 14th Century (New York: Viking, 2014)。
[15] 本段引文来源:Abbott of St. Vincent: Martin Bouquet et al., eds., Recueil des historiens des Gaules et de la France, 21:197。From Jordan, The Great Famine, 18.
[16] 本段参考了Rosen, The Third Horseman, 149–151。
[17] Wendy R. Childs, ed. and trans., Vita Edwardi Secundi:
The Life of Edward II (New York: Oxford University Press,
2005), 111.
[18] C. A. Spinage, Cattle Plague: A History (New York: Springer, 2003).
最早记载从北部诸地前往波多黎各的西班牙殖民地的情况的资料中,提到过一个叫作“比米尼”(Bimini)的岛屿。1513 年,西班牙探险家胡安·庞塞·德莱昂(Juan Ponce de León)沿着比米尼岛海岸航行,将这个神秘之地改名为“佛罗里达”。两度探险失败后,此人便放弃了野心勃勃的殖民计划,抱怨那里的气候不好,那里的人则“十分野蛮和好战”。在接下来的50年里,还有人往返于此地,全都大失所望。“佛罗里达”不是什么“新安达卢西亚”,不会给他们的祖国提供地中海各地可以找到的橄榄油和其他商品。大部分雨水都是在夏季的那几个月里降下,使得冬季作物很少,甚至根本就没有发芽所需的水分。那里也没有旱季来让作物成熟。年复一年,西班牙殖民者种植的庄稼全都烂在了地里。佛罗里达还深受猛烈的飓风和冬季极其寒冷的北风所害。大大小小的探险队曾经向西远行,到达了密西西比河与如今的得克萨斯州;其中的一次远征,是1538年至1543年间埃尔南多·德索托(Hernando de Soto)发动的损失惨重的入侵,这次远征因他们的苦难经历和暴行而令人瞩目。西班牙之所以殖民失败,部分原因就在于远征者无能且领导无方,同时也在于殖民者怀有不切实际的野心。这些远征,并不是王室经过了精心计划且持续提供资金支持的行动。一切都依赖于个人的开拓精神,可这又要靠西班牙贵族的财富来支持。王室国库负担不起实施这种计划所需的费用。
尽管有罗阿诺克岛之祸,可北美洲以及那里的原住民,还是深深地吸引着英国国内的民众。激情洋溢的支持者计划开拓新的殖民地,其中就有持乐观态度的理查德·哈克卢特(Richard Hakluyt);此人是一位大臣兼业余地理学家,他确信英国拥有巨大的潜力,能够掌控海外勘探和贸易。[14] 他曾经热情地吹嘘说,北美洲拥有丰富的黄金、白银、珍珠和充足的热带食物,其实这种说法并不正确。西班牙帝国在美洲进行扩张的流言,时断时续地传到了欧洲,因为西班牙人认为他们的发现属于国家机密,只有少数精英人士才能知晓。英国没人看过16世纪70年代至80年代编纂而成的《印第亚斯之地理关系》(Relaciones geográficas de Indias )一作,而此作也从未得到过广泛传播。这份具有里程碑意义的报告详细描述了当地的天气状况。对于任何一个打算到加勒比地区、佛罗里达以北和更往北的海岸进行航海探险的人而言,这种信息都属于无价之宝。除了地理方面的错误,哈克卢特还重申了一种错误的观点,即从卡罗来纳到缅因地区的整个东海岸都是地中海气候。他在作品中称,那里气候温和、土地肥沃、气温较高,是一个农民可以种植橄榄、葡萄、柑橘和其他各种作物的地方;这些作物,原本都是英国耗费巨资从地中海地区进口的。这片土地上,“气候、土壤皆似意大利、西班牙,以及吾等获取葡萄酒与油料之群岛”。[15]
这种前景确实诱人,也构成了弗吉尼亚公司在 1606 年派遣 3 艘船只前往美国东海岸时制定的《建议性指示》(Instructions by Way of Advice)的核心内容。当时的组织者,几乎没有从过去其他地方的错误中吸取经验教训。他们想当然地以为,尽管16世纪末的气候日益寒冷,但他们的目的地的气候会跟祖国的气候差不多。
[1] “红发”埃里克(Eirik the Red,950—1003),挪威维京时期的探险家兼海盗埃里克·瑟瓦尔德森(Erik Thorvaldsson), “红发”是其外号。——译者注
[2] 对于古代北欧人在格陵兰岛定居以及随后越过大洋前往北美洲
的航海活动,人们已经进行了深入的研究,其中包括丹麦考古学家在
格陵兰岛进行的出色发掘工作。参见Kristen A. Seaver, The Frozen
Echo: Greenland and the Exploration of North America, ca.
A.D. 1000–1500 (Stanford, CA: Stanford University Press,
1996)。至于兰塞奥兹牧草地,参见Helga Ingstad, ed., The Norse
Discovery of America (Oslo: Norwegian University Press, 1985)。
人们一直在质疑,兰塞奥兹牧草地究竟是不是埃里克过冬的地方。这
一争议尚未解决。
[3] Nicolás Young et al., “Glacier Maxima in Baffin Bay During the Medieval Warm Period Coeval with Norse Settlement,” Science Advances 10.1126/sciadv.1500806. 1, no. 11 (2015). doi:
[4] Brian Fagan, Fish on Fridays: Feasting, Fasting, and the
Discovery of the New World (New York: Basic Books, 2006),其中进行了综合论述。
[5] Sam W. White, A Cold Welcome: The Little Ice Age and Europe’s Encounter with North America (Cambridge, MA: Harvard University Press, 2017),此书是关于这一主题的权威资
料。在撰写本章余下的内容时,我们在很大程度上也参考了此书。
[6] White, A Cold Welcome, 9–19,怀特在书中此部分论述了气
候。亦请参见Karen Kupperman, “The Puzzle of the American
Climate in the Early Colonial Period,” American Historical
Review 87 (1982): 1262–1289。
[7] Anne Lawrence-Mathers, Medieval Meteorology: Forecasting
the Weather from Aristotle to the Almanac (Cambridge:
[20] Karen Kupperman, “Apathy and Death in Early Jamestown,”
Journal of American History 66 (1979): 24–40.
[21] Helen C. Rountree, The Powhatan Indians of Virginia:
Their Traditional Culture (Norman: University of Oklahoma
Press, 1989),这本书是一份重要的参考资料。
[22] 这个方面的文献资料正在快速增加。其中的概述之作,请参见
Martin Gallivan, “The Archaeology of Native Societies in
the Chesapeake: New Investigations and Interpretations,”
Journal of Archaeological Research 19 (2011): 281–325。
[23] Helen C. Rountree, Pocahontas, Powhatan, Opechancanough: Three Indian Lives Changed by Jamestown (Charlottesville: University of Virginia Press, 2005), 64.
[24] William M. Kelso, Jamestown: The Truth Revealed
(Charlottesville: University of Virginia Press, 2018).
[25] 努纳勒克因近期的考古发掘才为世人所知:Paul M. Ledger et
al., “Dating and Digging Stratified Archaeology in
Circumpolar North America: A View from Nunalleq, Southwestern
Alaska,” Arctic 69, no. 4 (2019): 278–390。亦请参见
Charlotta Hillerdal, Rick Knecht, and Warren Jones,
“Nunalleq: Archaeology, Climate Change, and Community
Engagement in a Yup’ik Village,” Arctic Anthropology 56
(2019): 18–38。
[26] Gideon Mailer and Nicola Hale, Decolonizing the Diet:
Nutrition, Immunity, and the Warning from Early America (New
York: Anthem Press, 2018),它是对这一新兴研究领域进行概述的
一部有益之作。
[27] A. Park Williams et al., “Large Contribution from
Anthropogenic Warming to an Emerging North American
[4] Hubert Lamb and Knud Frydendahl, Historic Storms of the
North Sea, British Isles, and Northwestern Europe (Cambridge:
Cambridge University Press, 1991),这是一项出色的研究,说明了“大曼德雷克”和其他风暴背后的气象状态。引自第93页。
[5] Ole J. Benedictow, The Black Death, 1346–1353: The Complete History (Woodbridge, UK: Boydell & Brewer, 2006).
[6] M. Harbeck et al., “Distinct Clones of Yersinia pestis
Caused the Black Death,” PLOS Pathology 9, no. 5 (2013):
c1003349.
[7] Boris V. Schmid et al., “Climate-Driven Introduction of
the Black Death and Successive Plague Reintroductions into
Europe,” Proceedings of the National Academy of Sciences
112, no. 10 (2015): 3020–3025.
[8] Fran.ois Matthes, “Report of Committee on Glaciers,” Transactions of the American Geophysical Union 20 (1939): 518–523.
[9] 近年来,环境史学家对“小冰期”极其关注,故如今有丰富的历
史资料,其中大部分都集中于16世纪与17世纪。我们尤其推荐这两
部著作:Philipp Blom, Nature’s Mutiny: How the Little Ice
Age of the Long Seventeenth Century Transformed the West and
Shaped the Present (New York: W. W. Norton, 2020),以及 Dagmar
Degroot, The Frigid Golden Age: Climate Change, the Little
Ice Age, and the Dutch Republic, 1560–1720 (Cambridge: Cambridge University Press, 2018)。亦请参见Geoffrey Parker, Global Crisis: War, Climate Change and Catastrophe in the Seventeenth Century (New Haven, CT: Yale University Press, 2013)。至于冰雪频现和“小冰期”的开始,请参见Martin M. Miles et al., “Evidence for Extreme Export of Arctic Sea Ice
Leading the Abrupt Onset of the Little Ice Age,” Science
[12] Dagmar Degroot, The Frigid Golden Age,是这一节参考的权
威资料。
[13] Dagmar Degroot, The Frigid Golden Age, 130.
[14] 相关论述见Dagmar Degroot, The Frigid Golden Age, 130
149。
[15] 荷兰工程师科尼利厄斯·费尔默伊登(Cornelius Vermuyden,
1595—1677)曾在英格兰的数个地区兴建排水工程,其中还包括英格
兰东部的沼泽。在人们开始使用蒸汽泵之前,他的努力只取得了一定
程度的成功。
[16] 原文为“incites to Venus”。维纳斯(Venus)为古罗马神话中十二主神之一,是爱与美的女神。——译者注
[17] 罗伯特·贝克维尔(Robert Bakewell,1725—1795)是一位农
学家,长于畜牧,尤其是绵羊的畜牧。他曾给牧场施肥,以改良牧草。
他饲养的绵羊盛产羊毛,被出口到远至澳大利亚和新西兰这样的地方,
同时他也是第一个饲养牛来获得牛肉的人,这种牛的体重在18世纪
翻了一倍多。
[18] 威廉·德勒姆(William Derham,1657—1735)曾是距伦敦不
远的阿普敏斯特的教区牧师。此人酷爱数学、哲学和科学,发明了最
早的以合理方式精准测量声速的办法。引自“Observations upon
the Spots That Have Been upon the Sun, from the Year 1703 to
1711. with a Letter of Mr. Crabtrie, in the Year 1640. upon
the Same Subject. by the Reverend Mr William Derham, F. R.
S,” Philosophical Transactions of the Royal Society 27
(1711): 270。
[19] 供普通读者阅读的关于太阳活动极小期的概述,请参见Dagmar
Degroot, The Frigid Golden Age, 30–49。
[20] J.-C. Thouret et al., “Reconstruction of the AD 1600
Huaynaputina Eruption Based on the Correlation of Geological
Evidence with Early Spanish Chronicles,” Journal of
Vulcanology and Geothermal Research 115, nos. 3–4 (2002): 529–570.
[21] Gary K. Waite, Eradicating the Devil’s Minions: Anabaptists and Witches in Reformation Europe, 1525–1600 (Toronto: University of Toronto Press, 2007).
[22] 本节主要参考了Degroot, The Frigid Golden Age, chaps. 2 and 3。关于荷兰东印度公司的部分见该书第81页至第108页。
火山爆发频繁的那些年,也是社会和政治动荡不安的时期。火山及其原生熔岩流与灾难性的爆炸,成了时髦的奇观。意大利维苏威火山喷发后形成的火山口不但成了一处旅游胜地,还是当时“壮游”[3] 中的一个亮点。一些不那么富有的寻欢作乐者,则可以在伦敦的休闲公园与剧院里一睹壮观的火山爆发场景。“维苏威火山大爆发,喷出滚滚烈焰”(The Eruption of Vesuvius Vomiting Forth Torrents of Fire)这样的标题,就有可能让一家报纸在竞争激烈的广告行业中大获成功。
布丰伯爵的理论当然属于无稽之谈,只不过在广大听众当中一直都很受欢迎。就连玛丽·雪莱也曾提到,弗兰肯斯坦的怪物就是在“退化”的美洲想要逃离文明的。对于造访欧洲的美国人来说,天气变成了一个敏感的话题。18世纪80年代初担任美国驻巴黎大使期间,杰斐逊曾是祖国的积极辩护者。他那部具有里程碑意义的作品《弗吉尼亚纪事》(Notes on the State of Virginia )对布丰伯爵的种种假说发起了一次正面进攻。他以业已灭绝的猛犸的硕大体形和“精神之充沛及活力与吾等无二”的美洲原住民为例,既为祖国的民众辩护,也为祖国的动物辩护。至于美国的西部,则是一幅健康与幸福的景象。[14] 对于美国,杰斐逊心怀一种充满激情的帝国愿景。他曾与布丰伯爵共进晚餐。两人用一种极其文明的方式,一致同意求同存异。
[5] 此处我们参考了Gillen D’Arcy Wood, Tambora: The Eruption That Changed the World (Princeton, NJ: Princeton University Press, 2014),这是描述那次火山喷发的一部优秀的通俗作品;还有William Klingaman and Nicholas P. Klingaman, The Year Without Summer: 1816 and the Volcano That Darkened the World and Changed History (New York: St. Martin’s Press, 2013)。
[6] Miranda Shelley, Mary Shelley (London: Simon & Schuster, 2018).
[7] 卡尔·弗赖尔·冯·德莱斯(Karl Freiherr von Drais,1785— 1851)是一位多产的发明家,他不但发明了脚踏车,还在1821年发明了最早的带有键盘的打字机,甚至发明了用脚来蹬踩的人力轨道车,即如今轨道手摇车的前身。1848年,作为对法国大革命一种迟到的致敬,他放弃了自己的贵族头衔,去世时身无分文。
[8] John D. Post, The Last Great Subsistence Crisis in the Western World (Baltimore: John Hopkins University Press, 1977),是一份权威的参考资料。
[14] Thomas Jefferson, Notes on the State of Virginia (Chapel Hill: University of North Carolina Press, 2006). 1784 年初版于巴黎。
[15] Thomas H. Painter et al., “End of the Little Ice Age in the Alps Forced by Industrial Black Carbon,” Proceedings of the National Academy of Sciences 110, no. 38 (2013):15216–15221.
[16] Richard H. Grove, Ecology, Climate, and Empire: Colonialism and Global Environmental History, 1400–1940(Cambridge, UK: White House Press, 1997).
[17] Rodney and Otamatea Times, Waitemata and Kaipara Gazette, August 14, 1912.
[18] Peter Brimblecombe, The Big Smoke: A History of Air Pollution in London Since Medieval Times (Abingdon, UK: Routledge, 1987). See also Stephen Halliday, The Great Stink of London: Sir Joseph Bazalgette and the Cleansing of the Victorian Metropolis (Stroud, UK: Sutton, 2001).
[19] C. S. Zerefos et al., “Atmospheric Effects of Volcanic Eruptions as Seen by Famous Artists and Depicted in Their Paintings,” Atmospheric Chemistry and Physics 7, no. 15(2007): 4027–4042; Hans Neuberger, “Climate in Art,”Weather 25, no. 2 (1970): 46–56.
[20] James Hanson, congressional testimony, June 23, 1988.
[1] Raphael Meukom et al., “No Evidence for Globally Coherent Warm and Cold Periods over the Preindustrial Common Era,” Nature 571 (2019): 550–554. [2] “过去有如他乡”(“The past is a foreign country”): L. P. Hartley, The Go Between (New York: New York Review Book Classics, 2011)。David Lowenthal, The Past Is a Foreign Country, 2nd ed. (Cambridge: Cambridge University Press, 2015),是最近对这个主题进行讨论的一部作品。 [3] 要想了解全球变暖的方方面面与潜在的解决之道,最有效的办法就是参见Paul Hawken, ed., Drawdown: The Most Comprehensive Plan Ever Proposed to Reverse Global Warming (New York: Penguin Books, 2017)。这部非凡之作中的论文,提供了一些观点与可能的解决办法;它们虽说有时极其简单,但总是具有前瞻性。
Table of Contents Introduction 1. The Immortal Gene and the Disposable Body 2. Live Fast and Die Young 3. Destroying the Master Controller 4. The Problem with Ends 5. Resetting the Biological Clock 6. Recycling the Garbage 7. Less Is More 8. Lessons from a Lowly Worm 9. The Stowaway Within Us 10. Aches, Pains, and Vampire Blood 11. Crackpots or Prophets? 12. Should We Live Forever? Acknowledgements Notes Index
Introduction
Almost exactly one hundred years ago, an expedition led by the Englishman Howard Carter unearthed some long-buried steps in the Valley of Kings in Egypt. The steps led to a doorway with royal seals, signifying that it was the tomb of a pharaoh. The seals were intact, meaning that nobody had entered for more than three thousand years. Even Carter, a seasoned Egyptologist, was awestruck by what they found inside: the mummified young pharaoh Tutankhamun, with his magnificent gold funerary mask, kept company in the tomb for millennia by a wealth of ornate and beautiful artifacts. The tombs had been secured shut so that mere mortals could not enter—the Egyptians had gone to enormous efforts to create objects never intended to be seen by other people.
The splendor of the tomb was part of an elaborate ritual aimed at transcending death. Guarding the entrance to a room of treasures was a gold and black statue of Anubis, the jackal-headed god of the underworld, whose role is described in The Egyptian Book of the Dead. A scroll of the book was often placed in the pharaoh’s sarcophagus. We may be tempted to think of it as a religious work, but it was more akin to a travel guide, containing instructions for navigating the treacherous underworld passage to reach a blissful afterlife. In one of the final tests, Anubis weighs the heart of the deceased against a feather. If the heart is found to be heavier, it is impure, and the person is condemned to a horrible fate. But if the examinee is pure, he would enter a beautiful land filled with eating, drinking, sex, and all the other pleasures of life.
The Egyptians were hardly alone in their beliefs of transcending death with an eternal afterlife. Although other human cultures may not have constructed such elaborate monuments as the Egyptians did for their royalty, all of them had beliefs and rituals around death.
It is fascinating to consider how we humans first became aware of our mortality. That we are aware of death at all is something of an accident, requiring the evolution of a brain that is capable of self-awareness. Very likely it needed the development of a certain level of cognition and the ability to generalize as well as the development of language to pass on that idea. Lower life forms and even complex ones such as plants, don’t perceive death. It simply happens. Animals and other sentient beings may instinctively fear danger and death. They recognize when one of their own has died, and some are even known to mourn them. But there is no evidence that animals are aware of their own mortality. I do not mean being killed by an act of violence, an accident, or a preventable illness. Instead, I mean the inevitability of death.
At some point, we humans realized that life is like an eternal feast that we join when we are born. While we are enjoying this banquet, we notice others arriving and departing. Eventually it is our turn to leave, even though the party is still in full swing. And we dread going out alone into the cold night. The knowledge of death is so terrifying that we live most of our lives in denial of it. And when someone dies, we struggle to acknowledge that straightforwardly, and instead use euphemisms such as “passed away” or “departed,” which suggest that death is not final but merely a transition to something else.
To help humans cope with their knowledge of mortality, all cultures have evolved a combination of beliefs and strategies that refuse to acknowledge the finality of death. Philosopher Stephen Cave argues that the quest for immortality has driven human civilization for centuries. He classifies our coping strategies into four plans. The first, or Plan A, is simply to try to live forever or as long as possible. If that fails, then Plan B is to be reborn physically after you die. In Plan C, even if our body decays and cannot be resurrected, our essence continues as an immortal soul. And finally, Plan D means living on through our legacy, whether that consists of works and monuments or biological offspring.
All of humanity has always incorporated Plan A into their lives, but cultures differ in the extent to which they fall back on the other plans. In India, where I grew up, Hindus and Buddhists gladly embrace Plan C, and the idea that each person has an immortal soul that lives on after death by being reincarnated in a new body, even in a completely different species. The Abrahamic religions, Judaism, Christianity, and Islam, subscribe to both Plans B and C. They believe in an immortal soul but also in the idea that we will rise bodily from the dead and be judged at some point in the future. Perhaps this is why traditionally these religions insisted on burial of the intact body and forbade cremation.
Some cultures, such as the ancient Egyptians, hedged their bets by incorporating all four plans into their belief systems. In grandiose tombs, they mummified the corpses of their pharaohs so that they might rise up bodily in the afterlife. But they also believed in a soul, called Ba, that represents the essence of the person and survives death. The first emperor of a unified China, Qin Shi Huang, took a similarly multipronged approach to immortality. Having escaped many attacks on his life, conquered warring states, and consolidated his power, he turned his attention to seeking the elixir of life. He sent emissaries to pursue even the faintest rumors of its existence. Facing certain execution for their failure to find it, many quite sensibly absconded and were never heard from again. In an extreme combination of Plans B and D, Qin also ordered the construction of a city-sized mausoleum for himself in Xian, employing 700,000 men in the process. The tomb contained an army of 7,000 terra-cotta warriors and horses—all meant to guard the deceased emperor until he could be reborn. Qin died at the age of forty-nine in 210 BCE. Ironically, it may have been toxic potions taken to prolong his life that ultimately cut it short.
Our ways of coping with death began to change with the arrival of the Enlightenment and modern science in the eighteenth century. The growth of rationality and skepticism means that although many of us still hang on to some forms of Plans B and C, deep down we have become less sure they are real alternatives. Our focus has shifted toward finding ways to stay alive and preserving our legacy after we die.
It is a curious facet of human psychology that even if we accept that we ourselves will be gone, we feel a strong need to be remembered. Today, instead of constructing tombs and monuments, the very rich engage in philanthropy, endowing buildings and foundations that will long outlast them. Throughout the ages, writers, artists, musicians, and scientists have sought immortality through their works. Ultimately, however, living on through our legacy is not an entirely satisfying prospect.
If you are neither a powerful monarch or billionaire, nor an Einstein, do not despair. The other way to leave a legacy and be remembered is accessible to nearly all living things, which is to live on through our offspring. The desire to procreate so that some part of us will live on is one of the strongest biological instincts to have evolved, and is so central to life that we will have much more to say about it later. But even though we love our children and grandchildren and want them to live on long after we are gone, we know that they are separate beings with their own consciousness. They are not us.
Nevertheless, most of us do not live in constant existential angst about our mortality. Rather, our brains appear to have evolved a protection mechanism by thinking of death as something that happens to other people, not ourselves. A separation of the dying reinforces the delusion. Unlike the past, when we were confronted by people dying all around us, today people often die in care homes and hospitals, isolated from the rest of the population. As a result, most of us, especially young people, go about our daily lives acting as though we are immortal. We work hard, engage in hobbies, strive after long-term goals—all useful distractions from potential worry about dying. However, no matter what tactics we employ, we cannot fully escape awareness of our mortality.
And that brings us back to Plan A. The one strategy that all sentient beings have had in common for millions of years is simply to try to stay alive for as long as possible. From a very young age, we instinctively avoid accidents, predators, enemies, and disease. Over millennia, that universal desire led us to protect ourselves from attacks by forming communities and fortifications and developing weapons and maintaining armies; but it also led to the search for potions and cures and eventually to the development of modern medicine and surgery.
For centuries, our life expectancy hardly changed. But over the last 150 years, we have doubled it, primarily because we better understood the causes of disease and its spread, and improved public health. This progress allowed us to make enormous strides in extending our average life span, largely as a result of reducing infant mortality. But extending maximum life span—the longest we can expect to live even in the best of circumstances—is a much tougher problem. Is our life span fixed, or could we slow down or even abolish aging as we learn more about our own biology?
Today the revolution in biology that began with the discovery of genes more than a hundred years ago has led us to a crossroads. For the first time, recent research on the fundamental causes of aging is raising the prospect not merely of improving our health in old age but also of extending human life span.
Demographics is driving a huge effort to identify the causes of aging and to find ways to ameliorate its effects. Much of the world is faced with a growing elderly population, and keeping them healthy for as long as possible has become an urgent social imperative. The result is that after a long period in which it was a scientific backwater, aging research—or gerontology—has taken off.
In the last ten years alone, more than 300,000 scientific articles on aging have been published. More than 700 start-up companies have invested a combined many tens of billions of dollars to tackle aging—and this is not counting large, established pharmaceutical companies that have programs of their own.
This enormous effort raises a number of questions. Could we eventually cheat disease and death and live for a very long time, possibly many times our current life span? Certainly some scientists make that claim. And California billionaires, who love their lifestyles and don’t want the party to end, are only too willing to fund them.
The immortality merchants of today—the researchers who propose trying to extend life indefinitely and the billionaires who fund them—are really a modern take on the prophets of old, promising a long life largely free of the fear of encroaching old age and death. Who would have this life? The tiny fraction of the population who could afford it? What would be the ethics of treating or modifying humans to achieve this? And if it becomes widely available, what sort of society would we have? Would we be sleepwalking into a future without considering the potential social, economic, and political consequences of humans living well beyond our current life spans? Given recent advances and the enormous amount of money pouring into aging research, we must ask where this research is leading us, as well as what it suggests about the limits of human beings.
The coronavirus pandemic that hit the world in late 2019 is a stark reminder that nature does not care about our plans. Life on Earth is governed by evolution, and we are yet again reminded that viruses have been here long before humans, are highly adaptable, and will be here long after we are gone. Is it arrogant to think that we can cheat death using science and technology? If it is, what should our goals be instead?
I have spent most of my long career studying the problem of how proteins are made in the cells that make up our body. The problem is so central that it impinges on virtually every aspect of biology, and over the last few decades, we have discovered that much of aging has to do with how our body regulates the production and destruction of proteins. But when I started my career, I had no idea that anything I did would be connected with the problem of why we age and die.
Although fascinated by the explosion in aging research that has led to some very real breakthroughs in our understanding, I have also watched with growing alarm the enormous amount of hype associated with it, which has led to widespread marketing of dubious remedies that have a highly tenuous connection with the actual science. Yet they continue to flourish because they capitalize on our very natural fear of growing old and disabled and eventually dying.
That natural fear is also the reason that growing old and facing death is the subject of innumerable books. They fall into a few categories. There are books that provide practical advice on how to age healthily; some are sensible, while others border on snake oil. Others are about how to face our mortality and accept our end gracefully. These serve both a philosophical and moral purpose. Then there are books that delve into the biology of aging. These too fall into a couple of categories. They are written either by journalists or by scientists who have considerable personal stake in the form of their own start-up anti-aging companies. This book is not any of these.
Considering how rapidly the field is advancing, the enormous amount of both public and private money invested in it, and the resulting hype, I thought it was an appropriate moment for someone like me, who works in molecular biology but has no real skin in the game, to take a hard, objective look at our current understanding of aging and death. Because I know many of the leading figures in this area personally, I have been able to have many frank conversations to gain an honest and deeper understanding of how they see aging research in its many aspects. I have deliberately refrained from talking to those scientists who have made their positions clear in their own books, especially when they are also tied closely to commercial ventures on aging, but I have discussed their highly publicized views.
Given the pace of discovery, any book that focuses just on the most recent aging research would be out of date even before it was published. Moreover, the most recent discoveries in any area of science often do not hold up to scrutiny and have to be revised or discarded. Accordingly, I have tried to concentrate on some of the essential principles behind the most promising approaches to understanding and tackling aging. These principles should not only stand the test of time, but also help readers realize how we got to our present state of knowledge. I also give a historical background to some of the basic research that led to our current understanding. It is both fascinating and important to realize how much of what we know began with scientists studying some completely different fundamental problem in biology.
I said I have no skin in the game, but, of course, all of us do. We are all concerned about how we will face the end of life—less so when we are young and feel immortal, but more so at my age of seventy-one, when I find that I can do only with difficulty, or not at all, things I could do easily even just ten or twenty years ago. It sometimes feels that life is like being constrained to a smaller and smaller portion of a house, as doors to rooms that we would like to explore slowly close shut as we age. It is natural to ask what the prospects are that science can pry those doors open again.
Because aging is connected intimately with so many biological processes, this book is also something of a romp through a lot of modern molecular biology. It will take us on a journey through the major advances that have led to our current understanding of why we age and die. Along the way, we will explore the program of life governed by our genes, and how it is disrupted as we age. We will look at the consequences of that disruption for our cells and tissues and ultimately ourselves as individual beings. We will examine the fascinating question of why even though all living creatures are subject to the same laws of biology, some species live so much longer than even closely related ones, and what this might mean for us humans. We will take a dispassionate look at the most recent efforts being made to extend life span and whether they live up to their hype. I will also challenge some fashionable ideas, such as whether we do our best work in old age. I hope to probe, as well, the crucial ethical question that runs beneath anti-aging research: Even if we can, should we?
The first step in our journey is to think about what exactly death is, the many ways it can manifest itself, and explore the fundamental question of why we die.
1. The Immortal Gene and the Disposable Body
Whenever I walk along the streets of London, I never cease to be amazed by a city where millions of people can work, travel, and socialize so seamlessly. A complex infrastructure, and hundreds of thousands of people, all work in concert to make it possible: the London Underground and buses to move us around the city; the post office and courier services to deliver the mail and goods; the supermarkets that supply us with food; the power companies that generate and distribute electricity; and the sanitation services that keep the city clean and remove the enormous quantities of waste we produce. As we go about our business, it is easy to take for granted this incredible feat of coordination that we call a civilized society.
The cell, our most basic form of life, has a similarly complex choreography. As the cell forms, it builds elaborate structures like the parts of a city. Thousands of synchronized processes are required to keep it functioning. It brings in nutrients and exports waste. Transporter molecules carry cargo from where they are made to distant parts of the cell where they are needed. Just as cities cannot exist in isolation but must exchange goods, services, and people with surrounding areas, the cells of a tissue need to communicate and cooperate with neighboring cells. Unlike cities, whose growth is not always constrained, the cell needs to know when to grow and divide but also when to stop doing so.
The complex organization of a cell has similarities to a city. Only some of the major components are shown, and for clarity, they are not drawn to scale.
Throughout history, cities were imagined by their inhabitants to be permanent. We don’t go about our lives thinking that the city we live in will one day cease to exist. Yet cities and entire societies, empires, and civilizations grow and die just as cells do. When we talk about death, we aren’t usually thinking about these other kinds of death; we mean as it occurs to each one of us as individuals. But it turns out to be tricky even to define an individual, let alone what we mean by its birth or death.
At the moment of our death, what exactly is it that dies? At this point, most of the cells in our body are still alive. We can donate entire organs, and they work just fine in someone else if transplanted quickly enough. The trillions of bacteria, which outnumber the human cells in our body, continue to thrive. Sometimes the reverse is also true: suppose we were to lose a limb in an accident. The limb would certainly die, but we don’t think of ourselves as dying as a result.
What we really mean when we say we die is that we stop functioning as a coherent whole. The collection of cells that forms our tissues and organs all communicate with one another to make us the sentient individuals we are. When they no longer work together as a unit, we die.
Death, in the inevitable sense we are considering in this book, is the result of aging. The simplest way to think of aging is that it is the accumulation of chemical damage to our molecules and cells over time. This damage diminishes our physical and mental capacity until we are unable to function coherently as an individual being—and then we die. I am reminded of the quote from Hemingway’s The Sun Also Rises, in which a character is asked how he went bankrupt, and he replies, “Two ways. Gradually, then suddenly.” Gradually, the slow decline of aging; suddenly, death. The process of aging can be thought of as starting gradually with small defects in the complex system that is our body; these lead to medium-sized ones that manifest as the morbidities of old age, leading eventually to the system-wide failure that is death.
Even then, it is hard to define exactly when this happens. Death used to mean when someone’s heart stopped beating, but today cardiac arrest can often be reversed by CPR. The loss of brain function is now taken as a more direct sign of death, but there are hints that even that can sometimes be reversed. Differences in the precise legal definition of death can have very real consequences. Harvesting organs for donation from two persons in two different US states could be perfectly legal in one and murder in the other, even if they were both considered dead using identical criteria. A girl who was declared brain dead in Oakland, California, was considered alive by the standards of New Jersey, where her family lived. Her family petitioned and eventually had her body transported with its life support equipment to New Jersey, where she died a few years later.
If the precise moment of our death is ill-defined, so too is the moment of our birth. We exist before we emerge from the womb and take our first breath. Many religions consider conception to be the beginning of life, but conception too is a fuzzy term. Rather, there is a window of time after a sperm has made contact with the surface of an egg during which a series of events has to take place before the genetic program of the fertilized egg is set into motion. After that, there is a multiday window during which the fertilized egg undergoes a few divisions, and the embryo—now called a blastocyst—has to implant itself in the lining of the womb. Still later, the beginning of a heart develops, and only long after that, with the development of a nervous system and its brain, can the growing fetus sense pain.
The question of when life begins is as much a social and cultural question as it is a scientific one, as can be seen by the continuing debate over abortion. Even in many countries where abortion is legal, including the United States and the United Kingdom, it is a crime to grow embryos for research beyond fourteen days, which corresponds roughly to the time when a groove called the primitive streak appears in the embryo and defines the left and right halves. After this stage, the embryo can no longer split and develop into identical twins. Although we think of birth and death as instantaneous events—in one instant we come into existence and in another we cease to exist—the boundaries of life are blurry. The same is true of larger organizational units. It is hard to pinpoint the exact time when a city came into existence or when it crumbled.
Death can occur at every scale, from molecules to nations, but there are common features of the growth, aging, and demise of these very different entities. In every case, there is a critical moment when the component parts no longer allow the organic whole to function. Molecules in our cells work in a coordinated way to allow the cell to function, but they themselves can suffer chemical damage and eventually break down. If the molecules are involved in vital processes, their cells will themselves begin to age and die. Moving up the scale hierarchy, the trillions of cells in a human being carry out their specialized duties and communicate with one another to allow an individual to function. Cells in our body die all the time, with no adverse effects. In fact, during the growth of an embryo, many cells are programmed to die at precise points of development—a phenomenon called apoptosis. But when enough essential cells die, whether in the heart or the brain or some equally critical organ, then the individual can no longer function and dies.
We human beings are not so different from our cells. We carry out roles in groups: companies, cities, societies. The departure of one employee will not normally affect the functioning of a large company, and even less that of a city or a country, just as the death of a single tree says nothing at all about the viability of a forest. But if key employees, such as the entire senior management, were to leave suddenly, the health and future of the company would be in doubt.
It is also interesting to see that longevity increases with the size of the entity. Most of the cells in our body have died and been replaced many times before we ourselves die, while companies tend to have much shorter life spans than the cities in which they operate. The principle of safety in numbers has driven the evolution of both life and societies. Life probably began with self-replicating molecules, which then organized in closed compartments that we know as cells. Some of those cells then banded together to form individual animals. Then animals themselves organized into herds—or, in our case, communities, cities, and nations. Each level of organization brought greater safety and a more interdependent world. Today hardly any of us could survive on our own.
STILL, WHEN WE THINK OF DEATH, we are generally thinking about our own: the end of our conscious existence as an individual. There is a stark paradox about that kind of death: although individuals die, life itself continues. I don’t mean just in the sense that our family, community, and society will all go on without us. Rather, it is remarkable that every creature alive today is a direct descendant of an ancestral cell that existed billions of years ago. So, although changing and evolving with time, some essence in all of us has lived continuously for a few billion years. That will continue to be true for every living thing for as long as life survives on Earth, unless we one day create an entirely artificial form of life.
If there is a direct line of succession from us to our ancient ancestors, then there must be something about each of us that doesn’t die. That something is information on how to create another cell or an entirely new organism, even after the original carrier of that information has died—just as the ideas and information here can persist in some form long after the physical copy of this book has deteriorated.
The information to continue life resides, of course, in our genes. Each gene is a section of our DNA, and is stored in the form of chromosomes in the nucleus, the specialized compartment that encapsulates genetic material in our cells. Most of our cells contain the same entire set of genes, known collectively as our genome. Every time our cells divide, they pass on the entire genome to each of the daughter cells. The vast majority of these cells are simply part of our body and will die with it. But some of our cells will outlive our body by developing into our children—the new individuals that make up the next generation. So what is special about these cells that allows them to live on?
The answer to this settled a raging controversy, one that came long before our knowledge of genes, let alone DNA. When people first began to accept that species could evolve, two opposing views emerged. The first, advanced by the Frenchman Jean-Baptiste Lamarck in the early nineteenth century, held that acquired characteristics could be inherited. For example, if a giraffe were to keep stretching its neck to reach higher branches for leaves to eat, its offspring would inherit the resulting longer neck. The second theory was natural selection, proposed by a pair of British biologists, Charles Darwin and Alfred Wallace. In this view, giraffes were variable, some with longer necks and others with shorter. Those with longer necks were more likely to find nourishment and thus be able to survive and have offspring. Progressively, with each generation, variants with longer and longer necks would be selected.
A relative outsider working in what was then the Malay Archipelago, thirty-five-year-old Alfred Wallace wrote to Darwin in 1858 expressing his ideas, not realizing that the older man had himself come to the same conclusion many years earlier. Because these ideas were so revolutionary, and had social and religious implications, Darwin had not yet summoned the courage to publish them, but the communication from Wallace spurred him into action. Darwin was at the heart of the British scientific establishment, and had he been less scrupulous, he could have simply ignored Wallace’s letter and hurriedly published his book. Nobody would have ever known Wallace’s name. Instead, Darwin arranged for himself and Wallace to make a joint presentation at the Linnean Society of London on July 1, 1858. The response to the lecture itself was relatively muted and had little immediate impact. In what was one of the worst pronouncements in the history of science, the society’s president said in his annual address, “The year has not, indeed, been marked by any of those striking discoveries which at once revolutionize, so to speak, the department of science on which they bear.” However, the lecture paved the way for the publication of Darwin’s book On the Origin of Species the following year, which changed our understanding of biology forever.
In 1892, thirty-three years after Darwin’s monumental tract was published, the German biologist August Weismann posited a neat rebuttal of Lamarck’s ideas. Although humans have known for a very long time that sex and procreation were connected, it is only in the last 300 years that we discovered that the key event is the fusion of a sperm with an egg to start the process. The fertilization of an egg by a sperm results in the seemingly miraculous creation of an entirely new individual. The individual consists of trillions of cells that carry out nearly all of the functions of the body and die with it. They are known collectively as somatic cells, from soma, the Latin and Greek word for “body.” The sperm and the egg, on the other hand, are germ-line cells. They reside in our gonads, which are testes in males and ovaries in females. And they are the sole transmitters of heritable information: our genes. Weismann proposed that germ-line cells can create the somatic cells of the next generation, but the reverse can never happen. This separation between the two kinds of cells is called the Weismann barrier. So if a giraffe stretches its neck, it might affect various somatic cells that make up its neck muscles and skin, but these cells would be incapable of passing on any changes to its offspring. The germ-line cells, protected in the gonads, would be impervious to the activities of the giraffe and any characteristics its neck acquired.
The germ-line cells that propagate our genes are immortal in the sense that a tiny fraction of them are used to create the next generation of both somatic and germ-line cells by sexual reproduction, which effectively resets the aging clock. In each generation, our bodies, or our soma, are simply vessels to facilitate the propagation of our genes, and they become dispensable once they have fulfilled their purpose. The death of an animal or a human is really the death of the vessel.
WHY DOES DEATH EVEN EXIST? Why don’t we simply live forever?
The twentieth-century Russian geneticist Theodosius Dobzhansky once wrote, “Nothing in biology makes sense except in the light of evolution.” In biology, the ultimate answer to a question about why something occurs is because it evolved that way. When I first began to consider the question of why we die, I thought naively that perhaps death was nature’s way of allowing a new generation to flourish and reproduce without having older ones hanging around to compete with it for resources, thus better ensuring the survival of the genes. Moreover, each member of a new generation would have a different combination of genes than its parents, and the constant reshuffling of life’s deck of cards would help facilitate survival of the species as a whole.
This idea has existed at least since the Roman poet Lucretius, who lived in the first century BCE. It is appealing—but it’s also wrong. The problem is that any genes that benefit the group at the expense of the individual cannot be stably maintained in the population because of the problem of cheaters. In evolution, a “cheater” is any mutation that benefits the individual at the expense of the group. For example, let us suppose there are genes that promote aging to ensure that people die off in a timely way to benefit the group. If an individual had a mutation that inactivated those genes and lived longer, that person would have more opportunity to have offspring, even though it did not benefit the group. In the end, the mutation would win out.
Unlike humans, many insects and most grain crops reproduce only once. Species such as the soil worm Caenorhabditis elegans, as well as salmon, produce lots of offspring in one big bang and die in the process, often recycling their own bodies as a form of suicide. This kind of reproductive behavior makes sense for worms, which usually live as inbred clones and are therefore genetically identical to their offspring. On the other hand, the reproductive behavior of salmon is a result of their life cycle: they have to swim thousands of miles in the ocean before returning to spawn. With little chance of surviving such a journey twice, they are better served by putting everything they can into breeding just once, using up their entire energy and even dying in the process, to produce enough offspring and maximize the chance that those offspring survive. For species that can reproduce multiple times, like humans, flies, or mice, it would not make genetic sense to die in the act of producing offspring to which they are only 50 percent related. In general, natural selection rarely acts for the good of species or even groups. Rather, nature selects for what evolutionary biologists call fitness, or the ability of individuals to propagate their genes.
If the goal is to ensure that our genes are passed on, why has evolution not prevented aging in the first place? Surely the longer humans survive, the more chance we have of producing offspring. The short answer is that through most of our history as a species, our lives were short. We were generally killed by an accident, disease, predator, or a fellow human before our thirtieth birthday. So there was no reason for evolution to have selected us for longevity. But now that we have made the world safer and healthier for us, why don’t we just keep living on?
The solution to this puzzle began in the 1930s with two members of the British scientific elite, J. B. S. Haldane and Ronald Fisher. Haldane was a polymath who worked on everything from the mechanisms of enzymes to the origin of life. He was a socialistwho late in life became disillusioned with Britain and emigrated to India, where he died. Fisher’s fundamental contributions to statistics have propelled our understanding of evolution and also form the basis of randomized clinical trials that are used to test the efficacy of new drugs or medical procedures and have saved millions of lives. More than fifty years after his death in 1962, he became controversial for his views on eugenics and race. A stained glass window that portrayed one of Fisher’s key ideas for the design of experiments was recently removed by Gonville and Caius College in Cambridge, where he was once a fellow, and its final disposition is still uncertain.
Around the same time, Fisher and Haldane independently came up with a revolutionary idea. A mutation that is harmful early in life, each realized, would be strongly selected against because those who carry it would not reproduce. However, the same could not be said for a gene that is deleterious to us only later in life, because by the time it causes harm, we will already have passed it on. For most of our history as a species, we would not have even noticed its harmful consequences, because long before these effects would be felt, we would have died. It is only relatively recently that we have become aware of the consequences of any mutations that are detrimental late in life. Huntington’s disease, for example, primarily affects people over thirty, by which time, historically, most of them would have already reproduced and died.
Fisher’s and Haldane’s ideas explain why certain deleterious genes persist in the human population, but their relevance to aging was not immediately obvious. That understanding came when British biologist Peter Medawar, another brilliant and colorful figure, turned his attention to the problem. Medawar, born in Brazil, was most famous for his ideas of how the immune system rejects organ transplants and acquires tolerance. Unlike many scientists who focus narrowly on one area, Medawar, like Haldane, had widespread interests, and wrote books that were famous for their erudition and elegant writing. Many scientists of my generation grew up reading his Advice to a Young Scientist (1981), which I found pompous, arrogant, thoughtful, engaging, and witty all at once.
Medawar proposed what has become known as the mutation accumulation theory of aging. Even if a person harbored multiple genetic mutations that didn’t noticeably impair health early on, in combination they brought about chronic problems later in life, resulting in aging.
Going one step further, the biologist George Williams suggested that aging occurs because nature selects for genetic variants, even if they are deleterious later in life, because they are beneficial at an earlier stage. This theory is called antagonistic pleiotropy. Pleiotropy is simply a fancy term for a situation in which a gene can exert multiple effects. So antagonistic pleiotropy means that the same gene could have opposite effects; with genes involved in aging, the effects could occur at different times, such as being helpful early in life and problematic later. For example, genes that help us grow early in life increase the risk of age-related diseases such as cancer and dementia when we are old.
Similarly, the disposable soma hypothesis posits that an organism with limited resources must apportion them between investing in early growth and reproduction and prolonging life by continuously repairing wear and tear in the cell. According to biologist Thomas Kirkwood, who first proposed this theory in the 1970s, the aging of an organism is an evolutionary trade-off between longevity and increased chances of passing on its genes through reproductive success.
Is there any evidence for these various ideas about aging? Scientists have experimented on fruit flies and worms, two favorite organisms because they are easy to grow in the laboratory and have short generation times. Exactly as these theories would predict,mutations that increase life span reduce fecundity (the rate at which an organism produces offspring). Similarly, reducing the caloric intake of the daily food given to these organisms also increases life span and reduces fecundity.
Apart from the ethics of experimenting on humans, the two to three decades between generations is too long for a typical academic career, let alone the handful of years a graduate student or research fellow might stick around. But an unusual analysis of British aristocrats over the past 1,200 years shows that among women who survived beyond sixty (to weed out factors such as disease, accidents, and dying in childbirth), those with fewer children lived the longest. The authors argue that in humans too, there is an inverse relationship between fecundity and longevity, although, of course, as any harried parent knows, there could have been many other reasons why having fewer children extends life expectancy.
THE INCREASE IN OUR LIFE span over the last century brings us to another curious feature of aging that is almost unique to humans: menopause. With the exception of a few other species, including killer whales, most female animals can reproduce almost to the end of their lives, whereas women suddenly lose the ability in midlife. The abruptness of this change in women, as opposed to the more gradual decline in male fertility, is also strange.
You might think that if evolution selects for our ability to pass on our genes, it should want us to reproduce for as much of our lives as possible. So why do women stop reproducing relatively early in life?
This may be asking the wrong question. Our closest relatives, such as the great apes, all stop having babies about the same age that we do: the late thirties. The difference is that they generally die soon afterward. And for most of human history, most women too died soon after menopause, if not earlier. Perhaps the real question is not why menopause occurs so early in life but why women live so long afterward.
People cannot be sure they have reproduced in the sense of passing on their genes until their youngest child has become self-sufficient, and humans have a particularly long childhood during which they are dependent on their parents. Menopause may have arisen to protect women from the increased risk of childbirth in later age, keeping them alive longer to take care of the children they had already. This might also explain why men—who don’t suffer such an increased risk—can be reproductive until much later in life. So perhaps menopause developed as an adaptation to maximize the chances of a woman’s children growing up—and thus propagating her genes. This is the so-called good mother hypothesis. Indeed, the few species where females live well beyond their reproductive years are ones whose offspring require extended maternal care. However, even in these species, there is a gradual loss of fertility rather than the abrupt change brought on by menopause. For example, although the fertility of elephants declines with age, they, unlike humans, can continue to have offspring until very late in life. Similarly, while living beyond childbearing age has also been observed in chimpanzees, menopause actually occurs near the end of their life span.
The grandmother hypothesis for the origin of menopause takes the idea one generation further. Proposed by the anthropologist Kristen Hawkes, it argues that living longer makes sense if a woman helps in the care of her grandchildren, thus improving their survival and ability to reproduce. But others contend that it is rarely better for a woman to give up the chance to pass on half her genes through continuing to have her own children for the sake of improving the survival of grandchildren, who only carry a quarter of her genes.
Another idea, based on studying killer whales, one of the few species that, like humans, has true menopause and lives in groups, is that menopause is a way to avoid intergenerational conflict. In some species that breed in groups, reproduction is suppressed in younger females, who act as helpers to older, reproducing females. But in humans, there is little overlap: women stop breeding when the next generation starts to breed. Women would have no interest in helping their mother-in-law have more children, since they would not have any genes in common. But a woman who helps her daughter-in-law reproduce will help to bequeath a quarter of her genes to her grandchildren. So her best strategy may be to stop breeding and help her daughter-in-law breed instead.
It could also simply be that the number of eggs in a female evolved to match its average life span in the wild. Steven Austad, now at the University of Alabama in Birmingham, points out that menopause may not be adaptive at all in the sense of favoring mothering or grandmothering. It was only about forty thousand years ago that we became much longer lived than Neanderthals and chimpanzees. So perhaps there has just not been enough time for the aging of human ovaries to adapt to that increased life span. In the absence of hard experiments, scientists, especially evolutionary biologists, love to argue.
THESE THEORIES OF WHY WE age depend on the idea of a disposable body being able to pass on its genes before it ages and dies. In doing so, the aging clock is somehow reset with each generation. Such theories should apply only to organisms where there is a clear distinction between parents and offspring. Certainly that distinction is true for all sexual reproduction. Sex evolved because it is an efficient mechanism to produce genetic variation in the offspring by generating different combinations of genes from each parent, allowing organisms to adapt to changing environments. In some sense, you could say that death is the price we pay for sex! While this may be a catchy statement, not all animals with a distinction between germ line and soma reproduce sexually. Moreover, scientists have found that even single-celled organisms such as yeast and bacteria age and die, as long as there is a clear distinction between mother and daughter cells.
The laws of evolution apply to all species, and all life forms are made up of the same substances. Biologists from Darwin onward have never ceased to be amazed that evolution, which is simply selecting for fitness—or the efficiency with which each species can pass on its genes—has given rise to the amazing variety of life forms on Earth. That variety includes a huge range of life spans, from those best measured in hours to those that may stretch more than a century. For human beings seeking to understand the potential limits of our own longevity, some surprising lessons can be learned from species across the animal kingdom.
2. Live Fast and Die Young
In springtime, my wife and I will often take a walk in Hardwick Wood near Cambridge to see the riot of bluebells that cover the forest ground. Once, we were walking along a path when we came upon a stone monument commemorating Oliver John Hardiment, a young man who died in 2006 at the age of twenty-five. Below his name was a quotation from the Indian writer Rabindranath Tagore: “The butterfly counts not months but moments and has time enough.”
The life of a butterfly can be as short as a week, and most live less than a month. As I considered the fleetingly short life of a typical butterfly, I was reminded of the contrast with something else that had fascinated me. I have often visited the American Museum of Natural History in New York, where there is an enormous section of the trunk of a giant sequoia tree. The tree was more than 1,300 years old when it was cut down in 1891. Some yew trees in Britain are estimated to be over 3,000 years old.
Of course, trees are fundamentally different from us because of their ability to regenerate. In the Cambridge University Botanic Garden there is an apple tree that was grown from a cutting from the tree under which a young Isaac Newton sat a few hundred years ago about a hundred miles north at Woolsthorpe Manor, the Newton family home. In fact, there are several “Newton” trees, all started as cuttings from the one with the famous apple that fell to the ground, allegedly inspiring Newton to formulate the theory of gravity. The question of whether these trees should be dated back to the root system of the original is interesting, but it is different from looking at the life span of animals.
Even in the animal kingdom, there are some species that possess tree-like properties. If you cut off one of a starfish’s arms, it can grow right back. A small aquatic animal called a hydra is even more impressive: it doesn’t seem to age at all and is able to regenerate tissue continuously. Still, it is a complex procedure. One study showed that a large number of genes are involved just for regenerating its head. All this for an organism that is barely half an inch in length.
If the hydra is remarkable, it is related to another sea dweller that can age backward—at least metaphorically. That species is Turritopsis dohrnii, also known as the immortal jellyfish. This jellyfish, when faced with injury or stress, will metamorphose into an earlier stage of development and live its life all over again. It is almost as if an injured butterfly could transform itself back into a caterpillar and start over.
Since hydra and the immortal jellyfish don’t exhibit obvious signs of aging, they are often called biologically immortal. This doesn’t mean they don’t die—they can and do die for all sorts of reasons. They still fear predators and must themselves obtain enough food to survive. Nor does it even mean that they cannot die of biological causes. But, unlike most every animal, their likelihood of dying does not increase with age.
Species such as hydra and the immortal jellyfish excite gerontologists because they may provide clues about how to defeat the aging process. But to me, their property of being able to regenerate entire body parts, or even a whole organism, makes them more similar to trees than to us. Although we may learn some fascinating things about their lack of apparent aging, it is not at all clear how relevant those findings will be to human aging. Sometimes biology is universal, especially if it relates to fundamental mechanisms. But in other cases, even discoveries in rats or mice, which are mammals and biologically much closer to us, are difficult to translate into humans. It may be a very long time before any findings gleaned from hydra or jellyfish are useful to us.
PERHAPS WE NEED TO LOOK at species that are more closely related to us—say, mammals, or at least vertebrates. Although this class of animals doesn’t span the enormous range of longevity from insects to trees, they still vary considerably. Some small fish live for just a few months, while a bowhead whale is known to have lived for more than 200 years, and a Greenland shark is thought to have lived almost 400 years.
What causes this large variation even among a particular group of animals such as mammals? Can we detect a pattern among these species just from some overall characteristics? Scientists have long looked for such relationships. Physicists, especially, love to look for general rules to make sense of disparate observations. Geoffrey West at the Santa Fe Institute is one such physicist who now works on complex systems, including aging. West takes a broad view, analyzing how cities and companies, as well as organisms, grow, age, and die. Along the way, he explores how some properties of animals scale across a wide range of sizes and longevities.
If you look at mammals, the larger the animal, generally speaking, the longer its life span. This makes evolutionary sense. A small animal is more vulnerable to predators, and there would be no point in having a long life span if it is going to be eaten long before it dies of old age. But the more fundamental reason for the relationship between size and life span is that size is related to metabolic rate, which is roughly the rate at which an animal burns fuel in the form of food to provide the energy it needs to function. Small mammals have more surface area for their size and so lose heat more easily. To compensate, they need to generate more heat, which means maintaining a higher metabolic rate and eating more for their weight. This means that the total number of calories burned per hour by an animal increases less slowly than the mass of the animal. An animal that is ten times as large burns only four to five times as many calories per hour. So for their weight, smaller animals burn more calories than larger animals. The relationship between how fast an animal burns calories and its mass is named Kleiber’s law after Max Kleiber, who showed in the 1930s that an animal’s metabolic rate scales to the ¾th power of its mass. The exact power is a matter of dispute and some show that for mammals, a ⅔rd power fits the data better.
Since heart rate also scales with metabolic rate, over a very wide range of sizes—from hamsters to whales—mammals typically have roughly the same number of heartbeats over their lifetime: about 1.5 billion. Humans currently have almost twice that, but, then, our life expectancy has doubled over the last hundred years. It is almost as if mammals were designed to last a certain number of heartbeats, much like a typical car can be driven about 150,000 miles. West points out that 1.5 billion is also roughly the number of total revolutions a car engine makes over its expected lifetime and asks, perhaps tongue in cheek, whether this is just a coincidence or whether it tells us something about the common mechanisms of aging!
These relationships suggest that there will be natural limits on life span because size and metabolic rate can vary only so much. For example, an animal cannot evolve to become arbitrarily large without collapsing under its own weight. Such an animal would also have great difficulty supplying its cells with the necessary oxygen. A metabolism must be fast enough for an animal to move and find food—and there are biological limits on how fast a metabolism is actually achievable if you are small. But within the allowable range, these rules hold remarkably well. Geoffrey West declares that just knowing the size of a mammal, he could use scaling laws to estimate almost everything about it: from its food consumption, to its heart rate, to its life span.
This is quite remarkable, and although it deals with averages, it sounds almost like a hard-and-fast rule that limits life span. But what of human beings’ marked increase in longevity over the past century? As West observes, this is a question of what one means by life span: we have almost doubled life expectancy in the last hundred years, but we have done nothing at all to increase the maximum human life span, which remains about 120 years. He argues that, according to the evidence, aging and mortality result from the wear and tear of being alive. Inexorable forces of entropy—a measure of disorder—that push in the direction of disorder and disintegration press against that dream of immortality. Unlike cars, which consist of mechanical components that we can swap out for new ones as they wear out, we cannot simply replace ourselves with new parts and keep going indefinitely.
WHILE THIS RULE-OF-THUMB CONNECTION AMONG size, metabolism, and life span is fascinating, biologists tend to be more interested in the exceptions. They love to study species that beat the system, in the hopes that they can tell us something about the underlying mechanisms of aging. One big question is whether there is a theoretical maximum life span or not. We have seen species such as hydra and jellyfish that seem not to age and can, in fact, continuously replace their worn-out parts. While biologists are well aware of the second law of thermodynamics—which states that in any natural process the amount of disorder or entropy increases with time—most would disagree that the law applies in some blanket form to aging and death, because living systems are not closed as the law requires but need a constant input of energy to exist. In fact, with a sufficient expenditure of energy, you can indeed reverse entropy when it comes to regularly cleaning your attic or hard drive; it is just that most of us don’t feel it is worth it.
As a result, biologists do not think that aging is inevitable. Rather, all evolution cares about is fitness: the ability to pass on our genes most efficiently. But living a long life is worth it only if you are not going to be eaten or die of disease or an accident long before you die of old age. Hence birds, which can escape predators by flying away, generally live longer than earthbound animals of about the same size. For those lucky animals that don’t have as much to fear from predators, living a longer life gives them more time to find a mate and reproduce. Slowing down their metabolism, so that they need not procure large amounts of food every day, may then simply be a way of surviving better into old age. In each case, the life span simply reflects how evolution has optimized the fitness of each species.
Steven Austad is a leader in aging research who studies exotic species with widely varying life spans. For a scientist, he has a highly unusual background: he majored in English literature at the University of California, Los Angeles, hoping to write the Great American Novel. Given that we’ve never heard of it, Austad jokes, one can see how that worked out. After graduation, while not writing his novel, he drove a taxi and worked as a newspaper reporter before spending several years taming lions, tigers, and other wild animals for the movie industry. This sparked an interest in science, and Austad went back to school to study animal behavior. From there, he became interested in the question of why animals age at different rates.
In 1991 Austad and his graduate student Kathleen Fischer examined the longevity of several hundred species. They discovered that, even among mammals, the relationship between body size and longevity disappears below a threshold of about one kilogram of body mass. Possessing a biologist’s instinct for the particular, the two of them then asked which species deviated most from this scaling law, coining what they called the longevity quotient. The LQ is the ratio of the average life span of the species to what it would be if it followed the scaling laws. This allowed them to focus on those species that deviate by either living much longer or much less than would be expected for their size.
The life span of animals generally increases with size. Estimates for the maximum life span of mammals are shown along with a line showing the general trend. In addition, points for the Major Mitchell’s cockatoo, Galapagos tortoise, and Greenland shark are shown. Data are taken from the AnAge database (https://genomics.senescence.info/species/index.html).
It turns out that humans already do rather well: we have an LQ of about 5, meaning that we live 5 times as long as would be expected. Nineteen mammalian species outperform us: eighteen species of bat and the naked mole rat. Over the years, Austad has studied these outlier species, and he describes them in colorful prose as befits his background in English literature. He poses this provocative question: Why do aging researchers study mice and rats, both of which have LQs of just 0.7, when they could be looking at these more exceptional species instead? There are many reasons why animals are chosen as model organisms, including ease of breeding and maintenance, and the ability to study their genetics. We have acquired tremendous knowledge of their biology over decades. Since the underlying mechanisms of aging are likely to be universal even if their rates are not, and studying short-lived animals could actually be an advantage by speeding up experiments, I am not sure that many in the gerontology community will rush to follow Austad’s advice. But I hope enough of them do, so that we learn how these unusually long-lived outliers have evolved such different rates of aging.
Among the species Austad describes are giant tortoises, such as the Galápagos tortoise, which holds the record for life span of a terrestrial vertebrate animal and can amble along for two centuries. There might well be a Galápagos tortoise still alive that was spotted by Darwin during his five-year voyage aboard the Royal Navy ship HMS Beagle from 1831 to 1836. Also, for much of their long life, they are remarkably free of diseases such as cancer. Determining the LQ of these tortoises is tricky, though. For one, their exact age is hard to determine, since their history is usually poorly documented and the subject of much exaggeration. Even thornier is the question of what a tortoise truly weighs. Much of their body mass consists of their protective shell, which is more like our hair and nails than highly active tissue, so drawing comparisons with other animals can be misleading.
These giant tortoises may not be alone in their longevity. Two studies that evaluated survival data from various turtles and other reptiles and amphibians found negligible senescence in a number of turtles and other species. The biologist’s term negligible senescence, which means little or no increase in mortality, has been interpreted popularly to mean “eternal life,” but this is a bit of a misnomer. Actually, it means that mortality, or the likelihood of dying, does not increase with age.
The relationship between mortality and age was worked out in 1825 by Benjamin Gompertz, a self-educated British mathematician. Gompertz worked for an insurance company, and so was naturally interested in the question of when a person seeking to purchase coverage might die. By digging through death records, he discovered that starting in our late twenties, the risk of dying increases at an exponential rate year after year. It doubles roughly every seven years. At age 25, our probability of dying in the next year is only about 0.1 percent. This rises to 1 percent at age 60, 6 percent at age eighty, and 16 percent at age 100. By the time a person reaches 108 years old, there is only about a 50 percent chance of making it another year.
Negligible senescence, when the probability of dying is constant rather than exponentially increasing with age, violates Gompertz’s law. But even if there is negligible or even negative senescence, you still face a probability of dying every year from age-related diseases, quite apart from dying of infections or accidents. Aging involves more than increasing mortality with age. It also depends on maintaining the physiology of the animal. The long-lived tortoises show unmistakable signs of aging. Like elderly humans, their eyesight and heart gradually fail. Some of them develop cataracts. Some become feeble to the point where they need to be fed by hand. So these animals do age, just slowly.
Moreover, biological time for tortoises is very different: they live life in the slow lane. They are not warm-blooded creatures like us mammals. They move slowly and reproduce slowly, often taking several decades to reach puberty in the wild. Their hearts beat only once every ten seconds, and they breathe slowly. Despite their long chronological lives, they fit the metabolic rate theory of longevity.
Other long-lived species are aquatic, such as the Beluga sturgeon and the aforementioned Greenland shark. Like the tortoise, they too aren’t in any hurry. Greenland sharks swim more slowly than a normal eighty-year-old human walks, and they seem to be scavengers, rather than catching prey. Perhaps more extraordinary than the Greenland shark is the bowhead whale. This baleen whale lives in freezing Arctic waters, but because it is a warm-blooded mammal, its internal body temperature is only a few degrees lower than that of most other mammals. Moreover, it eats about three times more than was previously suspected, implying a metabolic rate three times higher than was thought. How such an animal can survive for about 250 years is still a mystery.
The Greenland shark and the bowhead whale are large aquatic vertebrates, but there are much smaller terrestrial outliers too. One particularly interesting example is Major Mitchell’s cockatoo, a striking white bird with a pink face and a vibrant bright red and yellow crest that resembles a radiating sun. This cockatoo has been known to live to eighty-three years in a zoo. This would not be exceptional for a human, but the bird is far smaller. So this is definitely not a species that fits the general relationship among size, metabolic rate, and life span.
Remember how the relationship between mass and longevity for mammals disappeared below one kilogram? That’s largely due to bats. Bats do not live as long as Major Mitchell’s cockatoo, but they generally outlive nonflying mammals of the same size, which is exactly what evolutionary theories would predict, since their ability to fly allows them to evade predators. In keeping with this, bats that roost in caves, and are thus further protected from predators, live almost five years longer than those that don’t. The champion is Brandt’s bat, a small, brown animal that fits comfortably in the palm of your hand. A male of the species was recaptured in the wild forty-one years after it was originally banded. Austad estimates that its LQ of about 10 is the highest known for any mammal and about twice that of humans.
Another reason bats are thought to live longer is that they slow down their metabolism during their long periods of hibernation. On average, bats that hibernate live six years longer than those that don’t. But even bats that don’t hibernate live exceptionally long for their size, so clearly metabolic rate is not the only reason for their longevity. Rather, they may have special mechanisms that protect them from aging.
One curious feature is that the longest-lived Brandt’s bats on record are males. This is certainly different from humans. Austad speculates that this could be because female bats are less agile in flight and more susceptible to predators when they are pregnant, because they carry more than a quarter of their own body weight. They also face much greater energy demands in feeding their young.
Finally, no discussion of long-lived animals would be complete without mentioning the remarkably ugly, nearly hairless rodent that has become something of a darling of the aging research community: the naked mole rat. Despite the name, it is neither a mole nor a rat but a species of rodent that is indigenous to equatorial East Africa. It is about the same size as a mouse, but whereas a mouse lives roughly two years, a naked mole rat can live for more than thirty. This gives it an LQ of 6.7—not as high as Brandt’s bat, but a record for a terrestrial nonflying mammal. How do they do it?
Rochelle Buffenstein, currently at the University of Illinois in Chicago, has done more than perhaps anyone else to understand the biology of aging in the naked mole rat. As a result of work by her and many others, we know that naked mole rats are one of a small number of mammals that are referred to as eusocial: they live in underground colonies with a queen, and, in that sense, are reminiscent of ants. As one might expect, they have a very low metabolism and are tolerant of oxygen levels so low that they would kill mice—and us. In the wild, naked mole rat queens live much longer than workers: about seventeen years compared with two to three years. But in the lab, where worker naked mole rats live a comfortable, well-fed life with good health care and no predators, the difference is not so stark.
Not surprisingly, naked mole rats are extremely resistant to cancer, regardless of age—again, in marked contrast to mice. Even more strikingly, when Buffenstein and her colleagues tried to induce cancer in naked mole rat skin cells using techniques that worked reliably for other species, they could not do it. According to their 2010 study, instead of proliferating like cancerous cells, the naked mole rat cells entered a terminal state and were cleared away, suggesting that they respond to cancer-causing genes very differently.
One of the biggest headlines about naked mole rats was generated by the observation that they seem to violate Gompertz’s law: their risk of dying seems not to increase with age. As a result of these findings, no animal has been hyped as much as the naked mole rat, with both the popular press and news articles in scientific journals touting each discovery as a major breakthrough in the quest to defeat aging. This was too much for some scientists, who pointed out that naked mole rats do age, just more slowly than might be expected for their size. As we saw with long-lived tortoises, they show many signs of aging, including lighter, thinner, and less elastic skin resembling parchment, as well as muscle loss and cataracts. They are not like hydra and the immortal jellyfish, which can regenerate themselves with ease. Still, as exceptionally long-lived mammals, they could provide important clues into our own aging processes.
IT IS TIME TO LEAVE these unusually long-lived species and focus on the one that interests us most: ourselves. Most crucially: How long can human beings live? And is this limit fixed, or can it be changed?
For most of human history, life expectancy was just over thirty. But today, in developed countries, we can look forward to living into our mid-eighties. Even in poorer countries, a person born today can expect to live longer than the grandparents of people in the richest countries. The science writer Steven Johnson makes the point that this is like each of us acquiring an entire additional life.
When we say life expectancy, we mean life expectancy at birth, or the average number of years a newborn would live if current mortality rates remained unchanged. This value, as you can imagine, is greatly affected by infant mortality rates. Even in the nineteenth century, when life expectancy was forty years, a person who reached adulthood had a good chance of living to be sixty or more. Most of the increase in life expectancy has come about because of improvements in public health rather than groundbreaking advances in medicine. Johnson observes that the three biggest contributors have been modern sanitation and vaccines, which both prevented the spread of infection, and artificial fertilizers. Other significant innovations were antibiotics, blood transfusions (crucial for accidents and surgery), and sterilization of water and food by chlorination and pasteurization.
The inclusion of fertilizers may surprise you, but prior to the ready availability of food—which has brought about its own problems of obesity, diabetes, and cardiovascular diseases—humans were constantly struggling to get enough to eat. Chemical fertilizers include nitrogen-containing compounds and have increased crop yields several-fold. The ability to chemically capture nitrogen from the air, a discovery for which Fritz Haber received the Nobel Prize in 1918, made it much easier to synthesize fertilizers and helped to double the world’s population. Interestingly, almost half of the nitrogen atoms in our bodies went through a Haber-Bosch high-pressure steam chamber that converted atmospheric nitrogen to ammonia for use in fertilizers, which then ended up in the food we ate and became incorporated into ourselves.
Haber himself was a tragic figure. A German Jew, he was intensely loyal to Germany during World War I, and his method for fixing nitrogen into ammonia enabled the country to prolong the war by producing its own explosives. Prior to that, its military had been importing nitrates from Chile, which became impossible due to the Allied Powers’ wartime blockade. He also initiated the use of chemical warfare against the Allies, who denounced him as a war criminal. At the same time, his Jewishness trumped his loyalty to Germany. Soon after the Nazis assumed power, he had to flee Germany in 1933 although he was a world-famous scientist and director of a prestigious institute in Berlin. After a brief sojourn in England, he set out for Rehovot in what is now Israel, but died mid-journey of heart failure in a hotel in Basel, Switzerland.
Back to life expectancy: preventing infectious disease dramatically reduced infant mortality, which is now as low as 1 percent in advanced countries and about 3–4 percent worldwide. But there has been progress across the rest of the aging curve as well. Public health measures for safety, regulations against smoking, and better treatments for life-threatening illnesses such as cardiovascular disease and cancer have all added up to a slow but steady increase in life expectancy beyond sixty years of age. Does this mean that our life expectancy might go on increasing indefinitely?
Ever since humans became aware of their mortality, we have wondered whether our life span has a fixed limit. Scientists aren’t sure.
Jay Olshansky of the University of Illinois at Chicago says yes. He examined how much we would gain by eliminating various common causes of death such as cancer, heart disease, and other diseases. Based on statistical calculations, he argued that for life expectancy to increase dramatically, we would need to reduce mortality rates from all causes by 55 percent and even more at older ages. He and his colleagues contended that average life expectancy would likely not exceed eighty-five and that it would not exceed a hundred until everyone alive today had died. Even curing all forms of cancer would add only four to five years on average.
In the other corner was the late James Vaupel, who maintained that life span is elastic. If evolutionary theories were strictly correct, then our maximum life span should be adapted for life in the wild and thus not much more than about thirty to forty years. But, as you know, life expectancy has more than doubled. Moreover, in certain species, such as some tortoises, reptiles, and fish, mortality actually falls and then levels off, presumably because as these creatures grow larger, they can better resist starvation, predators, and disease; senescence is not inevitable.
The disagreements between the two boiled into a sort of scientific blood feud, with Vaupel refusing to attend any meetings where Olshansky was present, and attacking his findings as a “pernicious belief sustained by ex-cathedra pronouncements.” Olshansky, for his part, feels that demographers relying purely on statistics fail to consider biology. In agreement with this, an analysis of the lives of primates implies that there are biological constraints on how much the rate of human aging can be slowed.
Of course, life expectancy at birth is not the same as the maximum possible life span, and it is that maximum that tends to interest us more than averages. We want to know how long it is theoretically possible for humans to live. Most cultures have writings about prophets and sages who allegedly lived for hundreds of years. In Western culture, the name Methuselah has become synonymous with longevity, after the biblical prophet who is said to have lived 800 years. In somewhat more recent times, the Englishman Tom Parr, who died in 1635, was said to have lived for 152 years, but this has been thoroughly debunked. Unlike most people, for whom childhood memories are the strongest, “Old Tom” could remember nothing of his youth.
The oldest person for whom we have reliable records is Jeanne Calment, who died at the age of 122 in 1997. She lived in Arles, the town in southern France where van Gogh resided near the end of his life. She actually met the troubled artist in her teens, describing him as “very ugly, ungracious, impolite, and sick.” Apparently Calment had a sharp wit. As she grew older and older, journalists began to gather around her on each birthday. When one of them took leave by telling her, “Until next year, perhaps,” she retorted, “I don’t see why not! You don’t look so bad to me.”
Calment was in very good health for nearly her entire life, riding a bicycle until she was a hundred. It is hard to know what contributed to her longevity, beyond genetics. She smoked for all but the last five years of her life. While this is not an example we should follow, many of us might be tempted to emulate her habit of eating more than two pounds of chocolate every week. While Calment’s robust physical condition even late in life was extraordinary, it did not mean that she did not age; for instance, she was blind and deaf for many of her final years.
Calment is the record holder, but one has to remember that she was born almost 150 years ago, in 1875. It is almost a miracle that she survived for so long in the age before antibiotics and other advances in modern medicine. Given the even greater progress made since then, might we expect today’s humans to live much longer?
A few years ago, Jan Vijg and his colleagues at the Albert Einstein College of Medicine in the Bronx published a study that analyzed demographic data from several countries to look at shifts in the population of each age group. As life expectancy improves, the fastest growing segment of the population is usually the oldest, since many more people reach the threshold for that group. For example, in France in the 1920s, 85-year-old women were the fastest growing group. By the 1990s, the fastest growing group were 102-year-olds. You might expect that with time, this would shift to even older ages. But the study showed that improvements in survival decline after age 100, and the age of the oldest person has not increased since the 1990s. Vijg predicted that the natural limit of our life span is about 115 years; there will be occasional outliers such as Jeanne Calment, but he calculates that the probability of anyone exceeding 125 in any given year is less than 1 in 10,000.
This conclusion was contradicted a couple of years later by a study examining records of men and women in Italy who had reached the age of 105 between 2009 and 2015. It concluded that mortality rates plateaued after the age of 105, in an apparent violation of Gompertz’s law. The researchers went on to say that a limit to longevity, “if any, has not been reached.” This paper in turn was criticized by one of the authors of the earlier study, who felt that it was rather far-fetched that after increasing exponentially for most of one’s life, the chance of dying should plateau in extreme old age. Others pointed out that most of the cohort did, in fact, follow Gompertz’s law, so the plateau came from less than 5 percent of the mortality data. Moreover, they argued that even if mortality did plateau after age 105, the likelihood of anyone surviving much beyond Calment’s 122 years was remote, in the absence of major biomedical advances. It is a question of statistics. At today’s rates, the odds of surviving each year after 105 is only about 50 percent; to beat Jeanne Calment’s 122 would be like tossing a coin seventeen times and having it come up heads every time. Those odds are about 1 in 130,000.
Recent data support the views of Vijg, Olshansky, and other proponents of a limit to maximum life span. After climbing steadily for the last 150 years, the annual increase in life expectancy slowed down globally around 2011 to a fraction of what it had been in previous decades, and plateaued from 2015 to 2019 before falling precipitously as a result of the Covid-19 pandemic. The pandemic, like the influenza epidemic that gripped the world in 1918–19, killing an estimated 50 million people, was an exceptional situation. But we weren’t making progress even in the handful of years before the pandemic. Why not is unclear. It could be due to the rising epidemic of obesity and associated scourges such as type 2 diabetes and cardiovascular disease. As people live longer, Alzheimer’s and other neurodegenerative diseases are responsible for an increasing share of deaths, and there is currently little treatment for them.
In any case, although the number of people who live to be 100 keeps increasing, nobody has beaten Calment’s record of 122 in the twenty-five years since she died. The next oldest person, a Japanese woman named Kane Tanaka, died in 2022 at the age of 119. As I write this, the oldest living person is Maria Branyas Morera of Spain, who is 116 years old. What is striking is that these extremely long-lived people are all women. Now that death rates due to childbirth have been reduced dramatically, life expectancy for women is greater than that of men in nearly every country.
Even if nobody beats Calment’s record soon, there remains great interest in why some humans live exceptionally long. Thomas Perls, who heads the New England Centenarian Study, has been studying centenarians for several decades. As a practicing physician who specializes in geriatrics, he confronts the realities of aging in his patients every day. He investigates the health history, personal habits, and lifestyles of centenarians, along with what is known about their family histories and genetics. In one large study, Perls concluded that centenarians fell into three classes. About 38 percent were what he called Survivors, who had been diagnosed with at least one age-associated disease before the age of eighty; another 43 percent were Delayers, who developed such a disease after the age of eighty; and the last group consisted of Escapers, the 19 percent who reached their hundredth birthday without being diagnosed with any of the ten most common age-associated diseases. In fact, about half of centenarians celebrated turning one hundred without heart disease, stroke, or non–skin cancer, which is extraordinary.
Perls says that centenarians generally maintain their independence up through their early to mid-nineties. For those who live beyond 105, that independence can be observed at least through age 100. So it appears that centenarians survive for so long by staying healthy longer than most people, rather than going through a prolonged period of living with diseases of old age. Perls also told me that he has seen an increase in the number of people aged 100 to 103, a likely reflection of improvements in medicine and lifestyle over the last few decades, but, beyond that, he is not seeing an increase—perhaps because genetics play such an influential role in survival to those extreme ages. He agrees with Olshansky that currently there is a natural limit on our life span.
Perls and other researchers are now sequencing the genomes of centenarians, and he plans to also study the modifications in DNA that accumulate with age. These studies could reveal the underlying biology of extreme longevity in ways that could be very useful to the rest of us. In the meantime, based on what he has learned so far, Perls has developed a website, livingto100.com, which asks visitors questions about themselves, and spits out an estimated life span, along with suggestions for how to improve it. A few findings may surprise you: it recommends tea over coffee, reducing our intake of iron (often found in multivitamins), and flossing regularly. But many of the suggestions are what one might expect: eating moderately and healthily and avoiding fast food, processed meat, and excessive carbohydrate consumption, as well as exercising and maintaining a healthy weight, getting adequate sleep, reducing stress, staying mentally active, and having an optimistic outlook. It helps not to have diabetes, and having a close family member who lived to be over ninety is a big plus. Since my father, at ninety-seven, still does his own laundry, grocery shopping, and cooking—making complicated Indian recipes and his own ice cream from scratch—I may have lucked out.
The debate about whether there is a limit to human longevity led to a famous bet. At a 2001 meeting, a reporter asked Steven Austad when we would see the first 150-year-old human. None of the other scientists wanted to go out on a limb, but Austad blurted out, “I think that person is already alive.” When he read about this, Olshansky, who remains skeptical of exceptional longevity, called up Austad and challenged him to a friendly bet. You might think that this was a safe bet since they would both be dead before it could be decided, but they’d already thought of that. The two men agreed to put $150 each into a fund for 150 years, which, Austad notes, had a nice symmetry to it. A back-of-the-envelope calculation by Olshansky suggested that in 150 years, $150 could turn into about $500 million to be won by either them or one their descendants. A dozen years later, nobody had yet approached the age of Jeanne Calment, but both of them still felt confident, so they doubled the bet, with each putting another $150 into the pot, raising the potential stake to a cool $1 billion 150 years from now—although it is not clear what $1 billion would actually buy at that point.
Why did Austad make this bet? It is not as if he believes that just because we are getting better at treating diseases of old age such as cancer, stroke, and dementia, people will live thirty years more than Calment. In fact, on that point, he and Olshansky agree. Rather, Austad believes that research on aging will result in game-changing medical breakthroughs. The scientists disagree mainly on how rapidly these innovations will occur.
We have now explored how evolutionary theories help us understand why death occurs at all, and how the optimization of fitness by evolution has resulted in a huge range of life spans in different species. We have also explored whether there are biological limits to our own life span. But none of this tells us how aging occurs and how it leads to death.
The quest to defeat aging and death is centuries old, but findings from modern biology over the last half century have led to an explosion of knowledge about exactly what goes on in our bodies as we age. As we noted before, aging is simply an accumulation of damage to our molecules, cells, and tissues due to a variety of causes that bring about increasing debilitation and eventually death. An aging body changes in so many ways that it is hard to glean which factors cause aging and which are simply its consequences. But scientists have homed in on a small number of hallmarks of aging. According to them, such a hallmark should have three characteristics: first, it should be present in an aging body. Second, an increased presence of the hallmark should accelerate aging. Third, reducing or eliminating the hallmark should slow aging.
These hallmarks exist at every level of complexity, from molecules, to cells, to tissues, to the interconnected system we call our body. No hallmark exists in isolation; they all influence one another. Thus aging doesn’t have one or even a few independent causes. It is a highly intricate and interconnected process.
It is easiest to make sense of it all if we start at the most basic level of complexity: with the molecule that could be thought of as the ultimate command and control center of the cell.
3. Destroying the Master Controller
The ancient site of Hampi in South India offers a stark contrast to the thriving metropolis of London. The grand city that existed for more than a thousand years and at its peak in the early sixteenth century was second in wealth only to Beijing is now a collection of well-preserved granite ruins about fifteen miles from the nearest railway station. The once-bustling marketplaces and intricately carved temples and palaces are now only alive with camera-toting tourists. It was once the London of its time: the seat of an empire and a flourishing center of trade and culture. When I travel to London, I simply cannot imagine the city ever not existing, and the inhabitants of Hampi probably thought the same. This failure of imagination extends to us as individuals too. Even if we know we are going to age and die, in our daily lives, unless we are terminally ill, we carry on as if we are immortal.
How could a thriving, vibrant city like Hampi have disintegrated and no longer exist? Throughout history, one of the fastest ways for a society to crumble was the breakdown of law and order resulting from a government’s loss of control due to civil unrest or a war. And just as with society, loss of control and regulation in biology leads to decay and death, not only of the cell but of the entire organism.
Unlike a functioning society run by a government, there is no central authority in the cell that supervises its thousands of components as they go about their business. So is there even a counterpart in the cell of a command and control center? Perhaps the closest thing is our genes, which reside in our DNA. The nature of genetic information in our DNA and the ways it becomes corrupted over time are essential for understanding aging and death.
We didn’t even know about genes as an entity until the late nineteenth century. Most of us think of genes as traits that we inherit from our parents and pass on to our children. We may think of good genes, reflected in positive traits, or bad ones, characterized by disease or defects. But genes are better described as units of information. They contain information not only on how to reproduce an organism and pass on its traits, but also on how to build an entire organism from a single cell and keep it functioning.
Among the most important information that genes contain is how to make proteins. We normally think of proteins as essential components of our diet, and we know they are used to build muscle. In fact, our body contains thousands of proteins. Not only do they give the body form and strength, but they also carry out most of the chemical reactions that are essential for life. They regulate the flow of molecules in and out of cells. They allow our cells (and us) to communicate with one another. They are the reason we can sense light, smell, touch, and heat. Our nervous system depends on proteins to transmit nerve signals and even to store memory. The antibodies we use to fight infections are proteins. Proteins also enable the cell to manufacture all the other molecules it needs, including fat and carbohydrates, vitamins, and hormones, and—to complete the circle—even our genes. Proteins are everywhere. And every one of these proteins is made by following instructions in a gene.
Exactly how genetic information is stored and used remained a huge mystery until relatively recently. Even in the 1940s, scientists still didn’t understand the molecular nature of genes. Today we know that our genes reside in DNA, a long molecule that consists of two strands wrapped around each other in a double helix. Each strand of DNA has a backbone made up of alternating groups of phosphate and a sugar called deoxyribose. If that were all DNA was, it would just be like any other repeating polymer such as polyethylene or other plastics, and incapable of carrying information. But DNA is able to encode instructions because each sugar in its backbone is attached to one of four types of chemical groups called bases. These bases are adenine (A), guanine (G), thymine (T), and cytosine (C). This phosphate-sugar-base unit is the building block of DNA, known as a nucleotide.
You can think of each building block as a letter, and a DNA chain as a very long sentence written using this four-letter alphabet. Just as a particular sequence of letters can form a sentence that conveys meaning and information, suddenly you could imagine how DNA could too, but it was still not at all clear how. This changed dramatically in 1953 when the three-dimensional structure of DNA was deduced by James Watson and Francis Crick. Normally, the structure of a molecule only hints at how it might work, but DNA was different. Its structure immediately shed light on how the sequence of bases could transmit information, transformed our understanding of genetics, and ushered in the current revolution in molecular biology. Without it, we would have had no hope of understanding the workings of life or unlocking the secrets of why we age.
Genetic information stored in our chromosomes in the form of DNA is copied (transcribed) into mRNA in the nucleus. The mRNA then moves to the cytoplasm, where ribosomes read it to make proteins.
In DNA, two strands running in opposite directions are wrapped around each other in a double helix. A base from one strand chemically bonds, or pairs, with the base directly across from it in a very specific way: an A pairs only with a T or vice-versa, and a C with a G. Hence the magic of DNA: if you know the sequence of bases in one of the two strands, you can determine the sequence of the other. This also means that if you separate the two strands, each of them has the information to make the other, enabling you to create two identical copies of the molecule from an original. Suddenly an age-old problem was solved: How could you get two daughter cells, each of them possessing exactly the same genetic information as the single parent cell? Genetics had become chemistry: we could understand at the molecular level how genetic information could be duplicated and passed on to a new generation.
Still, there remained the second question of how genetic information in DNA actually codes for proteins. It turns out that the section of DNA that codes for a gene is copied into an intermediate molecule called ribonucleic acid. RNA is similar to DNA but with some important differences. Unlike DNA, it has only one strand, and instead of deoxyribose, it has a sugar called ribose. In RNA, the thymine (T) base is replaced by uracil (U), which is slightly different chemically but pairs with A just as T does.
Think of DNA as the collection of all our genes, much as the British Library or the US Library of Congress are collections of all the books published in their respective countries. Those libraries are not likely to let you take a valuable eighteenth-century book home to read at your leisure. But they can often provide a copy of it to take home. Similarly, RNA is a working copy of the gene that can be used by the cell.
Not every piece of DNA that is copied to RNA codes for a protein. Some RNAs are part of the machinery that is used to make proteins. Others can even control whether certain genes are turned on or off. But when an RNA is made from a gene that codes for a protein, it is called messenger RNA, or mRNA, because it carries the genetic message for how to make that protein. We’ve heard a lot about mRNA recently in connection with vaccines for Covid-19. These vaccines are made from mRNA molecules that contain instructions on how to make the spike proteins that are on the surface of the virus that causes Covid-19. When those mRNA molecules are injected into us, our cells read the instructions in it and produce the corresponding spike proteins, which in turn trains our immune system to be ready to fight the real Covid-19 virus.
How instructions in mRNA are read to make proteins was a hard puzzle that took over a decade to crack. The problem scientists faced was that proteins too are long chains, but of completely different types of building blocks called amino acids. Unlike DNA and RNA, which have four types of bases, there are at least twenty different types of amino acids. If proteins were like sentences written in a twenty-letter alphabet, how could they translate those sentences from the four-letter language of genes? The way nature has solved this problem is that groups of three bases (or letters) in mRNA are read as a code word, or codon, each of which specifies an amino acid. The whole process takes place on the ribosome, a giant, ancient molecular machine that consists of almost half a million atoms.
I have spent much of my life trying to understand how the ribosome carries out the complicated process of reading mRNA to synthesize a protein. What seems miraculous is that as the newly made protein chain emerges from the ribosome, the sequence of its amino acids contains within itself the information needed for the protein chain to fold up into a particular shape so that it can carry out its function. It is akin to writing different sentences on strips of paper and, depending on what I had written, each strip would magically fold itself into its unique shape. This ability of a protein chain to fold itself up is why the one-dimensional information contained in our genes allows us to build the complex three-dimensional structures that make up a cell—and, eventually, us.
The gene doesn’t just contain information on how to make a protein. The part that specifies that is called the coding sequence, but flanking it are regions (non-coding sequences) that signal when to make the protein, when to stop, and even whether to make it quickly or slowly, for a brief while or for a long time. These signals are turned on or off either by chemicals in the environment or by other genes. Genes, in other words, don’t act alone; they form a giant network with lots of other genes, as well as the broader environment. This is why some proteins are made by all our cells, but others only by specific cells, such as skin cells or neurons. And why some proteins are made only at certain stages in our development from a single cell to a complete human being. The precise orchestration of this network of thousands of genes is what makes life possible.
You could think of the process of life as an enormous program that somehow activates itself using the blueprint provided by DNA. The word blueprint is a convenient metaphor, but we should not take it too literally, because a blueprint implies a rigid manufacturing process that produces a strictly defined product. Unquestionably, DNA is the central hub for regulating the overall program of the cell. But I think of the cell as more like a democracy than a dictatorship. Just as an ideal government is not autocratic but responsive to the needs of its people over time, DNA does not dictate the entire process. Rather, conditions in the cell and its environment decide which parts of the DNA are used, as well as how often and when.
UNDERSTANDING THE MOLECULAR BASIS OF genetics has transformed modern biology, but what does it have to do with aging? If the genes in our DNA specify the program of the cell, why doesn’t the program just keep running forever? The problem is that the DNA itself changes and deteriorates with time.
Of course, genes and mutations were studied long before we knew about DNA. Prior to DNA, the only way to determine whether an organism had a genetic mutation was when it resulted in a change in an observable trait. Today we know that mutations are simply changes in the bases of DNA. Changing bases in DNA is the equivalent of changing letters in a sentence. Sumtymes we can still dicifer the same meening, but other times, just a single change can be confusing or even have the opposite meaning—for example, if we change the word hire to fire.
Now that we can sequence DNA—or determine the precise order of bases in any piece of DNA—we can see that mutations happen all the time. Many of them have no observable effect. This is because even with the change to the DNA, the altered gene functions just as well; or the organism has redundant genes, so that if one is defective, the others can compensate for it. Other mutations can be harmful to varying degrees because they result in proteins that are defective; or proteins that are produced in the wrong amounts or at the wrong time.
Sometimes, mutations can actually be beneficial. For instance, if the mutation occurs in a germ-line cell, it might very occasionally give offspring an advantage that facilitates their survival. A species that is uniformly the same could be wiped out by some pestilence, like trees susceptible to Dutch elm disease, or by sudden changes in the climate or geography. Mutations can give rise to genetic variability in a population and make it more resilient by increasing the likelihood that some strains might survive better than others as conditions change. Without mutations, there would be no evolution; we would never have emerged from primitive molecules. The cell, then, must strike a balance, tolerating enough mutations in the germ line to allow variability and evolution, but not allowing so many mutations in our somatic cells that the complex process of life begins to break down.
A societal breakdown of law and order can bring about chaos, mass starvation—even the annihilation of entire cities and civilizations. The worst criminal elements often take advantage during turbulent times, usurping power and making life miserable for everyone else. Similarly, loss of control in biology can lead to deterioration and death as well as to many diseases. One of the worst examples of cells misbehaving is cancer, in which aberrant cells are no longer inhibited by neighboring cells but instead multiply unchecked and take over entire tissues and organs, interfering with their functioning. In that sense, cancer and aging are intimately related: they both arise from a biological loss of control, and their ultimate source is often mutations in our genes, owing to changes in our DNA.
LONG BEFORE WE KNEW OF DNA, there were hints that environmental agents could cause what we now know to be genetic mutations. As early as the eighteenth century, the English surgeon Percival Pott discovered that the country’s chimney sweeps, many of them children, had abnormally high rates of cancer of the scrotum. He attributed this to their excessive, prolonged exposure to the soot and tar from burned coal. In 1915, Yamagiwa Katsusaburo, a professor of pathology at the Tokyo Imperial University, demonstrated that applying coal tar to the ears of rabbits caused skin cancer. These products of coal would later be identified as cancer-causing agents, or carcinogens, but when Pott made his observations, nobody had any idea what cancer was, and even when Katsusaburo reported his results, the link between cancer and genetic mutations was still decades away.
The first direct evidence linking an environmental agent to mutations was discovered by a scientist with a remarkably peripatetic life. Hermann Muller was a third-generation American who grew up in New York City and entered Columbia College (now Columbia University) at the precocious age of sixteen, graduating in 1910. He stayed on at Columbia for his PhD, working with the famous geneticist Thomas Morgan, who had used fruit flies to show that genes resided in the chromosomes in our cells.
Later, Muller moved to the University of Texas, where, in a key experiment in 1926, he subjected fruit flies to increasing doses of X-rays. As he ratcheted up the dose, the number of lethal mutations rose dramatically. Even a modest application of X-rays produced 35,000 times as many mutations than would have occurred spontaneously. Muller’s work advanced genetics tremendously by making it much easier to produce mutations, and also raised awareness of the danger of X-rays and other radiation. At the time, people used X-rays rather cavalierly—it was common for shoe sellers to X-ray the feet of their customers in the shoes they were considering.
Like many geneticists in the early twentieth century, Muller was a proponent of eugenics for much of his life and thought of it as a way for improving the human species. Oddly for a eugenicist, he was also quite left wing, a result of his disillusionment with capitalism in the wake of the Great Depression. He recruited lab members from the Soviet Union and as a faculty advisor, helped edit and distribute a leftist student newspaper called The Spark, which spurred the FBI to investigate him.
Partly as a result, in 1932 Muller left the United States for Berlin. Discouraged by the rise of Hitlerism, he left the following year for the Soviet Union, believing that the environment there would be more conducive to his left-wing views. He spent a year in Leningrad before moving to Moscow for a few years. He had not, however, reckoned with the rise of Trofim Lysenko, the Soviet biologist and charlatan who had ingratiated himself to Stalin. Lysenko viewed genetics as inconsistent with socialism, and instead espoused a number of crazy ideas in agriculture, while ruthlessly wielding his power to suppress or destroy any biologist who dared question him. In doing so, he contributed to famines that killed millions of people and set back Soviet biology by decades. Muller and other geneticists did what they could to counteract Lysenko, but eventually Muller incurred Stalin’s wrath for his views on both genetics and eugenics and had to flee.
Not yet ready to return to the United States, where the FBI was still investigating him, Muller ended up at the Institute for Animal Genetics at the University of Edinburgh in 1937. There he helped catalyze another important discovery. He joined a lively group of scientists, many of them refugees from totalitarian regimes, under the direction of pioneering medical geneticist Francis Crew.
One of Crew’s key collaborators, Charlotte Auerbach, had been born to an academic Jewish family in Krefeld, Germany. Auerbach, known as Lotte, was an independent thinker who did not take well to being told what to do. While studying for her PhD in Berlin, her professor refused her request to change her project, so she simply quit and became a high school teacher. She found teaching and keeping order in class exhausting, perhaps not helped by the increasing antisemitism of the time. In what turned out to be a blessing in disguise, she was summarily dismissed in 1933 at the age of thirty-four because she was Jewish. On her mother’s advice, she left Germany, and, with the help of friends of the family, was able to finish her PhD at the Institute for Animal Genetics, where she worked with Crew. In 1939 she became a British citizen; later that year, her mother showed up in Edinburgh without any money or baggage, having made it out of Germany just two weeks before World War II broke out.
Crew’s initial attempt to bring Auerbach and Muller together was not a success. He introduced her to Muller and simply told him, “This is Lotte, and she is going to do cytology for you.” But Auerbach had no interest in spending her time peering through a microscope to characterize Muller’s cells, and, independent minded as always, she refused. She told Muller that she was really interested in how genes enabled development. To his credit, Muller told her that he wouldn’t dream of having someone work with him on a project that didn’t interest her. However, he persuaded Auerbach that if she wanted to pursue her interest in understanding the role of genes in development, she needed to produce mutations in them and see their effects.
Around this time, a colleague of hers, Alfred J. Clark, had noticed that soldiers exposed to mustard gas in World War I exhibited lesions and ulcers that resembled the effects of exposure to X-rays. Auerbach, along with Clark and their colleagues, exposed fruit flies to mustard gas, checking for mutations using the methods Muller had pioneered. It says something about their dedication that their experiments were carried out on the roof of the Pharmacology Department in cold, wet, blustery Edinburgh. The experimental conditions would never pass a workplace health and safety inspection today: the fruit flies were exposed to the gas in vials and afterward were removed by hand, causing serious burns to the workers. In any case, the results were unambiguous. Exposure to mustard gas had resulted in ten times as many lethal genetic mutations. Chemicals, like radiation, could also cause mutations.
MULLER AND AUERBACH’S WORK SHOWED how our genetic blueprint could be damaged by environmental agents such as radiation or chemicals. At the time, we didn’t even know that DNA was the genetic material, let alone how the information it carried could be corrupted. But once Watson and Crick revealed its double-helical nature, the question naturally became how exactly did these agents cause changes in our DNA that resulted in mutations?
Studying the biological effects of radiation had been something of a stepchild of the life sciences before World War II. But once the world saw the horrible effects of radiation wrought by the two atomic bombs dropped on Japan in August 1945, the US government became very interested in this once sleepy field. After the war, many of the sites that had been used for the Manhattan Project to develop nuclear weapons were converted to radiation biology research centers. One of these was Tennessee’s Oak Ridge National Laboratory, which had originally been the site for producing large amounts of the uranium isotope used in the first atomic bomb, detonated over the city of Hiroshima. Remote from the large academic centers of the United States in the Northeast and the West Coast, Oak Ridge was nestled between the spectacular wilderness of the Cumberland and Smoky Mountains. These attractions, and the generous funding provided by the government, allowed Alexander Hollaender, a leading radiation biologist of his time, to recruit many excellent scientists to Oak Ridge, including Dick and Jane Setlow.
Dick and Jane Setlow met as undergraduates at Swarthmore College in the 1940s and married soon afterward. When Hollaender approached them around 1960, Dick was on the biophysics faculty at Yale University. It was one of the oldest biophysics programs in the country, but Hollaender lured away Dick with a shrewd move: he offered Jane, who had a temporary appointment working for someone else, a full position too. In those days, even women who had earned graduate degrees rarely had the opportunity to work as equals and ended up assisting some male scientist, frequently their husband. Hollaender’s gambit worked. Both Dick and Jane became leaders in the field, sometimes working together but just as often separately. They also raised a family of four children and hiked and hunted for fossils in the mountains around Oak Ridge before moving to another national lab in Brookhaven on Long Island about fifteen years later.
Brookhaven National Laboratory was where I first met them, in 1982. Dick was the chair of the department that hired me. It might have helped that I was desperately trying to leave Oak Ridge after only fifteen months there because the resources I had been promised never materialized. Dick, having made the same move himself, was sympathetic. At the time, I was thirty-one years old, and although they were only around sixty then, I regarded them as ancient fossils, like the ones they collected. Like some of the more mainstream molecular biologists, I severely underestimated the importance of their work, and I regret that I didn’t talk to them about their discoveries when I had the chance. It’s a reminder to me of how insular most scientists are, with little appreciation of what goes on outside their narrow specialties.
Even before X-rays were discovered, we knew about other forms of radiation. As early as 1877, the British scientists Arthur Downes and Thomas Blunt discovered that sunlight could kill bacteria. In the early twentieth century, Frederick Gates showed that it was the shorter wavelengths in sunlight—ultraviolet, or UV, radiation—that had the killing effect. Soon after Muller demonstrated that X-rays could cause genetic mutations, scientists started studying UV radiation too; after all, it was easier to produce and safer to handle. They found that for a given dose, UV light produced even more mutations. At Oak Ridge, Dick and Jane began by trying to understand exactly how UV caused mutations in DNA. One finding that intrigued them was that UV light links up two adjacent thymines (the T bases) on DNA. Virtually any sequence of DNA will occasionally have two thymines next to each other, and somehow UV was linking them together so that the two bases were no longer separate but acted as a single unit consisting of two building blocks—known as a thymine dimer, or sometimes as a thymidine dimer, if scientists want to refer to the larger unit that includes the sugar to which the thymine is attached. Was this how UV inactivated DNA and killed bacteria?
Dick and Jane experimented with inserting foreign DNA into a bacterium. This enabled them to introduce a gene that gave the bacterium new abilities, such as growing in the absence of a nutrient it would need otherwise or becoming resistant to an antibiotic. However, when they tried this using DNA containing thymine dimers, it was as if the DNA had become inactivated. Dick went on to show that thymine dimers prevent the DNA from being copied, so new DNA could not be made.
The next step was even more remarkable. Dick and his colleagues found that shortly after exposure to UV radiation, the thymine dimers disappeared from the DNA altogether. The dimers, including the sugar and phosphate to which the bases were attached, were cut out of the DNA, with the missing section filled in using the other strand as a guide, just as when DNA is copied. Discoveries in science are not made in a vacuum. The state of knowledge reaches a stage where the next advances are possible, so new breakthroughs are often made simultaneously. The same year, 1964, that Setlow reported his discovery, two other groups, led by Paul Howard-Flanders and Philip Hanawalt, respectively, made similar findings. The reports all confirmed that the cell clearly had some mechanism to not only recognize the thymine dimers but also to repair them, by a process called excision repair.
Excision repair was also found in a different context. Even in the 1940s, scientists realized that they could reverse the effects of UV light on bacteria by exposing them to visible light. The arrested bacteria would start growing again. Extracts from bacteria that had been exposed to visible light could repair damaged DNA. How it worked was something of a mystery until Aziz Sancar, a Turkish doctor turned scientist, got involved in the work and identified its mechanism, which also involved repairing thymine dimers using a different enzyme. Oddly, Hemophilus influenzae, the organism in which Dick Setlow had identified the same kind of repair, lacks this mechanism (as do we humans)—otherwise he might never have made his discovery. Just the fact that nature had evolved two completely different mechanisms to remove thymidine dimers tells us about the importance of repairing them.
These experiments established firmly that the cell could repair damaged DNA. But we’re rarely exposed to high doses of X-rays. Our clothes and the melanin pigment in our skin protect us from a lot of UV exposure. Also, we know enough to stay away from mustard gas, coal tar, and other nasty chemicals, which human beings never encountered in the wild in prehistoric times. Yet these mechanisms to repair damaged DNA evolved billions of years ago and are part of every life form.
It turns out that our DNA is constantly being assaulted, even in the normal course of living, without exposure to nasty chemicals or radiation. The person who did more than anyone to make us appreciate this was the Swedish scientist Tomas Lindahl. As a postdoctoral fellow at Princeton University, he was working on a relatively small RNA molecule. To his frustration, he found that it kept breaking down.
As we’ve discussed, RNA molecules use the sugar ribose rather than the deoxyribose found in DNA. Ribose differs from deoxyribose by just one additional oxygen atom. That extra atom makes RNA much more unstable, but also gives it the ability to form complex three-dimensional structures that can carry out chemical reactions. Because of these properties, scientists believe that life originally emerged in a primordial world in which RNA carried out chemical reactions as well as stored genetic information. As life evolved to become more complex, using an unstable molecule to store an increasingly large genome was not viable, and so the more stable DNA was used to store genetic information.
Lindahl knew that DNA was more stable than RNA, but he wanted to know how much more. It had to be stable enough to pass on information to the next generation without too much change. Or over the billions of cell divisions that occur by the time a single cell develops into a mature organism. That is a very long time.
Lindahl studied DNA in a variety of conditions and found that over time some of its bases changed. The most common change was that the base cytosine (C) was transformed into a different base called uracil (U), which is normally found in RNA, where it stands in for thymine (T). The problem is that, like T, U pairs with an A, while C pairs with a G. This transformation was like changing a letter in the DNA sentence. Having many of these changes throughout the genome would corrupt the encoded instructions to the point where they would become nonsensical.
Lindahl showed that the change from a C to a U can be caused simply by exposure to water, a ubiquitous occurrence for all living molecules in a cell. In one day, water could cause about ten thousand changes to the DNA in each of our cells. Lindahl estimated later that, taking into account all forms of spontaneous damage to DNA, about a hundred thousand changes are inflicted on the DNA in each of our cells every single day. It was hard to imagine how life could survive when the set of instructions that enabled it was being corrupted so rapidly. Clearly, there had to be a mechanism to correct these errors too. Over the next few decades, Lindahl and other scientists worked out how this change is repaired.
A much more drastic form of DNA damage occurs when both strands break, leaving two pieces that have to be rejoined. Sometimes there are even multiple breaks on different chromosomes. This can result in a complete mess, where half of one chromosome is joined to the other half of a completely different one, or where a broken-off piece has been reinserted backward. Again, if we think of DNA as a text consisting of sentences, changes to individual bases are like typos: although they will occasionally garble the meaning, often you can still make sense of them. But if you repair a double-strand break incorrectly, it is like cutting sentences or whole paragraphs from a long text and pasting them back in some random order. Occasionally, it might still sort of make sense, but other times it will be complete gibberish. So it is imperative for the cell to join broken ends of DNA as soon as it recognizes them, preferably before multiple breaks occur. Special proteins recognize the broken ends and join them together to make an intact DNA molecule. This process does take into account the DNA sequence at the ends, so if there is more than one break in the cell at any given time, there is always a chance that it will join the wrong ends. When our genome is scrambled in this way, it can lead to different kinds of problems. One is a loss of function, where the cell cannot do its job efficiently or perhaps not at all. In other cases, it can corrupt or lose the signals that control genes. As a result, the cell starts growing unchecked, leading to cancer.
Humans are what we call diploid, possessing two copies of each chromosome. The more common and accurate way that the body repairs double-stranded breaks is to use the undamaged DNA in the other chromosome as a guide. Even in organisms such as bacteria, a second copy is often present when cells are dividing and the DNA is being duplicated. Either way, the repair machinery lines up the broken ends against the matching sequence on the other (intact) copy of the DNA to form a complicated structure in which all four strands are intertwined. This is more accurate than simply grabbing random ends and joining them because it checks whether they are the right ends to be joined. By doing so, it restores the integrity of the genome and fills in any gaps that arise if the broken ends have been frayed.
Apart from chemical damage, mutations have another way of creeping into our genome. Each time a cell divides, the entire genome has to be duplicated, which is like copying a text three billion letters long. No process in biology is ever completely accurate. Just as with writing or typing, the faster you try to copy something, the more prone you are to making mistakes. The polymerase enzymes that replicate DNA are incredibly accurate; what’s more, they can proofread their work, so to speak, correcting mistakes as they go. Nevertheless, they still make an error once every million or so letters. In a genome with a few billion letters, that means several thousand mistakes occur each time the cell divides. The cell can’t take forever to divide, and in life there is always a compromise between speed and accuracy. Not surprisingly, the cell has evolved sophisticated machinery to correct these errors.
Relying on some very clever experiments, Paul Modrich figured out how enzymes in a bacterium recognize the mismatch, cut out a section of the new strand containing the mistake, and fill in the section so that the mistake is corrected. That mechanism is now well established in bacteria, but scientists are still debating exactly how these kinds of errors are corrected in higher organisms like humans.
It took a long time for the scientific community to realize the importance of DNA damage and repair. Muller received the Nobel Prize in 1946, a full twenty years after his discovery that X-rays cause mutations. But by the time the 2015 Nobel Prize in Chemistry went to Lindahl, Sancar, and Modrich, the field of DNA repair had long ceased to be a scientific backwater. Now it is widely recognized as crucial for life as well as for understanding the basis of both cancer and aging. As in most scientific areas, hundreds of scientists working in different labs throughout the world had contributed to these discoveries, but the Nobel Prize can be shared by only three people at most, so the committee has the unenviable job of choosing the three most important to honor, not always without controversy. The prize also cannot be given posthumously, and, sadly, Dick Setlow had died a few months before it was announced, at the age of ninety-four.
Over the years, scientists have isolated many different repair enzymes. Many of them are essentially the same in all life forms from bacteria to humans. DNA repair is so essential to life that it originated billions of years ago, before bacteria and higher organisms diverged. Maintaining the stability of the genome and its instructions is critical for the cell and demands constant surveillance and repair. You can think of these repair enzymes as the sentinels of our genome.
Because DNA damage occurs all the time, any defect in the repair machinery itself is particularly disastrous because it means that the damage would accumulate rapidly. Not surprisingly, many mutations in the repair machinery have been linked to cancers: for example, mutations in the BRCA1 gene predispose women primarily to cancers of the breast and ovary. Defects in the repair machinery also cause aging, but because we are also more likely to develop cancer as we age, it is hard to separate out the two effects. Perhaps more than any single person, the Dutch scientist Jan Hoeijmakers has worked extensively to explore how DNA repair defects can age a person prematurely. One condition he has focused on is Cockayne syndrome, which manifests symptoms associated with aging, such as neurodegeneration, atherosclerosis, and osteoporosis. In females, defects in how the cell responds to DNA damage can affect the age at which menopause begins. Generally, the more effectively our bodies can repair our DNA, the more we can resist aging.
WHEN A CELL SENSES SIGNIFICANT DNA damage, it triggers what is called the DNA damage response. This is not all good news: the damage response often has greater consequences for aging than the damage itself. Sometimes the cell will go into senescence, a state in which it is unable to divide further, and in extreme cases, the cell is triggered to commit suicide. It is odd to think that life would have evolved a mechanism to kill its own cells, but one individual cell among an organism’s billions is ultimately dispensable. If, however, that cell were allowed to become cancerous as a result of DNA damage, it could multiply and eventually kill the entire organism. Both cell death and senescent cells are important factors in aging, especially the latter, and we will have a lot more to say about them in later chapters. Suffice it to say here that the DNA damage response evolved to balance the risk between cancer and aging. It is one more mechanism that evolved to benefit us early in life, even if it costs us later, after we’ve already passed on our genes.
At the heart of the damage response is a protein called p53, the product of the TP53 tumor suppressor gene. This protein is so essential that it is often called the Guardian of the Genome. Almost 50 percent of all cancers have a mutation in p53; in some forms of cancer, the rate is as high as 70 percent. Normally, p53 is bound to a partner protein and is inactive. It is also turned over rapidly in the cell, so it is made and then degraded all the time. When DNA damage is sensed, p53 is activated and starts to accumulate. It is also freed from its partner protein, springs into action, and turns on the expression of many genes; in this context, expression means the production of the functional protein from the information coded by the genes. Some of them are genes for DNA repair proteins. Others stop the cell from dividing to give DNA repair genes a chance to do their job. When the damage is too extensive, p53 can turn on genes that induce cell death.
P53 may also hold the key to Peto’s paradox, an oddity observed in the 1970s by the British epidemiologist Richard Peto. Large animals such as elephants or whales can have a hundred times as many cells as we do. Even accounting for their slower metabolism, this means there is a much greater chance that one of their cells will mutate to become cancerous. Yet these large mammals are remarkably resistant to cancer and live almost as long or even longer than us. Humans inherit one copy of the gene for p53 from each of our parents, but it turns out that elephants have twenty copies. Therefore their cells are exquisitely sensitive to DNA damage and commit suicide when it is detected. Scientists are always worried about proving cause, so they wanted to find out what would happen if you increased the level of repair genes in other organisms. Curiously, in studies involving fruit flies, they found that repair gene overexpression did indeed increase longevity—but only if the genes were turned on throughout the fly’s entire life. If the repair genes weren’t activated until adulthood, there was no increase in life span.
Some of the long-lived species we encountered in chapter 2, such as certain whales and giant tortoises, also have unusual variations in the numbers and types of tumor suppressor genes. Perhaps without this, they would have died of cancer at much younger ages. In general, there seems to be a powerful correlation between strong DNA repair genes and longevity. Humans and naked mole rats, which can live up to 120 and 30 years, respectively, have a higher expression of DNA repair genes and their pathways than do mice, which live only up to 3 or 4 years. It remains to be seen whether exceptionally long-lived people have unusually efficient DNA repair mechanisms.
Paradoxically, many new cancer therapies work by inhibiting DNA repair. This is because cancer cells have defects in some of their repair machinery, so inhibiting other routes of repair closes off their options. Unable to repair their own DNA, the cancer cells die off. However, this is a short-term solution to combating aggressive cancers; normally, blocking DNA repair over an extended period could actually increase a person’s risk of both cancer and aging. Attempting to use our knowledge of DNA damage and repair to tackle aging is not straightforward because of the tricky interplay between aging and cancer.
Even if it is difficult to use DNA repair to directly improve longevity, our knowledge of it underpins our understanding of virtually every process of aging. Genes ultimately control the entire process of life: when and how much of each protein we make; whether our cells continue to live or suddenly stop dividing; how well our cells sense nutrients in their surroundings and respond to them; and how different molecules and cells communicate with one another. Genes control our immune system, which must maintain the delicate balance of reacting to invading pathogens without inducing chronic inflammation.
Direct damage to our DNA, and the cell’s seemingly paradoxical response to it, is only one of the ways our genetic program can be changed as to cause aging. For our DNA has two peculiarities. The first is that its end segments are special and protected, and the consequences of disrupting them are serious. The second is that the way our genome is used does not depend exclusively on the sequence of bases in the DNA itself. Our DNA exists as a tight complex with ancient proteins called histones, and both the DNA and its partner proteins can be altered by our environment to affect the way our genes are used. Our genome, it turns out, is not written in stone but can be modified on the fly.
4. The Problem with Ends
Over a century ago, a scientist in a New York laboratory peered at the cells he had cultivated in flasks and wondered whether he might have uncovered the secret of immortality.
Alexis Carrel was a French surgeon who by then was already famous for having pioneered techniques to reconnect blood vessels that had been severed in an accident or an act of violence such as a stabbing. His method for joining blood vessels end to end with tiny, almost invisible sutures transformed many kinds of surgery, and is the basis of organ transplants even today. In 1904 Carrel left France for Montreal and then Chicago. Two years later, he moved to New York City to become one of the earliest investigators at the newly created Rockefeller Institute for Medical Research (now Rockefeller University). The institute offered an unparalleled environment for an ambitious scientist, including superb laboratories and sizable endowments. And the thirty-three-year-old Carrel certainly had ambitions.
As a surgeon, Carrel dreamed of keeping tissues alive outside the human body. In the lab, we can grow cultures of bacteria or yeast indefinitely. Although individual bacteria or yeast can age and die, the culture continues to grow and is, in a sense, immortal. But that was not clear for cells and tissues from higher life forms such as us. At Rockefeller, Carrel began a long series of experiments to see whether a culture of cells from a tissue could be kept alive indefinitely. By placing the cells from the heart of a chicken embryo in a special flask, and steadily supplying them with nutrients, Carrel seemed to have made a breakthrough. The culture could be maintained for years. These cells, he claimed, were immortal.
The discovery was reported with great fanfare. If cells from a tissue could be made immortal, journalists reasoned, then so could entire tissues and eventually us. An editorial in the July 1921 issue of Scientific American gushed, “Perhaps the day is not far away when most of us may reasonably anticipate a hundred years of life. And if a hundred, why not a thousand?”
But Carrel was wrong.
Initially, his work went unchallenged because of his stature, and, over the years, the immortality of cultured cells became dogma. That is, until three decades later, when a young scientist at the Wistar Institute in Philadelphia, Leonard Hayflick, wanted to see if cells would change when exposed to extracts from cancer cells. He decided to use Carrel’s method to grow human embryonic cells in culture. To his disappointment, he found he could not grow these cells indefinitely. Initially, Hayflick, a recent PhD in medical microbiology and chemistry, thought he must have made a mistake. Perhaps he hadn’t correctly prepared the nutrient broth or was washing his glassware improperly. But over the next three years, he carefully ruled out any technical problems and concluded that the prevailing theory was simply incorrect: normal human cells would not replicate indefinitely in culture. They were not immortal.
Instead, Hayflick found that his cells would divide a finite number of times and then stop. In an ingenious experiment, he and his colleague Paul Moorhead took male cells that had already divided many times and mixed them with female cells that had divided only a few times. When they soon reached their limit, the male cells stopped dividing, while the female ones continued to grow to the point that they came to dominate the culture. Somehow the old cells remembered they were old, even when surrounded by young cells. They were not rejuvenated by the presence of the young cells, nor did they stop dividing because of some contaminating chemicals or viruses in the environment. Hayflick and Moorhead coined the term senescence to describe this state, in which the cells were arrested and could no longer divide further.
Another junior scientist might have been nervous about challenging such established ideas, but not the confident Hayflick. He and Moorhead wrote up their results in a meticulously detailed thirty-seven-page paper and submitted it to the same journal in which Carrel had published his original findings. Because it went counter to the prevailing dogma, and perhaps because the editor was a colleague of Carrel’s and more inclined to trust him than some young unknown scientist, the paper was rejected but eventually published in Experimental Cell Research in 1961. It has since become a classic in the field. The number of times a particular kind of cell can divide is now called the Hayflick limit.
How did Carrel get it so wrong? One possibility, suggested by Hayflick himself, is that the French scientist may have inadvertently introduced fresh cells into the culture each time he replenished the nutrient broth in which they were growing. Some have even suggested that fresh cells may have been incorporated deliberately, although this would be a case of either egregious misconduct or sabotage.
My sneaking suspicion is that by the time Carrel worked on these cells, fame and power had gone to his head, and he had become arrogant and less self-critical about his research. This attitude manifested itself in other ways. In 1935 he published a book titled Man, the Unknown, which recommended sterilizing the unfit and gas chambers for criminals and the insane, and commented about the superiority of Nordic people over southern Europeans. In the preface to the book’s 1936 German edition, he praised the Nazi government of Adolf Hitler for its new eugenics program. Given Carrel’s stature, it is quite possible that the Nazis used his remarks as one justification for their activities. His plaque in Rockefeller University was recently corrected to reflect his views.
Titia de Lange, a renowned biologist currently at the very same Rockefeller University, suggested a more straightforward explanation for Carrel’s results: the laboratory next door to Carrel’s was working with malignant tumors in domestic chickens, and these cancerous chicken cells might have contaminated Carrel’s cultures growing nearby. Cancer cells are the exception to the Hayflick limit: they don’t stop dividing after a certain number of divisions, and this uncontrolled growth is why cancer wreaks such havoc on the body.
Why don’t cancer cells stop growing unlike the normal ones studied by Hayflick? And how can a cell keep count of the number of times it has divided and know when to stop?
When a cell divides, each of the DNA molecules in our chromosomes has to be copied. Unlike bacteria, whose genome consists of a circular piece of DNA, the DNA in each of our forty-six chromosomes is linear. Like an arrow, each strand of the double-helical DNA molecule has a direction, and the two strands of the DNA molecule run in opposite directions. The complex machinery that copies each DNA molecule uses each strand as a guide to make the opposite or complementary strand, but it can do so only in one direction. In the early 1970s James Watson of DNA fame and a Russian molecular biologist named Alexey Olovnikov both noticed at about the same time that the way the cell’s machinery copies DNA would create a problem at the very ends of the molecule.
One day, Olovnikov was obsessing over this idea while standing on the platform of a train station in Moscow. He imagined the train in front of him as the DNA polymerase enzyme that copies DNA, and the railway tracks as the DNA to be copied. He realized that the train would be able to copy the rail track ahead of it, but not the part that lay immediately under it. And because the train could go in only one direction, even if it started at the very end of the track, there would always be a section underneath the train that could not be copied. This failure to copy the very end of a DNA strand meant that each newly made strand would be just a little shorter than the original. With each cell division, the chromosomes would progressively shorten, until eventually they lost essential genes and could no longer divide, thereby reaching their Hayflick limit. The end replication problem, as this is known, could explain at least in principle why cells stopped dividing, although the real answer, as we will see, is more complex.
A SEPARATE MYSTERY REMAINED UNANSWERED. Why didn’t the cell see the ends of chromosomes as breaks in the DNA and try to join them together? Why didn’t it induce some sort of DNA damage response?
In the 1930s and 1940s, around the time that Hermann Muller was investigating how X-rays might damage chromosomes, a young scientist named Barbara McClintock was looking at the genetics of maize. At some point, she discovered the phenomenon of “jumping genes”: where genes hop from their position on DNA to a completely different position on the chromosome or even to a completely different chromosome.
Even in the 1930s, both Muller and McClintock, working independently, noticed that there was something special about the ends of chromosomes. Unlike broken chromosome ends, which would often be joined up, the ends of intact chromosomes seemed to stay separate. Muller named the natural ends of chromosomes telomeres. He and McClintock both suggested that they had some special property that prevented them from being mistaken for breaks in the DNA and being joined with each other. This allowed chromosomes to be maintained stably as individual entities in cells instead of being combined randomly. But what made telomeres so special?
Elizabeth Blackburn grew up along with her seven siblings and a large menagerie of pets in the small town of Launceston on the north coast of Tasmania, Australia. She became interested in science and majored in biochemistry at the University of Melbourne, where she had the good fortune to meet Fred Sanger, the famous biochemist who was visiting from England. Encouraged by this encounter, and at a time when there were few women in molecular biology, Blackburn went on to do her doctoral work in Sanger’s laboratory in Cambridge. Her timing couldn’t have been better, for Sanger had just figured out how to sequence DNA. And there was a second fortuitous event in her life: in Cambridge, she met her future husband, American John Sedat, who soon accepted a position at Yale University. As a result, she decided to join Joseph Gall’s lab at Yale for her postdoctoral research.
Gall, a well-established cell biologist, was interested in chromosome structure, and Blackburn knew how to sequence DNA from her work with Sanger. They applied their combined expertise to identify the sequence of DNA specifically at the telomeres of chromosomes. Humans had a mere ninety-two telomeres in each cell; two for each of the forty-six chromosomes. This, they realized, was not enough material. Cleverly, they chose a single-celled organism called Tetrahymena, which in one phase of its life cycle has up to ten thousand small chromosomes. They found that the sequence of DNA at the telomeres of chromosomes was different not only from anything in the rest of the chromosomes but also from anything they’d ever seen before. TTGGGG (or the complementary CCCCAA on the other strand) was repeated anywhere from twenty to seventy times.
Shortly after Blackburn had characterized these repeats, she encountered Jack Szostak, who was working at Harvard Medical School and was trying to insert artificial chromosomes into yeast. The idea was to introduce new genes into yeast through these artificial chromosomes, which would be replicated along with the yeast’s own chromosomes. For some reason, however, they were unstable. The yeast cells were seeing the ends of these artificial DNA molecules as breaks due to damage and setting off a response. Szostak and Blackburn collaborated to see what would happen if they tacked on the telomere sequence of the Tetrahymena chromosomes to the ends of Szostak’s artificial chromosomes. It worked like a charm: the modified artificial chromosomes were now stable in yeast. Szostak went on to characterize the telomeric DNA from yeast itself. It turned out to have a similar repeat to Tetrahymena. Instead of TTGGGG, the repeat was a combination of TG, TGG, or TGGG. From later work, we know now that in humans and other mammals, the repeat is TTAGGG.
Somehow these short telomere sequences told the cell that they were special and should not be treated as ends of broken DNA. Amazingly, although Tetrahymena and yeast are separated by more than a billion years of evolution, the slightly different repeat sequence from Tetrahymena still works in yeast. This suggests a universal mechanism that protects the telomeres of chromosomes and depends on these repeated sequences.
You could think of these repeated sequences as extra, dispensable material tagged on to the ends of chromosomes. Each time the chromosome replicated, it would lose some repeats, but it wouldn’t matter until you eventually lost them all and started losing important genes near the ends of chromosomes. It could explain why cells divided only a certain number of times before they reached the Hayflick limit and stopped.
Even though this explained some things in principle, it still left several basic questions unanswered. What added these telomeric sequences? And why can some cells divide many more times than the Hayflick limit, such as cancer cells or our own germ-line cells?
The first big advance toward answering these questions came when Blackburn, who was now running her own lab at the University of California, San Francisco, was joined by a graduate student, Carol Greider. The two of them discovered an enzyme that adds the telomeric repeat sequences to the ends of chromosomes. They named it telomerase.
Cells from most tissues make very little or no telomerase, but cancer cells and some special cells such as germ-line cells do. Without telomerase, our telomeres get shorter and shorter with age until the cell is triggered into senescence and stops dividing. By contrast, cells with telomerase can simply rebuild their telomeres after each division and thus divide indefinitely. Even introducing telomerase into normal cells can extend their life spans.
As is often the case in biology, it is not quite this simple. Cells lose much more DNA during each division than Watson and Olovnikov would have predicted. Moreover, they stop dividing even before all of the telomeric region is lost. And finally, even if telomeres have a special sequence, it still wasn’t clear why the cell didn’t see them as breaks in the DNA and turn on its DNA damage response.
It turns out that the telomeric ends have a special structure in which one DNA strand extends beyond the other. This longer strand loops back and forms a special structure with the help of special proteins collectively called shelterin, because they shelter and protect the ends of the DNA. This crucial structure is why the cell doesn’t recognize the ends of chromosomes as double-strand breaks. A loss or deficiency in shelterin can be lethal, and even moderately defective shelterin can lead to chromosome abnormalities and premature aging, even when the telomeres are of normal length.
When enough of the telomere DNA is lost, these special structures cannot form. The cell then sees the unprotected ends of the DNA as breaks and sets off the damage response, instructing other cells to either commit suicide or go into senescence. We still don’t know how or why some cells, like the ones Leonard Hayflick studied, go into senescence while others self-destruct. Perhaps cells that are especially important for maintaining or regenerating tissues—such as stem cells—preferentially commit suicide to avoid passing on damaged DNA to their offspring.
This is all very well for understanding cells in culture, but does this have anything to do with why we age? Or our life spans? And why is telomerase switched off in most of our cells? If we switched it on again, would we simply stop aging?
People with defective telomerase, or who have less than the normal amount of it, prematurely develop a number of diseases associated with old age. Likewise, a stressful life can often make us appear to age faster. We look haggard, and even our hair can turn prematurely gray or white. Stress can also bring on many of the diseases we associate with old age. Stress has multiple effects on our physiology, and exactly how it affects the aging process is complex. But one of the things it does is to accelerate telomere shortening. When we are stressed, our body produces much more cortisol—referred to as the stress hormone—which reduces telomerase activity.
You might expect that species with longer telomeres would live longer, but mice, which typically live only about two years in the lab and much less in the wild, have much longer telomeres than we do. So it may be that the shortening of their telomeres occurs more rapidly. Nevertheless, if you reactivate telomerase in mice that are deficient in the enzyme, you can reverse the tissue degeneration that occurs with aging. According to a number of studies, mice engineered to have even longer telomeres showed fewer symptoms of aging and lived longer. Presumably, starting off with much longer telomeres compensated for their more rapid shortening in mice.
Based on studies like these, many biotech companies are introducing the gene for telomerase into cells or using drugs to activate the telomerase gene that already exists. Some of them are working on how to turn on the enzyme transiently, to avoid the potential problem of triggering cancer by having telomerase switched on permanently. Initially, many of these experiments are focusing on specific diseases where aberrant telomere shortening is thought to be the cause. But the efficacy and long-term consequences of these strategies remain unknown.
When telomerase was discovered, it stirred a lot of excitement in cancer research. Since cancer cells had activated telomerase, scientists thought of it as an anti-cancer target—if you could inhibit it or turn it off, you might kill cancer cells. On the other hand, turning it off could potentially accelerate the shortening of telomeres, which could not only lead to premature aging or other diseases, but by disrupting our telomeres, lead to chromosome rearrangements, which, ironically, could itself cause cancer. There seems to be a delicate balance between telomere loss and aging on the one hand and increased risk of cancer on the other, and it may be that our normal process of switching off telomerase in most of our cells is actually a mechanism to suppress cancer early in life. This balancing act is also apparent from a study showing that people with short telomeres are prone to degenerative diseases, including organ failure, fibrosis, and other symptoms of aging. On the other hand, those with long telomeres face increased risks of melanoma, leukemia, and other cancers. This suggests that we have some way to go before tinkering with telomerase can be a viable strategy for either cancer or aging.
In the last two chapters, we’ve talked about how genes contain the program to control the complex process of life. In chapter 5, we will see how even allowing for changes from damage to DNA or to our telomeres, the script of life written in our DNA is not fixed. It is modified and adapted on the fly, depending on its history and environment. The ability to annotate the script, much like a conductor would a score or a film director would a screenplay, is the basis of some of the most fundamental processes of life, including how an entire animal develops from a single cell. When the annotation goes awry, that too is a fundamental cause of disease and aging.
5. Resetting the Biological Clock
On June 26, 2000, President Bill Clinton and British prime minister Tony Blair, each flanked by some of the world’s most distinguished scientists, linked up via satellite to make a carefully choreographed announcement of “another great Anglo-American partnership.” The occasion was the publication of the draft sequence of the entire human genome: the precise order of bases in nearly all of our DNA.
Excitement over this milestone was unanimous across the belief spectrum. Clinton said, “Today we are learning the language in which God created life,” while Richard Dawkins, the evolutionary biologist and passionate atheist, said, “Along with Bach’s music, Shakespeare’s sonnets, and the Apollo space program, the Human Genome Project is one of those achievements of the human spirit that makes me proud to be human.”
Other scientists and the popular press gushed with similarly hyperbolic statements. The identification of every human gene would make possible new treatments against diseases and usher in a new era of truly personalized medicine. If we sequenced the genes of individuals, some suggested, we would be able to understand their fate in detail: their strengths and weaknesses, aptitudes and talents, susceptibility to disease, how quickly they would age, and how long they would survive.
The announcement ceremony was the culmination of a long and difficult path. For many years, an international consortium of scientists, mostly in the United States and the United Kingdom, and funded by government sources or biomedical charities such as the Wellcome Trust, had made slow but steady progress, releasing bits of sequence as they went along. They were called the public consortium because they received substantial public funding and had pledged to make their data available to all.
Then, in the early 1990s, J. Craig Venter, who had made his name by producing the first complete sequence of a bacterium, Haemophilus influenzae, entered the fray. Venter was something of a maverick in the field. He played the part of the American entrepreneur and capitalist, sailing around the world in his yacht, often flying by private jet. On one of the few occasions I saw him, he jetted into a meeting at the Cold Spring Harbor Laboratory to celebrate the 150th anniversary of Darwin’s On the Origin of Species, gave his talk, and left immediately because he clearly must have had more important things to do—unlike me, who stayed for the rest of the weeklong conference. Venter had already caused a huge fracas in the science community when he worked at the U.S. National Institutes of Health (NIH)—the large government biomedical research laboratories in Bethesda, Maryland—by attempting to patent pieces of human DNA sequences to allow their commercial exploitation for treatment and diagnosis. The decision by NIH to green-light this led James Watson to resign as the first director of the agency’s National Center for Human Genome Research. Although the NIH had filed the patents in his name, Venter said later that he was always against them.
Venter felt that the public consortium was too slow and that the method he had used for sequencing the million bases of a bacterium could be scaled up to sequence the roughly 3 billion bases in the human genome at much lower cost. So he started a private company, Celera, to do just that. Of course, Venter wasn’t above using the large portions of the human genome that had already been sequenced by the public consortium before he entered the race. Many in the human genome community were outraged by Venter’s audacity and were determined to ensure that the human genome, and, indeed, all other natural genomes, were not patented for the benefit of a private company but freely available to humanity.
One detractor was John Sulston, one of the leaders of the public consortium. Sulston presented a marked contrast to Venter. Despite his considerable fame and influence, the British scientist continued to dress in the sandals and other shabby attire reminiscent of a 1960s hippie. He lived in the same modest house and commuted to his lab on his ancient bicycle. A particularly passionate advocate of the genome being free for use by all, Sulston was sharply critical of Venter’s motives and contributions. In the run-up to the completion of the draft sequence, relations between members of the public consortium and Venter became so acrimonious that President Clinton had to intervene personally to get them to politely share the stage at the announcement.
Despite all the hoopla, the draft sequence that Clinton and Blair announced was just the beginning. Large sections of the genome were still missing, especially regions consisting of repeating letters and thus difficult to sequence, and scientists had to figure out how some stretches of DNA actually fit together. The sequence was declared finished three years later, although, in reality, even today a few gaps remain, including on the Y chromosome, the male sex chromosome. (Women have two X chromosomes; men, one X and one Y.)
The human genome sequence is often called “the book of life,” but this is somewhat misleading. In reality, even a perfectly complete sequence would be more like one long unpunctuated stream of text than a book. It would have no markings to denote individual chapters, paragraphs, or even sentences, nor cross-references to provide context. It would certainly be nothing at all like a well-edited encyclopedia in which you could look up your favorite gene and learn all about it and its relationship to everything else. And frankly, a lot of it was indecipherable. Only about 2 percent of our DNA actually codes for the proteins that carry out much of life’s functions. The rest consists of what biologists once dismissed as “junk DNA”; they now increasingly think it is important, but don’t fully understand how or why.
Initially, scientists didn’t even know where a lot of the protein-coding genes were, because the signals that indicate where a gene starts and ends on the DNA are not always obvious. They are made even harder to discern by the presence of what are called pseudogenes: regions that once might have coded for proteins but are no longer expressed or functional. Many pseudogenes originated from viruses that inserted their own genes into our DNA. Finally, even knowing the sequence of a gene does not automatically reveal its function. Nevertheless, sequencing the genome was an immensely useful start. It allowed us to ask questions and conduct experiments that would have been unthinkable before. It was a watershed in biology.
You might also think that the book of life would be able to tell us accurately how each of our individual stories develops and ultimately ends. After all, DNA is the carrier of all genetic information, the master controller that oversees biological processes. Shouldn’t knowing its entire sequence enable us to predict how an organism or cell will develop? Certainly mutations in individual genes have been associated with many diseases; examples include cystic fibrosis, breast cancer, Tay-Sachs disease, and sickle-cell anemia. But on the whole, biology is just not that deterministic.
Identical twins belie the view of DNA as destiny. They share the same genes and are often strikingly similar even when separated at birth. That’s not surprising. What is surprising is that identical twins raised in the same environment can sometimes be very different, even when it comes to conditions with a strong genetic basis, such as schizophrenia.
Every one of us is a living testament to the fact that DNA by itself does not determine fate. All of our cells are descended from a single cell, the fertilized egg, and as that cell divides, it produces new cells, each one containing the same genes. Yet these genes give rise to a multitude of different cells. A skin cell is very different from a neuron, or a muscle cell, or a white blood cell. As we know, different genes are turned on and off in response to changes in the environment. It makes sense, then, that as different cells find themselves in slightly different circumstances, they change which genes they express and go down different paths to form the various tissues in the body. Importantly, you cannot reverse this process—even if you try to culture these different cells in exactly the same medium, they maintain their identity, as though the cells still remember which tissue they came from.
This suggests that some more permanent change has occurred in the genetic program of the cells as a result of their environment. The study of this change is known as epigenetics, from the Greek prefix epi-, for “above,” to imply there was a second layer of control on top of our genes. The term was coined by the British polymath and professor of animal genetics Conrad Waddington in 1942. Waddington described the process in terms of a landscape. The original fertilized egg, he said, was like a ball on top of a mountain. Its progeny rolled down different paths into the various ravines and valleys at the foot of the mountain, each valley representing a different type of cell. Once there, it would be impossible to roll back up to the top or to roll up the ridge and down into a neighboring valley. In other words, once a cell had settled down into its final type, it couldn’t change into a different type; a skin cell could not become a lymphocyte, a type of white blood cell. Nor could a skin cell reverse its fate and become a fertilized egg to give rise to an entirely new body.
Initially, Waddington was vilified by many as a Lamarckian, or someone who, like the evolutionary biologist Lamarck, believed that acquired characteristics could be inherited, an idea discredited by Darwin and Wallace’s theory of evolution by natural selection. Waddington’s theory seemed to imply that our environment affected our genes in some irreversible way. Even for those who accepted his ideas, they raised questions. At what point did the cell have its genome so altered that it could no longer direct the development of an entire organism? And how far down Waddington’s mountain could a ball roll and still somehow go back to the top?
During Waddington’s time, we did not even know that DNA was the genetic material, let alone its structure or how it stored genetic information. But it was known already that the fertilized egg, or zygote, was a very special cell: it had the right genetic material, and its cytoplasm, the internal material of the cell, seemed to have everything needed for kick-starting the process of developing into a new organism. The fertilized egg is said to be totipotent, meaning that it can develop into all the cell types needed to make a new animal, including its body and placenta. After a few divisions, the embryo reaches a stage called the blastocyst, which has a couple of hundred cells surrounding a fluid-filled cavity. The outer cells go on to form the placental sac, while the inner cells develop into everything else that forms the new animal. Those inner cells that develop into every cell in the body are called pluripotent.
Waddington’s metaphorical mountain shows the development of special cell types from a pluripotent stem cell.Development of a blastocyst from the fertilization of an egg.
Was the special property of the fertilized egg a result of its genome or its environment? If the latter, could you take a nucleus containing the genes from a highly specialized cell, put it into an egg that had its own nucleus removed, and make it totipotent so that it developed into a normal animal? This was precisely the question that Robert Briggs and Thomas King at the Institute for Cancer Research and Lankenau Hospital Research Institute in Philadelphia sought to answer. In 1952 they tried this with the northern leopard frog (Rana pipiens), as frog eggs are large and transparent, and thus easy to manipulate under a microscope. Briggs and King found that if they took nuclei from cells in the blastocyst stage of the embryo and introduced them into enucleated eggs, the eggs could develop normally into tadpoles. But if they took nuclei from cells at a later stage of development, the egg would develop partly and then stop and die. By a relatively early stage of development, then, an embryo’s cells are already committed to their program. They are too far down Waddington’s metaphorical hill and can’t go all the way back to the top.
At this time, scientists simply did not know whether specialized cells had lost parts of their genome that were essential for growing an entire animal from scratch, or whether there was something else about them that prevented their development beyond a certain stage. Then along came a young scientist who would carry out one of the most famous experiments in modern biology.
WHEN I FIRST MET JOHN GURDON, I was immediately struck by his shock of golden hair that gave him a leonine appearance. By then, he was a world-renowned scientist in his seventies who worked in the institute named after him in central Cambridge, England, about three miles from my lab. Despite his stature in the world of science, he was unassuming and courteous to everyone, from a beginning graduate student to his senior colleagues. Long after many scientists would have retired, Gurdon remained passionate about science and carried out his own experiments. But his career had a rocky start.
Gurdon hailed from an aristocratic family whose Norman ancestor came with William the Conqueror in the 1066 invasion of England. Like many boys from privileged families, he went to Eton, the prestigious boarding school, at the age of thirteen. His time there did not begin well, for his biology teacher wrote a damning report at the end of his first science course. With the random capitalization that was already a couple of centuries out of date except in certain quarters of the British establishment, it said, “I believe he has ideas about becoming a Scientist; on his present showing, this is quite ridiculous, if he can’t learn simple Biological facts he would have no chance of doing the work of a Specialist, and it would be sheer waste of time, both on his part, and those who have to teach him.” Gurdon was not allowed to take any more science courses. He studied languages instead.
Nevertheless, Gurdon had a strong interest in biology and nature from childhood and was not so easily dissuaded. Fortunately for science, his parents were supportive and able to help him. Although they had already forked out several years’ worth of expensive tuition fees to Eton, they paid for him to study biology with a private tutor for an additional year after he had graduated. In an unusual arrangement, he was then admitted to the University of Oxford on the condition that he first pass exams in basic physics, chemistry, and biology in a preliminary year. Gurdon survived the ordeal, began his undergraduate studies in zoology, and went on to begin research for a PhD with Michael Fischberg, who was also at Oxford. This was just four years after Briggs and King’s experiment with frogs.
Fischberg suggested that Gurdon try to repeat their experiment but using a different kind of amphibian: the African clawed frog (Xenopus laevis). Referred to originally as a toad, it was first brought to the attention of biologists by Lancelot Hogben, a peripatetic British scientist who moved from England to Canada and then, in 1927, became a professor at the University of Cape Town in South Africa. While there, Hogben began studying the frog because of its chameleonlike properties. The clawed frog became a favorite model organism in embryology; not only were its eggs large like those of the frogs that Briggs and King had studied, but also it had a short life cycle and could be triggered by external hormones to lay eggs any time of the year.
After overcoming some technical difficulties, Gurdon finally pulled off an experiment using Xenopus laevis that would revolutionize the world of biology. He was able to take the nucleus from one of the cells lining the intestine of a tadpole and insert it into an egg whose own nucleus had been inactivated by subjecting it to a large dose of UV radiation. The resulting egg developed into a complete tadpole, suggesting that the intestinal cell nucleus had all of the information needed for development that an egg nucleus had. To rule out the possibility that the egg’s own nucleus had not been completely inactivated, Gurdon was careful to use two distinguishable strains of Xenopus for the cell that donated the nucleus and the egg that received it. There was no doubt that the donor nucleus had given rise to the tadpole. In fact, since the genes of the new tadpole were identical to those of the donor that contributed the nucleus, it was a clone of the parent. This was the first time that someone had taken the nucleus from the cell of a fully developed animal to clone an entirely new animal.
Gurdon’s work had a tremendous impact almost immediately. He had demonstrated that the nucleus of a somatic cell of a fully developed animal was capable of directing the development of an entirely new animal—which would be a clone of the animal that donated the nucleus. It meant that a somatic cell could be made to go backward in development; in fact, all the way back to the top of Waddington’s mountain. It could reverse the aging clock and start all over again to grow into a new animal. It also meant that cells that had developed into specialized tissues such as intestines retained all their genes. They were specialized not because they had preferentially lost genes but because they had somehow modified which genes would be turned on or off in each case.
Eventually other researchers reproduced Gurdon’s experiments with different species, but the procedure was not performed on mammals until 1996. Scientists at the Roslin Institute, outside Edinburgh, cloned a sheep named Dolly from a cell taken from the mammary gland of an adult animal. The news generated huge headlines around the world. There was widespread discussion of the ethics of cloning, with concerns ranging from animal welfare to a brave new world in which rich people who wanted to live on would clone themselves or a loved one they had lost. (Apparently the absurdity inherent in this was also lost.) Today cloning has been successful in a wide range of animals, although for obvious ethical reasons, it is internationally forbidden to attempt it in humans.
In spite of all the excitement, Gurdon’s early experiments were quite inefficient: only a small fraction of the nuclear transplantations actually worked. Others failed right away or developed into defective embryos that stopped growing and died. And in the sixty years since Gurdon’s original experiments and the more than twenty-five years since Dolly, scientists have toiled painstakingly to improve the efficiency of cloning; nevertheless, it remains an inefficient technique. Nature’s way of creating offspring works far better.
ONE OF THE BIG PROBLEMS with being human as opposed to, say, a starfish, is that we cannot generally regenerate our tissues. We cannot grow a new arm if one gets cut off. Soon after the first nuclear transplantation experiments, scientists began wondering whether the following might be the solution: Could you make these early embryonic cells grow on command into any type of tissue you wanted, such as heart muscle, neurons, or pancreatic cells? If that ever became a practical option, it would have enormous potential for medicine. Moreover, the deterioration of our tissues is one of the major problems we face as we age, and you could think of regenerating and rejuvenating them.
We might not be able to regrow a limb, but we already have the ability to regenerate certain kinds of tissue. Every time you cut or scrape yourself, your body creates new skin. Donate blood, and your body simply makes more. How does the body do this? While many of our cells are what we call terminally differentiated—they have reached a final state and will simply carry out their assigned tasks until they die—other, highly specialized cells are responsible for producing new cells to regenerate aging tissues. We call them stem cells.
Stem cells can be at many stages themselves. Many of them are already quite a way down Waddington’s mountain, capable of developing into only a few different cell types. For example, hematopoietic stem cells in our bone marrow can generate all the major cells in our blood, including red blood cells and the cells of our immune system. But they can’t become liver cells or heart muscle cells. However, the inner cells of the early embryo are pluripotent stem cells that can develop into every cell type in the body.
Scientists have been able to take these embryonic stem cells, or ES cells, maintain them in culture, and then alter conditions to nudge them into developing into one tissue type or another. Being able to grow ES cells in culture solved the problem of having to extract them from fresh embryos each time and fueled an explosive growth in stem cell research. However, the ultimate source of ES cells was still embryos, which would often be obtained from aborted fetuses, raising ethical questions and regulatory scrutiny. For some time, federal grants in the US could not be used to pay for research involving human ES cells, and labs had to clearly separate areas that were federally funded from those that were not.
It seemed almost miraculous that you could take any adult cell and coax it into developing into any tissue you wanted, let alone into an entirely new animal. What is it about stem cells, especially pluripotent stem cells, that makes them different from most cells in our body?
Molecular biologists had begun to identify transcription factors: proteins that regulate gene expression—that is, turning genes on or off, and by how much. The name comes from their control over whether a particular gene on DNA is “transcribed” into mRNA, which is then read to make the appropriate protein. Stem cells contained a large number of active transcription factors, some of which were needed to keep them growing in the laboratory. It was hypothesized that perhaps a newly fertilized egg possessed similar transcription factors that allowed it to develop into a new animal. Some of these same factors were also active in cancer cells, which can proliferate indefinitely.
Such was the state of affairs in the late 1990s, when a Japanese scientist, Shinya Yamanaka, turned his attention to the matter. Yamanaka was born in 1962, the same year as John Gurdon’s successful cloning of a frog. He began his career as a surgeon, influenced partly by his father, an engineer who ran a small factory in the city of Higashi-Osaka. Yamanaka’s enthusiasm for surgery soon waned, however: not only did he begin to lose confidence in his skills but also he came to see surgery as limited in terms of being able to treat many patients with intractable conditions such as rheumatoid arthritis and spinal cord injuries. Instead, Yamanaka thought, he ought to spend his life working as a basic scientist to find ways to cure them. He earned a PhD in Osaka and went on to postdoctoral research at the Gladstone Institute of Cardiovascular Diseases in San Francisco.
By the time Yamanaka returned to Japan to establish his own lab in the late 1990s, scientists knew that ES cells expressed quite a few transcription factors. If you turned on some or all of these factors in a normal cell, would you be able to trick it into behaving like a stem cell? Yamanaka and his student Kazutoshi Takahashi hoped so. They identified twenty-four factors that might be responsible for the pluripotent property of ES cells, and systematically introduced them into fibroblast cells found in skin and connective tissue—the same cells that Hayflick had attempted to culture. By experimenting with transcription factors in various combinations, they found that just four were enough to convert an adult fibroblast cell into a pluripotent cell.
As a result of Yamanaka’s work, we no longer need to harvest cells from embryos to generate pluripotent cells; we can make them from other adult cells. The pluripotent cells made using Yamanaka factors are called induced pluripotent cells or iPS cells. The increased ease of generating iPS cells has led to an even greater explosion in the field of stem cells. Scientists are constantly improving both the efficiency and safety of the process, as well as becoming increasingly sophisticated in determining the paths that the stem cells can take.
REMARKABLE AS THESE ADVANCES ARE, they don’t tell us exactly what is happening to our genome that makes cells behave so differently even though they all have the same DNA. Why do different cells have such different genetic programs? And why do cells remain true to type, so that one cell type doesn’t suddenly change into a different one? Even stem cells that are responsible for generating blood cells don’t start producing neurons or skin cells.
Each cell carries genes that are always expressed because every cell needs them. They’re referred to as housekeeping genes. But for other genes, which ones are turned on and which are kept switched off depends very much on what that particular cell needs. How does the cell control this process? You just read about transcription factors, proteins that control which genes are actively expressed or repressed. One of the first and simplest examples of such a factor was discovered in exploring how the bacterium E. coli digests the simple sugar lactose. Ordinarily, E. coli doesn’t encounter lactose, so it does not constantly make the enzymes necessary to digest it. Instead, it operates on an as-needed basis: when the bacterium senses lactose, it turns on the genes tasked with turning out the appropriate enzymes. As soon as there is no more lactose around, it shuts down those genes. It is a simple and elegant way to switch genes on or off in response to a change in the environment. A good deal of gene regulation works exactly like that, by controlling transcription in response to a stimulus. It is seldom as simple as the lactose case, and usually involves a complicated network where genes that are activated in turn activate or switch off other genes, which affect even more genes.
With E. coli, you can reverse the response to lactose simply by removing lactose from the culture. But if you took a skin cell and put it into, say, a liver, it wouldn’t suddenly start behaving like a liver cell. The transcription factors of a skin cell and a liver cell are different; in addition, the cell has a way of ensuring that some changes in the genetic program persist for a long time, which involves rewiring the code on DNA itself.
So far, we have thought of DNA as a simple four-letter script containing all the information to make the proteins that carry out various essential functions. But even before the structure of DNA was known, scientists understood that a small fraction of its four bases, A, T, C, and G (or U, the equivalent of T in RNA), had extra chemical groups attached to the base. In the early days, nobody knew what these modifications were for.
Today we know that many of them act as extra tags that serve as signals for whether a gene should be kept switched on or off over the longer term. The most common of these is the addition of methyl (-CH3) group to cytosine, the C base in DNA. When Cs at the right place are methylated in this way, the genes just ahead of them are kept switched off.
As cells develop, they will methylate their DNA in the region of genes they want to shut down, and leave unmethylated those regions that contain genes they need to actively use. So cells that differentiate into skin cells will have a different methylation pattern from, say, neurons.
You might expect that when cells divide and their DNA copied, the patterns of methylation would be lost because you’re making the new DNA with fresh building blocks, but the cell has an ingenious way of restoring the methylation pattern of the parent cell. What this means is that the exact pattern of methylation can be passed on to the daughter cell when a cell divides, so genes that are shut off in a particular cell lineage remain shut off. The flip side of this also occurs: there are demethylases that remove methyl groups, which then allow those genes to be turned back on. Apart from using transcription factors, modifying the DNA itself in this way offers a completely additional level of control over which genes are turned on and off. It is also a method of ensuring that these changes can be passed on to the next generation of cells. These modifications of DNA alter the way our genes are used. They are called epigenetic marks or changes because they are the molecular explanation for the phenomenon of epigenetics that Conrad Waddington had first described.
These epigenetic marks not only persist and even increase as we age—they can even be passed across generations. Toward the end of World War II, between September 1944 and May 1945, the Netherlands suffered from a devastating famine that would claim the lives of more than 20,000 people. A later study showed that despite the relatively brief duration of the famine, the children of women who were pregnant during the mass starvation suffered adverse physical and mental health consequences throughout their lives. They experienced higher rates of obesity, diabetes, and schizophrenia, and had a higher mortality than children who were not in utero during the famine. The effects were even different depending on whether the famine occurred in the early or late stages of pregnancy. Comparing the DNA of subjects who had experienced starvation in utero with those of their older and younger siblings was revealing: the famine had imposed on the fetus a methylation pattern that had consequences over the course of its life and accelerated both aging-related diseases and mortality. It is a striking example of how an external stress can cause epigenetic changes to DNA that last a lifetime.
IF THAT ISN’T COMPLICATED ENOUGH for you, just wait: DNA isn’t present in cells as a naked molecule. Rather, it is heavily coated with proteins called histones, and this mixture of proteins and DNA is called chromatin. These histones help us understand how all of our DNA can fit into a cell’s tiny nucleus. If you could stretch out the DNA in a cell, it would measure approximately two meters (six and a half feet). The nucleus, in contrast, is only microns in diameter—or about a million times smaller. Histones are positively charged and neutralize the negative charges on the phosphate groups of the DNA. By doing so, they allow DNA to condense into a highly compacted form.
The first level of DNA compaction is the nucleosome, in which DNA is wound around a ball-like core consisting of eight histone proteins. The nucleosomes further organize themselves into filaments that are then woven back and forth until it all fits comfortably in the nucleus. When cells divide, the duplicated chromosomes have to move into each daughter cell, and just as you would cram the belongings from your entire household into a truck before you move, chromosomes are most compact just before cell division. That is when they have the familiar X shape that we see in most popular images of chromosomes. But for most of the life of the cell, chromatin is much more extended.
The problem with compacting chromatin is that the cell needs to be able to access information on the DNA when needed. It’s like owning a large collection of books but not having sufficient space in your home to have all of them within easy reach. You might box most of them and store them in the attic but keep the books you’re currently reading or planning to read soon easily accessible on a bookshelf or piled on your nightstand. The cell too has to make sure that appropriate regions of chromatin are accessible, even if it wants to shut down much of it. It does so by tagging histones by adding certain chemical groups to them. Just as with methyl groups on DNA, there are enzymes that add these histone tags and others that take them off. Tags on histones can act as a signal for the cell to recruit other proteins to that region and either inactivate chromatin or open it up, so they too act as epigenetic marks. With histones, one common tag is called an acetyl group, and the enzymes that add them to histones are called histone acetylases.
In general, DNA methylation and histone acetylation exert opposite effects. DNA methylation usually silences the gene that follows the methylated region, while histone acetylation signals that the gene is to be actively transcribed. Both can be reversed by the action of demethylases or deacetylases.
What both modifications do is to overlay on top of the DNA sequence itself a second and longer-lasting way of modifying the program of a particular cell. They allow cells to maintain a stable identity as neurons, skin cells, or heart muscle cells. As a cell develops from the fertilized egg, different epigenetic marks must be laid down as it develops into different cell types.
WE ALL KNOW THAT PEOPLE age at different rates. Some people look old at fifty, while others are remarkably youthful into their eighties. Some of this comes down to genetics, but aging can also be accelerated by stress and hardship. From the moment we are conceived, our cells don’t just acquire mutations in the DNA affecting the underlying code itself. They also acquire epigenetic marks. As we saw with the Dutch famine survivors, some of those marks are the result of environmental stress.
Steve Horvath, while working at the University of California, Los Angeles, was not interested in epigenetics, believing it to be too messy, indirect, and unlikely to show much useful connection to aging. But one day, a colleague was collecting saliva from identical twins who differed in sexual orientation, and he wanted Horvath to help him see if there were any epigenetic differences between them. Horvath is a twin; his brother is gay, while he is heterosexual. In the spirit of scientific inquiry, they contributed some of their own spit to the study. When they looked at the methylation of cytosines, they found absolutely no relationship between the pattern and sexual orientation.
But Horvath now had a lot of data from twins of various ages. He decided to mine it further to see what else he could learn. He discovered a very strong correlation between the DNA methylation pattern and age. He then looked at cells in other tissues and correlated the methylation pattern with actual markers of aging—for example, the sort of things your doctor would analyze from your blood, such as liver and kidney function. He was able to identify 513 sites of methylation that could predict not only mortality but also cancers, health span, and the risk of developing Alzheimer’s disease.
These patterns help scientists approach a fundamental problem. People age biologically at different rates, so how do you measure aging? Methylation patterns are like a biological clock; in fact, they are more accurate than chronological age alone at predicting age-related diseases and mortality. Many other research groups developed their own methylation clocks with slightly different markers, all correlating well with biological age. Still, as Horvath and his colleagues themselves point out, these clocks are useful for research but are not yet a substitute for tests that measure loss of physiological function or provide early diagnosis of diseases.
We don’t think of young children as aging; in fact, throughout much of childhood and adolescence, they become stronger and their odds of dying decline. But it turns out that while the methylation patterns reverse very early in the embryo, suggesting a resetting of the clock or a rejuvenation, from that point on, methylation follows an inexorable pattern. So we age from even before we are born! Similarly, the long-lived naked mole rat is thought not to age because its risk of dying doesn’t increase with time. In fact, its methylation pattern shows that it does age, just more slowly than other rodents.
For an extreme example of the effect of epigenetics on longevity, look no further than a beehive. Bees, like ants, have a queen that can live many times longer than other bees that share exactly the same genes: queen honeybees live two to three years, while worker bees die after only about six weeks. This is partly because once the queen is selected, she is treated very differently. She is kept deep in the hive, pampered and protected against predators, whereas worker bees and ants must go out and risk their lives foraging for food. She is fed an exclusive diet of royal jelly, which has a different composition and a much higher nutritional value than the ordinary nectar and honey that worker bees live on. But the impact of these factors goes deeper. Something about her diet and stress-free environment results in her having different epigenetic marks from worker bees, and she ages at a far slower pace.
The question of why epigenetic marks should cause aging is complicated. The patterns are associated with an increase in inflammatory pathways and a decrease in pathways for making RNA and proteins as well as DNA repair, so it is easy to see how they might result in aging.
The epigenetic changes also seem to occur on a timetable. This doesn’t mean that aging itself is programmed. It could simply be that the epigenetic changes take place when they are needed at some stage, but they are not switched off when their work is done because evolution doesn’t care what happens to you after you have passed on your genes. By shutting down many genes in a stable way, epigenetics may also prevent cells from becoming cancerous early in life. Like telomere loss, and the response to DNA damage, this may be yet another example of the trade-off between preventing cancer and preventing aging.
It is also possible that many epigenetic changes are not programmed but caused by random changes in the environment. Remember the case of identical twins? Those epigenetic changes in their DNA diverge right from birth, so while they still have largely the same DNA sequence, they acquire very different epigenetic marks.
CAN THE AGING CLOCK EVER run backward? Yes, and it has happened to every single one of us: at conception, when the aging clock is reset to zero. When a forty-year-old woman gives birth, that newborn is not twenty years older than a baby born to a twenty-year-old woman. Even though the germ-line cells are older in the forty-year-old woman, both children start at the same age. The aging that takes place in the parents is reset in the child.
We have evolved at least three ways to reset the aging clock. The first is that germ-line cells have superior DNA repair and accumulate fewer mutations than somatic cells do.
Second: the egg and the sperm each undergo a rigorous selection process prior to fertilization. A woman produces all the eggs she will ever have while she is still a fetus. These number perhaps a few million to start with but are down to about a million by the time she is born. By puberty, this number drops to about a quarter million, and by the time a woman is thirty, only about 25,000 eggs remain. However, a mere 500 of those eggs get used up by ovulation during the menstrual cycle over a woman’s lifetime. With sperm, this ratio is even more dramatic: males produce millions of sperm cells from puberty on. So there is a huge surplus of both eggs and sperm. Why? Prior to ovulation—that monthly event in which the ovary releases one mature egg, or ovum, into the fallopian tube for the purpose of potentially being fertilized—the eggs in the ovary are somehow inspected and destroyed if damage is detected. Only those that pass the test make it to ovulation. As damage is likely to increase with age, this might explain why the egg count drops precipitously and the chance of becoming pregnant decreases. Perhaps the monitoring process also becomes less effective, since genetic defects in the baby also increase with the age of the mother.
Similarly, sperm cells may undergo selection as well, and a sperm must swim and outcompete all the millions of others to be the first one to fertilize the egg. Even after fertilization, many embryos are rejected early in development if they are sensed as being defective. And even within an embryo that is developing normally overall, there is competition to eliminate abnormal cells. The process isn’t perfect, but nature has done its best to ensure that our offspring are free of our own cellular damage and aging.
The third method for resetting the aging clock is to actually reprogram the genome. Immediately after impregnation, the fertilized ovum, or zygote, temporarily bears two nuclei (pronuclei): one from the mother and the other contributed by the father. The enzymes and chemicals in the zygote proceed to erase nearly all the epigenetic marks in the DNA of both pronuclei, and then add new ones to start the fertilized egg on the path to making a baby. Notice that I said “nearly all.” An egg with both pronuclei coming from just a male or female parent alone would not develop normally. This is because the pronuclei donated by the mother and father have a different but complementary pattern of epigenetic marks, also called imprinting, which together provide the proper program for development.
Considering all the intricacies of normal development we just described, it is amazing that cloning frogs or Dolly the sheep ever worked at all. For one thing, the genome of cloned animals came from adult somatic cells, with an entire lifetime of accumulated damage. Animals conceived normally, on the other hand, start off from much more protected germ-line cells and go through a rigorous selection process both before and after fertilization. In addition, changing the program of a somatic cell is very different from an egg’s normal task. Given these difficulties, how could these cloned animals possibly be normal? Would they not show signs of premature aging or other abnormalities compared with naturally conceived animals? In truth, it didn’t work so well. Most of the transplants never made it to fully formed animals. Still some, like Dolly, did.
And the truth is, Dolly was quite a sick sheep. She had abnormally short telomeres and, at the age of one, was judged as older than her chronological age by several criteria. Sheep normally live ten to twelve years, but at six, poor Dolly developed tumors in her lungs and had to be put down. It turns out, however, that Dolly was not the only sheep cloned. There were also the lesser-known Daisy, Diana, Debbie, and Denise, who, surprisingly, all lived healthy lives with a normal life span. This suggests that, at least in principle, it may be possible to reverse the effects of aging and reset the clock even if you start from an adult somatic cell, just by reprogramming the cell. Erasing the epigenetic marks and initiating a new program of gene expression can enable a newly cloned animal to begin from scratch.
Cloning, though, is not the main aim of reprogramming cells, even for farm animals or crops. The real payoff would be in using stem cells for regenerative medicine: repairing or replacing tissue that has died or sustained damage. If we can overcome the technical problems, the possibilities are enormous and wide-ranging. Perhaps we could introduce new pancreatic cells that produce insulin in patients with diabetes, replace damaged heart muscles after a heart attack, or even regrow neurons in people who have suffered a stroke or a neurodegenerative disease like Alzheimer’s. The potential for such breakthroughs is why billions of dollars are being invested in stem cell research today.
Even though they’re not going all the way back to zero and creating a new cloned animal, these stem cells are effectively trying to reverse the aging clock by regenerating or even replacing individual parts of an animal that have aged. Both embryonic stem cells and induced pluripotent stem cells (iPS cells) are capable of differentiating into numerous cell types, but the two are not exactly the same. ES cells are natural early embryonic stem cells that scientists have figured out how to keep cultured and then program to follow different paths to make different tissues, whereas iPS cells are reprogrammed not by the action of factors in the egg but by using the four Yamanaka factors in a somatic cell. This means their behavior is not exactly the same. Still, because of the convenience of generating iPS cells (without the added burden of having to contend with the legal and ethical issues surrounding ES cells), many scientists are working hard to improve Yamanaka’s original method for reprogramming cells.
We will soon see how scientists are trying to reverse aging using this approach. There is also much interest in reprogramming the cell by using specific compounds that inhibit DNA methylation or histone deacetylases. This route to rejuvenating tissues, and even the whole animal, is a major focus of current research. As with telomerase, it may well be the case that our epigenetics have evolved to strike a fine balance between reducing the risk of cancer early in life and accelerating aging. Thus, any approaches to slow down aging or attempt to reverse it by rejuvenation may have to contend with how to do it safely. Indeed, many tissues that have been generated using the four Yamanaka factors have been associated with an unusually high proportion of tumors.
In the last three chapters, we have seen how the genetic program that controls life can be disrupted by damage to our genome, accumulated with age. We have seen how the program itself is modified on the fly to suit the organism’s needs at any given stage. The product of the program is the ensemble of proteins in our cells. These proteins carry out a huge number of complex and interconnected tasks and are like players in a large symphony orchestra.
Now we will see what happens when that orchestra becomes discordant and breaks down.
6. Recycling the Garbage
These days, whenever I forget an appointment or misplace my gloves, umbrella, or hat, I panic for a moment. I have just turned seventy as I write this, and these occurrences immediately strike me as signs of an inevitable and worsening decline. I cheer up when I remember that in my early twenties, I once invited a friend to dinner, forgot about it, and wasn’t even home when he called; or that a couple of years later, I was so preoccupied with finishing my work that I forgot to attend my own going-away party that a neighbor was going to throw for me. And that I’ve been notorious for losing things all my life.
Still, there is a good reason for my foreboding. We all face the prospect of suffering from neurodegenerative diseases that cause us not just to forget but also to completely lose our sense of who we are.
Today more than 50 million people suffer from dementia, and as the proportion of older people in the population is increasing in almost every country in the world, that number is expected to grow to 78 million by 2030 and 139 million by 2050. In England and Wales, it recently overtook heart disease as the leading cause of death, partly because treatment of heart disease has vastly improved, while there is still no effective treatment for dementia. In the United States, it still lags behind the more established killers such as heart disease, cancer, and accidents, but its proportion is gradually rising. It is estimated that about one-third of people born in 2015 will go on to suffer from some form of dementia.
Over half of those with dementia have Alzheimer’s disease, named after the German psychiatrist Alois Alzheimer, who, around 1900, characterized the onset of the then-unnamed disease. His patients, he wrote, would oscillate from periods of calm and lucidity to being unable to identify common objects, feeling increasingly disoriented, forgetful, agitated, and even unhinged. That is just the beginning. As the disease progresses, many Alzheimer’s sufferers are unable to recognize their family and friends. They can no longer carry out basic activities such as speaking, eating, and drinking. They become increasingly terrified at their loss of control, their loss of self-identity, and their increasing inability to make sense of the world around them. Their loved ones may have it even worse, though, having to watch this person—a spouse, a grandparent, a cherished friend—gradually vanish.
In the century-plus since Dr. Alzheimer’s description, we have made tremendous progress in understanding the biology behind Alzheimer’s disease. The same is true of other neurodegenerative maladies, such as Parkinson’s and Pick’s diseases. They all have two things in common: the likelihood of the disease increases as we grow older; and they are caused by a malfunction of our own proteins.
Proteins, as we have seen, are long chains of amino acids that miraculously fold up as they are made. Well, not miraculously. The reason that they fold up is that some amino acids, like oils, are hydrophobic, meaning that they do not like to be exposed to water. Hydrophilic amino acids, on the other hand, are happy to interact with water molecules. As a protein chain emerges, it folds into its characteristic shape by tucking away most of the hydrophobic amino acids on the inside of the protein and exposing the hydrophilic ones on the outside where they are in contact with the surrounding water. Most protein chains have a particular shape or fold that is stable and functional. Sometimes a protein chain folds up along with others to form a complex of several chains. But the principle is the same. In an amazing display of coordination, each of our cells makes not one but thousands of proteins in the amounts it needs and at the time it needs them, and they all must work together as a well-orchestrated ensemble. But the process can, of course, go wrong.
Think of the many ways a household item can become useless. Even a brand-new product can be poorly made and arrive saddled with manufacturing defects. You could damage it accidentally while using it. Or it could slowly wear out or rust and become dangerous to use or stop working entirely. Then there are products, once essential, that we no longer need. Perhaps our children have grown up, and we no longer require baby bottles or cribs. Or technology has changed, and we have no use for a cassette recorder or a film camera. Or our possessions simply go out of style, and we no longer want them. Food has an even shorter shelf life. In our daily lives, we deal with all this as a matter of course. We throw out leftover food that has perished, mend or throw out old clothes, and fix or get rid of broken gadgets. If we didn’t do that, our homes would quickly fill up with junk and become unlivable.
It is the same with cells and their proteins. Proteins can have manufacturing defects too. The protein chain may be made incorrectly or be incomplete. It might not have folded into its appropriate shape. During its lifetime, it could lose its shape by unfolding or be damaged by chemicals or other agents. Just as we may need items only during a particular phase in our lives, many proteins are needed only briefly at a particular stage during a cell’s development or in response to some environmental stimulus. And just as we dispose of or recycle products that are faulty or have simply worn out or been damaged, the cell has evolved ways to detect and then destroy proteins that are defective to begin with or when they become aberrant later. It also has ways of getting rid of perfectly normal proteins that it no longer needs. In all these cases, the cell breaks down defective proteins into their amino acid building blocks, which it can then use to make new proteins or to produce energy.
However, there are crucial differences between the proteins in a cell and a home full of household items. Manufacturers don’t usually much care what happens to their products after they are sold (except during the warranty period, of course). Moreover, the manufacturer of your washing machine does not have to make it compatible with other appliances and therefore isn’t concerned about which brand of refrigerator or microwave oven you own, or whether you own one at all. Cells, on the other hand, both manufacture proteins and use them, and have to ensure that the many thousands of proteins all work together without problems.
As we age, the quality control and recycling machinery of the cell deteriorates, leading not only to neurodegenerative but also many other diseases of old age, including inflammation, osteoarthritis, and cancer. Accordingly, the cell has come up with multiple ways of ensuring the quality and integrity of its collection of proteins.
Proteins can be defective in many ways. The birth of a protein chain takes place on the ribosome, the large molecular machine that I have studied for the last forty-five years. As the ribosome chugs along, it reads the genetic instructions on mRNA to stitch together amino acids in a precise order to make a protein chain. The process has evolved to a high level of perfection over billions of years, but it still occasionally gives rise to defective products. Sometimes the mRNA contains mistakes; sometimes the ribosome misreads it. In these cases, the newly made protein has the wrong sequence of amino acids, so it malfunctions—a bit like a brand-new gadget with a manufacturing defect. These days, many of my colleagues and I are trying to understand how the cell recognizes these mistakes and homes in on them for removal.
Even if the new protein chain has the correct sequence of amino acids, as it emerges from a tunnel in the ribosome, it still faces the challenge of folding into its proper shape. Although the protein chain contains within it all the information needed to form that shape, the process doesn’t usually work spontaneously. With larger proteins, it is difficult to keep the hydrophobic sections from different parts of the chain apart so that they do not stick to one another (or even worse, to other chains that are being made at the same time) while the protein is folding. There are many ways that the folding process can go awry, so cells ranging from bacteria to humans have evolved special proteins whose purpose is to assist other proteins to fold correctly. Ron Laskey, one of my fellow scientists in Cambridge, humorously named these proteins chaperones. (Among other things, Laskey is a folk singer who has written and recorded witty songs about life as a scientist. One of his songs is about how, as a young man, he was part of a double bill with Paul Simon in a small venue in England when neither of them was well known—and realized immediately that he had better stick to science.) Like Victorian chaperones during courtship, these proteins prevent improper interactions between different parts of the chain or between chains. Even so, proteins occasionally misfold.
Even after a protein has already folded into the right shape, you can make it unfold. The proteins in a chicken egg are all folded correctly to carry out their collective function of helping a fertilized egg grow into a chick. But if you take that egg and boil it, its proteins unfold. Similarly, if you add lemon juice to milk and stir, the acid unravels the proteins in the milk. In either case, when the protein chains unfold, the water-avoiding hydrophobic amino acids that were on the inside now become exposed to the surrounding liquid. This makes the proteins stick to one another and become tangled, and the egg or milk turns into a gelatinous solid.
Even without being boiled or treated with acidic lemon juice, proteins are not rocklike, static entities. The atoms in a protein jiggle around all the time, and the proteins themselves breathe and oscillate around their average shapes. Over time, they can unfold, either spontaneously or in response to environmental stress. Often the proteins will then fold back into their original shapes, but sometimes they will clump together instead. As we age, more clumps means more proteins that have lost their function. Even more seriously, the protein aggregates themselves can lead to diseases such as dementia.
We can thus have proteins that are incorrectly made to begin with, or proteins that misfold later. But that’s not all. Many proteins have extra sugar molecules added to specific points on their surface after they are made. This process, called glycosylation, is essential for their work. But as we age, sugar molecules are added randomly to proteins, a process called glycation, to distinguish it from the normal and orderly process of glycosylation. Glycation causes a number of common health problems. For instance, eye diseases such as cataracts and macular degeneration result from proteins in the lens or retina of our eye being modified by sugar molecules, which changes their properties and prevents them from functioning normally. These proteins too need to be recognized and destroyed before they become a problem.
The first line of defense are the chaperones, which refold misshapen proteins into their correct shapes. But if unfolded proteins accumulate, more drastic action becomes necessary. Cells have an elaborate sensor to detect the buildup of unfolded proteins. The unfolded protein response, as this is known, is multipronged: First, more chaperones are synthesized to aid in folding these aberrant proteins. Second, they are tagged and targeted for destruction. Since there is clearly a problem with proteins folding properly, the cell also slows down protein production or shuts it down entirely. In extreme cases, where these measures are inadequate, the unfolded protein response can simply direct the cell to commit suicide.
How can a cell destroy proteins that it senses as defective or unwanted? When it senses that something is wrong, it tags the protein with a molecule called ubiquitin, which is itself a small protein. Ubiquitin was discovered in the mid-1970s and got its name from the fact that it was ubiquitous—scientists found it in almost every tissue they examined. It seemed to have something to do with regulating proteins in the cell, but exactly how wasn’t clear.
Eventually researchers discovered a huge molecular machine called the proteasome, which acts as a giant garbage disposal. When a ubiquitin-tagged protein is fed into the proteasome, it gets chopped up into pieces that can be recycled. Of course, you can imagine that such a powerful degrading machine could be quite dangerous if it were free to act on proteins at will. So the entire process is highly regulated. It is used not just for defective proteins but also for perfectly functional proteins that are no longer required.
Any defect in the proteasome or the ubiquitin tagging system means that unwanted proteins hang around the cell and cause problems. Proteasome activity declines with age, and we have reason to believe it is a cause of aging. Deliberately introducing defects in the proteasome or the ubiquitin tagging machinery can be lethal, and even minor defects can lead to diseases associated with old age, such as Alzheimer’s and Parkinson’s.
The ubiquitin-proteasome system is beautifully tuned to get rid of unwanted or aberrant proteins. It works by chewing away the strand of a single protein at any given time. Like the garbage disposal in your kitchen sink, it can handle only one scrap at a time. But what if a cell wanted to get rid of a lot of very large junk, much as we would want to get rid of a used sofa, old furniture, or appliances? Not to worry. Nature has this covered with an apparatus that, oddly enough, was discovered decades before the proteasome.
Scientists have long known that cells from higher organisms have a nucleus that contains our chromosomes, but as they studied the cell in greater detail with ever more powerful microscopes, they discovered that they have many other specialized structures called organelles. How these structures worked together to facilitate cell function remained a mystery. One of those structures turned out to be hugely important for recycling the cell’s garbage.
In 1955, Christian de Duve, who split his time between Rockefeller University in New York and the Catholic University of Leuven in Belgium, discovered an organelle called the lysosome. He and his Leuven colleagues found they were full of digestive enzymes that would break down any of the major constituents of living matter. Initially the lysosome was considered rather boring—about as exciting as a landfill site in a city. But things became more interesting when scientists showed that lysosomes often contained remnants of other parts of the cell. All kinds of unwanted structures were taken to lysosomes for disposal. De Duve coined the term autophagy, from the Greek for “self-eating,” because the cell was digesting away parts of itself. But how did the cell’s garbage make its way to the lysosomes?
In the cell, membranous structures called autophagosomes form and grow in size, gradually engulfing everything the cell targets for disposal. Think of autophagosomes as large garbage trucks. The garbage they collect can be anything from protein aggregates all the way to large organelles. An autophagosome eventually merges with a lysosome to deliver its contents to be digested and recycled. If the proteasome is akin to the garbage disposal in your kitchen sink, the lysosome is the huge garbage recycling center in your city.
While this process goes on perpetually, it is highly regulated. If you stress or starve the cell, autophagy goes up. It makes sense to break down proteins and other structures and recycle their components to survive a difficult time.
However, this still doesn’t tell us how the cell decides when and what to deliver to lysosomes. Science would have to wait almost fifty years to make headway on this problem. In the late 1980s and early 1990s, Yoshinori Ohsumi, a young assistant professor at Tokyo University, hatched a clever idea.
Biology often advances by studying simple organisms that are easy to grow and mutate, and the discoveries made there can then easily be generalized to more complex ones such as humans. Ohsumi turned to that favorite of molecular biologists, baker’s yeast, in which the equivalent of the lysosome is called a vacuole. By isolating strains in which the vacuole had accumulated cellular debris, he was able to find a dozen genes that were essential for activating autophagy.
As a result of these breakthroughs, we know now that autophagy happens continuously as part of the general maintenance of the cell. Its rate can go up or down, depending on the cell’s needs. It can also be triggered when the cell needs to get rid of invading viruses or bacteria. This kind of autophagy requires special adaptor proteins that recognize these foreign objects and bring them to the autophagosome, which then delivers them to lysosomes to be destroyed. Autophagy is the only process by which the cell can destroy such enormous structures.
You might think that the only function of autophagy is to deal with problems, but it is also essential for a single fertilized egg’s development into an adult animal. Imagine that you have a perfectly serviceable house, but you want to remodel it. Maybe you’ve had a new addition to your family, or you suddenly need more space so that you can work from home during a pandemic. Or you simply want a larger kitchen. When you remodel a structure, you have to break down parts of it before you can start building. You may have to take down walls, plumbing, and counters, or get rid of furniture that won’t fit in the new space. Our cells go through this same process as they develop from that original fertilized egg into specialized cells such as neurons and muscles, which have very different internal organization and structures. Autophagy makes it happen.
In short, autophagy is used both to ensure cells develop normally and to jettison defective proteins or aging structures, as well as to destroy bacteria and viruses. It has so many essential functions that when it fails even partially, we develop serious problems, from cancer to neurodegenerative diseases.
So far, we have talked about how cells deal with proteins and larger structures that are defective or they don’t need anymore. If there are just too many defective proteins piling up, it becomes hard for the recycling machinery to keep up. In that case, it would make sense to quickly shut down the synthesis of new proteins, a bit like turning off the main water supply when you have a flood in the bathroom. Also, it makes no sense for cells to produce new proteins and grow when they face starvation or stress.
One way the cell does this is to stop ribosomes from starting the process of reading mRNA to make proteins. It is a way of slowing down the production of new proteins while it handles crises, which is a bit like seeing a traffic jam on a freeway and preventing cars from entering the on-ramp and making the problem worse. While this process shuts down the production of most proteins, it also turns on the production of proteins that help the cell survive the stress and alleviate it. In the traffic jam analogy, this would be like sending a signal that stops new cars from entering the freeway and at the same time bringing in tow trucks to clear the accident that caused the jam.
This process of shutting down the synthesis of most proteins while allowing a few useful proteins to be made can be triggered by starvation, a viral infection, or too many unfolded proteins. Since it is a unified response to many kinds of stress, it is called the integrated stress response, or ISR.
You would think that these problems with protein quality and quantity would worsen with aging, making a strong ISR useful. That is exactly what some groups have found. If you delete the genes that turned on ISR in mice, the rodents were more prone to various pathologies caused by abnormal protein production. When mice suffering from a pathology due to unfolded proteins were treated with a compound that allowed ISR to persist, it alleviated their symptoms, whereas, conversely, suppressing ISR made them worse and hastened their demise. Compounds such as guanabenz or its derivative Sephin1 that strengthen the integrated stress responses prevent diseases caused by poor quality control of protein production. They also extend life span, although in at least one case, there was disagreement about how these compounds acted, and whether they even affected ISR directly.
If all this makes a strong case for restoring or strengthening ISR as we age, some research groups have found the exact opposite. According to their studies, deleting the genes that turn on ISR alleviated some of the symptoms of Alzheimer’s disease in mice, including memory deficits. A molecule that shut down ISR enhances cognitive memory and reverses cognitive defects following traumatic injury to the brain. Even more surprisingly, the effects were seen even when the experimental drug being tested, an integrated stress response inhibitor—ISRIB, for short—was administered a month after the trauma.
Why would turning off a universal control mechanism be beneficial? Nahum Sonenberg, an expert on translation at McGill University in Montreal and a coauthor of the ISRIB study, believes there are pathological conditions in which the ISR itself is chronic and out of control. It may be suppressing protein synthesis when it shouldn’t or to a much greater degree than it should. It’s like driving a car in which the brake is activated all the time instead of only in response to a signal to slow down or an accident ahead. Instead of being a lifesaver, it becomes a nuisance. Even as we age, we still need to make new proteins. For example, forming new memories requires synthesizing new proteins that strengthen connections between brain cells. But when ISR is itself out of control, we are unable to make proteins in the amounts we need. In cases such as this, turning off ISR may be beneficial.
ISRIB has been touted in the press as a “miracle molecule” that could boost fading memory and treat brain injuries. The San Francisco company Calico Life Sciences, owned by Alphabet, the parent company of Google, started conducting clinical trials on ISRIB-like compounds that inactivated ISR. Peter Walter, one of the discoverers of the unfolded protein response and of ISRIB, recently gave up a prestigious professorship at the University of California, San Francisco, to join Altos Labs, a private company that operates research institutes to tackle aging, with campuses in California and Cambridge, England.
How this will play out is unclear. It is well to remember that ISR is a universal control mechanism precisely to deal with situations that are problematic for the cell, such as an accumulation of unfolded proteins, amino acid starvation, and viral infections. As we discussed above, initially, scientists found that prolonging ISR was beneficial for certain pathologies. So there may be situations when it would be helpful to enhance ISR and others in which it would be better to inhibit it. Figuring out exactly how much ISR is optimal at any given stage is unlikely to be straightforward, and we may have some way to go before it can be used with any confidence as a long-term treatment for combating diseases of aging.
We have covered a lot of ground in this chapter, but a common thread runs throughout. For cells to be able to function, their thousands of proteins have to work together. They must be produced at just the right time and in the right amount, and they must be the correct shapes. It is not unlike all the instruments in a symphony orchestra that all have to play their parts together. As with some modern orchestras, there is no conductor. And if parts of the orchestra don’t perform properly, the whole thing falls apart.
Everything we have discussed so far is about the different ways that cells sense when things are not right and what they do to correct that. This is an amazingly complicated web of interactions, which is itself controlled by yet more proteins. If the control proteins themselves become defective, the problems are amplified. That is just what happens as we age.
WE BEGAN THIS CHAPTER WITH the terrible scourge of Alzheimer’s disease. The disease, which is increasingly a dread of old age, turns out to be related to a curious group of diseases whose cause was uncovered in a most unexpected way. The key person to unravel its mystery was Carleton Gajdusek, a scientist with the unique and unfortunate distinction of being both a Nobel Prize winner and a convicted child molester.
After earning his medical degree from Harvard, Gajdusek was serving a fellowship in Boston when he was drafted into the army. He ended up in the Korean War, where he showed that a fever that was killing American soldiers was spread by migrating birds. On the strength of this, he was offered a job with the US government’s Center for Disease Control, but chose instead to work with the famous immunologist MacFarlane Burnet in Melbourne, Australia. Burnet sent him to Port Moresby, New Guinea, to set up part of a multinational study on child development, behavior, and disease. It could not have been easy carrying out fieldwork in such a remote area, far away from any modern research laboratory, but Gajdusek was an unusual character. Burnet once described him as someone who “had an intelligence quotient up in the 180s and the emotional immaturity of a 15-year-old,” adding candidly that his protégé was completely self-centered, thick-skinned, and inconsiderate. At the same time, said Burnet, the young man from the United States would not let the threat of danger, physical hardship—or other people’s feelings—interfere in the least with what he wanted to do.
While in Port Moresby, Gajdusek heard about a mysterious illness called kuru and set out for the Eastern Highlands Province, about 200 miles away, where the disease was prevalent among the native Fore tribe. Patients with the disease showed no symptoms of fever or inflammation but died of a progressive brain disease that caused tremors and highly abnormal behavior such as uncontrolled fits of laughter. Two anthropologists, Shirley Lindenbaum and Robert Glasse, observed that women and children, but not adult men, ate the entire bodies of deceased family members, even the bones. This was a recent practice among the Fore, and by collecting detailed evidence of cannibal feasts which could be matched with the subsequent appearance of the disease in participants, they concluded that this practice of cannibalism may have had something to do with transmission of the disease. Gajdusek and a colleague named Vincent Zigas had observed that one of the practices of the tribe was to cook and eat the brains of deceased family members following funerals. So Gajdusek suspected that something in the diseased brain was transmitting the disease to the people who ate it. Following up on this hunch, he was able to show that you could transmit kuru to chimpanzees by injecting their brains with extracts from the brains of diseased patients.
The autopsied brains of the Fore tribe, when examined under a microscope, were full of holes, like a sponge. Kuru is one of many brain diseases with this pattern, called spongiform encephalopathies, including a variant form of Creutzfeldt-Jakob disease. (Variant refers to the transmissible rather than inherited form of a disease.) About 10 percent of all cases are inherited, and just as he had done for kuru, Gajdusek was able to show that brain extracts from infected patients could transmit the disease to chimpanzees. The idea that a disease could be inherited in some instances but also transmitted like an infection in other cases was unprecedented. Gajdusek was awarded a Nobel Prize in 1976.
Unfortunately, the end of Gajdusek’s career was not so glorious. Over the course of many years, he brought back more than fifty children to the United States from New Guinea and Micronesia, and acted as their guardian. In the 1990s, in response to a tip-off from a member of his lab, the FBI began to investigate the scientist. The bureau persuaded one of the boys to tape a phone conversation in which Gajdusek admitted that he and the boy had sexual contact. In a plea bargain that would be unthinkable today, he served a year in jail in 1997 and then left the United States as soon as he was released to spend the rest of his life in Europe. During his self-imposed exile, he stayed active scientifically and was affiliated with several universities. He showed no remorse for his behavior, dismissing his treatment as American prudishness. Many of the boys continued to have contact with him, some adopting his name and even naming their own children after him. In 2008 he died in a hotel room in Tromso, Norway, where he was a frequent visitor to the university there.
Gajdusek’s concept of transmissibility had a huge impact on our thinking about this class of diseases. Mad cow disease (bovine spongiform encephalopathy) afflicted cows in Britain, notably in the 1980s, as a result of cows being fed the remnants of infected animals. Around this time, more than a hundred people died of Creutzfeldt-Jakob disease. Scientists began to suspect that this was because they had eaten meat from diseased cows. The connection with eating infected beef was then not universally accepted, and John Gummer, a UK government minister, famously encouraged his four-year-old daughter, Cordelia, to eat a hamburger on television, declaring British beef to be completely safe. (The girl did not get sick.) Nevertheless, many countries prudently banned the importation of British beef and lifted it only after several million cows had been slaughtered and farming practices had been changed.
Although the transmissibility of these diseases was established, it was not clear exactly how they spread. Ever since the nineteenth and early twentieth centuries, it has become a firm dogma that every infectious disease is transmitted by living organisms that can multiply in the host, whether they are parasites or microbial organisms such as bacteria, fungi, or viruses. In the early 1980s Stanley Prusiner, an American neurologist at the University of California, San Francisco, began trying to isolate the infectious agent for scrapie, a spongiform encephalopathy of sheep and goats. The brain extracts that transmit scrapie remained infectious even after they were sterilized using standard methods such as heat, so the prevailing view was that the infectious agent was a virus that was resistant to inactivation and had a long incubation time. When Prusiner gradually isolated the infectious agent, it turned out to be a protein—a notion that was greeted with a chorus of skepticism. After all, unlike bacteria or viruses, proteins could not multiply, so how could they possibly cause an infection that spread from one animal to another?
Over the next several years, Prusiner identified the protein and showed that although it was a normal component of brains, its shape in a scrapie-infected brain was abnormal. Prusiner called the protein a prion and proposed there were two forms: a normal version and a scrapie version. Like an evil character who corrupts all the good people around him, this aberrant, misfolded, scrapie version of the protein acts as a mold, or template, and induces each normal prion protein it encounters to switch to the misfolded version. The result is that the misfolded form spreads like an infection throughout the cell and across cells throughout the tissue, bringing about disease.
At first glance, the only commonality between diseases such as kuru or scrapie and Alzheimer’s is that they are lethal brain diseases, but as we shall see, the similarity runs deeper. Dr. Alois Alzheimer himself autopsied the brains of deceased patients and discovered deposits of plaques outside cells as well as tangles of fibrils inside some nerve cells. It wasn’t initially clear whether the formation of these deposits was a cause of the disease or a symptom.
In 1984, scientists identified that the major component of the plaques was a protein called amyloid-beta, which itself is produced by trimming a much larger amyloid precursor protein, or APP. Alzheimer’s is normally a disease of old age and not necessarily inherited, but some patients with inherited forms develop the disease earlier in life. They turn out to have mutations in the APP gene. Scientists have also identified the enzymes that trim the APP to the mature amyloid-beta and, in a nod to their involvement in causing senility, called them presenilins. Mutations in these proteins also led to familial Alzheimer’s disease. The case that the disease was caused by accumulating either too much or incorrectly processed amyloid-beta protein seemed overwhelming. Much of the research community then focused on the details of what caused the plaques to develop and how they could be prevented.
However, in science, things are often never quite so straightforward. For one thing, the plaques typically develop outside nerve cells, so why are they killing them? Another curious feature is that other tissues—for example, blood vessels—also contain amyloid-beta deposits, but it is the diseased brain that kills people. A feature of the disease that was ignored earlier on is that inside some neurons of patients, there are filaments made of a different protein called tau. Perhaps these tau filaments were the cause of the disease?
Although scientists were skeptical at first, evidence incriminating tau also began to mount when three groups found independently that patients with an inherited form of dementia related to Parkinson’s disease had mutations in the tau gene. Also, it was not hard to imagine how tau could cause disease. The tau filaments could block the narrow axons and dendrites that connect neurons, and, not surprisingly, it is these connections that are the first to go, causing cognitive impairment.
Recently, scientists have found that the filaments characteristic of diseased brains are not just random clumps of unfolded proteins. Rather, the aberrant molecules come together to form filaments that are distinct for each type of dementia. Studies show consistently that the tangles we see in diseased brains actually have very well-defined structures, each of which is a hallmark of a particular disease. This is something we did not know even a few years ago.
Therefore, as things stand, we have very compelling evidence that amyloid-beta, tau, and other filaments are implicated in disease. One problem is that nobody really understands what these proteins are doing normally. We do know that if you delete the genes for them in mice, the animals exhibit some abnormalities, but they don’t develop plaques or Alzheimer’s disease. This means that the reason amyloid-beta or tau causes disease is not because it has ceased to function normally. Rather, it is because the unfolded forms can give rise to filaments that spread throughout the brain.
Alzheimer’s and prion diseases are both caused by aberrant forms of proteins that come together to form tangles or plaques. In prion diseases, the prion form assumes a different shape from the normal form, and spreads because it switches the normal version into the prion form when it comes into contact with it. There is a growing feeling that exactly the same thing happens in Alzheimer’s and other neurodegenerative diseases: an abnormal, unfolded form can seed the formation of filaments, which then spread throughout the brain. Injecting brain extracts from Alzheimer’s disease patients into mice stimulates the premature formation of plaques or tangles. But, unlike prion diseases such as kuru and bovine spongiform encephalopathy, nobody has demonstrated that Alzheimer’s, Parkinson’s, or similar diseases are actually infectious. That could be because we don’t eat the brains of patients with dementia or inject extracts of their diseased brains into our own.
What causes Alzheimer’s disease is a burning question because that holds the key to preventing it. The answer depends on how you define cause. The immediate cause may well be the formation of tau or amyloid-beta filaments in the brain. However, an earlier and root cause is the cell’s inability to manage the excess of unfolded proteins that aggregate to form these filaments in the first place. This in turn is caused by damage to our control systems: the quality control and recycling machinery of the cell that we discussed earlier in the chapter. And that damage to our control systems is a result of aging.
So you could say it all boils down to our living long enough for the damage to occur. It is particularly ironic that one of the consequences of our increased life expectancy over the last century is the greater likelihood of spending our final years with the terrible effects of diseases such as Alzheimer’s.
Can anything be done about it? The difficult truth is that there are still no effective treatments for these dementias, despite several decades of work. Just as cancer is so hard to treat because it is our own cells that have gone out of control, Alzheimer’s is caused by our own proteins misbehaving. And just as with cancer, there may be both genetic factors and chemicals or infectious agents that accelerate the process. This creates a fundamental difficulty for treatments. Very recently, therapies based on antibodies that bind to the amyloid-beta protein were shown to halt cognitive decline by about 25 percent after eighteen months. They were most effective at slowing the progression of the disease if treated early, and in patients that had only a modest level of tau aggregates. They carried a serious risk of side effects, including seizures and bleeding in the brain. However, they did demonstrate that targeting beta-amyloid showed some clinical effect, and against the bleak backdrop of having next to nothing to offer Alzheimer’s patients, even an expensive and complicated treatment with a relatively modest gain was heralded as a huge breakthrough.
All the recent breakthroughs in our understanding the basis of the disease offer some hope, however. Now that we know that the filaments are not random but consist of very specific contacts to form their structure, perhaps drugs can be developed to prevent their formation. Others are attempting to inhibit the production of the protein itself. And scientists are busy at work on the ultimate causes as well, including how to modify aging cells so they can handle aberrant proteins as effectively as younger cells do. We also need to identify suitable biomarkers that are an early warning of incipient disease. As we learn much more about the underlying biology involved, we can be hopeful that we will find more ways to prevent the disease in the first place, and diagnose it early and treat it when it occurs.
7. Less Is More
The India in which I grew up is a land of many religions, and there never seemed to be a time when one or another group wasn’t fasting. Hindus fasted before certain religious occasions—or if they were strict, every week. Muslims fasted from dawn to dusk for the entire month of Ramadan, not drinking a drop of water even when the holiday fell amid the long, hot summer days of the subcontinent. Christians fasted during Lent. And fasting was not only a religious imperative. Nearly all cultures considered fasting, and moderation in general, a key to a long and healthy life, and gluttony to be a vice.
For much of our existence as a species, we were hunter-gatherers, feasting occasionally between prolonged periods of involuntary fasting. Perhaps our metabolism evolved to adapt to that lifestyle. It is different today, especially in the rich countries of the West. Like millions of others, I gained an inordinate amount of weight during the early days of the Covid-19 pandemic, when most people were stuck at home, and food was only as far away as the refrigerator. Indeed, today we face a widespread epidemic of obesity, which is linked not only to cardiovascular disease and type 2 diabetes but also to certain cancers and even Alzheimer’s disease. It is also a major risk factor in infections: Covid-19 patients who were obese were far more likely to die from the virus. Clearly it has far-reaching consequences, both for ill health in old age and our likelihood of dying from those disorders.
The reasons for the rise in obesity in recent times are complex. One popular theory is that throughout most of our history, food was scarce and sporadic, and those who had “thrifty genes” that could store fat more efficiently could better survive times of scarcity. Now, in a time of plenty, those very genes efficiently keep storing away all the excess fat we eat and cause obesity. This idea was so prevalent that it became a truism, but it is now being questioned. Even today, less than half the population in the United States is obese. John Speakman, who has studied the relationship between energy intake and weight in organisms, has argued convincingly that it is simply that the population had a lot of genetic variability in how efficiently they could store fat, a variability he calls “drifty genes.” When food was generally scarce, even those individuals who might be prone to becoming obese rarely were. But now, an abundance of calorie-rich food has driven a rise in obesity, especially in the portion of people who have inherited genes that in previous eras would not have caused any harm. Also, historically there was no reason for us to have evolved to be abstemious.
Regardless of the reasons for the rise in obesity, nobody doubts that moderation and maintaining a healthy weight are recipes for good health. Clearly, overeating is bad for your health, but is the converse also true? Would stringently restricting our diet to less than what we eat normally actually make us live much longer? The first studies to test this, carried out in 1917, were not taken seriously, perhaps because for most of our existence as a species, being undernourished was a much greater threat to life than overeating. Nevertheless, the idea persisted, and later studies showed that rats fed a calorie-restricted diet lived longer and were healthier than those allowed to eat without limit.
During caloric restriction, or CR, an animal is fed 30–50 percent fewer calories than it would consume if it ate as much as it liked (ad libitum), while making sure that it consumes enough essential nutrients to not become malnourished. In rodents and other species, animals on CR lived 20–50 percent longer, as judged by both average life span and maximum life span. Moreover, they appeared to have delayed the onset of several diseases of aging, including diabetes, cardiovascular disease, cognitive decline, and cancer.
Mice are small, however, with short life spans. What about animals more similar to us? In 2009 a long-term study from the University of Wisconsin found that rhesus monkeys lived longer and were healthier and more youthful when subjected to caloric restriction. But this was contradicted only a few years later by a twenty-five-year study at the National Institute on Aging (NIA). The Wisconsin diet was richer and had a higher sugar content, so perhaps eating a healthy diet rather than fewer calories might have made the difference. The NIA control animals were not allowed to eat ad libitum but were fed an apportioned amount to prevent obesity. More than 40 percent of the Wisconsin control group developed diabetes, while only 12.5 percent of the NIA control group did. In tandem, the studies suggest that for animals already on a healthy diet and not overweight, further caloric restriction has little additional effect on longevity. Interestingly, all the animals in both groups, even the CR animals, weighed more than animals found in the wild, suggesting that even the restricted diet provided more food than they would eat naturally.
Experimenting with monkeys is hard enough. They can live between twenty-five and forty years, and the studies from NIH and Wisconsin have gone on for over two decades and already cost millions of dollars. Conducting similar studies with humans—who live more than twice as long and whose dietary intake is much harder to track—seems out of the question. Any evidence for the effect of CR on human longevity is purely anecdotal at this point, but that hasn’t stopped individuals from experimenting on themselves and even writing books to tout their lifestyles.
There have also been persistent claims that fasting is beneficial for health beyond simply reducing the overall intake of food. There is 5:2 fasting, whose adherents eat as little as 500–600 calories per day twice a week but eat normally on the other five. Another method advocates eating all your food in a window of a few hours each day. Recently, scientists examined the effects not just of CR and intermittent fasting in mice but also of aligning feeding times to their daily biological rhythms. They concluded that matching feeding times to our biological circadian rhythm greatly improved the benefit of intermittent fasting. This might seem like the home run the field wanted, but, as the accompanying commentary points out, much of the additional benefit may have nothing to do with the time of feeding as such. Rather, if you allowed mice to eat only during the day—when they would normally be asleep—they were faced with the unenviable choice between starving and not sleeping. The test animals chose to disrupt their sleep. Even if you distributed the restricted diet throughout the twenty-four-hour period, the mice would not get enough to eat when they were awake and would choose to disrupt their sleep to get the rest.
I know what a wreck I am when I am sleep deprived. As I get older, my problems with jet lag are getting worse, and I am barely able to function right after I show up on some other continent. So I am always struck by how sleep, which is so intimately related to our health, is ignored by scientists in other fields. We think of sleep as something that is connected with our brains and especially our eyes and vision. But as Matthew Walker explains so well in his book Why We Sleep, you don’t need a brain or even a nervous system to sleep. In fact, sleep is ancient and highly conserved across the entire kingdom of life. Even single-celled life forms follow a daily rhythm that is related to sleep. Considering that sleep can be perilous—animals are vulnerable to attack when they are asleep—it must have huge biological benefits for it to persist through evolution. The consequences of sleep on our health are profound and widespread. In particular, sleep deprivation increases the risk of many diseases of aging, including cardiovascular disease, obesity, cancer, and Alzheimer’s disease. According to a recent study, one of the ways that a lack of sleep accelerates aging and death is by altering repair mechanisms that prevent the buildup of damage to our cells.
But going back to the study matching feeding times with when mice are awake, although it did not explicitly monitor the sleep patterns of the mice, the researchers suggest that as long as you don’t deliberately disrupt sleep, CR has a significant positive effect on both health and longevity. Over the decades, study after study have confirmed the benefits of CR over an ad libitum diet in multiple species.
If all this seems too good to be true, it might be. In one study, the effects of CR varied greatly depending on the strain and sex of the mice; in fact, in a majority of the test animals, CR actually reduced life span. Indeed, one of the pioneers of the aging research field, Leonard Hayflick, expressed skepticism that dietary restriction had any effect on aging. He felt that animals on an ad libitum diet were overfed, and unhealthy as a result, and caloric restriction simply brought their diets closer to conditions in the wild. Moreover, when scientists look outside typical lab conditions to animals in the wild, the link between eating less and living longer becomes much more tenuous.
Nevertheless, in multiple laboratory studies, at least compared to an ad libitum diet, CR appears to be beneficial not only in rats and mice but also in diverse organisms ranging from worms, to flies, to even the humble unicellular yeast. Most scientists working on aging agree that dietary restriction can extend both healthy life and overall life span in mice and also leads to reductions in cancer, diabetes, and overall mortality in humans. On a more granular level, limiting protein intake or even just reducing consumption of specific amino acids such as methionine and tryptophan (both of which are essential in our diets because our bodies don’t produce them) can confer at least some of the advantages of overall dietary restriction.
It might seem counterintuitive that eating the bare minimum to avoid malnutrition would be good for you. In fact, the results of CR may be yet another example of the evolutionary theories of aging. Consuming lots of calories allows us to grow fast and reproduce more at a younger age, but it comes at the cost of accelerated disease and death later on.
So why aren’t we all on CR diets? For the same reason that rich countries face an epidemic of obesity: we now live in a time of plentiful food, and we have not evolved to be abstemious. Moreover, caloric restriction is not without its drawbacks. It can slow down wound healing, make you more prone to infection, and cause you to lose muscle mass, all serious problems in old age. Among its other reported downsides are a feeling of being cold due to reduced body temperature, and a loss of libido. And, of course, a side effect that to most readers will seem blindingly obvious: people on calorically restricted diets feel perpetually hungry. In fact, animals on CR diets all revert to eating as much as possible when permitted.
The anti-aging industry would love to produce a pill that can mimic the effects of CR without our having to forego the ice cream and blueberry pie. For that to happen, we need to understand exactly what caloric restriction does to our metabolism. It’s a story full of unusual twists and turns and the discovery of some completely new processes in our cells.
IN 1964 A GROUP OF Canadian scientists set out on a voyage to Easter Island, a remote spot in the South Pacific that is about 1,500 miles away from its nearest inhabited neighbor. Their goal was to study the common diseases of the island’s Indigenous people, who had little contact with the outside world. In particular, they wanted to know why the islanders did not develop tetanus, even though they walked around barefoot. The researchers collected sixty-seven soil samples from different parts of the island. Only one of them had any tetanus spores, which are typically more common in cultivated soil that has less diversity of microbes than virgin soil does. Nothing further might have come out of this expedition had not one of the scientists given the soil samples to the Montreal lab of Ayerst Laboratories, a pharmaceutical manufacturer. The company was looking for medicinal compounds produced by bacteria. By then, it was well known that soil bacteria, notably the genus Streptomyces, produced all kinds of interesting chemicals, including many of the most useful antibiotics today. Part of the reason they produce them is thought to be biological warfare among soil microbes, where some species make compounds that are toxic to others.
To identify anything useful from an unknown bacterium in a soil sample, you first have to isolate it and coax it to grow in the lab. Then you need to analyze the hundreds or thousands of compounds that it makes and screen them for useful properties. Through this painstaking venture, the Ayerst scientists found that one of the vials contained a bacterium, Streptomyces hygroscopicus, that made a compound that could inhibit the growth of fungi. Because fungi are more similar to us than bacteria are, it is hard to find compounds that will treat fungal infections without also harming our own cells. So it seemed worthwhile to follow up on their initial observation. It took Ayerst two years to isolate the active compound, which the company named rapamycin after Rapa Nui, the Indigenous name for Easter Island.
The scientists soon discovered that rapamycin had another, potentially much more useful property. It was a potent immunosuppressant and stopped cells from multiplying. Suren Sehgal, a scientist at Ayerst, sent off some of the compound to the US National Cancer Institute. Researchers there found the drug to be effective against solid tumors, which are ordinarily difficult to treat. Despite these promising early results, work on rapamycin ground to a halt when Ayerst closed its Montreal lab and relocated the staff to a new research facility in Princeton, New Jersey, in 1982.
Sehgal, however, was convinced that rapamycin was going to be useful. Just before moving to the States, he grew a large batch of Streptomyces hygroscopicus and packed it into vials. At home, he stored them in his freezer next to a carton of ice cream, with a label cautioning, “Don’t Eat!” The vials remained there for years. In 1987 Ayerst merged with Wyeth Laboratories, and Sehgal persuaded his new boss there to pursue rapamycin. He was given the go-ahead to look at its immunosuppressive properties, which could be useful to prevent transplant rejection. Eventually rapamycin was approved as an immunosuppressant for transplant rejection, but nobody had any real idea of how it worked. How could it inhibit the growth of fungi, prevent cells from multiplying, and be an immunosuppressant, all at once?
Here our story shifts to Basel, Switzerland, where two Americans and an Indian chanced upon an unexpected breakthrough. One of the Americans, Michael Hall, had an unusually international childhood: he was born in Puerto Rico to a father who worked for a multinational company and a mother who had a degree in Spanish. They both liked Latin American culture and decided to make their home in South America, where Hall grew up, first in Peru and then in Venezuela. When he was thirteen, his parents decided he needed a rigorous American education; Hall was suddenly ejected from his carefree life wearing T-shirts, shorts, and sandals in warm and sunny Venezuela, and dropped into a boarding school in the freezing winters of Massachusetts. From there he attended the University of North Carolina, intending to major in art but eventually settling on zoology, with the intention of going to medical school. An undergraduate research project whetted his appetite for science, and Hall went on to earn a PhD from Harvard and then put in time pursuing postdoctoral research at the University of California, San Francisco. In between, he spent almost a year at the famous Pasteur Institute in Paris, where he met Sabine, the Frenchwoman who would become his wife. Thus, unlike many American scientists who see leaving the United States as equivalent to falling off the map, Hall cast a broad net in the job search that followed his postdoc. He had not originally thought of moving to Switzerland, but when he interviewed for a starting faculty job at the Biozentrum at the University of Basel, he fell in love with the institute and the city.
Shortly after he started his lab in Basel, Hall was joined by another young American, Joe Heitman, who was in an MD-PhD program that combined medical studies at Cornell Medical School with research at Rockefeller University. After his PhD research, rather than go back immediately and finish his medical degree, Heitman decided to do some postdoctoral research, partly because his wife would be starting her own postdoctoral work in Lausanne, Switzerland. Looking for suitable labs in the vicinity, he identified Hall as someone he wanted to work with. His initial project there turned out to be frustrating, however, and Heitman briefly considered going back to medical school, when he read a scientific paper describing mutants of a mold, Neurospora, that were resistant to the immunosuppressive drug cyclosporine. He approached Hall with the idea of studying immunosuppressants using yeast.
By sheer chance, Heitman could not have found a more receptive mentor. It turned out that cyclosporine was a blockbuster drug for Sandoz, the pharmaceutical company located right in Basel, and Hall had already begun working with a scientist there who was interested in how it and other immunosuppressants worked. That scientist, Rao Movva, who grew up in a small village in India, had already enjoyed quite a bit of success in using yeast to understand the mechanism of cyclosporine, and he was keen to study rapamycin, which was still being developed for use in patients.
To most in the field, this must have seemed a crazy idea. What could yeast—a unicellular organism that doesn’t have an immune system—teach them about immunosuppressive drugs and human beings? But Hall points out that these compounds were produced as part of biological warfare among soil microbes, so, really, yeast was their natural target; it is administering them to humans that is actually unnatural. As soon as Heitman had expressed interest in the problem, Hall put him in touch with Movva. This was a huge advantage, because at a large pharmaceutical company such as Sandoz, Movva had the resources to produce enough rapamycin. One day he came into Hall’s lab with a small vial and told Heitman, “Okay, this is the world’s supply of rapamycin. Think very carefully about the next experiments you’re going to do. Don’t blow it, because this is all we have.”
The gamble paid off. The trio looked for mutant strains of yeast that would grow even in the presence of rapamycin, and their experiments revealed that many of the mutations occurred on two closely related new genes that coded for some of the largest proteins in yeast. Names of genes and proteins from yeast typically consist of a three-letter acronym that makes little sense to those outside a particular field. In this case, from a long list of possibilities, they chose TOR1 and TOR2, to denote “target of rapamycin.” The names held additional appeal for Heitman because he lived near one of the picturesque medieval gates of Basel, and the German word for gate is Tor.
This was a big breakthrough. Rapamycin’s immunosuppressive activity was thought to derive from its ability to inhibit cell growth. The compound also arrests yeast growth, however, so identifying its protein targets would enable scientists to understand exactly how. The mutants identified two genes, but without cloning and sequencing them, nothing was known about the proteins they coded for, let alone what they did.
At this point, the problem almost fizzled out in Hall’s lab. Heitman stayed as long as he could, but he had to return to New York to finish his medical studies. At the time, although it was acknowledged that rapamycin was a potentially important immunosuppressive drug, nobody had any idea of how important their discovery would turn out to be. Meanwhile, Heitman’s mutants were sitting in the lab freezer until a new student was frustrated when her original project was not working. She, along with another student and others in the lab, used the mutants to clone and sequence the TOR1 and TOR2 genes. In those days, sequencing had to be done manually. What’s more, this was no trivial project, because they were both among the largest genes in yeast, and were similar but not identical. One of them was lethal when deleted, proving that it was essential in order for yeast to survive, while the other was not.
Understanding the mechanism of an immunosuppressive drug that was also a potential anticancer drug was of great medical importance, so while Hall and his colleagues carried on their work, they were participants in an intense race to discover the target of rapamycin. Three groups in the United States directly purified the protein target of rapamycin in mammals. It turned out to be the mammalian counterpart of the genes that Hall and his colleagues had identified. Now, scientists can be fiercely competitive and don’t like to come in second place. It’s a bit like leading the second expedition to climb Mount Everest or being the second pair of astronauts to walk on the moon—you just don’t get the same level of recognition. In the case of the two genes, prickly egos and difficulty accepting one’s also-ran status led to a profusion of names in the field, sowing confusion.
The US research groups realized that they had discovered the mammalian version of essentially the same protein that Hall and his colleagues had identified already. Nevertheless, some of them gave it entirely different names. Eventually they all agreed to christen it mTOR, with the m denoting “mammalian,” to distinguish their findings from the yeast TOR. When the same protein was identified in a variety of organisms, including flies, fish, and worms, things began to get a little silly, with scientists studying zebrafish calling their version zTOR or DrTOR (the scientific name for zebrafish is Danio rerio). Eventually everyone settled on mTOR for all species—except, paradoxically, the original yeast!—with the m now standing for mechanistic, which makes no sense at all, since it implies that there is also some other target of rapamycin that is nonmechanistic (whatever that means). Why they didn’t simply revert to the original TOR remains a mystery to me. For consistency, and in deference to the original discoverers, I will refer to the molecule as TOR, but if you read elsewhere about TOR with a small letter before it, it is basically referring to the same protein.
From the start, it was known that rapamycin would prevent cultures of cells from growing, but it wasn’t clear how. Did it limit the number of cells or the average size of each cell? At first, Hall thought that rapamycin would simply stop cells from dividing, but after pushback from a famous expert in that field, he realized that TOR actually controlled cell growth by activating the synthesis of proteins in the cell when nutrients are available. Among other things, Hall and his colleagues showed that in the presence of rapamycin, or mutants of TOR, cells would appear starved and stop growing even when plenty of nutrients were available.
Biologists have known for a very long time that the size and shape of cells is highly controlled. Cell size varies not only in different species but also in different tissues and organs. For example, an egg cell is about thirty times the diameter of the head of a sperm cell, and neurons can have protrusions, the nerve axons, as long as three feet. How cell size and shape are controlled is still a very active area of research. But the general belief was that cells would simply keep growing and dividing as long as you provided them nutrients—unless, that is, they received specific signals to stop growing. Hall’s experiments turned this dogma around. Cell growth, they suggested, was not passive; rather, TOR had to actively stimulate it, by sensing when nutrients were present.
It is a bit like the difference between an old steam locomotive and a gasoline-powered car. Once a locomotive gets going, as long as it has plenty of burning coal in the furnace and water in the boiler, it will keep rumbling down the track unless you take action to stop it. But a car, even with a full tank of gas, requires a foot on the accelerator in order for the vehicle to remain in motion; you have to actively do something to use the fuel. TOR is the driver that presses on the gas pedal to ensure that available nutrients are used to drive cell growth.
Hall’s conclusions represented a paradigm shift in our understanding of how cells grow and ran counter to decades of understanding. His paper was rejected seven times before it found a home in the journal Molecular Biology of the Cell in 1996. Around the same time, Hall also collaborated with Nahum Sonenberg, the same scientist we encountered in chapter 6 for his studies on the integrated stress response, and who is best known for his work on how ribosomes initiate; in other words, how they find the beginning of the coding sequence on mRNA and start reading it to make proteins. They found that without TOR actively making it possible, cells could not begin the process of translating mRNA to produce proteins, and would stop growing.
The initial discoveries by Hall and the other groups opened up the floodgates. Since then, TOR has become one of the most studied molecules in biology with about 7,500 research articles in 2021 alone. There is no question that finding out how rapamycin was immunosuppressive was important. But not even the brilliant scientists first working on it could have imagined that they would later uncover one of the oldest and most important metabolic hubs of the cell. In metabolism, proteins seldom act in isolation; they influence the actions of other proteins. If you think of such proteins as nodes that connect to one another—picture an airline map of its routes—TOR would be a major hub like London, Chicago, or Singapore, making direct connections to a large number of cities all over the world.
How could one protein have such widespread effects on the cell, and how exactly was it linked to caloric restriction? Ever since Michael Hall and his colleagues sequenced the two TOR genes, we have known that TOR is a member of a family of proteins called kinases. These enzymes often act as switches by adding phosphate groups to other proteins, which then act as tags or flags to turn them on or off. (The act of adding phosphate groups is called phosphorylation, and the proteins with the added phosphates are described as phosphorylated.) Sometimes kinases activate other kinases, which in turn activate other enzymes. You can think of kinases as part of a huge relay system, where many different proteins in a large network are turned on or off in response to some cue in the environment or the state of the cell. A map of all the proteins involved in activating or being activated by TOR is enormously complicated. So it is not surprising that by responding to many different environmental cues and then switching on or off many different targets, TOR has such widespread effects within the cell. Some of these environmental cues are not sensed directly by TOR but by other proteins, which in turn activate TOR.
TOR is not a protein chain that functions all by itself. It is part of two larger complexes called TORC1 and TORC2. Much more is known about TORC1, which is activated by proteins that sense the level of nutrients such as individual amino acids and hormones, including those that stimulate growth, known as growth factors. It is also affected by energy levels in the cell. If conditions are right, TORC1 promotes the synthesis not only of proteins but also nucleotides, which are the building blocks of DNA and RNA, and also lipids, which make up the membranes of all cells and organelles.
An important function of TOR is that when nutrients are available and the cell is not stressed, it inhibits autophagy, which, as you learned in chapter 6, is the process by which damaged or unneeded components of the cell are taken to the lysosome to be destroyed and recycled. This makes sense because these are exactly the conditions in which you want to stimulate cell growth and proliferation, not the opposite.
We can now see how TOR is connected to caloric restriction. Under CR, there are fewer nutrients around, and TOR, recognizing that, can switch off protein synthesis and other growth pathways, and also green-light autophagy. We have already seen how important both controlling protein synthesis and clearing defective proteins and other structures through autophagy are to keep the cell working optimally, and to aging in general.
But what if we didn’t need caloric restriction to reap its benefits—if we could inhibit a normal TOR and mimic its effects, with no change to the human diet? TOR was discovered precisely because it was the target of rapamycin. Might rapamycin be the long-sought pill that could imitate CR without our having to cut down on how much we eat?
It turns out that both a defective TOR and inhibiting TOR with rapamycin can enhance health as well as longevity in a range of organisms, from the simple yeast, to flies, to worms, and to mice. Strikingly, even short courses of rapamycin, or initiating treatment relatively late in the life of mice (equivalent to age sixty in men and women), conferred significant improvements in both health and life span. Rapamycin also delayed the onset of Huntington’s disease in a specially engineered strain of mice, presumably because it increased autophagy and prevented the accumulation of misfolded proteins. This shows that rapamycin not only improves longevity, but may also keep the mice healthier. In fact, the two may be closely related—perhaps the mice in these experiments live longer precisely because they are protected against various disorders of aging.
Though rapamycin is an immunosuppressive drug, it also, counterintuitively, improves some aspects of our immune response. There are two important components of our immune system: one is B cells, a type of white blood cell that churns out antibodies for identifying and then binding to the surfaces of bacteria, viruses, and other foreign invaders, or antigens, so that other foot soldiers in the body’s self-defense corps can race to the crime scene and finish off the culprit. The other is T cells, another type of white blood cell: helper T cells stimulate B cells to manufacture antibodies, while killer T cells, as their name implies, recognize and destroy cells that have been infected by a pathogen. While rapamycin inhibits those parts of the immune system responsible for rejecting grafts of tissue from a donor (such as kidney, bone marrow, or liver transplantation) and triggering inflammation in general, it actually increases the functional quality of certain helper T cells, thus potentially improving a person’s response to vaccines. Another study, from 2009, showed that administering rapamycin in mice rejuvenates aging hematopoietic stem cells, the precursors of the cells of the immune system, and boosts the body’s response to the influenza vaccination.
These results generated a great deal of excitement about rapamycin in the anti-aging community, but before we charge ahead with an immunosuppressive drug as a long-term panacea against aging, a note of caution is warranted. As one might expect, numerous studies have warned that long-term rapamycin use increases the risk of infection, such as with cancer patients. In fact, in that seemingly encouraging 2009 mouse study, treatment with rapamycin had to be paused for two weeks prior to administering the vaccine, the authors acknowledged, to “avoid the possible suppression of the immune response by rapamycin.” It makes one wonder whether the results would have been as promising without the pause to clear away the rapamycin.
Moreover, it is possible that some of the effects of rapamycin and TOR inhibitors are due to a general reduction of inflammation. Yet other research contends that optimal health calls for a fine balance between excessive inflammation and heightened susceptibility to infection. In a recent study, scientists show that TOR inhibitors dramatically increase the susceptibility of zebrafish to pathogenic mycobacteria closely related to the bacteria that cause TB in humans, and point out that this “warrants caution in their use as anti-aging or immune boosting therapies in the many areas of the world with a high burden of TB.”
Still, rapamycin’s draw as a potential wonder drug endures. In some quarters, the excitement has overtaken the data: one prominent aging researcher told me that he knew several scientists who were quietly self-medicating with rapamycin. I asked Michael Hall what he thought about using an immunosuppressive drug to combat aging, and he replied, “I suppose the rapamycin advocates are following Paracelsus’s adage that the poison is in the dose.” He was alluding to the Renaissance Era Swiss physician who defended his use of substances that he believed were medicinal even though they were toxic at higher doses. In fact, most drugs, even relatively safe ones such as aspirin, can be toxic if the dose is high enough. It may well be that low or intermittent doses of rapamycin or other TOR inhibitors can confer most of their benefits without serious risks. But we need long-term studies on their safety and efficacy before they can be used to target aging in humans.
A problem with laboratory animals, including mice, is that they are kept in a highly protected and relatively sterile environment that does not mimic real-life conditions. To address this, Matt Kaeberlein at the University of Washington in Seattle is leading a nationwide US consortium to study the health and longevity of domestic dogs. Canines not only vary greatly in size but also live in environments as diverse as their owners’, so this is a way to conduct controlled studies in a natural setting outside of a laboratory environment. The consortium will analyze various aspects of dogs’ metabolism, including their microbiome and the differences between how large dogs age compared to small dogs. It will also carry out a randomized study on the effect of rapamycin in large middle-aged dogs. Experiments like these will go a long way to establishing whether rapamycin will turn out to be useful for general health in old age.
It is curious that using rapamycin to shut down a major pathway in the cell could actually be beneficial. As is often the case, the answer to this paradox lies in the evolutionary theories of aging discussed earlier. In a 2009 paper published in the journal Aging, Michael Hall, of the University of Basel, and the Russian-born evolutionary biologist Mikhail Blagosklonny suggest an explanation: TOR promotes cell growth, which is essential in early life. Later, however, it is unable to switch itself off even when the growth it drives becomes excessive, leading to cell deterioration and the onset of age-related diseases. They go on to suggest that while these pathways that cause aging cannot be completely switched off by a mutation (because that would be harmful or even lethal early in life), perhaps they can be inhibited by drugs such as rapamycin years later, when an uninhibited TOR becomes a problem after individuals have reached middle age.
This chapter began with how the age-old idea of fasting as a beneficial practice gained credence with scientific studies on caloric restriction. However, the journey to discover a potential drug that could replicate the advantages of restricting calories without requiring unwavering self-control is nothing short of extraordinary. It began with a completely open-ended fishing expedition by Canadian scientists to find something interesting in the soil of the remote island of Rapa Nui. Just one of many soil samples they collected had a bacterium that produced a promising compound, and that nearly died in a scientist’s freezer as he moved from one country to another. The baton was taken up years later by two Americans and an Indian working in Switzerland. None of the scientists involved had any idea that they would be revealing one of the cell’s most important pathways with connections to both cancer and aging. This is often how science works: people follow their curiosity, and one thing leads to another. It is a story of persistence, insight, brilliance, and vision, but also chance encounters and sheer luck. If this strange journey ends up unlocking a key to protecting us from the relentless onslaught of old age, it would indeed be a scientific miracle.
8. Lessons from a Lowly Worm
We all know families of long-lived individuals. But exactly how much do genes influence longevity? A study of 2,700 Danish twins suggested that the heritability of human longevity—a quantitative measure of how much differences in genes account for differences in their ages at death—was only about 25 percent. Further, these genetic factors were thought to be due to the sum of small effects from a large number of genes, and therefore difficult to pinpoint on the level of an individual gene. By the time that the Danish study was carried out in 1996, a lowly worm was already helping to overturn that idea.
That lowly worm was the soil nematode Caenorhabditis elegans, introduced into modern biology by Sydney Brenner, a giant of the field known for his caustic wit. Born and initially educated in South Africa, he spent much of his productive life in Cambridge, England, before he established labs all over the world from California to Singapore, leading some of us to remark that the sun never set on the Brenner Empire. He first became famous for having discovered mRNA. More generally, he worked closely with Francis Crick on the nature of the genetic code and how it was read to make proteins. Once he and Crick decided that they’d solved that fundamental problem, Brenner turned his attention to investigating how a complex animal develops from a single cell, and how the brain and its nervous system work.
Brenner identified C. elegans as an ideal organism to study because it could be grown easily, had a relatively short generation time, and was transparent, so you could see the cells that made up the worm. He trained a number of scientists at the MRC Laboratory of Molecular Biology in Cambridge and spawned an entire worldwide community of researchers studying C. elegans for everything from development to behavior. Among his colleagues was biologist John Sulston, whom you met in chapter 5. One of Sulston’s more remarkable projects was to painstakingly trace the lineage of each of the roughly 900 cells in the mature worm all the way from the single original cell, which led to an unexpected discovery: certain cells are programmed to die at precise stages of development. Scientists went on to identify the genes that sent these cells to commit suicide at just the right time in order for the organism to develop.
For an animal with only 900 cells, these worms are incredibly complex. They have some of the same organs as larger animals but in simpler form: a mouth, an intestine, muscles, and a brain and nervous system. They don’t have a circulatory or respiratory system. Though tiny—only about a millimeter long—nematodes can easily be seen wriggling around under a microscope. Being hermaphrodites, they produce both sperm and egg, but C. elegans can also reproduce asexually under some conditions. They are normally social, but scientists have found mutations that make them antisocial. Worms feed on bacteria, and just like bacteria, they are cultivated in petri dishes in the lab. They can be frozen away indefinitely in small vials in liquid nitrogen and simply thawed and revived when needed.
Worms typically live for a couple of weeks. However, when faced with starvation, they can go into a dormant state called dauer (related to the German word for endurance), in which they can survive for up to two months before reemerging when nutrients are plentiful again. Relative to humans’ life span, this would be the equivalent of 300 years. Somehow these worms have managed to suspend the normal process of aging. There is a caveat, though: only juvenile worms can enter the dauer state. Once animals go through puberty and become adults, they no longer have this option.
David Hirsh became interested in C. elegans while he was a research fellow under Brenner in Cambridge, then continued working with the worms upon joining the faculty at the University of Colorado. There he took on a postdoc named Michael Klass, who wanted to focus on aging. This was at a time when aging was simply thought to be a normal and inevitable process of wear and tear, and mainstream biologists viewed aging research with some disdain. However, things were beginning to change, partly because the US government was concerned about an aging population. As Hirsh recalled, the National Institutes of Health had just established the National Institute on Aging, and at least some of his and Klass’s motivation for working in the area was that they knew they stood a good chance of receiving federal funding.
Hirsh and Klass first showed that, by many criteria, worms age little if at all in the dauer state. Next, Klass wanted to see if he could isolate mutants of worms that would live longer but not necessarily go into dormancy. This would help him identify genes that affected life span. To rapidly produce mutants that he could screen for longevity, he treated the nematodes with mutagenic chemicals. He ended up with thousands of plates of worms, which he continued studying after starting his own lab in Texas. In 1983 Klass published a paper about a few long-lived mutant nematodes, but eventually he shut down his lab and joined Abbott Laboratories near Chicago. Before doing so, however, he sent a frozen batch of his mutant worms to a former colleague from Colorado, Tom Johnson, who by then was at the University of California, Irvine.
By inbreeding some of the mutant worms, Johnson found that their mean life span varied from ten to thirty-one days, from which he deduced that, at least in worms, life span involved a substantial genetic component. It still wasn’t clear how many genes affected life span, but in 1988 Johnson, working with an enthusiastic undergraduate student named David Friedman, came to a striking conclusion that ran completely counter to the conventional wisdom that many genes, each making small contributions, influenced longevity. Instead, it turned out that a mutation in a single gene, which the two called age-1, conferred a longer life span. Johnson went on to show that worms with the age-1 mutation had lower mortality at all ages, while their maximum life span was more than double that of normal worms. Maximum life span, defined as the life span of the top 10 percent of the population, is considered a better measure of aging effects because mean life span can be affected by all sorts of other factors that don’t necessarily have to do with aging, such as environmental hazards and resistance to diseases.
At the time, Tom Johnson was not a famous scientist, and his premise that a single gene could affect aging to such a degree defied the consensus view. Thus it took almost two years for his paper to be published. Even after it finally appeared in the prestigious journal Science in 1990, Johnson’s work was viewed with some skepticism by the scientific community.
But then, a few years later, came a second mutant worm. This effort was led by Cynthia Kenyon, already a rising star in the C. elegans field. Kenyon had a golden career: PhD from MIT; postdoctoral work with Sydney Brenner at the MRC Laboratory of Molecular Biology in Cambridge, where the first studies on the genetics of the worm were being carried out; faculty member at the University of California, San Francisco, another world-renowned center for molecular biology and medicine. Kenyon had established herself as a leader in the worm’s pattern development, which is the process by which it lays down its body plan as it grows. She was interested in aging research, but since it was still an unfashionable discipline, she found it difficult to enlist students to work on the problem. After hearing Tom Johnson speak about his work on age-1 at a meeting in Lake Arrowhead just outside Los Angeles, though, she felt inspired to work on the problem of aging and began her own screening for new mutants.
Like Hirsh, Klass, and Johnson, Kenyon focused on dauer formation. In the previous decade, scientists had identified many genes that affected dauer formation, usually prefixed by the letters daf. Scientists traditionally italicize the names of genes; when not italicized, the letters refer to the proteins that the genes encode. Under normal conditions, these mutations would predispose worms to enter the dauer state. But Kenyon had a hunch that some of these genes would affect longevity even outside the dauer state. She employed a trick in which she used mutant worms that were temperature sensitive: they would not enter the dormant state at a lower temperature (68°F, or 20°C). They were allowed to develop at this lower temperature until they were no longer juveniles and dauer formation was no longer an option. At that point, they were shifted to a higher temperature of 77°F (25°C) and allowed to mature into adulthood so that their life span could be measured.
From these studies, Kenyon and her colleagues identified a mutation in a gene, daf-2, that lived twice as long as the average worm. In marked contrast to the skepticism Johnson faced, Kenyon had no trouble publishing her work: her 1993 paper in Nature was received with great fanfare. Apart from her stellar academic pedigree and scientific abilities, Kenyon was also lucid and charismatic, so she was extolled by the media. In an unfortunate omission, neither Kenyon’s paper nor the accompanying commentary mentioned Johnson’s earlier work on age-1, and much of the reporting of Kenyon’s work gave the impression that it was the first time that a mutation that extends longevity had been discovered.
At this point, nobody had any real idea of what the genes identified by Johnson and Kenyon actually did. Enter Gary Ruvkun. Today Ruvkun is most famous for discovering how small RNA molecules called microRNAs regulate gene expression, but he has led a varied and colorful life, both personally and scientifically. When I met him about ten years ago at a meeting in Crete, he became increasingly gregarious after a few drinks; at one point, he donned a bandanna and pretended to smoke a cigarette while pouring himself some strong Greek liquor, which, with his luxuriant but well-tended mustache, made him look like a sailor on shore leave in a Greek taverna. All the while, he incongruously continued to hold forth on RNA biology. In the mid-1990s he too was using the worm and had been studying dauer mutants, including daf-2, for reasons unconnected with aging. Apparently he did not hold the field in high regard, because he recollected that when Kenyon’s report came out, “I thought, ‘Oh, gosh, now I’m in aging research.’ Your IQ halves every year you’re in it.”
The big breakthrough came when Ruvkun isolated and sequenced the daf-2 gene. It coded for a receptor that sticks out of the cell’s surface and responds to a molecule very similar to insulin: IGF-1 (insulin-like growth factor). Both insulin and IGF-1 are hormones that bind to their receptors in the cell. Both receptors are also kinases that activate downstream molecules, which in turn affect metabolic pathways that play a role in longevity. These hormones or their counterparts exist in nearly all organisms, so they must have originated very early in the evolution of life. That these ancient hormones control aging was a stunning finding.
These discoveries led to a general understanding of how this pathway would work. IGF-1 binds to the daf-2 receptor, which is a kinase, and activates it. This sets off a cascade of events in which one kinase acts upon another until a protein called daf-16 is phosphorylated. It’s basically the domino effect. The last domino in the chain, daf-16, is a transcription factor, so its role is to turn on genes. When it is phosphorylated, it cannot be transported to the nucleus, where the genes reside on the chromosomes, so it cannot act on its target genes. But if we disrupt the pathway—for example, by mutations in any of the proteins in this cascade—daf-16 can move into the nucleus and turn on a large number of genes that help the worm survive in the dauer state during stress or starvation, thus extending its life span. As it turns out, the age-1 gene originally identified by Tom Johnson is somewhere in the middle of the cascade that starts with daf-2 and ends in daf-16.
Daf-16 turns on genes that are involved in coping with stress triggered by starvation or increased temperature, as well as genes that code for the chaperones that help proteins fold or rescue unfolded or misfolded proteins before they become a problem for the cell. Kenyon wrote in a 2010 review that these genes “constitute a treasure trove of discovery for the future.” The pathway explained a puzzling paradox. Aging or longevity was thought to be the effect of a large number of genes, each of which would have a small effect. How could a mutation in a single gene, such as age-1 or daf-2, effectively double the life span of the worm? Clearly the reason was that they were part of a cascade that ended up activating daf-16, which then turned on multiple genes that collectively exerted a cumulative effect on life span.
The idea that a growth hormone pathway might be involved in longevity also explains a curious fact. Larger species generally live longer than smaller ones because they have slower metabolisms and can also escape predation. But within species, smaller breeds generally live longer than larger ones. For example, small dogs can live twice as long as large dogs. This may have to do partly with how much growth hormone they make.
Remember that queen ants live many times longer than worker ants. Among the many reasons for this is that queens produce a protein that binds insulin-like molecules and shuts down the IGF-like pathways in ants.
But what of quality of life? Are these long-lived worms sickly and barely surviving? In a word, no. The nematodes don’t just live longer, they look and act like much younger worms. We all know that one of the horrors of aging is the onset of Alzheimer’s disease. Researchers can generate a model for Alzheimer’s disease by making a genetic strain of worms that manufactures amyloid-beta protein in their muscle cells, paralyzing them. However, if the experiment is repeated—but this time using a strain of long-lived worms with mutations in the IGF-1 pathway—paralysis is reduced or delayed. Thus, the same mutations that extend life may also protect you from Alzheimer’s and other age-related diseases that are caused by proteins misfolding and forming tangles. In fact, these mutations may prolong life precisely because they protect against some of the scourges of old age.
It is all very well to make worms live longer and healthier, but what about other species? Evidence elsewhere in the animal kingdom suggests similarly a strong relationship between the IGF-1 pathway and life span. Deleting the gene that codes for a protein called CHICO, which activates the IGF-1 pathway in flies, made them live 40–50 percent longer. They were significantly smaller but seemed healthy otherwise. The IGF-1 receptor is essential, but mice, like humans, have two copies of it (from their maternal and paternal chromosomes), and knocking out one of them made the mice live longer without any noticeable ill effects.
Scientists, of course, are not doing all this work to help mice. We want to know what happens in humans, but you can’t just mutagenize people. There are people who naturally have mutations in the insulin receptor. Some of them suffer from a disease called leprechaunism, which stunts growth, and seldom reach adulthood. An analysis of subjects with the disease showed that the same mutations in daf-2 would affect dauer formation in the worm, yet the consequences were rather different. Still, there are hints that this pathway plays a role in human longevity. Mutations known to impair IGF-1 function are overrepresented in a study of Ashkenazi Jewish centenarians, and variants in the insulin receptor gene are linked to longevity in a Japanese group. Variants in proteins identified as part of the IGF-1 cascade have also been associated with longevity. It may be tempting to see the IGF-1 and insulin pathway as a straightforward route to tackling aging. But just the complexity of the pathway and the range of effects it produces tells us it is a finely tuned system, and tinkering with it while avoiding unforeseen ill effects could be difficult.
When food intake is restricted, the levels of both IGF-1 and insulin decline. If the IGF-1 pathway is inhibited already, you might not expect caloric restriction to have much additional effect. Exactly as you might predict, caloric restriction did not further increase the life span of daf-2 mutant worms; moreover, its full effect depended on daf-16. But this too is puzzling, because the other, completely different TOR pathway is also affected by caloric restriction. So even if the IGF-1 pathway was disrupted, shouldn’t caloric restriction have had at least some effect through the TOR pathway? It turns out that these two pathways are not completely independent. They are two large hubs in a large network, but there is lots of cross talk between them. In other words, proteins that are activated as part of one pathway will activate ones in the other pathway, so they are interconnected. In particular, TOR is activated by elements of the IGF-1 pathway as well as by nutrient sensing.
While the two pathways are highly coordinated, they are not the whole story behind caloric restriction. Two scientists found a mutant that causes partial starvation of the worm by disrupting its feeding organ, the equivalent of the throat. The mutant, eat-1, lengthens life span by up to 50 percent and does not require the activity of daf-16. Also, double mutants of daf-2 and eat-1 live even longer than the daf-2 mutants alone. This means that caloric restriction affects other pathways besides TOR and IGF-1.
Mutations that affect longevity dramatically might seem to suggest that aging is under the control of a genetic program. This idea might seem to contradict evolutionary theories of aging, but, in fact, it doesn’t. When worms were subjected to alternative cycles of food and scarcity, it turned out that the long-lived mutant worms simply could not compete reproductively with shorter-lived, wild-type worms. These pathways allow organisms to have more offspring at the cost of shortening life later on, exactly as one might predict from the antagonistic pleiotropy or disposable soma theories of the evolution of aging.
We have seen what rapamycin can do, but is there a drug that acts elsewhere, such as on the IGF-1 pathway? There is a great deal of interest in metformin, a diabetes treatment. Diabetes, of course, is related to deficient insulin secretion or regulation rather than to IGF-1, although the two molecules are closely related. To understand the difference between these two hormones, I took a short walk from my own lab to the nearby Wellcome-MRC Institute of Metabolic Science on the Addenbrooke’s Biomedical Campus in Cambridge, England, to meet Steve O’Rahilly, one of the world’s experts on insulin metabolism and its consequences for diabetes and obesity.
Despite his many distinctions and his job as the director of a major institute, Steve lacks even a hint of self-importance. He is a jolly man who in his talks often jokes that his physique makes him particularly qualified to study obesity and its causes; while far from obese, he certainly looks well fed. But underneath the jovial demeanor, he is a sharp and critical scientist who has advanced a messy field by imbuing it with intellectual rigor. Among his many contributions is demonstrating the importance of appetite genes in obesity. Here too Steve has a highly personal interest: he told me that appetite can be such a strong urge that when he is hungry, he can hardly concentrate on anything besides food.
Steve pointed out that while insulin and IGF-1 are similar in structure and have similar effects when they act on the cell, they have some major differences. Insulin has to act very quickly and in just the right amounts. Getting insulin regulation wrong can be lethal. The brain needs glucose for fuel, so hypoglycemia, a drop in blood sugar caused by too much insulin in the circulation, is very dangerous even if it only lasts a few minutes.
Insulin receptors are particularly abundant in liver, muscle, and fat cells. In the fasting state, insulin levels are relatively low, and the liver produces the glucose needed constantly by the brain from stored carbohydrates and other sources. But even that low level of insulin is needed to prevent the liver from making too much glucose or ketone bodies (a product of metabolizing fat). After a meal, the level of insulin surges by between ten- and fifty-fold, promoting the uptake of glucose into muscle cells, the synthesis of lipids (fat) in the liver, and the storage of lipid in fat cells.
Newly secreted insulin does not last long in the bloodstream, with a half-life of only about four minutes. If insulin is like a speedboat racing to its destination, IGF-1 is more like an oil tanker. Its effect lasts much longer, and, in the circulation, it is often bound to other proteins and not active. It needs to be released from them to act, and exactly how this happens is not clear, but that too may be under hormonal control. Also, unlike insulin receptors, IGF-1 receptors are distributed much more broadly throughout all the cells in the body, and there are more of them during development, when the organism has to grow.
IGF-1 is produced in response to the secretion of growth hormone, but its action controls the amount of growth hormone in a complicated feedback loop. When IGF-1 levels are low or IGF-1 is defective, the body responds by producing more growth hormone. The problem is that growth hormone has other effects apart from stimulating the production of IGF-1. Most notably, it releases fat from fat cells. Not storing away fat in these cells is the cause of much human pathology, such as clogged arteries, or messing up the metabolism in our liver and muscle. So it is not surprising that mutations in the receptor for insulin or IGF-1 can cause diabetes. On the other hand, with caloric restriction, you are consuming the bare minimum of calories. So you actually have less spare fat because you are burning it off to provide energy. This means that caloric restriction does not have the same consequences as simply reducing the level of IGF-1, where excess fat is released to cause damage. Because of this fundamental difference, drugs that try to mimic caloric restriction by acting on the IGF-1 pathway could be particularly challenging to develop. It is hard to cheat our bodies’ finely tuned system.
That is what explains the current interest in metformin. The drug is already used by millions of people with diabetes all over the world, so it has gone through various clinical trials for safety. Its use, in fact, dates all the way back to medieval Europe, where extracts of the plant Galega officinalis, commonly known as French lilac or goat’s rue, were used to relieve the symptoms of diabetes. One of the products of the extract, galegine, could lower blood glucose but was too toxic. Eventually a derivative, metformin, was synthesized and tested and is now the first-line treatment for type 2 diabetes, which is more common later in life and is caused not by a lack of insulin but because the insulin doesn’t bind well to its receptor.
How metformin works as a treatment for type 2 diabetes is not entirely clear. Traditionally, most charts of metformin interactions resemble an incredibly complicated wiring diagram. Because of recent advances in our ability to visualize biological molecules, we can now see exactly how metformin binds and inhibits its target protein. This target protein is a crucial component in the process of respiration, in which oxygen is used to burn glucose to produce energy in our cells. Disrupting our ability to utilize glucose in turn affects our energy metabolism and acts on components of the IGF pathway, including an enzyme that regulates glucose uptake. Although some studies have claimed that metformin reduces glucose production in the liver, others show that it actually increases it in healthy people and those with mild diabetes. According to another study, the drug alters our gut microbiome in a way that is at least partly responsible for its effects. Steve O’Rahilly’s work demonstrates that metformin also works by elevating the levels of a hormone that suppresses appetite.
It may seem odd that a drug whose mode of action is so complex and poorly understood should be so widely prescribed for people with diabetes, but this is often the case in medicine. For almost a hundred years, we had no idea how aspirin worked, yet people consumed billions of tablets for their aches and pains. Still, given the uncertainties, it is rather surprising that metformin has now become interesting as a potential drug to combat aging. This is partly because of a couple of early studies. In the first, from the National Institute on Aging, long-term treatment with metformin in mice improved both their health and life span. A second study, in humans, showed that diabetics on metformin lived longer not only than diabetics on other drugs but also longer than nondiabetics—a significant finding, since diabetes itself is a risk factor for aging and death.
Such promising outcomes certainly raised optimism about using metformin to prolong healthy life even in people without diabetes, but subsequent studies have questioned these results. One, from 2016, concluded that metformin was merely better than other diabetes drugs, so that diabetics on metformin had about the same survival rate as the general population. More than metformin, it was the family of cholesterol-lowering medications known as statins that dramatically reduced mortality, especially in patients with a history of cardiovascular disease. Metformin did extend the life of worms if treatment was initiated at a young age, but it was highly toxic and actually shortened life span when treatment commenced at an older age. Curiously, some of the toxicity was alleviated by giving the worms rapamycin at the same time. Metformin also undermined the health benefits of exercise, which itself is well established as one of the best remedies against diseases of aging. And one study claimed that diabetics on metformin exhibited an increased risk of dementia, including Alzheimer’s disease.
Given these uncertainties, Nir Barzilai, a gerontologist at Einstein College of Medicine in New York, is the principal investigator for a large clinical trial of about three thousand volunteers between the ages of sixty-five and seventy-nine called Targeting Aging with Metformin (TAME). The study’s goal is to see if metformin delays the onset of age-related chronic diseases such as heart disease, cancer, and dementia, as well as monitor for adverse side effects.
To date, however, despite considerable effort, the evidence for metformin concerning longevity is not at all clear. Its effect isn’t nearly as strong or as well established as that of rapamycin, which inhibits the TOR pathway. One reason for the interest in metformin is that its long-term safety has been established in diabetics. Those with diabetes will be perfectly happy to take metformin, as their risk of poor health and eventually dying of complications of diabetes is much higher without treatment. But given the potential drawbacks noted here, it is quite a different matter to recommend its long-term use in healthy adults just yet.
WE HAVE COME A LONG way from the age-old idea that exerting self-control over one’s diet is good for you and that gluttony comes at a steep price to our health. First there was the scientific evidence that caloric restriction could prolong healthy life compared to an ad libitum diet. Then in the last few decades, two previously unknown pathways, the TOR and the IGF-1, were shown to be major processes in the cell that responded to caloric restriction. This in turn has opened up the possibility of extending healthy living and even life span by tinkering with these pathways. The world of medical science has compiled a tremendous amount of research regarding the effects of rapamycin, metformin, and related compounds on aging and life span; rapamycin and its chemical analogs are among the more promising avenues for tackling aging. Still, bear in mind that inhibiting these pathways individually is not the same as caloric restriction, and a lot more work needs to be done to establish both the efficacy and safety of these approaches.
Several things strike me about the discovery of TOR and the IGF-1 pathways. First, the mere existence of these pathways came as a complete surprise. Second, at least in the case of TOR, scientists were not even looking originally for a connection with caloric restriction, let alone aging. By sheer chance, they uncovered major processes in the cell that have ramifications not only for aging but also for many diseases. Third, they involved organisms that might not seem obvious for studying aging, such as yeast and worms. Finally, the discovery that a single gene could impact life span so dramatically was quite unexpected.
Before we leave the complicated maze of caloric restriction and its pathways, let us visit a third strand that, like the story of TOR, begins with baker’s yeast. Unlike the discoverers of TOR, who were not even investigating anything pertaining to the aging process, this story is about scientists who deliberately used yeast to discover genes related to aging. A yeast cell divides by budding off smaller daughter cells. The mother cell acquires scars on its surface with each budding and can only undergo a finite number of divisions. This inability to divide further is called replicative aging. Still, you might not think that studying this rather specialized property of a single-celled organism such as yeast would have any relevance at all for a phenomenon as complex as human aging. That was exactly the skepticism that Leonard Guarente encountered from his colleagues at MIT when he said he was planning to tackle aging using yeast.
Like many molecular biologists, Guarente had relied on yeast to study how genes are turned on and off by controlling the transcription of DNA into mRNA. By 1991, three years after Johnson’s report on the long-lived age-1 mutant in worms, Guarente was a tenured faculty member at MIT. He was already established and professionally secure, so when two of his students, Brian Kennedy and Nicanor Austriaco, told him they wanted to work on aging, Guarente agreed to embark on what for him was an entirely new area, dramatically altering the trajectory of his career.
Initially, Guarente and his students identified a trio of genes belonging to a family called SIR genes, for silent information regulator. The SIR family in turn controls genes that define the mating type or “sex” of yeast. (Yeast mating is complicated, and they can switch their “sex” from one type to another.) Eventually Guarente’s team showed that just one of these genes, Sir2, had the biggest effect on yeast life span. Increasing the amount of Sir2 in cells extended life span, while mutating it reduced life span. The effect was not as large as the factor of 2 seen for the age-1 or daf-2 mutants in worms. But they had clearly identified a gene in yeast that controlled how many times a mother cell could divide before it was exhausted. Even more promising, Sir2 was a highly conserved gene: it had counterparts in other species, including flies, worms, and humans. They soon found, with mounting excitement, that increasing the amount of Sir2 in flies and worms also extended their lives.
But how did it work? Recall that our genome can be recoded using epigenetic marks—chemical tags—on either the DNA itself or on the histone proteins tightly associated with it. In general, adding acetyl groups to histones activates those regions of chromatin, whereas removing acetyl groups silences them. Sir2 turns out to be a deacetylase, which you might recall are enzymes that remove acetyl groups from proteins such as histones, and there is evidence that this activity silences genes near the boundary of telomeres and affects life span. Sir2 also requires a molecule called nicotinamide adenine dinucleotide (NAD), which is required for metabolizing energy in the cell. This was a hint that when there is starvation, there is not enough free NAD to activate Sir2. Suddenly you could make a plausible link between Sir2 and caloric restriction, which had long been implicated in aging in many organisms, including yeast. Sure enough, in both flies and yeast, mutation of Sir2 eliminated the benefits of caloric restriction in prolonging life, and, in worms, the effect of Sir2 required the presence of daf-16, the same transcription factor that had already been identified as the target of the IGF-1 pathway in worms. Suddenly things appeared to come together: a mutant affecting life span in yeast was associated with a pathway affecting aging in worms that in turn was connected with caloric restriction.
Finding mutants that increased longevity in both worms and yeast prompted Guarente and Kenyon to publish a highly enthusiastic article in the journal Nature extolling the prospects of curing the aging problem. “When single genes are changed,” they wrote, “animals that should be old stay young. In humans, these mutants would be analogous to a ninety-year-old who looks and feels forty-five. On this basis, we begin to think of ageing as a disease that can be cured, or at least postponed.” They went on to found a company in Cambridge, Massachusetts, with the equally optimistic name Elixir Pharmaceuticals.
Not long after Guarente had made his initial breakthrough, he gave a talk in Sydney, Australia. In the audience sat David Sinclair, a brash young graduate student working on his PhD at the University of New South Wales. Sinclair was clearly both impressed and excited by Guarente’s results because he persuaded the latter to take him on as a postdoctoral fellow at MIT. Following his fellowship, Sinclair started his own lab at Harvard Medical School, across the river in Boston, and continued to work on Sir2 and aging, in effect becoming a competitor of his former mentor. Next, Sinclair started his own company, bearing the more descriptive and modest name of Sirtris Pharmaceuticals.
By then, researchers were keen to see if the counterpart of Sir2 in humans and other mammals would have similarly beneficial effects on life span and health. In mammals, there are seven members of this family, numbered SIRT1 through SIRT7. These proteins, like the equivalents of Sir2 in other organisms, were collectively called sirtuins. (Proteins that activate other proteins are often given names ending in in; sirtuins is simply a play on “Sir2-ins.” SIRT1 seemed the most similar to Sir2, so it drew the bulk of early attention. The goal was to find a pill—or magic elixir—that would activate sirtuins in some beneficial way.
Here the story takes a rather strange, and rather French, turn. It has long been speculated that the French have a relatively low prevalence of heart disease despite their rich diet because they also drink copious quantities of red wine. Sinclair, collaborating with a biotech company in Boston, identified resveratrol as one of the compounds that stimulated SIRT1. Oenophiles around the world rejoiced, for resveratrol was a compound present in red wine. Finally, here was scientific evidence for the benefits of a French lifestyle. Their enthusiasm was apparently not tempered by the realization that it would take about a thousand bottles of wine to produce the amount of resveratrol used as a dose in those studies.
Sinclair’s team and a competing group appeared to clinch the issue when they administered resveratrol to mice fed a diet high in sugar and fat. Although the mice remained overweight, and their maximum life span was unaffected, they were protected against the diseases of overeating: more of them survived to old age, and their organs were not diseased like those in typically obese mice.
This seemed exactly the Get Out of Kale Free card people were waiting for: permission to overindulge on an unhealthy diet without any ill effects. Never shy when it came to self-promotion, Sinclair was all over the news again when the pharmaceutical giant GlaxoSmithKline bought Sirtris for an astonishing $720 million in 2008. He had hit both the scientific and commercial jackpots—or so it seemed. But even at the time, there was considerable skepticism in the industry about the purchase.
There has been significant pushback against the claims made by sirtuin advocates, some of it coming, oddly enough, from two of Sinclair’s former colleagues in the Guarente lab: Brian Kennedy and Matt Kaeberlein. Among other things, their work showed that contrary to earlier findings, caloric restriction results in an even greater life span extension in yeast cells lacking Sir2, suggesting that the two were not likely to be linked. Rather, Sir2 may have been acting in other ways by modifying the program of gene expression by deacetylating histones on DNA. The two went on to reveal that the activity of resveratrol on SIRT1 was due to the presence of a fluorescent molecule that was used to detect the activation. Without this additional molecule, no increase in activity was observed, so it was not even clear whether resveratrol had any effect on SIRT1. Not only that, but they did not find any effect of resveratrol on Sir2 activity in yeast, including life span. Pharmaceutical companies do not usually spend time proving one another wrong, but in an unusual step, scientists at Pfizer published a report stating that several of the other compounds identified by Sirtris did not directly activate SIRT1 either.
With any machinery, it is much easier to do something that will stop it from working than to improve its performance. It is the same with drug development; many drugs work by inhibiting an enzyme, and manufacturing a new drug that makes an enzyme more effective is always a challenge and relatively rare. So Glaxo’s very expensive purchase of Sirtris raised eyebrows in the industry. Eventually it gave up on the lead compounds it had acquired from Sirtris and shut down the division. Five years after the sale, an article in Forbes magazine concluded that the best way to experience the benefits of red wine was to drink it in moderation.
Of course, following the dictum of the German theoretical physicist Max Planck that scientists rarely change their minds in light of contradictory evidence, Sinclair and others stuck to their guns. They countered the new findings by reporting that resveratrol worked alongside other helper compounds in the cell that had properties similar to the fluorescent molecules they had used to monitor Sir2 activity in the test tube. This led to another commentary, this time in the journal Science, titled, “Red Wine, Toast of the Town (Again).”
However, this optimistic assessment must be weighed against a systematic 2013 study by the National Institute on Aging that evaluated several compounds proposed to increase healthy life or overall life span, including resveratrol. None of them had any significant effect on the longevity of mice. Among the others were curcumin, which is present in the herb turmeric, and green tea extract—not that these findings seem to have put many health food stores out of business.
Beyond resveratrol, skeptics began to question the very premise of the sirtuin idea. Sir2 extends replicative life span, but losing the ability to keep reproducing is only one kind of aging in yeast. There is also chronological life span, which measures how long yeast can survive in a semi-dormant state—for example, when it has run out of nutrients. Sir2 activation actually reduces chronological life span in yeast. We humans—with the exception, perhaps, of a few very rich old men—are not mainly concerned with our ability to reproduce in old age, but with increasing life span and improving health.
Later studies also contradicted some of the early studies about the effect of Sir2 on life span. If you ascribe an effect to a mutation, you need to take care that in creating the mutant strain, you have not changed any of the thousands of other genes in the organism. Scientists clarified that overproduction of Sir2 in worms and flies had no effect on the life span of either worms or flies as long as they did not change anything else about the genetic makeup of their organisms. This considerably deflated enthusiasm for sirtuins as a potential boon to extending life, as illustrated by journal articles titled “Midlife Crisis for Sirtuins” and “Ageing: Longevity Hits a Roadblock.” Feeling embattled, Leonard Guarente repeated the experiment in worms by overproducing Sir2 without changing the genetic background, and had to revise his previous estimate of an up to 50 percent increase in life span down to about 15 percent.
The sirtuin with the most dramatic effect may actually turn out to be SIRT6; mice deficient in SIRT6 develop severe abnormalities within two to three weeks and die in about four weeks. The protein is also a histone deacetylase that may affect how genes are expressed in telomeric chromatin, and some studies suggest that it increases life span in mice, with one study theorizing it does so because it stimulates DNA repair.
It is telling that two of the pioneers of sirtuins in Guarente’s own lab, Kennedy and Kaeberlein, both well-established, respected researchers in their own right, have now entirely moved away from sirtuins to focus on other aspects of aging research such as the TOR pathway and how rapamycin affects it. Sirtuins, through their action on histones, may be involved in patterns of gene expression and genome stability, and are important for human physiology in ways that still need to be understood. But enthusiasm for their use in aging has declined except among the faithful. Many in the gerontology community are highly dubious that they have any direct connection with caloric restriction or extension of life span.
There is one related molecule that has retained considerable prominence regardless of the fate of sirtuins: NAD. Nicotinamide adenine dinucleotide plays many essential roles in the cell, including for sirtuin function. It is made by the body using nicotinic acid (niacin) or nicotinamide, both slightly different forms of vitamin B3, although it can also be made by our cells from the amino acid tryptophan or by salvaging some recycled molecules.
In the cell, NAD cycles between an oxidized and reduced form to help our cells burn glucose to convert it into other forms of energy. This process, called respiration, is absolutely essential for our ability to use glucose as a fuel; however, it does not use up NAD rapidly, since it simply cycles back and forth between its two forms. But NAD performs other essential functions, such as repairing DNA and altering gene expression through sirtuins, and these functions deplete it. Thus, as we grow older, our levels of NAD decline. The brain is one of the body’s biggest consumers of glucose as a source of energy, and you can imagine how a decline in NAD levels might harm brain function. It can also cause a host of other problems, from increased inflammation to neurodegeneration. If that seems a lot for a single molecule, it simply says something about how central NAD is to our metabolism.
Our cells can’t take up NAD directly from our diet. But we can utilize molecules that are direct precursors of NAD, of which two popular ones are called NR (nicotinamide riboside) and NMN (nicotine mononucleotide). Search for them on the internet, and you will find countless websites arguing that one or the other is better as an anti-aging supplement depending on which one they are selling. According to one study, increasing NAD levels by providing NR or NMN to mice slowed their loss of stem cells and protected them from muscle degeneration and other symptoms of decline; in another report, higher NAD levels led to an increase in life span. However, since NAD is so central to the chemistry of life, it may have benefits that have nothing to do with an increase in life span. Indeed, Charles Brenner, a longtime expert on NAD metabolism, says, “I expressly tell people NR is not a life extension drug and that the case for its use has nothing to do with sirtuins and everything to do with acute or chronic losses of redox [reduction/oxidation reactions involved in respiration] and repair functions in the conditions that attack the NAD system. The NR trial I am most interested in is promoting healing from scratches and burns.” The results of taking either NR or NMN in humans are not yet definitive, and so far there have been no long-term studies in humans on their benefits or side effects. However, this has not stopped them from being heavily marketed as anti-aging nutraceuticals, or dietary supplements with real or alleged physiological benefits that don’t require approval from agencies like the FDA. Global sales of NMN register about $280 million annually and are forecast to reach almost $1 billion by 2028.
We have seen how our cells orchestrate a finely tuned protein production program—and how this program starts to wobble as we age. A simple corrective—restricting our calories and eating well—can do much to slow this deterioration through complex interconnected pathways. Much excitement in aging research is about the prospect of producing drugs that inhibit these pathways and produce the benefits of caloric restriction.
The cell, though, is not merely a bag of proteins. It contains large structures and entire organelles that must work together in harmony. When and why those relationships break down is a topic at the forefront of aging research. And it all comes back, strangely enough, to an ancient parasite. We normally think of parasites as harmful, but this one was a mixed blessing. On the one hand, it enabled us to evolve from small unicellular organisms into the complex creatures we are today. On the other hand, it is also a major reason why we age.
9. The Stowaway Within Us
A couple of times a year, I visit my ten-year-old grandson in New York and experience something that must be familiar to all grandparents. Although I am physically fit for my age, I am exhausted after spending a day with him. How does he have such boundless energy that just watching him makes me tired? One reason I lack his energy also explains why we both exist as complex creatures, and it dates back to an event that occurred about 2 billion years ago.
The earliest life forms were single-celled creatures swimming around in a primordial soup. How did they become us? Each cell in our body is much larger and more complex than a typical bacterium, so even how just one of these complex cells evolved was a mystery. In the early 1900s a Russian botanist named Konstantin Mereschkowski proposed that one cell swallowed up another simpler, smaller cell. On its own, this was not remarkable; normally, either the smaller cell was killed and digested, or the cell doing the swallowing bit off more than it could chew and perished from the indigestion. But in one such case, Mereschkowski proposed, the swallower and swallowed both survived—and have continued to coexist and replicate ever since.
The theory hung around for decades but really gained credence in the 1960s when a biologist named Lynn Margulis began working on the idea. Margulis was an iconoclast. She was married to the astronomer Carl Sagan before marrying Thomas Margulis, a chemist, whom she also soon divorced, and is quoted as saying, “I quit my job as a wife twice. It’s not humanly possible to be a good wife, a good mother, and a first-class scientist. No one can do it—something has to go.” One of her more controversial theories is the Gaia hypothesis she proposed with scientist James Lovelock, which states that the entire biosphere—the Earth, its atmosphere, geology, and all the life forms that inhabit it—is a self-regulating, living organism. She also had more extreme, and troubling, views. Margulis wrote an essay suggesting that the 9/11 attacks on the World Trade Center were part of a conspiracy orchestrated by the US government, and questioned whether the human immunodeficiency virus (HIV) was really the cause of acquired immunodeficiency syndrome, or AIDS. Her view of herself as a maverick may have attracted her to conspiracy theories, but this attitude also allowed her to make a major contribution to our understanding of life.
Margulis believed that symbiosis was widespread and that eukaryotes—more complex cells that have a nucleus—evolved as a result of symbiotic relationships among bacteria. At the time, the dogma was that simpler bacteria evolved slowly into more complex forms of cells. You could think of Margulis’s idea as an extension of the one Mereschkowski had proposed almost six decades earlier, but it was still sufficiently controversial that her work was rejected by fifteen academic journals before being published in 1967 by the Journal of Theoretical Biology (under the byline Lynn Sagan). Margulis proposed that the descendants of the bacteria that were swallowed up now exist as organelles in the larger cell. In animal cells, we know these as mitochondria. In addition to mitochondria, plants have another bacterial descendant inside them: chloroplasts, which turn sunlight into sugar through photosynthesis. Neither we nor plants can exist without these stowaways inside us.
Today scientists believe that the key event that led to the formation of eukaryotes occurred about 2 billion years ago, when a single-cell organism called an archaeon swallowed a smaller bacterium. Against the odds, the bacterium survived, and eventually entered into a symbiotic relationship with its archaeon host. In the intervening 2 billion years, the bacterium evolved into mitochondria. In the 170 years since mitochondria were first discovered, scientists have learned that they are highly specialized centers of energy production in the cell. It is that ability to generate energy that allowed our primitive ancestor to evolve into today’s huge and complex variety of cells and spurred the growth of complex life forms. But we also know that energy is conserved and cannot be created out of nothing. So what does it mean to say that mitochondria generate energy?
Contrast today’s world with a primitive, preindustrial one. In a primitive world, there were many different sources of energy. You could use the energy of the sun to warm things; you could burn wood and other fuel to generate heat; you could use the flow of a river or the power of wind to turn a mill wheel; or use wind to sail across oceans. However, these different sources of energy are not interconvertible, and they can be used only in very limited ways. You could not, for example, use wind to cook your food.
Now think of today’s world: virtually every source of energy, from solar and wind, to fossil fuels and nuclear fission, can be converted to electricity. Electricity in turn can be used for almost everything. It provides heat and light, moves us around in cars and trains, entertains us through our television sets and other gadgets, and enables instant communication around the world. Electricity has become the universal currency of energy, in much the same way that monetary currency replaced barter trade hundreds of years ago.
That is exactly what mitochondria do in a cell. They take less versatile forms of energy—for example, the carbohydrates that we consume—and convert them into the universal energy currency of the cell, which is the molecule adenosine triphosphate, or ATP. We have come across ATP before: it is one of the building blocks of RNA and consists of the adenine base attached to a ribose sugar and a string of three phosphates. The bonds between the phosphate groups are what chemists call high-energy bonds. It takes energy to form them, and that energy is released when they are broken. When the cell needs energy for any particular process in the cell, it can break the bond between the second and third phosphate groups and use the energy released as a result. ATP is like a tiny, highly mobile molecular battery.
When we digest food, especially carbohydrates, we are effectively burning the sugar that we obtain by breaking down carbohydrates. In fact, chemically it is the same as if we actually burned sugar in a flame, except that our cells do it in a very controlled way. In both cases, the result is the same: sugar combines with oxygen and releases carbon dioxide and water, and releases energy in the process. That is exactly what we do when we breathe in and out. The energy released during respiration is used by mitochondria to make ATP.
This process is chemically similar to the way we produce electricity using hydroelectric power. Unlike our own cells, which have a single membrane enveloping them, mitochondria, like their bacterial ancestors, have two membranes: each one a thin double layer of fatty molecules called lipids, which separate aqueous compartments from one another. Inside the inner membrane is a large complex of protein molecules that uses the energy of respiration to move hydrogen ions (H+), or protons, across the inner membrane, creating a proton gradient, where one side of the membrane has a higher concentration of protons than the other. And just as water flows downhill, the protons want to go down the concentration gradient. But because the membrane is not generally permeable to protons, they can do so only by traveling through a specialized molecule that acts like a molecular turbine. In the same way that water is made to go down a hydroelectric dam through large pipes to turn turbines that generate electricity, protons go through that special molecule, ATP synthase, which, as a result, actually turns like a turbine, and makes a molecule of ATP by adding on the third phosphate to adenosine diphosphate, or ADP, which has just two phosphates.
Production of energy in our mitochondria.
Just as monetary currency increased trade and prosperity dramatically, enabling complex societies to evolve, and just as the energy currency of electricity allowed societies to become incredibly complex technologically, the efficient production of ATP allowed cells to become ever more complex and specialized. ATP is a small molecule and makes its way, as needed, all over the cell. It provides the energy for everything from making the components of the cell, to moving around parts of the cell, to enabling cells themselves to move. Our muscles use ATP to generate the power to contract. In our brain, ATP maintains the voltage across membranes in our neurons while they transmit electrical signals and fire impulses. The human body has to generate roughly its own weight in ATP every day, and the brain alone uses about a fifth of that. Just thinking uses hundreds of calories a day. And mitochondria provide nearly all of that ATP.
The stowaways within us, which may well have begun their lives as parasites, have made themselves indispensable by producing the ATP we need to survive. Mitochondria differ from their bacterial ancestors in other ways too. For one thing, they’ve shed most of their genes, so the mitochondrial genome is now tiny, typically coding for only a dozen protein genes. More than 99 percent of the mitochondria’s components are made by translating genes that now reside on the chromosomes in our nucleus. These proteins are made in the cytoplasm of our cells and then imported across one or both membranes of the mitochondria using a complicated machinery. How and why mitochondria managed to move most of their genes to their host’s genome, or why they retained any genome at all, is not well understood. This small mitochondrial genome is the source of many problems, though, because mutations in the mitochondrial DNA can give rise to diseases, including diabetes, and heart and liver failure, as well as conditions such as deafness.
We inherit our mitochondria exclusively from our mothers because the sperm contributes none of its mitochondria to the fertilized egg. As a result, diseases due to defects in the mitochondrial genome are inherited entirely from the mother. A few years ago, the United Kingdom made it legal for parents to produce a “three-parent” baby. The nucleus from the egg of a potential mother with defective mitochondria is introduced into the egg of a healthy woman donor that has had its own nucleus removed. This egg is then fertilized with the father’s sperm and placed in the womb of the potential mother. The child will carry mostly the genes of its father and mother, but all of his or her mitochondria, with their tiny genome, will come from the egg donor.
Cells can contain between tens to thousands of mitochondria. These mitochondria don’t lead entirely separate lives as they might if they were bacteria in a culture. Rather, they are constantly fusing and splitting. Mitochondria may be fusing to intermix their contents, partly as a way to compensate for partially damaged components in each of them. They also split in different ways. When cells divide, mitochondria will also split, often down the middle. But sometimes they will also split off parts that are defective so that they can be sent off to be degraded and recycled using processes such as autophagy, which we discussed in chapter 6.
Mitochondria don’t just fuse with one another; they also interact with a cell’s other organelles in interesting ways. It turns out that lipids—the fatty molecules that make up our membranes—are highly specialized, so different organelles and cell types have different compositions of lipids. Mitochondria often exchange components with other organelles so that they can help one another make the specialized lipids they need. Excessive contacts between these organelles and mitochondria can be just as harmful as having too little.
Finally, they do many other things besides making ATP. For example, they are also the place where the final stages of sugar burning occurs. They are the sites of burning our stored fat, which is especially important when our carbohydrate intake is insufficient, such as when we are starving or dieting. The energy from burning fat is also used to make ATP. Beyond energy production, mitochondria are now part of a complicated signaling network with the rest of the cell. They tell the cell when energy levels are low or high, so that it can adapt accordingly by turning on or off appropriate genes and pathways.
Thus, mitochondria are no longer just energy factories but have become a central hub of the cell’s metabolism, which is a far cry from the bacterial stowaway in our cells that they once were. We now coexist in a complex relationship with them. As we age, our mitochondria still work, but they have accumulated defects. Not only do they produce energy less efficiently, but they have become creakier and less effective at their myriad other tasks. Perhaps no other structure in the cell is so intimately connected to the energy of youth and the decline of the old. Aging mitochondria even acquire a different shape as they degrade, transitioning from elongated ovals to spherical blobs. You can see why my grandson, with his young, healthy mitochondria, might feel so much more energetic—and generally healthier—than I do.
IF MITOCHONDRIA ARE UNABLE TO function at some minimum level, we die. Remember, in most countries, death is defined by when our brain stops functioning. If we are unable to provide oxygen and sugar to our brain—which could be for a variety of reasons, such as a heart attack—the mitochondria in our brain tissue can no longer produce enough ATP for neurons to function, leading to brain death. A sudden loss of oxygen from a heart attack is a drastic occurrence, but even over the normal course of life, mitochondria gradually decline until they no longer function at the required level.
What brings mitochondria to this point? Mitochondria age for all the same reasons the rest of the cell does, but they have their own particular burden as well. In 1954, Denham Harman proposed something called the free-radical theory of aging. His idea was that chemically reactive species of molecules, some of them called free radicals, are produced normally as a byproduct of metabolism, and cause damage to the cell over time, accelerating aging. Harman’s idea would seem to help explain the benefits of caloric restriction. If you eat less, you burn fewer calories every day, and you don’t produce as many damaging chemical byproducts. Harman’s theory also explained why animals with high metabolic rates tend to live shorter lives than those with slower metabolism.
Free radicals can be produced throughout the cell, but they and other reactive species are produced in abundance in mitochondria. A primary function of mitochondria is burning sugar by oxidizing it. The oxygen we breathe consists of two oxygen atoms bound tightly together to form the O2 molecule. In mitochondria, this oxygen is reduced ultimately to two water molecules, each of which is H2O. If the reduction of oxygen is not complete, the partially reduced molecules are highly reactive intermediates called reactive oxygen species, or ROS. These highly reactive forms of oxygen can damage other components of the cell, including proteins and DNA. Anyone who has ever had an old car knows what reactive oxygen can do to the chassis; in that case, the reaction is speeded up when there is common salt around, which is why cars in climates where roads are salted in the winter tend to corrode more quickly. So you can think of damage to mitochondria from oxidation as a case of our cells rusting from within.
Normally mitochondria have enzymes to scavenge away these reactive species before they cause harm, but the process is not perfect. A fraction of reactive molecules escape. Over time, they damage the molecules around them, including the proteins that make our cells work. The general breakdown in the function of the cell leads to aging. Apart from causing immediate damage, these reactive species can also affect future generations of mitochondria by damaging our mitochondrial DNA. That DNA codes for parts of the essential machinery for oxidizing sugar and generating ATP, and if it acquires too many mutations, the machinery produced will be defective. This in turn makes the reduction of oxygen less efficient, resulting in even more reactive species, kicking off a vicious cycle. The reactive species can also diffuse to other parts of the cell and generally cause havoc. Slowly with age, mitochondria will perform less and less effectively.
Harman’s mitochondrial free-radical theory didn’t gain much traction at first, but a number of observations supported it. For one thing, the production of these reactive species increases with age; by contrast, the activity of the scavenging enzymes that remove them decreases with age, compounding the harm. But it wasn’t clear whether these changes were simply a result of aging or whether they themselves were further driving the aging process. Strains of mice that made more of an enzyme that scavenged hydrogen peroxide lived about five months longer than average, which is quite an increase in longevity for a mouse. As recently as 2022, scientists in Germany showed that a parasite increases the longevity of its ant hosts severalfold by secreting a cocktail that includes two antioxidant proteins as well as other compounds. You may remember that germ-line cells such as oocytes boast superior DNA repair. One way they may minimize damage is by suppressing one of the enzymes that generates reactive oxygen species.
As the free-radical theory gained credibility, antioxidants took center stage. These compounds, which combat reactive oxygen species, were touted as a panacea for everything from cancer to aging. Sales of antioxidants such as vitamin E, beta-carotene, and vitamin C soared. Cosmetic companies included vitamin E, retinoic acid, and other antioxidants in their lotions and creams to keep skin youthful. People were exhorted to eat foods rich in antioxidants, such as broccoli and kale.
Alas, although there were isolated reports of benefits from antioxidants, an analysis of sixty-eight randomized clinical trials of antioxidant supplements, encompassing a total of 230,000 participants, suggested that not only did they not reduce mortality, but some of them—beta-carotene, vitamin A, vitamin E—actually increased it. This by itself doesn’t mean that the free-radical theory has no merit. But it does mean that you cannot just pop antioxidant supplement pills and expect to get much protection against free-radical damage. Still, don’t give up on the kale just yet; eating fresh fruits and vegetables is beneficial for all sorts of other reasons.
There are many potential reasons why the results from antioxidant dietary supplements have been disappointing. They may be metabolized in a way that doesn’t maintain a lasting effect, or they may not properly mimic the natural process by which enzymes scavenge free radicals and reactive oxygen species. But over the last ten to fifteen years, some in the field have come to doubt that oxidative damage from reactive oxygen species and free radicals are a major cause of aging at all. Studies with other animals, including worms and flies, showed no clear correlation between the level of scavenging enzymes and life span. In fact, contrary to the report on mice I just mentioned above, studies in species as varied as yeast, worms, and mice reveal that increased levels of scavenging enzymes or other defenses don’t extend life span. On the contrary, in one study, mutant worms with higher levels of free radicals lived about a third longer. Giving them a herbicide that stimulates a surge of free-radical activity prolonged their lives even more, while reducing the level of free radicals by giving the worms antioxidant supplements reduced their lives. The naked mole rat lives many times longer than other animals of the same size, yet it has higher levels of reactive oxygen species.
What could possibly be going on? This may be an example of something called hormesis, in which exposure to low levels of a toxin is actually beneficial, whereas those same toxins are harmful at higher levels. Or, as the German philosopher Nietzsche said, that which does not kill us makes us stronger. Free radicals and reactive oxygen species send signals to stimulate the production of detoxification enzymes and repair proteins, which actually have a protective effect. Moreover, these reactive oxygen species have widespread roles as signaling molecules that convey the state of mitochondria to other parts of the cell.
So if free radicals and reactive oxygen species are by themselves not the major problem, what else about mitochondria might make them factors in aging? We know that mitochondrial DNA mutations increase with age, and accumulation of these mutations is correlated with disease. But does it cause aging? One way to settle this was to genetically engineer strains of mice in which the DNA polymerase enzyme that replicates mitochondrial DNA was made more error prone; consequently, mutations would accumulate at a much faster rate. These mutator mice were apparently normal at birth, but they soon showed many of the symptoms of premature aging, including gray hair, hearing loss, and heart disease. At the age of about sixty weeks, most of them were dead, while normal mice were still alive. This is strong evidence that damage to our mitochondrial DNA is an important factor in aging. Tellingly, these mutator mice did not have a higher level of reactive oxygen species, so it was not as if increased mutations led to defective enzymes, which then worsened the problem by accumulating reactive oxygen species. The ultimate reason these mutator mice age rapidly is still not settled. There are reports of a complicated interplay between errors in mitochondrial DNA and the stability of the bulk of the genome in the cell’s nucleus, which can cause all of the more general problems associated with DNA damage.
There is no question that damage to mitochondria is bad for the cell and accelerates aging, but it is remarkably difficult to tease out the precise sources of damage. Each human cell can house tens to thousands of mitochondria, each with its own genome. So if some of them acquire serious errors in their DNA, there will still be lots of healthy mitochondria to keep the cell working. But at some point, a threshold is reached where there are simply too many defective mitochondria in the cell, which cause so many problems that they overwhelm the good mitochondria. There are also situations where some of these defective mitochondria can multiply more quickly because they don’t actually do much of the work that healthy mitochondria do. In these cases, clones of these defective mitochondria can dominate, leading to serious problems for the cell.
Mitochondria are not just energy factories but also are intimately involved in the cell’s metabolism. So as they acquire defects with age, they contribute to the decline of the cells they inhabit and speed up aging. The effect is most pronounced when they contribute to the decline of stem cells, because those cells play such important and diverse roles: when they become dysfunctional, they not only fail to regenerate tissue but also cause cellular senescence and chronic inflammation, all of which are hallmarks of aging.
One characteristic of aging is a chronic low level of inflammation, cleverly dubbed “inflammaging.” Inflammaging owes its existence in part to our mitochondria’s ancient bacterial origins. Older, defective mitochondria are more prone to rupture and can leak their DNA and other molecules into the cytoplasm of the cell. The cell mistakes these as coming from bacterial invaders, triggering inflammation. Our neurons, which are either very long lived or do not regenerate at all, are particularly prone to aging mitochondria. It may be one reason that our cognitive abilities decline. Neurons with aging mitochondria are also less able to use the recycling pathways to clear away defective proteins and organelles, all of which expend energy. As a result, we become more prone to dementia with age.
For all these reasons, maintaining healthy mitochondria is a key to good health. How the cell does this is closely related to some of the pathways involved in caloric restriction that we have come across already. It also uses autophagy to get rid of entire mitochondria that it deems defective, or even just defective parts of mitochondria that are broken off. This process, called mitophagy, targets the mitochondria for destruction and recycling. Some proteins can sense when things are going wrong and coat the surface of defective mitochondria with markers that signal the autophagy apparatus to target them for destruction. The same caloric restriction that increases levels of autophagy by the TOR pathway also increases levels of mitophagy.
If a cell disposes of defective mitochondria, it must replace them with new mitochondria; here too, caloric restriction plays a role. The inhibition of TOR by caloric restriction, or the drug rapamycin, shuts down the synthesis of many proteins but turns on the synthesis of other proteins involved in turning out mitochondria. In studies, the increased mitochondrial activity from this process was tied directly to longer life spans in fruit flies.
Besides TOR, other signals also stimulate production of new mitochondria. Sometimes, though, this effort is futile: if the cell senses a problem with mitochondrial function, it may simply end up making more defective mitochondria.
WHILE SCIENTISTS AND THE PHARMACEUTICAL industry strive to produce a pill that will combat mitochondrial dysfunction, there is a simple way to stimulate the production of new mitochondria, and it doesn’t have to cost a penny: exercise. Physical activity turns on some of the same pathways that stimulate mitochondrial production in tissues ranging from our muscles to our brain. Exercise too is an example of hormesis. Too much exercise can be harmful, and even moderate exercise can temporarily increase blood pressure, oxidative stress, and inflammation, all of which are potentially problematic. Yet as long as the amount of exercise is not so excessive as to injure us, which depends on our health and many individual factors, it is highly beneficial. One way it spurs mitochondrial function is by generating the reactive oxygen species produced by incomplete oxidation when we breathe, which, as discussed earlier in this chapter, can be beneficial in the right amounts. Of course, exercise does far more than that and benefits us in many ways: reducing stress, maintaining muscle and bone mass, countering diabetes and obesity, improving sleep, and strengthening immunity. Add to this list the healthful effects of fresh mitochondria.
Eventually, despite the cell’s best efforts to both recycle defective mitochondria and manufacture new ones, our mitochondria inexorably age, and in turn accelerate other aspects of our overall aging. If accumulated mutations in mitochondrial DNA are a factor in their aging, why does a baby—or my grandson—have healthy mitochondria? The same question we asked for us as individuals could be asked here too. Why is the clock reset at each generation? Recall that the resetting of the aging clock has a few reasons. The first is that germ-line cells that form the next generation have better DNA repair and age more slowly. The second is that the epigenetic marks on DNA get reset with each new generation when germ-line cells are formed. Unlike our nuclear DNA, mitochondrial DNA doesn’t have the same sophisticated epigenetic mechanisms, but it is better repaired in germ-line cells. Moreover, there is a strong selection against mutations in mitochondrial DNA, so defective oocytes are not used for fertilization. There is also a strong selection against defective sperm and even defective early embryos, so any participants with deficient mitochondria should be weeded out. Nevertheless, selection is not perfect: at least some of the loss of fertility with age is due to aging mitochondria.
By now, it should be clear that all the causes of aging described so far are highly interconnected. We started off with perhaps the most fundamental molecule of all: our DNA, which contains the information necessary to make the thousands of proteins in a cell at just the right time and in the right amounts. That information needs to be protected against damage. Those thousands of proteins must work in harmony to ensure the functioning of a healthy cell, and the cell has many mechanisms to deal with problems as they arise. Beyond proteins, entire organelles such as mitochondria need to work in a symbiotic relationship with the rest of the cell. These mitochondria may have started off as an engulfed bacterium inside a larger ancestral cell, but today they have become a central hub in our metabolism. Any defects they acquire with age set off a whole sequence of events that themselves accelerate aging. All of these affect the aging of individual cells.
If individual cells in our body were to age or die, we would hardly notice it—after all, we have trillions of cells. But except in primitive life forms, cells don’t exist in isolation. In our bodies, they have to communicate with one another, and work together as part of our tissues and organs. It is when a sufficient number of cells accumulate defects with age that the symptoms of aging manifest themselves: arthritis, fatigue, susceptibility to infection, decreased cognition, and more generally, bodies that simply do not work as well as they did in our youth. It is time to look at how the aging of individual cells leads to some of the morbidities of old age.
10. Aches, Pains, and Vampire Blood
The coast-to-coast walk is one of the great long-distance treks in England. Starting in St. Bees Head on the west coast, it cuts through the most picturesque parts of the country before ending at Robin Hood’s Bay on the east coast, near Whitby, Dracula’s port of entry to England in the Bram Stoker novel. The entire walk runs about 200 miles. I figured when I finished it, I could get an “I Did the Coast-to-Coast Walk” T-shirt and disingenuously wear it in the States to impress people.
My opportunity came in the summer of 2013, when a group of friends and I set off. Everything was fine for the first week, but then my knee started to become more and more inflamed until I had to abandon the walk with only a few days to go. On my return, a surgeon looked at it and discovered a torn and inflamed meniscus, the result of moderate osteoarthritis. As soon as I had the knee repaired, my right shoulder started to ache—osteoarthritis striking again. I receive little sympathy from my similarly aged friends: aches and pains in our joints are simply part of life as we get older.
Joint pain is a symptom of just one kind of inflammation, and its causes are often physical, such as the wear and tear on the bones in the joint, which then pinch and inflame the soft tissue in it. But as we age, there is a much more pervasive yet less obvious inflammation that affects our health as well as our response to disease.
One cause of inflammation comes from cells that reach a senescent state because they have aged or become damaged. We’ve seen that when a cell senses DNA damage, it can do one of three things. If the damage is mild, it can turn on repair mechanisms. If the damage is more extensive, it can trigger signals that kill the cell; or it can send the cell into a senescent state, in which it is no longer able to divide. We saw an example of the latter when we discussed how cells stop dividing when the telomeres at the ends of their chromosomes shorten beyond a certain point. Whether a cell is killed off or whether it enters senescence, the purpose is the same: to prevent cells with a damaged genome from reproducing. Such cells run the risk of being cancerous; indeed, the entire response to DNA damage can be thought of as a mechanism to prevent cancer. As we saw earlier, nearly half of cancers have mutations in a single protein, p53, that plays a key role in the DNA damage response. These tumor suppressor genes can induce premature senescence to prevent cancer.
Just as evolutionary theories would predict, processes that prevent us from developing cancer early in life can become a problem later on. Our tissues, for instance, would stop functioning if their cells kept getting killed off without being replaced. And even though they are alive and present, senescent cells also lead to problems. The transition from a normal cell to a senescent cell is not clearly understood. It occurs because of extensive changes to the genetic program of the cell triggered by the DNA damage response. In their altered state, senescent cells no longer contribute to the normal functioning of the tissues they serve. If they are no longer functioning as they should, you might well wonder why cells go into senescence at all instead of simply being destroyed, and why they persist.
In fact, senescent cells often don’t just sit there quietly doing nothing. They secrete molecules such as cytokines that cause inflammation and disrupt the surrounding tissue. This is by design. Senescent cells are often produced in response to injury or other damage, and the same secretions that set off inflammation also promote wound healing and tissue regeneration, while at the same time signaling the immune system to clear them from the tissue. But our immune system ages along with the rest of us, and its ability to clear senescent cells declines. As damage to our DNA accumulates and our telomeres shorten, we produce senescent cells in places where they don’t serve any purpose and at a faster rate than our immune system can handle, leading to chronic, widespread inflammation.
In all of the causes of aging we have discussed so far, the processes are so complex and interconnected that it is always a problem to separate cause and effect. Here too, there is the nagging question of whether an increase in senescent cells and accompanying inflammation is just a consequence of aging or whether it accelerates aging further. This question was tackled in a key study led by Jan van Deursen, who was then at the Mayo Clinic in Minnesota. He and his team used a biomarker that identified senescent cells and devised a clever method to eliminate cells with that marker. Using mice that age prematurely—called progeroid mice—they showed that removing senescent cells delayed age-related pathologies in adipose (fatty) tissue, skeletal muscle, and the eye. Even late in life, removing senescent cells delayed the progression of disorders that had already been established. The study concluded by saying that removal of senescent cells could prevent or delay aging disorders and extend healthy life. A few years later, the same team demonstrated that mice whose senescent cells were killed off were healthier in many ways than those in whom these cells were allowed to build up. Their kidneys functioned better, their hearts were more resilient to stress, they were more active, and they fended off cancers for longer. They also lived about 20–30 percent longer.
According to a follow-up study, transplanting even small numbers of senescent cells into young mice was sufficient to cause persistent physical dysfunction, and even spread senescence throughout the tissues. With older mice, introducing even fewer senescent cells had the same effect. When researchers used an oral cocktail that selectively killed senescent cells, it alleviated the symptoms of both the young and old mice and reduced their mortality significantly.
These studies have led to an explosion of experiments examining senescent cells as they relate to aging. The selective targeting of these cells for destruction, called senolytics, is growing rapidly in popularity, both in academic research and industry. But destroying problematic cells like these is only one side of the coin. Most of our tissues are constantly regenerated, and if cells are destroyed either naturally or deliberately, they need to be replaced.
An old saw holds that the human body replaces itself every seven years; in other words, after seven years, you’re an entirely new collection of cells. But this isn’t strictly true. Our tissues don’t all regenerate at the same rate. Some, such as blood and skin cells, are regenerated rapidly. Cuts, bruises, and minor burns will heal over quickly with new skin, and if you donate blood, your body replenishes it in just a few weeks. Other organs are renewed more slowly; for example, most of the cells in your liver are replaced within three years. Heart tissue is replaced even more slowly, with only 40 percent of its muscle cells replaced in a lifetime, which is why the damage caused by a heart attack is often permanent. And it was thought that the neurons in our brain are never renewed—that we are born with every neuron we will ever have. Recently, however, scientists have shown that some brain cells are renewed, albeit very slowly, at a rate of about 1.75 percent annually. Still, most of our neurons were present at birth, and the inability to replenish them is why diseases that destroy them—either suddenly in a stroke or more gradually as in Alzheimer’s—are so horrific.
The majority of our cells, however, are replaced with some regularity, and the key actors responsible for regenerating tissue are those stem cells we discussed earlier. Remember that the ultimate stem cells are the pluripotent stem cells in the early embryo that can give rise to any tissue type in the body as they differentiate. But other stem cells are halfway down the path to development of the complete organism and can regenerate only specific tissues. As Leonard Hayflick discovered in the 1950s, the cells in most tissues can undergo only a certain number of divisions, but stem cells, because they are required for regenerating tissues, are not subject to this limit.
Stem cells that maintain and regenerate tissue must strike a delicate balance. They cannot all differentiate into the mature cells of the tissues, or there would be no stem cells left to carry on this task. And the stem cells that remain behind have to keep dividing into more stem cells to replenish the ones that have differentiated into specific tissue cells. As we age, our stem cells begin to lose this balance between producing more of themselves and regenerating tissue.
Stem cells do not divide and proliferate indiscriminately; rather, they are activated by specific signals that they receive when the body senses a need for tissue regeneration. These signals and their ability to activate stem cells decline with age, for the many reasons we have discussed before, including damage to our genome, and epigenetic marks that our DNA acquires with age. This is one reason our muscles, skin, and other tissues degenerate with age.
Apart from not being activated, stem cells themselves eventually suffer from DNA damage and telomere loss, and accumulate metabolic defects. Eventually they trigger a response such as the DNA damage response, which can lead to either cell death or senescence. With stem cells, death is more likely, partly because a stem cell that has damaged DNA might be too much of a cancer risk to keep around. The result is a gradual depletion of stem cells throughout the body, diminishing the ability to regenerate tissue. When our bones, muscles, and skin cannot regenerate, we become increasingly frail. A particularly significant decline is the population of hematopoietic stem cells, which give rise to all our blood cells, including the cells of our immune system. This leads to immune system decline or even immune dysfunction—something called immunosenescence, which is associated with an increase in disorders such as inflammation, anemia, and various cancers, as well as in increased susceptibility to infections.
Apart from a gradual loss in the number of stem cells, there is a problem with the remaining stem cells. During much of our life, we have a healthy diversity of cells that have acquired different mutations, making us a mosaic of genomes. As we age, our stem cells acquire mutations, some of which cause them to proliferate more rapidly. These rapidly multiplying stem cells are not necessarily the best for regenerating tissues, but because they have a growth advantage, they outcompete their counterparts. Consequently, old age leaves us with stem cells that have all descended from just a few clones. Not only are they less effective, but—of greater concern—the clonal mutants themselves can become sources of cancer.
If the number of stem cells declines with age, and those that remain are descendants of a few clones, some of which may be problematic, can we somehow reverse this process? In chapter 5 on epigenetics, I explained about how turning on just a few genes that code for the so-called Yamanaka factors can reprogram cells so that they can return to being pluripotent stem cells—and thus can again give rise to any tissue in the body. Might scientists learn to regenerate stem cells in the body and reverse some of the effects of aging?
When cells are reprogrammed fully with Yamanaka factors to form induced pluripotent stem cells (iPS cells) and used to grow new tissues, they often produce tumors such as teratomas, which can be benign or malignant. One reason for this is that the Yamanaka factors are not precisely reversing the normal process of development. The truth is, we don’t fully understand what they do or how, but the resulting induced pluripotent stem cells are not exactly the same as our own embryonic stem cells, which develop into our body—after all, teratomas are quite rare in normal development. Given the potential risks associated with the use of Yamanaka factors, one idea is to expose cells to them only transiently, so that they would not go all the way back to being pluripotent stem cells again, but just part of the way back developmentally so they would be transformed into the specialized stem cells for whichever tissue they came from. Even this transient and partial reversal could help rejuvenate tissue.
Many scientists had been working on this in cells in culture, but it wasn’t clear what turning on these factors even transiently in an entire animal would do. A group led by Juan Carlos Izpisua Belmonte at the Salk Institute in La Jolla, California, did exactly this by turning on the Yamanaka factors in entire mice for a short burst. After six weeks, the mice appeared younger, with better skin and muscle tone. They had straighter spines, improved cardiovascular health, healed more quickly when injured, and lived 30 percent longer. These studies involved a special strain of progeroid mice that aged prematurely. Recently, though, both Belmonte’s own group as well as groups led by Manuel Serrano and Wolf Reik, both in Cambridge, England, found that doing the same thing in naturally aged mice—as well as in human cells—induced similar effects. Not only did the animals (or cells) seem younger based on various criteria, but the epigenetic marks on their DNA, and the various markers in their blood and cells, were all characteristic of a more youthful state.
David Sinclair, who had spent much of his earlier career working on sirtuins, has also begun using the Yamanaka factors to reprogram cells. A newborn mouse can regenerate the optic nerve that transmits signals from the eye to the brain, but this ability disappears as the mouse develops. Sinclair and his colleagues crushed the optic nerves of adult mice, and then introduced three of the four Yamanaka factors. They omitted the fourth, c-Myc, because it is known to have cancer-causing properties. The factors prevented the injured cells from dying and prompted some of them to grow new nerve cells reaching out to the brain. In the same study, they introduced the three factors into middle-aged mice and found that their vision was as good as younger ones. Their DNA methylation epigenetic marks resembled those of younger animals. In another experiment, the team deliberately introduced breaks in the DNA of mice, which accelerated aging by inducing the DNA repair response. One of the effects was that the pattern of epigenetic marks in the genome were characteristic of an aged animal. All of these effects could be reversed by introducing the same three Yamanaka factors.
Stem cells have been the basis of a very large biotech industry for a long time because of the promise of regenerating new cells and tissues. But it was still quite astonishing that introducing Yamanaka factors into an entire animal, where they could affect virtually every tissue, could apparently reverse aging without any obvious ill effects, at least in the short term. For example, even though two of the three Yamanaka factors used in Sinclair’s experiments are also linked to cancer, his mice were tumor free for nearly a year and a half after treatment. These studies generated huge excitement in the aging community because, unlike other approaches, which can slow down the inexorable progress of aging, these studies actually promise to reverse aging by restoring cells and tissues to an earlier state. Not surprisingly, Belmonte, Serrano, and Reik, all leading researchers originally in academic labs, were snapped up by Altos Labs, the private company set up to tackle aging, which had also snapped up Peter Walter, whom we encountered in chapter 6. We will have more to say about these anti-aging enterprises later.
BEFORE WE LEAVE THIS CHAPTER, let us turn to blood. Most of us don’t think of blood as an organ in the same way that we consider the liver, kidney, heart, and brain. But perhaps we should. For in many ways, blood circulation is one of the most important systems in the body. It supplies essential nutrients, including oxygen and glucose, to the other organs, as well as disposes of their waste products. It enables our response to hormones, promotes healing by forming structures at the site of injuries, and fights off infections with the immune cells that circulate in our bloodstream. If we have old, defective blood—clonal or not—that is a problem.
The idea of living forever by drinking young blood has been around for a long time. I remember being terrified when I saw my first Dracula movie at the age of ten. But Transylvanian myths and Gothic novels aside, is it possible to replace old blood with young?
Parabiosis attempts to do just that, by surgically connecting the circulatory systems of two animals. Some of the earliest experiments date back to the nineteenth-century French biologist Paul Bert, who was interested in tissue transplantation rather than aging. He not only connected two rats but, amazingly, is reported to have attached a rat to a cat and successfully maintained this state for several months.
Sharing blood between two different animals, let alone different species, could obviously be problematic not only because of the possibility that one or both animals’ immune systems will reject the transfused blood due to incompatibility (this is why blood donors have to be matched to recipients with compatible blood groups), but also psychological issues. Indeed, Clive McCay of Cornell University in Ithaca, New York, is quoted as saying, “If two rats are not adjusted to each other, one will chew the head of the other until it is destroyed.” Nowadays the animals are inbred and matched genetically to avoid biochemical incompatibilities. Then they are socialized with each other for several weeks before attachment.
Early experiments on parabiosis probed questions such as the role that blood plays in metabolic disorders, including obesity. There were, however, some scientists, like McCay, who were looking at the effects on aging as early as the 1950s. His group found that when aged rats were joined to young ones for about a year, their bones became more similar in weight and density to those of their young partners. Other studies showed that the older partners in old-young pairings lived four to five months longer than normal, which for a two-year life span is a significant extension of life. But for some reason, these studies died out in the 1970s.
The field was resuscitated in the early 2000s when Irina and Michael Conboy, a husband-and-wife team in Thomas Rando’s lab at California’s Stanford University, again began pairing old and young mice. Within five weeks, the young blood restored muscle and liver cells in the older subjects. Their wounds healed more easily. The fresh blood even made their fur shinier. By the same criteria, the younger partner in each of the pairs tended to fare worse than usual; it, of course, was receiving older blood in the exchange.
Rando and his colleagues had left out of their 2013 published paper that they had also seen enhanced growth of the older mice’s brain cells. We know that neurons, for the most part, do not regenerate. But these early results motivated one of Rando’s Stanford colleagues, the neurobiologist Tony Wyss-Coray, to investigate the effects of parabiosis on the brain. He showed that old blood could impair memory in young animals, while, conversely, young blood could improve the memories of older animals. There was a threefold increase in the number of new neurons in the older mice. By contrast, the younger mice that received old blood from their conjoined partners generated far fewer nerve cells than young mice allowed to roam free did.
Against the centuries-old backdrop of the vampire myth, these reports captured people’s imaginations. Rando and Wyss-Coray were deluged with phone calls from reporters and from the general public—some of them dubious, not to mention scary. There were reports of rich old men—and, yes, it usually seems to be men—procuring a ready supply of young blood to prolong their lives.
The scientists involved were more circumspect. In a 2013 journal article, the Conboys and Rando pointed out that even in highly inbred strains of mice and rats, the risk of parabiotic disease was as high as 20–30 percent. Moreover, it was not obvious whether all of the positive effects of parabiosis could be attributed to the blood; the older animal would have also benefited from the better-functioning organs of the younger partner, such as its liver and kidneys. To test this, the Conboys conducted a study in which they exchanged blood between two animals that were not joined. They found that the adverse effects of old blood were more pronounced than the beneficial effects of young blood.
Such cautionary views did not stop lots of companies from trying to capitalize on the hype, rushing ahead before any careful human trials were completed. One company, Ambrosia, offered blood plasma from donors aged sixteen to twenty-five for $8,000 a liter. Alarmed, the US Food and Drug Administration (FDA) issued a warning that these treatments were unproven and should not be assumed to be safe, and strongly discouraged consumers from pursuing this therapy outside of clinical trials with appropriate regulatory oversight. In response, Ambrosia stopped offering the treatment, but only briefly: the people involved soon began marketing it again under the aegis of a new but short-lived business named Ivy Plasma—before returning to its original name. Ambrosia’s CEO, Jesse Karmazin, said, “Our patients really want the treatment. The treatment is available now. Trials are very expensive, and they take a really long time.” Most serious scientists, including those who pioneered the discoveries, believe it is premature and potentially dangerous to offer these kinds of treatments to humans without proper clinical trials.
Beyond all the hype, Thomas Rando’s initial findings set off an extensive search for specific protein factors in blood that could be related to aging. In theory, you could have factors in young blood that stimulate growth and improve function; by the same token, old blood might contain factors that made things worse. Wyss-Coray and his colleagues showed that it was both. As they described in a 2017 article in the journal Nature, proteins from umbilical cord plasma revitalized the function of the hippocampus—a part of the brain crucial for the formation of both episodic and spatial memory. As for old blood, they zeroed in on a protein that impaired hippocampus activity; blocking it relieved some of the adverse effects.
Of course, in the parabiosis experiments, young blood improved many organs, not just the brain. Amy Wagers of Harvard University, who was a member of Rando’s original team at Stanford, screened the hundreds of protein factors in blood to pinpoint the ones more prevalent in old or young blood. A factor called GDF11 was abundant in young mice but not in old, and it could rejuvenate heart tissue. But it didn’t just act on heart tissue. She and her colleagues showed that the factor reversed age-related deterioration of muscle tissue by reviving stem cells in old muscles and making them stronger. In a second study with her Harvard colleague Lee Rubin, they showed that it spurred the growth of blood vessels and olfactory neurons in the brain.
Stem cells can decline in number and lose function with age, and clearly some of the factors in blood work by reactivating them. But what about the old blood making the young mice worse off? A recent study by the Conboys and Judith Campisi, another leading aging researcher, showed that treating young mice with old blood quickly increased the number of senescent cells in their circulation. This means that senescence is not just a response to stress and damage from the environment, nor is it something that simply happens over time. It can also be induced rapidly. Clearing those senescent cells reversed some of the harmful effects of old blood on multiple tissues.
Blood need not even be from young animals to confer benefits. We saw in chapter 8 that exercise has a real benefit on many aspects of our metabolism, including insulin sensitivity and mitochondrial biology. It turns out that blood from adult mice that had been subjected to an exercise program can improve cognitive function and regeneration of neuronal tissue. Rando and Wyss-Coray showed that exercised blood can also rejuvenate muscle stem cells. Using a new way of measuring effect based on which mRNAs are made in different tissues, they showed that young blood and exercised blood act in different ways. Parabiosis from young animals reduced the activity of genes that caused inflammation, whereas exercise increased the activity of genes that decline with age. Although they both stimulated growth of brain tissue, each stimulated different types of cells.
Identifying aging factors in blood and understanding how they work is now a major area of research. Scientists hope that one day it might be possible to administer a cocktail of a few factors with real anti-aging effects. This hope is spurring not only basic research but also has resulted in the creation of many biotech companies, including ones founded by some of the pioneers in the field.
While science is advancing to find out precisely which combination of blood factors is most beneficial, some billionaires are unwilling to wait. They continue to be drawn to the Dracula-like allure of young blood. For instance, Bryan Johnson, the middle-aged tech mogul behind the company Braintree Payment Solutions, spends $2 million a year on his anti-aging regimen, which includes two dozen supplements, a strict vegan diet, and, as befits a techie, lots of data, including more than 33,000 images of his bowels. He went to Resurgence Wellness, a Texas outfit that describes itself as a comprehensive health and wellness clinic–slash-spa. There he was transfused with blood from his seventeen-year-old son, Talmage, and in turn donated his own blood to his father in a series of multigenerational blood exchanges that lent new meaning to “all in the family.” Johnson stopped the transfusions from his son after seeing no benefits himself, but still felt that “young plasma exchange may be beneficial for biologically older populations or certain conditions.”
IN THIS AND EARLIER CHAPTERS, we have covered the broad landscape of aging at various levels, from our genes, to the proteins they encode, and how they affect cells and their ability to function as part of an entire animal. These levels are all interconnected, so the state of our proteins and our cells influences how and which genes are expressed, which in turn affects them. By their very nature, the causes of aging encompass virtually all of biology, and as new areas of research emerge, we find new and sometimes surprising connections with aging. So why we age and die is an ongoing story, and this book has focused on processes of the greatest interest or promise.
The quest to defeat aging and death is centuries old, but it is only in the last half century that we have accumulated a detailed biological understanding of the processes that lead to them. That knowledge has brought about an explosion of efforts by both academic institutions and for-profit companies to combat aging. Now we come to these efforts, ranging from sound mainstream science to the wildest crackpot ideas.
11. Crackpots or Prophets?
Last Christmas, when my son’s family was visiting from America, there was a special exhibition at the British Museum about the Rosetta Stone and how it led to the decipherment of Egyptian hieroglyphics. So we trudged off to London, and since it was a cold and wet day during the Christmas break, we found to our dismay that the museum was packed. After we battled the crowds milling about the exhibition, we were naturally curious to see the rest of the Egyptian artifacts in the museum, including its unparalleled collection of mummies. We went over to the long hall with cases enclosing one mummy after another. It was both thrilling and sobering. Thrilling that these mummies had been preserved for a few thousand years and were right there for us to see. Sobering that each of them represented a person who had been alive.
Their corpses, now in varied states of preservation, lay underneath the wrappings and caskets. It was a stark reminder yet again of the extent to which people will go to deny death. After all, Egyptians mummified their pharaohs so that they could arise corporeally at some point in the future for their journey in the afterworld. Surely now, a few millennia after the pharaohs and with more than a century of modern biology behind us, we would not do anything even remotely so superstitious. But in fact, there is a modern equivalent.
Biologists have long wanted to be able to freeze specimens so that they can store and use them later. This is not so straightforward because all living things are composed mostly of water. When this water freezes into ice and expands, it has the nasty habit of bursting open cells and tissues. This is partly why if you freeze fresh strawberries and thaw them, you wind up with goopy, unappetizing mush.
An entire field of biology, cryopreservation, studies how to freeze samples so that they are still viable when thawed later. It has developed useful techniques, such as how to store stem cells and other important samples in liquid nitrogen. It has figured out how to safely freeze semen from sperm donors and human embryos for in vitro fertilization treatment down the road. Animal embryos are routinely frozen to preserve specific strains, and biologists’ favorite worms can be frozen as larvae and revived. For many types of cells and tissues, cryopreservation works. It is often done by using additives such as glycerol, which allow cooling to very low temperatures without letting the water turn into ice—effectively like adding an antifreeze to the sample. In this case, the water forms a glass-like state rather than ice, and the process should be called vitrification rather than freezing (the word vitreous derives from the Latin root for glass), but even scientists casually refer to it as freezing and the specimens as frozen.
Enter cryonics, in which entire people are frozen immediately after death with the idea of defrosting them later when a cure for whatever ailed them has been found. The idea has been around a long time, but it gained traction through the work of Robert Ettinger, a college physics and math teacher from Michigan who also wrote science fiction. Ettinger had a vision of future scientists reviving these frozen bodies and not only curing whatever had ailed them but also making them young again. In 1976 he founded the Cryonics Institute near Detroit and persuaded more than a hundred people to pay $28,000 each to have their bodies preserved in liquid nitrogen in large containers. One of the first people to be frozen was his own mother, Rhea, who died in 1977. His two wives are also stored there—it is not clear exactly how happy they were to be stored next to each other or their mother-in-law for years or decades to come. Continuing this tradition of family closeness, when Ettinger died in 2011 at age ninety-two, he joined them.
Today there are several such cryonics facilities. Another popular one, Alcor Life Extension Foundation, headquartered in Scottsdale, Arizona, charges about $200,000 for whole-body storage. How do these facilities work? Essentially, as soon as a person dies, the blood is drained and replaced with an antifreeze, and the body is then stored in liquid nitrogen. Theoretically, indefinitely.
Then there are the transhumanists who want to transcend our bodies entirely. But they don’t want humanity as we know it to end before we have figured out a way to preserve our minds and consciousnesses indefinitely in some other form. In their view, intelligence and reason may be unique to human beings in the universe (or at least they see no evidence for extraterrestrial intelligence). To them, it is of cosmic importance to preserve our consciousnesses and minds and spread them throughout the universe. After all, what is the point of the universe if there is no intelligence to appreciate it?
These transhumanists are content to have only their brains frozen. This takes up less space and costs less. Moreover, it could be faster to infuse the magic antifreeze directly into the brain after death, increasing the odds of successful preservation. The brain is the seat of memories, consciousness, and reasoning, and that is their sole concern. At some point in the future, when the technology is ripe, the information in the brain will simply be downloaded to a computer or some similar entity. That entity will possess the person’s consciousness and memories and will resume “life.” It won’t be limited by human concerns such as the needs for food, water, oxygen, and a narrow range of temperature. We will have transcended our bodies, with the possibility of traveling anywhere in the universe. Not surprisingly, transhumanists are generally ardent about space travel, viewing it as our only chance to escape destruction on Earth. One such proponent is Elon Musk, said to be the wealthiest person in the world, depending on the year, who is well known for his desire to “die on Mars, just not on impact.” Presumably one of his first goals upon reaching the red planet will be to construct a cryonics facility.
The bad news is that there is not a shred of credible evidence that human cryogenics will ever work. The potential problems are myriad. By the time a technician can infuse the body, minutes or even hours may have elapsed since the moment of death—even if the “client” moved right next to a facility in preparation. During that time, each cell in the deceased person’s body is undergoing dramatic biochemical changes due to the lack of oxygen and nutrients, so that the state of a cryogenically frozen body is not the state of a live human being.
No matter, say cryo advocates: we simply must preserve the physical structure of the brain. As long as it is preserved enough that we can see the connections between all the billions of brain cells, we will be able to reconstruct the person’s entire brain. Mapping all the neurons in a brain is an emerging science called connectomics. Although it has made tremendous advances, researchers are still ironing out the kinks on flies and other tiny organisms. And we don’t yet have the know-how to properly maintain a corpse brain while we wait for connectomics to catch up. Only recently, after many years, has it been possible to preserve a mouse brain, and that requires infusing it with the embalming fluid while the mouse’s heart is still beating—a process that kills the mouse. Not one of these cryonics companies has produced any evidence that its procedures preserve the human brain in a way that would allow future scientists to obtain a complete map of its neuronal connections.
Even if we could develop such a map, it would not be nearly enough to simulate a brain. The idea of each neuron as a mere transistor in a computer circuit is hopelessly naive. Much of this book has emphasized the complexity of cells. Each cell in the brain has a constantly changing program being executed inside it, one that involves thousands of genes and proteins, and its relationship with other cells is ever shifting. Mapping the connections in the brain would be a major step forward in our understanding, but even that would be a static snapshot. It would not allow us to reconstruct the actual state of the frozen brain, let alone predict how it would “think” from that point on. It would be like trying to deduce the entire state of a country and its people, and predict its future development, from a detailed road map.
I spoke to Albert Cardona, a colleague of mine at the MRC Laboratory of Molecular Biology who is a leading expert on the connectomics of the fly brain. Albert stresses that, in addition to the practical difficulties, the brain’s architecture and its very nature are shaped by its relationship to the rest of the body. Our brain evolved along with the rest of our body, and is constantly receiving and acting upon sensory inputs from the body. It is also not stable: new connections are added every day and pruned at night when we sleep. There are both daily and seasonal rhythms involving growth and death of neurons and this constant remodeling of the brain is poorly understood.
Moreover, a brain without a body would be a very different thing altogether. The brain is not driven solely by electrical impulses that travel through connections between neurons. It also responds to chemicals both within the brain and emanating from the rest of the body. Its motivation is driven very much by hormones, which originate in the organs, and includes basic needs such as hunger but also intrinsic desires. The pleasures our brains derive are mostly of the flesh. A good meal. Climbing a mountain. Exercise. Sex. Moreover, if we wait until we age and die, we would be pickling an old, decrepit brain, not the finely tuned machine of a twenty-five-year-old. What would be the point of preserving that brain?
Transhumanists argue that these problems can be solved with knowledge that mankind will acquire in the future. But they are basing their beliefs on the assumption that the brain is purely a computer, just different and more complex than our silicon-based machines. Of course, the brain is a computational organ, but the biological state of its neurons are as important as the connections between them in order to reconstruct its state at any given time. In any case, there is no evidence that freezing either the body or the brain and restoring it to a living state is remotely close to viable. Even if I were one of the customers who was sold on cryonics, I would worry about the longevity of these facilities, and even the societies and countries in which they exist. America, after all, is only about 250 years old.
Despite this, many people have bought into the idea of cryonics. In the United Kingdom, a fourteen-year-old girl who was dying of cancer wanted to have her body cryogenically frozen. She needed the consent of both parents, but they were separated, and her father, who himself suffered from cancer, and was not part of her life, was opposed. She took the matter to court, and the judge ruled that she was entitled to have her wishes followed—but they should be made public only after her death. This elicited an outcry from prominent UK scientists, who called for restrictions on the marketing of cryonics to vulnerable people.
In almost a mirror image of this case, the renowned baseball player Ted Williams wanted to be cremated. Upon his death in 2002 at the age of eighty-three, two of his three children insisted on having his remains frozen, igniting a bitter family feud. In the end, a compromise was reached: only the great athlete’s head would be put on ice, so to speak.
According to press reports, well-known people who intend to be cryopreserved include entrepreneur Peter Thiel, one of the cofounders of PayPal; computer scientist Ray Kurzweil, best known for his prediction that in 2045 we will reach the singularity where machines will become more intelligent than all humans combined; philosopher Nick Bostrom, who is concerned that such machine superintelligence could spell an existential catastrophe for humans; and computer scientist turned gerontologist Aubrey de Grey. More about him in a moment.
Because the brain decays rapidly following death, many cryonics facilities recommend that their clients move somewhere nearby when it’s known that the end is nigh. However, this may not be good enough. Remember that the only way cryopreservation has been shown to merely preserve connections in a mouse brain was by infusing embalming chemicals into its blood while it was still alive, in a procedure that kills the animal. In 2018, a San Francisco company called Nectome was reported to have plans to do exactly that to human beings: infusing a mixture of embalming chemicals into the carotid arteries in the neck—killing the customer immediately in the process. This would be carried out under general anesthesia, although what the embalming would do to the state of the brain was not clear. The company’s cofounder claimed that this assisted suicide will be completely legal under California’s End of Life Option Act. One might think that the prospect of certain euthanasia coupled with an uncertain outcome would be a tough sell, but the same article claimed that twenty-five people had already signed on as customers, and one of them was reported to be thirty-eight-year-old Sam Altman, cofounder of OpenAI, the artificial intelligence research lab that launched ChatGPT, who believes that minds will be digitized in his lifetime and that his own brain will one day be uploaded to the cloud. In response, Robert McIntyre, the founder of Nectome, said that those people were early supporters of his research and had not been promised or even offered anything, certainly not silicon-based mental immortality.
LET US MOVE FURTHER UP the plausibility scale, from cryonics to Aubrey de Grey. With his two-foot-long beard and a matching messianic zeal, de Grey looks the very stereotype of an upper-class English eccentric and has amassed a large cultlike following. He began his career as a computer scientist and, although not a professional mathematician, contributed a major advance toward solving a sixty-year-old mathematics problem. At some point, he met the American fly geneticist Adelaide Carpenter at a party in Cambridge and eventually married her. This sparked his interest in biology—in particular, the mitochondrial free-radical theory of aging. De Grey came to believe that aging was a solvable problem. He asserts that the first humans who will live to be 1,000 years old have already been born. De Grey’s central idea is that if we can improve average life expectancy faster than we age—if, in other words, life expectancy increases by more than a year annually—we can hope to escape death altogether. He calls this “escape velocity.”
To reach escape velocity, de Grey has a plan. Bucking the conventional wisdom of the biological community, he proposes that we can defeat aging if we crack seven key problems: (1) replenish cells that are lost or damaged over time, (2) remove senescent cells, (3) prevent stiffening of structures around the cell with age, (4) prevent mitochondrial mutations, for example by engineering mitochondria so that they don’t make any proteins themselves using their own genome but import them exclusively from the rest of the cell, (5) restore the elasticity and flexibility of the structural support to cells that stiffen with age, (6) do away with telomere lengthening machinery so that we don’t get cancer, and (7) figure out how to reengineer stem cells so that our cells and tissues don’t atrophy. He calls his program to solve these problems SENS: strategies for engineered negligible senescence.
De Grey has learned enough biology to pinpoint many of the things that go wrong as we age. But with the characteristic arrogance that many physicists and computer scientists display toward biologists, he is wildly optimistic about the feasibility of addressing them. In response to his claims, twenty-eight leading gerontologists, including many you’ve come across in this book, wrote a scathing rebuttal arguing that many of his ideas were neither sufficiently well formulated nor justified to even provide a basis for debate, let alone research, and that not a single one of de Grey’s proposed strategies has been shown to extend life span. The coauthors included Steven Austad and Jay Olshansky. Other mainstream researchers too dismissed SENS as pseudoscience. One of them, Richard Miller of the University of Michigan, penned a hilarious parody of SENS in a satirical open letter to de Grey in the journal MIT Technology Review. Since the aging problem had been solved, Miller proposed, perhaps we could turn now to the challenge of producing flying pigs; there are a mere seven reasons why pigs, at present, cannot fly, and we could fix all of them easily. De Grey, in response, huffed that the gerontology community was short-sighted, comparing the field to Lord Kelvin, the famous physicist and former president of the Royal Society who once scoffed that heavier-than-air flying machines were impossible.
Dissatisfied with the lack of support from the academic community and the funding prospects in England, de Grey left for the United States in 2009. He set up the SENS Foundation in well-heeled Mountain View, California, with a private endowment, and initially with the support of some well-known gerontologists. Around this point, he began liaisons with other women, two of whom were forty-five and twenty-four years old. Adelaide Carpenter de Grey, then sixty-five, did not want to move to California to be part of this lifestyle, and they eventually divorced. De Grey remarked that as we solved the aging problem, “There’s going to be much less difference between people of different chronological ages,” and the expectation of living a very long time might very well lead to a reevaluation of the value of permanent monogamy. In 2021 he made the news again after being accused of sexual harassment by two young women, one of whom was only seventeen when she encountered de Grey. He denied the allegations and was suspended by his own foundation initially. But following charges that he’d interfered with an investigation into his conduct, the SENS Foundation fired him. A company report eventually cleared de Grey of being a sexual predator but criticized him over instances of poor judgment and boundary-crossing behavior. De Grey, undaunted, founded the new LEV Foundation, with the letters standing unsurprisingly for Longevity Escape Velocity. His longevity in longevity research is remarkable, as is his ability to continue to obtain funding from rich benefactors.
Even the more mainstream anti-aging industry has some extreme optimists. Among them is David Sinclair, who, unlike the charlatans of the aging field, is a Harvard professor who has published a number of high-profile papers on aging in top journals, including two recent papers on reprogramming cells that made considerable waves. At the same time, Sinclair is known for excessive self-promotion and highly enthusiastic claims. For example, he has predicted that it will be normal to go to a doctor and take a medicine that will make us a decade younger, and that there is no reason why we couldn’t live to be 200. Such statements cause some of his critics to cringe and even fellow scientists who respect his ability to be embarrassed for him. I discussed the fate of resveratrol and his company Sirtris in chapter 8, but it appears to have had no effect on his ability to raise money to found several new companies—or indeed on his large public following, one that rivals de Grey’s. His recent popular book, which doubles down on his beliefs, shows that he is completely unfazed by any criticisms of his work. I doubt whether he would have been bothered much by a scathing review of the book by Charles Brenner.
Although resveratrol has long been discounted by the mainstream community, Sinclair still stands by it. In an essay on LinkedIn, he said coyly that he does not give medical advice—then proceeded to say that he takes resveratrol, metformin, and NMN (an NAD precursor) daily. We have come across these compounds in these pages. There is no evidence that any of them improves life span in humans; they haven’t been tested for this purpose in rigorous clinical trials, and, therefore, have not been approved by the FDA. Moreover, the evidence that metformin is beneficial in healthy adults is mixed; as we saw earlier, there are also problems associated with its use. For a Harvard professor to make this sort of statement on social media is essentially advocating their use, which strikes me as both ethically questionable and potentially dangerous. In the piece, Sinclair also bragged that he had a heart rate of 57 despite not being an athlete and that his lungs functioned as though he were multiple decades younger. Oddly, I am seventy-one, and although I’m no athlete either, my resting heart rate has been in the low 50s for much of my adult life—without taking Sinclair’s nutraceutical supplements. Since he is a scientist, at least he ought to compare himself to close relatives who don’t take the supplements, and also see what would happen if he went off his regimen but preserved his general lifestyle.
Starting a few decades ago, all sorts of dubious commercial enterprises started selling various compounds or procedures purporting to extend health or life. They would often make the most tenuous connection with some genuine research finding to hawk their wares. Respectable scientists founded their own companies—in many cases, several—and some of them gave the impression that the problem of aging would soon be solved. After all, investors are unlikely to fund companies if the payoff is many decades down the road. All of this led to a feeling that the fountain of youth was just around the corner.
Even back in 2002, fifty-one leading gerontologists were already alarmed enough by the hype to write a position statement laying out their views on what was known and what was fantasy or science fiction. They were particularly anxious to draw a clear distinction between serious anti-aging research and questionable claims about extending health and life. Among their key points:
Eliminating all aging-related causes of death would not increase life expectancy by more than fifteen years.
The prospects of humans living forever is as unlikely today as it has ever been.
Antioxidants may have some health benefits for some people, but there is no evidence that they have any effect on human aging.
Telomere shortening may play a role in limiting cellular life span, but long-lived species often have shorter telomeres than do short-lived ones, and there is no evidence that telomere shortening plays a role in determining human longevity.
Hormone supplements sold under the guise of anti-aging medicine should not be used by anyone unless they are prescribed for approved medical uses.
Caloric restriction might extend longevity in humans, since it does so in many species. But there is no study in humans that has proved it will work, since most people prefer quality of life to quantity of life; but drugs that mimic caloric restriction deserve further study.
It is not possible for individuals to grow younger, since that would require performing the impossible feat of replacing all of their cells, tissues, and organs as a means of circumventing aging processes.
While advances in cloning and stem cells may make replacement of tissues and organs possible, replacing and reprogramming the brain is more the subject of science fiction than likely science fact.
Despite these many reservations, the gerontologists enthusiastically supported research in genetic engineering, stem cells, geriatric medicine, and therapies to slow the rate of aging and postpone age-related diseases.
Interestingly, Aubrey de Grey was a signatory to this statement. Notable omissions, though, included Leonard Guarente and David Sinclair, both of sirtuin fame, and Cynthia Kenyon, who had discovered the daf-2 mutant in worms. All three of them were involved with various longevity companies at the time and were on record as being highly optimistic about the prospects of major breakthroughs.
Nevertheless, the explosion in the anti-aging industry has proceeded unabated. Today there are more than 700 biotech companies focused on aging and longevity, with a combined market cap of at least $30 billion. Some of these firms have been around for almost two decades but have yet to produce a single product. Others generate revenue by selling nutraceuticals; these supplements do not require FDA approval, and no randomized clinical trials to assess their safety and effectiveness have been carried out. Many of these companies have highly distinguished scientists on their advisory boards—including some Nobel laureates who have no particular expertise in aging, apart from being old. To the public, the presence of these distinguished scientists lends an air of credibility to the enterprise. How has such an enormous industry flourished for so long with so few actual advances to show for it?
AGING RESEARCH TAPS INTO OUR primeval fear of death, with many people willing to subscribe to anything that might postpone or banish it. California tech billionaires, especially. Many of them made their money in the software industry, and because they were able to write programs to carry out rapid financial transactions or swap information of various sorts, they believe aging to be just another engineering problem to be solved by hacking the code of life. The pace of success in the software industry has made them impatient. They are used to making major breakthroughs in a couple of years, sometimes even a couple of months, and they underestimate the complexity of aging. They want to “move fast and break things.” We all know how that attitude worked out for social media, with consequences for social cohesion and politics that we could never have imagined twenty years ago. Currently, these same people have prematurely unleashed AI on the world while at the same time warning us of its dangers. One can only shudder at applying that attitude to something as profound as aging and longevity.
These enthusiastic tech billionaires are mostly middle-aged men (sometimes married to younger women) who made their money very young, enjoy their lifestyles, and don’t want the party to end. When they were young, they wanted to be rich, and now that they’re rich, they want to be young. But youth is the one thing that they cannot instantly buy, so, not surprisingly, many of the celebrity tech billionaires—such as Elon Musk, Peter Thiel, Larry Page, Sergey Brin, Yuri Milner, Jeff Bezos, and Mark Zuckerberg—have all expressed an interest in anti-aging research. And in many cases, they are funding it. One notable exception is Bill Gates, who recognizes realistically that the best way to improve overall life expectancy remains addressing the serious health care inequalities in the world.
Recently, the company Altos Labs made a big splash, announcing a war chest of several billion dollars of investment money. It was founded by Richard Klausner and Hans Bishop with the active encouragement and financial support of Yuri Milner and several wealthy benefactors, mostly in California, reportedly including Jeff Bezos. Milner, a software billionaire originally from Russia, has had a long-standing interest in science. He founded the Breakthrough Prizes, which are among the most prestigious—and certainly the most lucrative—international awards in science. Recently, he wrote a tract titled Eureka Manifesto: The Mission for Our Civilization, which explains some of his thinking about aging. Some of what he believes seems to be similar to the transhumanists: our evolution of reason, and all the knowledge we humans have accumulated, is precious and should not be lost. Having Earth as our only home could be a huge risk, so we may need to populate other parts of the universe. As I read his essay, I suddenly saw why Milner would want to tackle aging. Outer space is vast, and if we have to travel hundreds if not thousands of years toward a new home, it might be nice to be able to survive the voyage. There is nothing particularly illogical about Milner’s views, but they display the grandiosity—and the optimism bordering on arrogance—typical of this subset of the tech community. In any case, Altos Labs was launched with a big bang in 2022. In one swoop, the company netted some of the biggest stars in anti-aging research, luring them away from their academic positions by offering them huge resources and salaries. Altos now has campuses in both Northern and Southern California (naturally), and also in Cambridge, England, not far from my own lab.
When news of Altos Labs first leaked in the press, it was touted as a company that wanted to defeat death. Rick Klausner, its chief scientist and cochair, denied this and said that its objective is to improve healthy life span. At the launch of the Cambridge campus, he said, “Our goal is for everyone to die young—after a long time.” Klausner and others also pointed out that Altos Labs offers a highly collaborative way of doing science that allows it to tackle big problems in a way that academic labs dependent on individual grants cannot. Some mentioned to me that the company hoped to be gerontology’s version of Bell Labs, the famous private and commercial laboratory in New Jersey where small groups worked in highly collaborative settings to produce major breakthroughs such as the transistor, information theory, and lasers.
If tech billionaires are interested in curing aging in a hurry, many scientists are only too happy to enable them. Many truly distinguished scientists now have financial stakes in the industry, either through their own companies or as employees or consultants. This is not at all a bad thing in itself, but when I see some of them constantly touting their findings or their companies’ prospects, I wonder whether they can all really believe what they are saying. Do they not understand the complexities and difficulties ahead? Or, in the words of Upton Sinclair, is it simply that “It is difficult to get a man to understand something when his salary depends on his not understanding it”?
OF ALL THE LIVING SCIENTISTS I have described in this book, Michael Hall, who led the team that discovered TOR, is one of the most distinguished. Of aging research, he told me, “I went through a period about fifteen years ago when I was thinking a lot about TOR and aging, but was then turned off by the aging meetings I attended. They were three-ring circuses: light science and wackos walking around looking like Father Time. However, I think the field has evolved. It is now on firm ground with rigorous science.”
What has changed? Mainly, gerontology has gone from being a somewhat disrespectable soft science scorned by mainstream biologists to becoming a major research priority, partly because of the need to deal with aging populations in the developed world and, increasingly, worldwide. The result is that we now have a much better handle on the complicated biological causes of aging. Of these, DNA repair, although fundamental to aging, has been used far more to target cancer than aging. Virtually every other aspect of aging is also the target of therapeutic interventions to slow it down or reverse it. We have discussed many of them in context throughout the book, but some of them seem to be more promising than others—and have certainly attracted more investment.
One promising approach is to prevent the accumulation of “bad” proteins and other molecules as we age, either by recognizing them and disposing of them, or by slowing down or altering the rate or program of protein production, which allows the body to cope with these changes. Drugs that essentially mimic caloric restriction fall into this class, and the ones that are most actively investigated are those that target TOR, such as rapamycin and similar drugs, and others like the antidiabetic drug metformin, whose mechanism of action is still not well understood. The vitamin-like precursors of NAD and other nutrients that need to be supplemented with age are also an active area of research. Other drugs aim to target senescent cells, which are the source of inflammation and its accompanying problems, while still others seek to identify factors found in young blood that can slow down aging in various ways.
Some of the biggest excitement today concerns the reprogramming of cells to reverse the effects of aging. You have already read in chapter 10 about how scientists are using transient exposure to Yamanaka factors to try to rejuvenate animals while also trying to minimize the risk of cancer. The early results of this approach have been promising enough that a huge number of start-up companies has sprouted up around this strategy. It is a major focus of Altos Labs, which hired Shinya Yamanaka himself as an adviser. Stem-cell therapy was already a major area of biotechnology because of its potential to regenerate damaged tissue and restore function to organs. Many of these companies already have expertise in reprogramming to generate various kinds of stem cells and have now jumped onto the anti-aging bandwagon. However, patients will be more receptive to stem-cell treatment for serious diseases such as replacing damaged muscle after a heart attack or restoring functional cells in a pancreas to treat diabetes, because the benefits will clearly outweigh the risks. It is not yet clear when this will happen with efforts to tackle aging—clearly the bar for safety and efficacy will be much higher.
That brings us to another, more fundamental problem with aging research. How can researchers tell if their treatments are working? The customary way for any new treatment in medicine would be to carry out a randomized clinical trial. Patients are divided into two groups, with one given either a placebo or the current standard therapy for a particular condition, and the other the agent being tested, to see if the patients given the experimental medicine fare better, or worse. The equivalent for anti-aging medicine would be to see if the treatment prolongs health and life. But this could take years to assess. This long wait for results makes it more difficult to find volunteers for properly randomized trials.
In management, as well as in science and technology, there is a well-known saying that you can’t improve what you can’t measure. The fifty-one gerontologists who criticized the hyperbolic statements from the anti-aging industry pointed out that aging was highly variable from individual to individual. They added pointedly: “Despite intensive study, scientists have not been able to discover reliable measures of the processes that contribute to aging. For these reasons, any claim that a person’s biological or ‘real age’ can currently be measured, let alone modified, by any means must be regarded as entertainment, not science.”
That was true twenty years ago when the authors wrote it. But today, increasingly, there are so-called biomarkers that correlate well with our underlying physiology and the characteristics that arise from it. Some characteristics of age are obvious. Our hair gets thinner and grayer or whiter, our skin becomes more wrinkled and less elastic, our arteries narrow and become more rigid, our brains are— Well, you get the picture. These traits are subjective and tricky to quantify, but if we can come up with measurable biomarkers that are proxies for them, that would be a big step forward. In addition to epigenetic changes to our DNA such as the Horvath clock, explained in chapter 5, there are now a variety of markers that measure inflammation, senescence, hormone levels, and various blood and metabolic markers, as well as the pattern of gene expression in different cell types. So scientists may be able to measure if their treatments are having any effect on aging without having to wait an interminably—or terminably—long time. Although these biomarkers or aging clocks have been rapidly taken up by the industry, their underlying basis is often not clear, and there are few studies that compare them to see how well they agree with one another.
Anti-aging researchers run into a regulatory problem as well: clinical trials are usually only approved for treatment of disease. In the scientific community, debate rages over whether aging is simply a normal progression of life or a disease. The traditional view is that something that happens to everyone and is inevitable can hardly be termed a disease. Gerontologists who subscribe to this view would argue that aging is the result of molecular changes that occur over time, which make us function less optimally and become more prone to diseases. Aging may be a cause of disease but is not a disease in itself. Another stark difference is that disease is usually subject to a clear definition: whether one has it and when one got it. But there is no clear consensus on when you become old. For these reasons, the latest International Classification of Diseases by the World Health Organization (WHO) omitted aging. While many in the gerontology community were disappointed by this decision, others welcomed it because they worried that classifying aging itself as a disease could lead to inadequate care from physicians: rather than pinpoint the cause of a condition, they would simply dismiss it as an unavoidable consequence of old age.
Still, the biggest risk factor for many diseases is age. Even during the recent Covid-19 pandemic, the risk of dying from being infected roughly doubled with every seven to eight years of age, so that an eighty-year-old was about 200 times as likely as a twenty-year-old to die if he or she caught Covid. Drawing on this, some gerontologists argue that we should regard aging as a disease, one that manifests itself in various ways such as diabetes, heart disease and dementia, or indeed being more prone to pneumonia or Covid-19. Of course, with billions of investment and research dollars at stake, there is currently fierce lobbying both by elements of the gerontology community and the anti-aging industry to have aging classified as a disease. So far, the FDA has refused, although it approved clinical trials for progeria, a disease in which patients age prematurely, dying around fifteen years of age. More surprisingly, in 2015 it authorized the TAME trial on the use of metformin in a study of aging in healthy adults; perhaps the federal agency was swayed by the fact that metformin was already an approved drug for diabetes, and at least some data on diabetics suggested a beneficial effect. But unless companies invested in longevity succeed in persuading the FDA to allow clinical trials for normal aging, they will face difficulty carrying out rigorous patient studies and will have to resort to other criteria to show the efficacy of their treatments.
MOST PEOPLE SAY THEY DO not fear death so much as the prolonged debilitation that precedes it. Almost everyone would agree that it is a worthy goal to increase health span, or the number of years of healthy life, by reducing the fraction of years of life that we spend in poor health as a result of age-related diseases. This goal was termed compression of morbidity by James Fries in 1980. Or as Klausner phrased it, we should all die young after a long time. Compression of morbidity rests on two assumptions: that we can alter the process of aging to postpone the onset of the diseases of aging; and that the length of life is fixed. The first, of course, is the goal of much of anti-aging research.
However, there is some debate about the second assumption. Much of the gain in life expectancy in the last hundred years was by reducing infant mortality. However, in the last few decades, tremendous advances have been made in the treatment of diseases that occur as we age, including diabetes, cardiovascular disease, and cancer. These advances have inevitably increased our life expectancy. Aubrey de Grey has argued convincingly that the gerontology community is hypocritical in rejecting life extension because treating the causes of aging will inevitably extend life and that compressing morbidity will “forever remain quixotic.” Even if we accept that there is currently a natural limit of about 120 years to our life span, the reasons for that limit are not well understood beyond a vague notion that it has to do with a general breakdown of our complex biology that leads to general frailty. As de Grey points out, compression of morbidity would require us to eliminate or slow down various causes of aging, while at the same time deliberately not tackle the causes of frailty that eventually make us die. Even Steven Austad, who is far more in the mainstream of the gerontology community than de Grey, made his famous bet that advances in combating aging would enable someone currently alive to live over 150 years.
If anything, data from the Office of National Statistics in the UK suggest that rather than compressing morbidity, advances in treatment of age-related diseases have done the opposite: they show that the number of years we spend with four or more morbidities has not declined but actually slightly increased as a fraction of our lives. A United Nations report on the trend worldwide is similar and concludes that both life span and disability-free years increased but the fraction of our lives spent in disability has not decreased. In short, we are living more years and possibly a greater fraction of our lives in poor health.
Is compression of morbidity even possible? When I first heard the idea, I thought it was absurd: if someone was “young” in Klausner’s sense of being healthy, what would suddenly cause him or her to collapse and die? It would be like a car that was running perfectly suddenly falling apart. In his original 1980 article on compression of morbidity, Fries himself likened the idea to the titular one-hoss-shay of the 1858 Oliver Wendell Holmes poem “The Deacon’s Masterpiece or, the Wonderful ‘One-Hoss Shay’” in which a shay—a horse-drawn carriage for one or two people—was designed so perfectly that all its parts were equally strong and long-lasting. A farmer was merrily riding it when all of a sudden the shay disintegrated under him—“Just as bubbles do when they burst”—and he found himself on the ground in a heap of dust.
There are animals that live a healthy and vigorous life, reproducing right up to the point of death. In his book Methuselah’s Zoo, Steven Austad describes an albatross that lives many decades in perfect health until it dies. However, the albatross’s demise is not the death we might wish for, as centenarians in the peak of health quietly slipping away in our sleep. In nature, life is brutish and merciless. The bird probably reached a point where it could no longer make the long journey to return to its nest and collapsed after a struggle, or it was killed by a predator. Similarly, our hunter-gatherer ancestors probably did not spend many years with the morbidities of old age; instead, they often starved, died of disease, were eaten by predators, or killed by a fellow human being the moment they were not absolutely healthy and fit. Their morbidity was highly compressed but it’s not exactly what most of us are striving for. If compressing morbidity were the only goal, we could squish it all the way to zero if we chose. In Aldous Huxley’s classic 1932 dystopian novel Brave New World, perfectly healthy people are simply euthanized at their appointed time. It is not clear that many people would opt for such a world especially if the timing of “compression” was not up to us. If we were faced with many years of decrepitude, some of us might well consider it, but if we were perfectly healthy, why would we want to die? I don’t think these examples represent true compression of morbidity, because the death of an otherwise healthy being occurs rather suddenly as the result of some unpleasant external cause.
If all this sounds bleak, there is some hope that true compression of morbidity is actually possible. Thomas Perls of the New England Centenarian Study points out that although the number of centenarians has grown in recent decades, the numbers of semisupercentenarians and supercentenarians (those that reach 105 and 110 years of age, respectively) have not and remain very small. This is contrary to what we would expect given medical advances and a general population increase in life expectancy. While many centenarians live extraordinarily long lives in good health, about 40 percent of them had age-related diseases prior to 80. By contrast, supercentenarians are healthy nearly their entire lives. As they approached the limit of the human life span at around 120 years, like the one-hoss-shay they experienced a rapid terminal decline in function and died. This would argue in favor of a fixed life span, with supercentenarians managing to compress morbidity as much as possible and pushing close to the maximum life span of the species.
Perhaps by studying their genetics, metabolism, and lifestyles, we can understand what it would take to achieve a life that is healthy right up to the very end. There may be hundreds of genetic changes that each contribute in a subtle way to longevity, and there may be no magic combination of genes that allows you to live very long. Moreover, although scientists have been able to isolate single genes that extended life in highly artificial situations, we know that those mutants are unable to compete with normal wild-type worms or flies because these genes are detrimental to fitness in other ways. Similarly, a variant of a gene called APOE is overrepresented in centenarians and is thought to protect against Alzheimer’s disease, but this same variant increases the risk of metastatic cancer, and also makes people more likely to die of Covid-19. Findings like these should temper any dreams of using future advances to engineer humans with extremely long lives. Genetic variants that are associated with longevity could make us vulnerable in other unforeseen ways.
Anyway, even these supercentenarians are hardly as fit as they were in their twenties, nor indeed would you mistake them for a younger person. Something about them has still aged, and they become increasingly frail. As I pointed out earlier, Jeanne Calment was deaf and blind near the end. So the question of what characterizes good health or a lack of morbidity bears closer examination.
It is conceptually easy to define mortality, but morbidity is much fuzzier. It is defined as a disease, but many chronic illnesses such as diabetes, high-blood pressure, or atherosclerosis can be treated with medication and people can lead perfectly normal and satisfactory lives. I take medication for high cholesterol and high blood pressure, which might be termed chronic diseases, but I can do most things I like, including bicycling and hiking. If you simply count diagnoses for diseases as morbidities, then you are not capturing a true picture of whether the person is living a reasonably healthy life or is decrepit, incapacitated, and suffering. Statistics regarding morbidities in old age must be looked at carefully.
The efforts to combat aging today span a wide range. At one end are a small and highly vocal minority, including both high-profile scientists and investors, who want to defeat death altogether. They have large, cultlike followings, and I suspect there are many more who want this goal but are too embarrassed to profess it openly. At the other end are those focused strictly on treating specific diseases of old age using what we have learned about their various causes. The broad spectrum in the middle want to tackle aging directly to compress morbidity so that humans might live healthy lives into old age.
Today there is a vast amount of money invested in aging research, both by governments and by private commercial companies. In a decade or two, we will have a clear idea of whether they will succeed and to what extent. If they succeed even partly, it could have profound and unpredictable consequences for society. Let’s now look at what some of those might be.
12. Should We Live Forever?
I am now roughly the age my grandparents were when they died. The physically active lifestyle I lead is something they could not have imagined in their final decade. Today it is increasingly common for people to die in their nineties or later. My personal experience is simply a reflection of demographic changes in the world over the last few decades. Virtually every part of the world is experiencing a growth in the size and proportion of the population over the age of sixty-five. The share of older people is currently almost 20 percent in high-income countries and expected to double between now and 2050 in many regions of the world.
At the same time, people are having fewer children. We first saw this in developed countries and are increasingly seeing it now across the globe. This means that fewer and fewer workers will support an ever larger population of retirees. In some Asian countries, there may eventually be twice as many retired people as there are workers. Many of the elderly will also require expensive medical care for a decade or even two. In countries with weak social safety nets, they will either be at the mercy of their families or will have to be self-reliant, for which they will need to be mentally and physically fit. Even in countries with more robust state support, an aging population will put tremendous strain on pension and social security programs.
The social consequences of extending life span are immense. Nearly all state-backed retirement programs assume that people will stop working around age sixty-five. These measures were introduced when people generally lived only a few years past retirement age, but now they can live two decades beyond it. In both social and economic terms, this is a ticking time bomb, and it is no surprise that governments the world over are enthusiastically funding aging research to improve health in old age in the hopes that this segment of the population can be both more productive and independent for a longer time, and in less need of costly care.
If we increase life span without compressing morbidity, it will simply make our current problems worse. But if researchers manage to combat aging and compress morbidity, we could well see a scenario where people routinely live healthily beyond 100 years, possibly approaching our current natural limit of about 120 years of age. In the context of any one individual that might seem a wonderful outcome, but it will also have profound and unpredictable consequences for society.
When major, disruptive technologies arrive, we are not always good at understanding their long-term ramifications. For example, not so long ago, people gladly adopted social media while giving scarcely a thought to its potential consequences, such as a loss of privacy, monetization of the individual by large corporations, surveillance by governments, and the spread of misinformation, prejudice, and hatred. We cannot afford to repeat that mistake by blindly adopting new anti-aging technologies and sleepwalking into a world for which we are ill-prepared. What might some of the consequences of life extension be?
One of them is even greater inequality. There is already a wide gap in life expectancy between the rich and poor. Even in England, which has a national health service providing universal coverage, this disparity is about ten years. However, the difference in the number of healthy years is almost twice that. The poor not only live shorter lives but also spend more of it in poor health. Things are even worse in the United States, where the richest live about fifteen years longer than the poorest, and the disparity actually increased between 2001 and 2014.
Advances in medicine have always had the potential to increase inequality. Historically, the rich in advanced countries have benefited first. Later, others in these countries may benefit, depending on whether health-care systems and insurance companies view these treatments as necessities. Only then will they eventually spread to the rest of the world, where only those individuals who can afford them will be able to benefit. We already see this in the health and economic status of people from different parts of the world. So any advances in aging research is likely to similarly increase inequality. But unlike other kinds of inequality, an inequality in both the quality and extent of life has the potential to be not just self-sustaining but actually to drive even larger increases in inequality. The economically well off in white-collar jobs will now be able to live and work longer and pass on even more generational wealth to their descendants, thus exacerbating the inequality. Unless treatments become very cheap and generic—such as cholesterol-lowering statins or blood pressure medications—there is a serious risk that we will be creating two permanent classes of humans: those who enjoy much longer lives in good health, and the rest.
Another concern is overpopulation. Such a large increase in life expectancy could lead to a dramatic increase in the world’s population at a time when there are already too many people on Earth. Our current population, and its predicted increase in the coming decades, is partly why we face so many existential disasters, including climate change, loss of biodiversity, and dwindling access to natural resources like fresh water.
Past increases in longevity have indeed led to dramatic increases in the population. This is because fertility rates remained high for some decades after life expectancy increased. Similarly, today, Africa has experienced significant increases in life expectancy, but fertility rates remain high at about 4.2, which is why the population of Africa is still increasing rapidly. However, improvements in life expectancy and standard of living are almost inevitably followed by a demographic transition in which the birth rate gradually falls. For example, in the late eighteenth century, European women had about five children on average at a time when life expectancy was low due to high infant mortality, but that fertility rate now ranges from 1.4 to 2.6, depending on the country. Eventually the birth and death rates became roughly equal, and the population has stabilized at some new higher level. Over the course of the nineteenth and twentieth centuries, this happened in much of the West, as well as in many Asian countries such as Japan and South Korea.
In the past, improvements in infant and childhood mortality meant more people lived to reach reproductive age, which naturally led to rapid population growth. But it is not inevitable that in advanced countries that have already gone through a demographic transition, further increases in life expectancy will necessarily lead to a growth in population. In Japan, people live longer than they did a few decades ago, yet the population of Japan has actually fallen since 2010, because of lower birth rates.
The fertility rate has dropped and is below replacement level in many countries. The average age of childbearing has also been steadily increasing in developed countries. Currently, it is increasingly common for women to have their first child in their thirties, and sometimes even around forty, which is almost a decade or two later than the norms a century ago. Both of these trends are the result of more security and prosperity, the expectation of a long life, and the emancipation of women and their entry into the workforce. Together these factors have slowed down or stopped population growth in many parts of the world, which has been hugely beneficial in many important ways, not least the effect on our environment and natural world. I am puzzled by economists who talk about it as a problem, especially in reference to China’s decline in population growth. Elon Musk believes that an impending global population collapse is a much bigger problem than climate change, which strikes me as absurd.
Nevertheless, as people live longer, the population will grow unless one of two things happens: either the fertility rate decreases even more, or the average age of childbearing increases along with life expectancy. However, both of these scenarios have some problems. In many countries, the average age of childbirth has gradually increased until it is pushing up against the realities of biology. Women from their midthirties on have increasing difficulty in conceiving and soon afterward face menopause. If menopause can be delayed as we increase life expectancy, this would solve the problem of delaying childbirth and would be much fairer to women, many of whom face the problem of deciding whether to have children right when their career is taking off. However, menopause is the result of very complex biology, and there is no evidence that we will be able to alter the age of its onset. Of course, there are ways for women to have children even beyond menopause—for example, by freezing eggs for later implantation along with hormone treatment—but these are expensive and cumbersome, and not without considerable risk. The other solution to prevent population growth in the face of increasing longevity is to have even fewer children, which means that an even greater proportion of the population will be elderly, which has its own consequences.
Let us assume an optimistic scenario: life expectancy surges beyond a hundred years and they are mostly healthy years. The population has stabilized; people are having fewer children and having them as late as possible. If we can’t ask a smaller and smaller fraction of younger people to support an increasing cohort of older people in retirement, there’s really only one solution: careers are going to get longer.
WORKING INTO YOUR SEVENTIES OR eighties—or even longer—is a rather different prospect depending on what your job is. As Paul Root Wolpe, director of the Emory University Center for Ethics, asks: Would hard laborers or people doing menial jobs at the age of sixty-five relish the prospect of doing this for another fifty years? Large percentages of people dislike their jobs and look forward to retirement. In 2023 more than 1.2 million people marched in France to protest against the government’s proposal to raise the retirement age a mere two years from sixty-two to sixty-four. Reacting to the French protests, some have argued that the United States should actually lower retirement age, pointing out that the people who advocate that Americans should work until they are seventy are typically in cushy, remunerative white-collar jobs that are fun and intellectually engaging for octogenarians, and it is different for people who want to stop changing tires or working a cash register for $11 an hour at age sixty-two. In my own institute, I have found that nonscientists on the staff retire as soon as they qualify, while the scientists try to hang on for as long as they can.
When I ask some of my scientific colleagues about their retirement plans, especially in America, where it is not uncommon to see academics work well into their eighties or even longer, the typical response is “I’m having far too much fun to retire!” Some of them go on to claim they are doing the best work of their lives. But the evidence says otherwise. We are all willing to accept that we cannot run a hundred-meter race as fast as we could when we were twenty, but we persist in the delusion that we are intellectually just as capable as we were when we were younger. This may be because we identify too closely with our own thoughts—they define who we are. All the evidence suggests that in general, we are no longer as creative and bold as when we were younger.
One way to assess this is to retrospectively ask how old someone was when they did their best work. In the sciences, Nobel Prize winners nearly always make their key breakthroughs when they are young and not very powerful. Biologists and chemists often achieve their big breakthroughs a decade or so later than physicists and mathematicians, perhaps because it takes time to assimilate a huge body of knowledge, acquire the practical experience, and build up the resources needed. Indeed, the famous mathematician G. H. Hardy wrote in his 1940 book, A Mathematician’s Apology, “No mathematician should ever allow himself to forget that mathematics, more than any other art or science, is a young man’s game. . . . I do not know of an instance of a major mathematical advance initiated by a man past fifty.” In recent times, one of the great achievements of mathematics, the proof of the 350-year-old Fermat’s Last Theorem, was made by Andrew Wiles when he was about forty.
When they are older, many scientists continue to churn out first-rate work from their labs. However, this is not because they themselves are sharp and innovative. Rather, they have become a brand name, have amassed resources and funding, and can attract first-rate young scientists to do the work. Many, if not all, of the new ideas—and certainly the lion’s share of the work—come from these young scientists. Even so, it is very rare for an older scientist—even one who is doing very good work and has a team of young scientists to help—to truly break new ground. Often they are doing more of the same. For example, I have had the good fortune to attract very talented young people thanks to whom my laboratory continues to publish papers in top journals. But it is also true that in some sense, they are extensions of my previous work. The few really new directions have come not from me but from the young people who work with me. It is true that everyone can point to an exception: the chemist Karl Sharpless won his second Nobel Prize at the age of eighty-one for work he had begun when he was around sixty. But that is remarkable because it is so rare.
It is not just in science and mathematics that our creative powers peak when we are relatively young. This is also true in business and industry. Thomas Edison was under thirty when he started the Menlo Park laboratory in New Jersey and invented his version of the lightbulb soon afterward. In today’s world, many of the most innovative companies, such as Google, Apple, Microsoft, and the AI company DeepMind, were started by people in their twenties or thirties.
You might think that things are different in literature, where experience of life and accumulated wisdom would make you more profound as you aged. However, at a Hay Literary Festival event in 2005, the Nobel Prize–winning novelist Kazuo Ishiguro outraged his fellow writers by suggesting that most authors produce their best work when they are young. He said it was hard to find cases where an author’s most renowned work had come after the age of forty-five and pointed out that War and Peace, Ulysses, Bleak House, Pride and Prejudice, Wuthering Heights, and The Trial were all written by writers in their twenties and thirties. Many great writers—Chekhov, Kafka, Jane Austen, the Brontë sisters—died before they reached their midforties. Ishiguro says he is not suggesting that novelists cannot do good work later in life, just that their best work tends to come before their midforties. His main point was actually that authors should not wait until they are older to attempt a great novel. He may have contradicted his own thesis with Klara and the Sun, which he wrote in his midsixties. It was received as one of his finer novels, although only time will tell whether it will rank as highly as his earlier work. Similarly, Margaret Atwood’s recent Booker Prize–winning novel, The Testaments, was published when she was over eighty. It is brilliantly gripping and disturbing, but the novel is really a further exploration of the world she conjured in The Handmaid’s Tale almost forty years before.
Ishiguro posited a theory for why some types of creativity decline with age. As we grow older, one of the first mental abilities to decline is our short-term memory. Perhaps writing a novel requires holding disparate facts and ideas in our heads while we synthesize something new from them. This may well be true in science and mathematics. The process of creativity may be different in other disciplines. For example, many film directors, conductors, and musicians continue to perform at the highest level well into old age, as do many artists.
Advances in healthy aging would not necessarily make us as creative and imaginative later in life as we are in our younger years. Young people see the world with fresh eyes, and in new ways. Ishiguro wonders whether in writing, the proximity to childhood and the experiences of growing up—a time of life when one’s perspective changed from year to year, even month to month, because one was oneself changing so profoundly—is central to the creation of satisfying novels. In science and mathematics, younger practitioners may be less biased by a lifetime accumulation of knowledge, and bolder about questioning paradigms.
So far, we have been talking about big creative breakthroughs declining with age in a variety of fields, but these breakthroughs are outliers and represent a tiny fraction of the whole enterprise. Even in science, the big breakthroughs are built on the vast foundations laid by the majority of scientists productively going about their jobs of gradually advancing our state of knowledge. It would hardly be appropriate to formulate social policy based on these outliers. How would the bulk of white-collar work be affected by age?
Most studies say our general cognitive abilities also decline with age, but there has been some debate about when exactly that happens, with some arguing that it begins as early as age eighteen, and others arguing that it is significant only after sixty. A ten-year study that followed a large cohort of British civil-service workers showed that cognitive scores on tests of memory, reasoning, and verbal fluency all declined from the age of forty-five, with faster decline in older people. The one category not to show a major decline was vocabulary. Other studies also make a distinction between so-called “crystallized abilities” such as vocabulary and “fluid abilities” such as processing speed. The latter declines steadily from the age of twenty, while the former increases and then remains steady, and only declines gradually from about age sixty. All of this affects our ability to learn new tasks and be as mentally agile. Any adult who doubts these findings should try learning the piano, a new language, or advanced mathematics for the first time.
It is of course theoretically possible that as we learn to combat the causes of aging, we can also do something about the deterioration of our mental abilities. But so far, the brain has proved the most difficult frontier to conquer. Neurons regenerate very slowly if at all, and many of the processes that lead to deterioration and eventual disease in the brain remain intractable. It is true that at least one approach, inhibiting the integrative stress response in protein synthesis, has been shown to improve memory, but there is no evidence that it reverses general cognitive decline and ability to learn.
Many argue that any cognitive decline is offset by increased wisdom, a vague and poorly defined trait. It’s true that young people often do lack wisdom and foresight, leading to rash behavior. But there is no evidence that wisdom continues to increase beyond a certain age. In recent elections in both the United States and Great Britain, older age groups have tended to be conservative and swayed by demagoguery and an appeal to their sense of nostalgia. They have acquired a lifetime of biases and prejudices and are generally less open to new ideas. My guess is that we acquire most of our wisdom by our thirties. After that, we become increasingly set in our ways, as likely to be reactionary as wise.
Today there is an imbalance of power that favors the old. This is partly because they have accumulated a great deal of wealth: in both Britain and American, households where the head is over seventy have about fifteen to twenty times the median wealth of those under thirty-five. But it is also because as people age, they accumulate power and a powerful network of connections. Even if they are no longer as qualified or competent to do their job as their younger peers might be, they may cling to power and authority, using their connections and reputation. It is hard to dislodge them from their positions even if they are no longer on top of their game and could be replaced by many more competent people. More generally, Wolpe argues that the political ramifications of a long life span are huge because the elderly vote at much higher rates than the young, and the highest echelons of power have become the preserve of the over-seventies. The United States is led by President Joe Biden, who will be eighty-one as of the 2024 presidential election; his chief rival, Republican Donald Trump, will be seventy-eight. Elsewhere, Rupert Murdoch, until recently the chair of Fox Corporation and executive chairman of News Corp, retains enormous media influence (and with it, political clout) in several countries at the age of ninety-three. Politically, Wolpe argues, young people will be squeezed out, and the fresh ideas they bring to politics and innovation will be suppressed. By contrast, the vast majority of the great innovations, including social advances such as gay marriage, diversity inclusion movements, and before that civil rights and women’s rights, were driven by young people.
The imbalance of power is particularly egregious in academia, where the concept of tenure, which was introduced so faculty members could not be fired for expressing unorthodox opinions, is now being wielded by faculty members to remain in their posts for as long as they possibly can. Many universities in the United States and United Kingdom have abolished mandatory retirement age, and those that haven’t, such as Oxford and Cambridge, are facing lawsuits from disgruntled professors. Recently, Oxford lost a tribunal case brought by three professors who accused the university of ageism, claiming, not surprisingly, that they were dismissed “at the peak of their careers.”
Even if they are not doing groundbreaking work or at the peak of their careers, as long as they are being productive, what harm is there in allowing them to stay on? Some of my academic colleagues argue that established senior scientists have the resources, wisdom, vision, and perspective to provide a great environment to train and mentor the next generation of younger scientists. Not everyone agrees. Fred Sanger, who won two Nobel Prizes, hung up his hat the day he turned sixty-five and spent the rest of his life pursuing hobbies such as building a boat that he sailed around Britain and growing roses. My own mentor, Peter Moore, retired after a long and distinguished career at Yale at the age of seventy. It is not as if he suddenly became intellectually dead. He continues to edit journals, write books, and carry on other intellectual activities that take neither resources nor money from his institution. He had this to say: “I had been telling my colleagues for years that it is an abuse of the privilege of tenure for elderly faculty to hang on to the bitter end, not least because there are no seventy-year-old scientists so wonderful that a thirty-five-year-old scientist who is better cannot be found.”
In academia, the combination of tenure and a lack of retirement age is particularly problematic. Some senior academics have rightly complained that they are far more productive than some younger faculty who have burned out by the age of forty. But this can be solved by abolishing both tenure and retirement age and having regular assessments of productivity.
Moore’s comment goes to the heart of intergenerational fairness. The most senior faculty tend to draw very large salaries, which would often be sufficient to hire two young scientists in their stead. Even if they are not drawing a salary, they are taking up precious resources such as laboratory space that could otherwise be used to recruit new young faculty who would go on to make the breakthroughs of the future and open up entirely new areas. Older researchers also have the clout to influence the agenda at their institution and in science more generally, and tend to be conservative and incremental rather than bold and innovative. The same is true broadly in other sectors of work, including corporate careers.
The problem of intergenerational fairness conflicts with the push for people to work longer as the population ages. So what is to be done?
Ageism is now considered a sin along with other -isms such as racism and sexism. However, ageism is different because we all actually decline with age. Still, it is important to recognize that the rate at which people’s physical and mental abilities decline is highly variable. We must not use chronological age as a proxy for ability, and a rigid retirement age that applies to everyone is highly inappropriate. Moreover, despite the well-documented decline in people’s ability with age, two surveys of the literature concluded that the relationship between age and productivity is more complex. One concluded that as they aged, people did less well at tasks that required problem-solving, learning, and speed, but maintained high productivity in jobs where experience and verbal abilities are important. The other concluded that 41 percent of the reports showed no differences between younger and older workers, and 28 percent reported that older workers had better productivity than younger workers, citing experience and emotional maturity as possible factors.
All of this suggests that we need to be flexible in our approach to work and retirement. As we have seen, many professions are physically or mentally demanding, and people may need to retire earlier. They may be able to switch to less demanding jobs and continue working if they are able. Rather than apply a one-size-fits-all approach, we need to bring in objective measures of assessment that can apply to all age groups, which will also ensure fairness to both young and old. Moreover, even after they can no longer do the job they did for much of their career and have to retire, older people can still be useful and productive in many ways for as much of the rest of their lives as possible.
There is a lot of evidence that having a purpose in life reduces mortality from all causes as well as the incidence of stroke, heart disease, mild cognitive decline, and Alzheimer’s. And elderly professionals do have a wealth of experience and a deep knowledge of their field. They can be unparalleled sources of advice and mentorship; they can participate in civic activities. Peter Moore, whom I mentioned earlier, is a great example of someone who has retired from his professorship but still makes himself extremely valuable to the scientific community.
Even after they have retired, we need to think of ways that allow older citizens to remain independent for as long as possible. This means paying attention to the way houses are constructed, with bedrooms on ground floors, and communities are planned, with nearby amenities such as shopping and mass transit. Social isolation and loneliness are detrimental for the well-being of all people but especially for the elderly. Currently, many Western societies seem to treat the old as a problem to be hidden away in separate retirement enclaves rather than an integral part of society. Perhaps it is better to integrate them fully into the broader community, where they live interspersed with the rest of the population, and through their social and civic activities, they interact routinely and regularly across the entire generational spectrum of society. Their active participation will also benefit the rest of society.
These are all problems we may plausibly soon encounter, if biologists succeed in pushing life spans ever closer to a natural limit of roughly 120 years. Yet there is no hard scientific law that necessarily precludes far more drastic increases in life expectancy. After all, we know of species that live many hundreds of years and others that show no signs of biological aging. If, someday, humans breach our current limit and live for several hundred years as Aubrey de Grey prophecies, all of these issues would only be magnified. Advocates for extreme life extension have no real solutions except to say that we will learn to deal with problems as we encounter them. Some have said that if we have a population crisis as a result of extreme longevity, we should be made to leave Earth and settle other planets once we reach a certain age. As always, the answer to problems created by technology seems to be even more far-fetched technology.
I AM NOT SURE THAT if we lived so much longer, we would be any more satisfied. Now that we live twice as long as we did a century ago, we still aren’t content with that entire extra life. Rather, we seem to be even more obsessed with death. If we live to be 120 or 150 years old, we will fret about why we can’t live to 300. The quest for life extension is like chasing a mirage: nothing will ever be enough short of true immortality. And there is no such thing. Even if we conquer aging, we will die of accidents, wars, viral pandemics, or environmental catastrophes. It may be simpler to accept that our life is limited.
Moreover, our very mortality may give us the incentive and desire to make the most of our time on Earth. A greatly extended life span would deprive our lives of urgency and meaning, a desire to make each day count. It is not clear that even with an entire extra lifetime, we are accomplishing more than the great writers, composers, artists, and scientists of past eras. We may well end up living a very much longer life bored and lacking in purpose. As I mentioned earlier, it could also lead to a stagnant society, since many of the big social changes have been spearheaded by younger generations.
This obsession with mortality is probably unique to humans. It is only the accidental evolution of our brain and consciousness, and our development of language to communicate our fears, that has made our species so fixated on the end. The writer and editor Allison Arieff has pointed out the irony that the same Silicon Valley culture that produces gadgets designed to be obsolete and discarded every few years seems to be obsessed with living forever. She quotes the writer Barbara Ehrenreich, “You can think of death bitterly or with resignation and take every possible measure to postpone it. Or, more realistically, you can think of life as an interruption of an eternity of personal nonexistence, and seize it as a brief opportunity to observe and interact with the living, ever-surprising world around us.” Arieff believes that our very humanness is intertwined with the fact of our mortality.
On a recent trip to India, I met Ganesh Devy, a linguist who works with dozens of rural, forest-dwelling tribes in the country. India has well over a hundred languages, many facing a different kind of death: some of them are now spoken by only a few people and will soon become extinct. He said he himself did not fear death. I was skeptical, but he pointed out that on a field trip once he was bitten by a highly poisonous snake and he felt no fear or panic at the thought of dying. I asked him why. Devy said that we have to regard our individual selves as parts of larger entities like family, community, and society, just as all the cells in our body are part of tissues and organs and us. Millions of our cells die every day. Not only do we not mourn their passing, but we are not even aware of it. So even if we as individuals die, our society and indeed life on Earth will go on. Our own genes will live on through our offspring or other family members. Life has been going on continuously for several billion years while we individuals come and go.
Still, if someone were to offer a pill that would add ten years of healthy life, hardly anyone would decline it. I view myself as more in the philosophical camp, yet take several anti-aging medicines a day: pills for my blood pressure, a statin for high cholesterol, and a low-dose aspirin to protect against thrombosis. All of these are to prevent heart attacks or strokes and have the effect of prolonging my life. I would be a hypocrite to dismiss attempts to alleviate the problems of aging. Physicians are struck by how many people, even faced with terminal illnesses that inflict appalling pain, want every measure taken to prolong their lives, even if only by a few weeks or even days. The will to live is deeply ingrained in us, even if we are sanguine in our more rational moments.
About ten years ago, the Pew Research Center explored American attitudes on living much longer. Respondents were optimistic about cures for cancer and artificial limbs, and they viewed advances that prolong life as generally good. However, over half said that slowing the aging process would be bad for society. When asked if they themselves would take treatments to live longer, a majority of them said no, but two-thirds thought that other people would. Most doubted that an average person living to 120 would happen before 2050. A large majority felt that everyone should be able to get these treatments if they wanted, but two-thirds felt that only the wealthy would actually have access. About two-thirds also said that longer lives would strain our natural resources. About six in ten said that medical scientists would offer treatments before they fully understood how doing so could affect people’s health and that such treatments would be fundamentally unnatural. The clear-eyed view of the American public in the face of relentless hype is certainly heartening.
In this book, I have discussed how advances in molecular biology have shed light on virtually every aspect of aging, often taking a skeptical look at some of the hype. In doing so, I hope that readers acquire not only an appreciation of the underlying causes of aging, but are able to more knowledgeably interpret news reports and PR blurbs about each new “advance” and judge for themselves how realistic various claims are. How long it takes to go from a fundamental discovery to a practical application is hugely variable and unpredictable. It took three centuries for Newton’s laws of motion to be translated into rockets and satellites. It took over a hundred years for Einstein’s theories of relativity to be used in the GPS systems that our phones use to tell us where we are on a map. Neither Newton nor Einstein could have remotely anticipated the use we made of their discoveries. Other advances are much faster: from Alexander Fleming’s discovery of penicillin in 1928 to its use in humans was less than twenty years. With the money and urgency that drive current research on aging, major advances might well come in years rather than decades, but the sheer complexity of aging makes any prediction highly uncertain.
We are at a crossroads. The revolution in biology continues unabated. Artificial intelligence and computing, physics, chemistry, and engineering are all being brought to bear on what was the domain of traditional biologists. Together they are creating new technologies and increasingly sophisticated tools to manipulate cells and genes to advance every aspect of the life sciences, including aging.
I have highlighted the relationship between cancer and aging many times throughout this book. Both are rooted in highly complex biology. Just as cancer is not a single disease, aging too has many interconnected causes. It has now been half a century since President Nixon declared a “war on cancer” in 1971. Since then, our biological understanding of cancer has advanced enormously, resulting in a steady stream of new and improved treatments that continues to this day, saving or prolonging millions of lives. Today, the sheer talent and money committed to aging research is reminiscent of our efforts to combat cancer. This means that just as with cancer, we will eventually make breakthroughs, even if it takes time for them to actually improve and extend our lives. It is well to remember that even today, after a half century of intense effort, cancer is not “solved.” It remains one of the largest killers in most societies. Our progress with aging may follow a similar trajectory, given the similar complexity of both problems.
The American futurist and scientist Roy Amara said that we tend to overestimate the effect of a technology in the short run and underestimate its effect in the long run. This has been true for many things, including the internet and artificial intelligence. If Amara’s law holds, all the hype in the anti-aging industry will lead to considerable disappointment in the short term, but it also means that once we get past the winter of disillusionment and discontent, there will be major advances eventually.
As a society, it is important for us to think about the possibly profound consequences of these changes. However, this task is not just for governments and citizens alone: the anti-aging industry should not repeat the mistakes of the computer industry and plunge ahead without any thought of where it will all lead and leave the rest of us to try and clean up the mess when it is too late. These companies stand to benefit hugely from any breakthroughs in aging research but do not seem to have put much effort into either the social or ethical consequences of their work. In their blurbs, their work is always portrayed as an unmitigated and universal good for humanity.
In the meantime, we need not sit around and wait for a long period of decrepitude and decline. Ironically, the very same advances in biology that are the basis of the anti-aging industry also thoroughly validate some age-old advice for living a long and healthy life: diet, exercise, and sleep. In his book In Defense of Food: An Eater’s Manifesto, Michael Pollan advises us, “Eat food. Not too much. Mostly plants.” This advice is entirely consistent with everything we know about caloric restriction pathways. Exercise and sleep, as we discussed earlier, affect a large number of factors in aging, including our insulin sensitivity, muscle mass, mitochondrial function, blood pressure, stress, and the risk of dementia. These remedies currently work better than any anti-aging medicine on the market, cost nothing, and have no side-effects.
While we wait for the vast gerontology enterprise to solve the problem of death, we can enjoy life in all its beauty. When our time comes, we can go into the sunset with good grace, knowing that we were fortunate to have taken part in that eternal banquet.
Notes
Introduction
Even Carter, a seasoned Egyptologist: Maite Mascort, “Close Call: How Howard Carter Almost Missed King Tut’s Tomb,” National Geographic online, last modified March 4, 2018, https://www.nationalgeographic.com/history/magazine/2018/03-04/findingkingtutstomb.
We may be tempted to think of it: Nuria Castellano, “The Book of the Dead Was Egyptians’ Inside Guide to the Underworld,” National Geographic online, last modified February 8, 2019; Tom Holland, “The Egyptian Book of the Dead at the British Museum,” Guardian online, last modified November 6, 2019, https://www.theguardian.com/culture/2010/nov/06/egyptian-book-of-dead-tom-holland.
They recognize when one: For example, see this study of elephants: S. S. Pokharel, N. Sharma, and R. Sukumar, “Viewing the Rare Through Public Lenses: Insights into Dead Calf Carrying and Other Thanatological Responses in Asian Elephants Using YouTube Videos,” Royal Society Open Science 9, no. 5 (May 2022), https://doi.org/10.1098/rsos.211740, described in Elizabeth Preston, “Elephants in Mourning Spotted on YouTube by Scientists,” New York Times online, May 17, 2022, https://www.nytimes.com/2022/05/17/science/elephants-mourning-grief.html.
But there is no evidence: James R. Anderson, “Responses to Death and Dying: Primates and Other Mammals,” Primates 61 (2020): 1–7; Marc Bekoff, “What Do Animals Know and Feel About Death and Dying?,” Psychology Today online, last modified February 24, 2020, https://www.psychologytoday.com/gb/blog/animal-emotions/202002/what-do-animals-know-and-feel-about-death-and-dying.
Philosopher Stephen Cave argues: Stephen Cave, Immortality: The Quest to Live Forever and How It Drives Civilization (New York: Crown, 2012).
The first emperor of a unified China: Ibid.
Rather, our brains appear: Y. Dor-Ziderman, A. Lutz, and A. Goldstein, “Prediction-Based Neural Mechanisms for Shielding the Self from Existential Threat,” NeuroImage 202 (November 15, 2019): art. 116080, https://doi.org/10.1016/j.neuroimage.2019.116080, cited in Ian Sample, “Doubting Death: How Our Brains Shield Us from Mortal Truth,” Guardian online, last modified October 19, 2019, https://www.theguardian.com/science/2019/oct/19/doubting-death-how-our-brains-shield-us-from-mortal-truth.
1. The Immortal Gene and the Disposable Body
But it turns out to be tricky: A group at the Santa Fe Institute led by David Krakauer and Geoffrey West has held several workshops to define both death as it applies to various entities and the definition of the individual.
The loss of brain function: A meeting about the issue of resuscitation and death was held at the New York Academy of Sciences in 2019. See “What Happens When We Die? Insights from Resuscitation Science” (symposium, New York Academy of Sciences, New York, November 18, 2019), https://www.nyas.org/events/2019/what-happens-when-we-die-insights-from-resuscitation-science/. There is also a movement to make the definition of brain death uniform to prevent legal anomalies such as the one I described.
Her family petitioned: S. Biel and J. Durrant, “Controversies in Brain Death Declaration: Legal and Ethical Implications in the ICU,” Current Treatment Options in Neurology 22, no. 4 (2020): 12, https://doi.org/10.1007/s11940-020-0618-6.
After that, there is a multiday window: Two popular books that discuss these early events are Magdalena Zernicka-Goetz and Roger Highfield, The Dance of Life: The New Science of How a Single Cell Becomes a Human Being (New York: Basic Books, 2020), and Daniel M. Davis, The Secret Body: How the New Science of the Human Body Is Changing the Way We Live (London: Bodley Head, 2021).
Death can occur at every scale: Geoffrey West, Scale: The Universal Laws of Growth, Innovation, Sustainability, and the Pace of Life in Organisms, Cities, Economies, and Companies (New York: Penguin Press, 2020).
However, the lecture paved: R. England, “Natural Selection Before the Origin: Public Reactions of Some Naturalists to the Darwin-Wallace Papers,” Journal of the History of Biology 30 (June 1997): 267–90, https://doi.org/10.1023/a:1004287720654.
Although humans have known: Matthew Cobb, The Egg and Sperm Race: The Seventeenth-Century Scientists Who Unlocked the Secret of Sex, Life and Growth (London: Simon & Schuster, 2007).
The germ-line cells, protected in the gonads: Today we know that the Weismann barrier is not perfect and that the germ line also ages and is susceptible to changes from the environment, although much more slowly. P. Monaghan and N. B. Metcalfe, “The Deteriorating Soma and the Indispensable Germline: Gamete Senescence and Offspring Fitness,” Proceedings of the Royal Society B (Biological Sciences) 286, no. 1917 (December 18, 2019): art. 20192187, https://doi.org/10.1098/rspb.2019.2187.
“Nothing in biology makes sense”: T. Dobzhansky, “Nothing in Biology Makes Sense Except in the Light of Evolution,” American Biology Teacher 35, no. 3 (March 1973): 125–29, https://doi.org/10.2307/4444260.
If an individual had a mutation: T. B. Kirkwood, “Understanding the Odd Science of Aging,” Cell 120, no. 4 (February 25, 2005): 437–47, https://doi.org/10.1016/j.cell.2005.01.027; T. Kirkwood and S. Melov, “On the Programmed/Non-Programmed Nature of Ageing Within the Life History,” Current Biology 21 (September 27, 2011): R701–R707, https://doi.org/10.1016/j.cub.2011.07.020. There are some exceptions to this rule against group selection, but they apply only under very special circumstances and usually involve species where the members of the colonies are all genetically either identical or very closely related, such as insects. J. Maynard Smith, “Group Selection and Kin Selection,” Nature 201 (March 14, 1964): 1145–47, https://doi.org/10.1038/2011145a0.
Species such as the soil worm: Species that reproduce multiple times in a lifetime are called iteroparous, and those that reproduce only once are semelparous. See T. P. Young, “Semelparity and Iteroparity,” Nature Education Knowledge 3, no. 10 (2010): 2, https://www.nature.com/scitable/knowledge/library/semelparity-and-iteroparity-13260334/.
He was a socialist: N. W. Pirie, “John Burdon Sanderson Haldane, 1892–1964,” Biographical Memoirs of Fellows of the Royal Society 12 (November 1966): 218–49, https://doi.org/10.1098/rsbm.1966.0010; C. P. Blacker, “JBS Haldane on Eugenics,” Eugenics Review 44, no. 3 October (1952): 146–51, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2973346/.
A stained glass window: Two opposing views of Fisher can be found in A. Rutherford, “Race, Eugenics, and the Canceling of Great Scientists,” American Journal of Physical Anthropology 175, no. 2 (June 2021): 448–52, https://doi.org/10.1002/ajpa.24192, and W. Bodmer et al., “The Outstanding Scientist, R. A. Fisher: His Views on Eugenics and Race,” Heredity 126 (April 2021): 565–76, https://doi.org/10.1038/s41437-020-00394-6.
However, the same could not be said: T. Flatt and L. Partridge, “Horizons in the Evolution of Aging,” BMC Biology 16 (2018): art. 93, https://doi.org/10.1186/s12915-018-0562-z.
That understanding came when British biologist Peter Medawar: N. A. Mitchison, “Peter Brian Medawar, 28 February 1915–2 October 1987,” Biographical Memoirs of Fellows of the Royal Society 35 (March 1990): 281–301, https://doi.org/10.1098/rsbm.1990.0013.
But an unusual analysis: R. G. Westendorp and T. B. Kirkwood, “Human Longevity at the Cost of Reproductive Success,” Nature 396 (December 24, 1998): 743–46, https://doi.org/10.1038/25519. See also the letter responding to this article: D. E. Promislow, “Longevity and the Barren Aristocrat,” Nature 396 (December 24, 1998): 719–20, https://doi.org/10.1038/25440.
Menopause may have arisen: G. C. Williams, “Pleiotropy, Natural Selection and the Evolution of Senescence,” Evolution 11, no. 4 (December 1957): 398–411.
For example, although the fertility of elephants: M. Lahdenperä, K. U. Mar, and V. Lummaa, “Reproductive Cessation and Post-Reproductive Lifespan in Asian Elephants and Pre-Industrial Humans,” Frontiers in Zoology 11 (2014): art. 54, https://doi.org/10.1186/s12983-014-0054-0.
Similarly, while living beyond: J. G. Herndon et al., “Menopause Occurs Late in Life in the Captive Chimpanzee (Pan Troglodytes),” AGE 34 (October 2012): 1145–56, https://doi.org/10.1007/s11357-011-9351-0.
The grandmother hypothesis: K. Hawkes, “Grandmothers and the Evolution of Human Longevity,” American Journal of Human Biology 15, no. 3 (May/June 2003): 380–400, https://doi.org/10.1002/ajhb.10156; P. S. Kim, J. S. McQueen, and K. Hawkes, “Why Does Women’s Fertility End in Mid-Life? Grandmothering and Age at Last Birth,” Journal of Theoretical Biology 461 (January 14, 2019): 84–91, https://doi.org/10.1016/j.jtbi.2018.10.035.
Another idea, based on studying killer whales: D. P. Croft et al., “Reproductive Conflict and the Evolution of Menopause in Killer Whales,” Current Biology 27, no. 2 (January 23, 2017): 298–304, https://doi.org/10.1016/j.cub.2016.12.015.
Moreover, scientists have found: R. K. Mortimer and J. R. Johnston, “Life Span of Individual Yeast Cells,” Nature 183, no. 4677 (June 20, 1959): 1751–52, https://doi.org/10.1038/1831751a0; E. J. Stewart et al., “Aging and Death in an Organism That Reproduces by Morphologically Symmetric Division.” PLoS Biology 3, no. 2 (February 2005): e45, https://doi.org/10.1371/journal.pbio.0030045.
2. Live Fast and Die Young
A small aquatic animal: T. C. Bosch, “Why Polyps Regenerate and We Don’t: Towards a Cellular and Molecular Framework for Hydra Regeneration,” Developmental Biology 303, no. 2 (March 15, 2007): 421–33, https://doi.org/10.1016/j.ydbio.2006.12.012.
Still, it is a complex procedure: R. Murad et al., “Coordinated Gene Expression and Chromatin Regulation During Hydra Head Regeneration,” Genome Biology and Evolution 13, no. 12 (December 2021): evab221, https://doi.org/10.1093/gbe/evab221; see also a popular account of this work and hydra in general in Corryn Wetzel, “How Tiny, ‘Immortal’ Hydras Regrow Their Lost Heads,” Smithsonian online, last modified December 13, 2021, https://www.smithsonianmag.com/smart-news/were-closer-to-understanding-how-immortal-hydras-regrow-lost-heads-180979209/.
It is almost as if an injured butterfly: Y. Matsumoto and M. P. Miglietta, “Cellular Reprogramming and Immortality: Expression Profiling Reveals Putative Genes Involved in Turritopsis dohrnii’s Life Cycle Reversal,” Genome Biology and Evolution 13, no. 7 (July 2021): evab136, https://doi.org/10.1093/gbe/evab136; M. Pascual-Torner et al., “Comparative Genomics of Mortal and Immortal Cnidarians Unveils Novel Keys Behind Rejuvenation,” Proceedings of the National Academy of Sciences (PNAS) of the United States of America 119, no. 36 (September 6, 2022): e2118763119, https://doi.org/10.1073/pnas.2118763119; see also a popular account by Veronique Greenwood, “This Jellyfish Can Live Forever. Its Genes May Tell Us How,” New York Times online, September 6, 2022, https://www.nytimes.com/2022/09/06/science/immortal-jellyfish-gene-protein.html.
Along the way, he explores: West, Scale. Many of the original findings for relationships between longevity, size, and metabolic rates can be found here.
As a result, biologists do not think: For a biologist’s view of the second law of thermodynamics and the wear-and-tear theory of aging, see Tom Kirkwood, chap. 5, “The Unnecessary Nature of Ageing,” in Time of Our Lives: The Science of Human Aging (New York: Oxford University Press, 1999), 52–62.
From there, he became interested: See Austad’s academic website: University of Alabama at Birmingham online, College of Arts and Science, Department of Biology, https://www.uab.edu/cas/biology/people/faculty/steven-n-austad; see also a description about him and a podcast interview, https://blog.insidetracker.com/longevity-by-design-steven-austad.
The LQ is the ratio: S. N. Austad and K. E. Fischer, “Mammalian Aging, Metabolism, and Ecology: Evidence from the Bats and Marsupials,” Journal of Gerontology 46, no. 2 (March 1991): B47–B53, https://doi.org/10.1093/geronj/46.2.b47.
Over the years, Austad has studied: Austad, Methuselah’s Zoo. There is also a previous short and more technical version of this: S. N. Austad, “Methusaleh’s Zoo: How Nature Provides Us with Clues for Extending Human Health Span,” Journal of Comparative Pathology 142, suppl. 1 (January 2010): S10–S21, https://doi.org/10.1016/j.jcpa.2009.10.024. Much of this section on the life span of various animals is from these two sources.
Two studies that evaluated survival data: B. A. Reinke et al., “Diverse Aging Rates in Ectothermic Tetrapods Provide Insights for the Evolution of Aging and Longevity,” Science 376, no. 6600 (June 23, 2022): 1459–66, https://doi.org/10.1126/science.abm0151; R. da Silva et al., “Slow and Negligible Senescence Among Testudines Challenges Evolutionary Theories of Senescence,” Science 376, no. 6600 (June 23, 2022): 1466–70, https://doi.org/10.1126/science.abl7811.
By the time a person: “Actuarial Life Table,” Social Security Administration online, accessed August 7, 2023, https://www.ssa.gov/oact/STATS/table4c6.html.
Like elderly humans: S. N. Austad and C. E. Finch, “How Ubiquitous Is Aging in Vertebrates?,” Science 376, no. 6600 (June 23, 2022): 1384–85, https://doi.org/10.1126/science.adc9442; Finch is quoted in Jack Tamisiea, “Centenarian Tortoises May Set the Standard for Anti-aging,” New York Times online, June 23, 2022, https://www.nytimes.com/2022/06/23/science/tortoises-turtles-aging.html.
Bats do not live as long: G. S. Wilkinson and J. M. South, “Life History, Ecology and Longevity in Bats,” Aging Cell 1, no. 2 (December 2002): 124–31, https://doi.org/10.1046/j.1474-9728.2002.00020.x.
Austad estimates that its LQ: A. J. Podlutsky et al., “A New Field Record for Bat Longevity,” Journals of Gerontology: Series A 60, no. 11 (November 2005): 1366–68, https://doi.org/10.1093/gerona/60.11.1366.
Instead of proliferating: S. Liang et al., “Resistance to Experimental Tumorigenesis in Cells of a Long-Lived Mammal, the Naked Mole-Rat (Heterocephalus glaber),” Aging Cell 9, no. 4 (August 2010): 626–35, https://doi.org/10.1111/j.1474-9726.2010.00588.x.
One of the biggest headlines: J. G. Ruby, M. Smith, and R. Buffenstein, “Naked Mole-Rat Mortality Rates Defy Gompertzian Laws by Not Increasing with Age,” eLife 7 (January 24, 2018): e31157, https://doi.org/10.7554/eLife.31157.
This was too much for some scientists: S. Braude et al., “Surprisingly Long Survival of Premature Conclusions About Naked Mole-Rat Biology,” Biological Reviews of the Cambridge Philosophical Society 96, no. 2 (April 2021): 376–93, https://doi.org/10.1111/brv.12660.
As we saw with long-lived tortoises: R. Buffenstein, et al., “The Naked Truth: A Comprehensive Clarification and Classification of Current ‘Myths’ in Naked Mole-Rat Biology,” Biological Reviews of the Cambridge Philosophical Society 97, no. 1 (February 2022): 115–40, https://doi.org/10.1111/brv.12791.
The ability to chemically capture nitrogen: The dramatic impact of fertilizers on humanity is told in Thomas Hager’s fascinating book The Alchemy of Air: A Jewish Genius, a Doomed Tycoon, and the Scientific Discovery That Fed the World but Fueled the Rise of Hitler (New York: Crown, 2009).
He and his colleagues contended: S. J. Olshansky, B. A. Carnes, and C. Cassel. “In Search of Methuselah: Estimating the Upper Limits to Human Longevity,” Science 250, no. 4981 (November 2, 1990): 634–40, https://doi.org/10.1126/science.2237414; S. J. Olshansky, B. A. Carnes, and A. Désesquelles, “Prospects for Human Longevity,” Science 291, no. 5508 (February 23, 2001): 1491–92, https://doi.org/10.1126/science.291.5508.1491.
Moreover, in certain species: A. Baudisch and J. W. Vaupel, “Getting to the Root of Aging: Why Do Patterns of Aging Differ Widely Across the Tree of Life?,” Science 338, no. 6107 (November 2, 2012): 618–19, https://doi.org/10.1126/science.1226467; O. R. Jones and J. W. Vaupel, “Senescence Is Not Inevitable,” Biogerontology 18, no. 6 (December 2017): 965–71, https://doi.org/10.1007/s10522-017-9727-3.
The disagreements between the two boiled: See J. Couzin-Frankel, “A Pitched Battle over Life Span,” Science 338, no. 6042 (July 29, 2011): 549–50, https://doi.org/10.1126/science.333.6042.549.
“pernicious belief”: J. Oeppen and J. W. Vaupel, “Demography. Broken Limits to Life Expectancy,” Science 296, no. 5570 (May 10, 2022): 1029–1031, https://doi.org/10.1126/science.1069675.
In agreement with this: F. Colchero et al., “The Long Lives of Primates and the ‘Invariant Rate of Ageing’ Hypothesis,” Nature Communications 12, no. 1 (June 16, 2021): 3666, https://doi.org/10.1038/s41467-021-23894-3.
Unlike most people: There is an entertaining account of Parr in Austad, Methuselah’s Zoo, pages 262–63.
“Until next year, perhaps”: Craig R. Whitney, “Jeanne Calment, World’s Elder, Dies at 122,” New York Times, August 5, 1997, B8.
Vijg predicted: X. Dong, B. Milholland, and J. Vijg, “Evidence for a Limit to Human Lifespan,” Nature 538, no. 7624 (October 13, 2016): 257–59, https://doi.org/10.1038/nature19793.
“if any”: E. Barbi et al., “The Plateau of Human Mortality: Demography of Longevity Pioneers,” Science 360, no. 6396 (June 29, 2018): 1459–61, https://doi.org/10.1126/science.aat3119.
This paper in turn was criticized: Carl Zimmer, “How Long Can We Live? The Limit Hasn’t Been Reached, Study Finds,” New York Times online, June 28, 2018, https://www.nytimes.com/2018/06/28/science/human-age-limit.html.
Others pointed out: H. Beltrán-Sánchez, S. N. Austad, and C. E. Finch, “The Plateau of Human Mortality: Demography of Longevity Pioneers,” Science 361, no. 6409 (September 28, 2018): eaav1200, https://doi.org/10.1126/science.aav1200.
After climbing steadily for the last 150 years: C. Cardona and D. Bishai, “The Slowing Pace of Life Expectancy Gains Since 1950,” BMC Public Health 18, no. 1 (January 17, 2018): 151, https://doi.org/10.1186/s12889-018-5058-9; J. Schöley et al., “Life Expectancy Changes Since COVID-19,” Nature Human Behaviour 6, no. 12 (December 2022): 1649–59, https://doi.org/10.1038/s41562-022-01450-3.
As I write this: “List of the Verified Oldest People,” Wikipedia, last accessed July 10, 2023, https://en.wikipedia.org/wiki/List_of_the_verified_oldest_people.
In fact, about half of centenarians: J. Evert et al., “Morbidity Profiles of Centenarians: Survivors, Delayers, and Escapers,” Journals of Gerontology: Series A, Biological Sciences and Medical Sciences 58, no. 3 (March 2003): 232–37, https://doi.org/10.1093/gerona/58.3.m232.
He agrees with Olshansky: Thomas Perls, email messages to the author, November 27, 2021, and January 17, 2022.
But scientists have homed in: C. López-Otín et al., “The Hallmarks of Aging,” Cell 153, no. 6 (June 6, 2013): 1194–217, https://doi.org/10.1016/j.cell.2013.05.039. This classic paper has recently been updated on the tenth anniversary of the original: C. López-Otín et al. “Hallmarks of Aging: An Expanding Universe,” Cell 186, no. 1 (January 19, 2023): 243–78, https://doi.org/10.1016/j.cell.2022.11.001.
3. Destroying the Master Controller
Today we know that our genes: Two very readable accounts of the history of genetics can be found in Matthew Cobb, Life’s Greatest Secret: The Race to Crack the Genetic Code (London: Profile Books, 2015), and Siddhartha Mukherjee, The Gene: An Intimate History (New York: Scribner, 2017).
How instructions in mRNA are read: The decade-long effort to crack the genetic code and understand how proteins are made is described in Cobb, Life’s Greatest Secret.
I have spent much of my life: Venki Ramakrishnan, Gene Machine: The Race to Decipher the Secrets of the Ribosome (London: Oneworld, 2018).
As early as the eighteenth century: H. W. Herr, “Percivall Pott, the Environment and Cancer,” BJU International 108, no. 4 (August 2011): 479–81, https://doi.org/10.1111/j.1464-410x.2011.10487.x.
Hermann Muller was a third-generation American who grew up in New York City: G. Pontecorvo, “Hermann Joseph Muller, 1890–1967,” Biographical Memoirs of Fellows of the Royal Society 14 (November 1968): 348–89, https://doi.org/10.1098/rsbm.1968.0015; Elof Axel Carlson, Hermann Joseph Muller 1890–1967: A Biographical Memoir (Washington, DC: National Academy of Sciences, 2009), available at http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/muller-hermann.pdf.
Even a modest application: Errol Friedberg, chap. 1, “In the Beginning,” in Correcting the Blueprint of Life: An Historical Account of the Discovery of DNA Repair Mechanisms (Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 1997).
One of Crew’s key collaborators: Geoffrey Beale, “Charlotte Auerbach, 14 May 1899–1917 March 1994,” Biographical Memoirs of Fellows of the Royal Society 41 (November 1995): 20–42, https://doi.org/10.1098/rsbm.1995.0002
Sunlight could kill bacteria: A. Downes and T. P. Blunt, “The Influence of Light upon the Development of Bacteria,” Nature, 16 (July 12, 1877), 218, https://doi.org/10.1038/016218a0; F. L. Gates, “A Study of the Bactericidal Action of Ultraviolet Light,” Journal of General Physicology, 14, No. 1 (September 20, 1930): 31–42, https://doi.org/10.1085/jgp.14.1.31.
However, when they tried this: R. B. Setlow and J. K. Setlow, “Evidence That Ultraviolet-Induced Thymine Dimers in DNA Cause Biological Damage,” Proceedings of the National Academy of Sciences (PNAS) of the United States of America 48, no. 7 (July 1, 1962): 1250–57, https://doi.org/10.1073/pnas.48.7.1250.
Dick and his colleagues found: R. B. Setlow, P. A. Swenson, and W. L. Carrier, “Thymine Dimers and Inhibition of DNA Synthesis by Ultraviolet Irradiation of Cells,” Science 142, no. 3698 (December 13, 1963): 1464–66, https://doi.org/10.1126/science.142.3598.1464; R. B. Setlow and W. L. Carrier, “The Disappearance of Thymine Dimers from DNA: An Error-Correcting Mechanism, Proceedings of the National Academy of Sciences (PNAS) of the United States of America 51, no. 2 (April 1964): 226–31, https://doi.org/10.1073/pnas.51.2.226.
The same year: R. P. Boyce and P. Howard-Flanders, “Release of Ultraviolet Light-Induced Thymine Dimers from DNA in E. coli K-12,” Proceedings of the National Academy of Sciences (PNAS) of the United States of America 51, no. 2 (February 1, 1964): 293–300, https://doi.org/10.1073/pnas.51.2.293; D. Pettijohn and P. Hanawalt, “Evidence for Repair-Replication of Ultraviolet Damaged DNA in Bacteria,” Journal of Molecular Biology 9, no. 2 (August 1964): 395–410, https://doi.org/10.1016/s0022-2836(64)80216-3.
How it worked was something of a mystery: Aziz Sancar, “Mechanisms of DNA Repair by Photolyase and Excision Nuclease (Nobel Lecture, December 8, 2015), available at https://www.nobelprize.org/uploads/2018/06/sancar-lecture.pdf.
That is a very long time: A great account of Thomas Lindahl’s discoveries can be found in his “The Intrinsic Fragility of DNA” (Nobel Lecture, December 8, 2015), available at https://www.nobelprize.org/uploads/2018/06/lindahl-lecture.pdf.
Lindahl estimated later: Tomas Lindahl, “Instability and Decay of the Primary Structure of DNA,” Nature 362, no. 6422 (April 22, 1993): 709–715.
Not surprisingly, the cell: Paul Modrich, “Mechanisms in E. coli and Human Mismatch Repair” (Nobel Lecture, December 8, 2015, https://www.nobelprize.org/uploads/2018/06/modrich-lecture.pdf).
The prize also cannot be given: As is increasingly the case because of the limitation of the Nobel Prize to three people, the prize for DNA repair was not without its controversy: David Kroll, “This Year’s Nobel Prize in Chemistry Sparks Questions About How Winners Are Selected,” Chemical & Engineering News (C&EN) online, last modified November 11, 2015, https://cen.acs.org/articles/93/i45/Years-Nobel-Prize-Chemistry-Sparks.html.
One condition he has focused on: B. Schumacher et al., “The Central Role of DNA Damage in the Ageing Process,” Nature 592, no. 7856 (April 2021): 695–703, https://doi.org/10.1038/s41586-021-03307-7.
In females, defects in how the cell: K. T. Zondervan, “Genomic Analysis Identifies Variants That Can Predict the Timing of Menopause,” Nature 596, no. 7872 (August 2021): 345–46, https://doi.org/10.1038/d41586-021-01710-8; K. S. Ruth et al., “Genetic Insights into Biological Mechanisms Governing Human Ovarian Ageing,” Nature 596, no. 7872 (August 2021): 393–97, https://doi.org/10.1038/s41586-021-03779-7. See also the commentary by H. Ledford, “Genetic Variations Could One Day Help Predict Timing of Menopause,” Nature online, last modified August 4, 2021, https://doi.org/10.1038/d41586-021-02128-y.
Sometimes the cell: Apoptosis, or programmed cell death, is also a feature of normal development, as specific cells die at precise points during the development of an organism from a single cell into the adult animal. This was first discovered by studying how the worm C. elegans develops from a single fertilized egg into an adult of almost a thousand cells, and resulted in the award of the 2002 Nobel Prize to Sydney Brenner, John Sulston, and Robert Horvitz.
When the damage is too extensive: A. J. Levine and G. Lozano, eds., The P53 Protein: From Cell Regulation to Cancer, Cold Spring Harbor Perspectives in Medicine (Cold Spring Harbor, NY: Cold Spring Harbor Laboratory, 2016).
Humans inherit one copy: L. M. Abegglen et al., “Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans,” Journal of the American Medical Association (JAMA) 314, no. 17 (November 3, 2015): 1850–60, https://doi.org/10.1001/jama.2015.13134; M. Sulak et al., “TP53 Copy Number Expansion Is Associated with the Evolution of Increased Body Size and an Enhanced TP Damage Response in Elephants,” eLife 5 (2016): e11994, https://doi.org/10.7554/eLife.11994.
Curiously, in studies: M. Shaposhnikov et al., “Lifespan and Stress Resistance in Drosophila with Overexpressed DNA Repair Genes,” Scientific Reports 5 (October 19, 2015): art. 15299, https://doi.org/10.1038/srep15299.
Some of the long-lived species: D. Tejada-Martinez, J. P. de Magalhães, and J. C. Opazo, “Positive Selection and Gene Duplications in Tumour Suppressor Genes Reveal Clues About How Cetaceans Resist Cancer,” Proceedings of the Royal Society B (Biological Sciences) 288, no. 1945 (February 24, 2021): art. 20202592, https://doi.org/10.1098/rspb.2020.2592; V. Quesada et al., “Giant Tortoise Genomes Provide Insights into Longevity and Age-Related Disease,” Nature Ecology & Evolution 3 (January 2019): 87–95, https://doi.org/10.1038/s41559-018-0733-x.
Humans and naked mole rats: S. L. MacRae et al., “DNA Repair in Species with Extreme Lifespan Differences,” Aging 7, no. 12 (December 2015): 1171–84, https://doi.org/10.18632/aging.100866.
Paradoxically, many new cancer therapies: See, for example, Liam Drew, “PARP Inhibitors: Halting Cancer by Halting DNA Repair,” Cancer Research UK online, last modified September 24, 2020, https://news.cancerresearchuk.org/2020/09/24/parp-inhibitors-halting-cancer-by-halting-dna-repair/.
4. The Problem with Ends
“Perhaps the day”: Scientific American, July 1921, quoted in Mark Fischetti, comp., “1921: Immortality for Humans,” Scientific American online, July 2021, 79, https://robinsonlab.cellbio.jhmi.edu/wp-content/uploads/2021/06/SciAm_2021_07.pdf.
They were not immortal: An engaging history of Hayflick’s discovery and its aftermath is J. W. Shay and W. E. Wright, “Hayflick, His Limit, and Cellular Ageing,” Nature Reviews Molecular Cell Biology 1, no. 1 (October 2000): 72–76, https://doi.org/10.1038/35036093.
It has since become a classic: L. Hayflick and P. S. Moorhead, “The Serial Cultivation of Human Diploid Cell Strains,” Experimental Cell Research 25, no. 3 (December 1961): 585–621, https://doi.org/10.1016/0014-4827(61)90192-6.
Some have even suggested: J. Witkowski, “The Myth of Cell Immortality,” Trends in Biochemical Sciences 10, no. 7 (July 1985): 258–60, https://doi.org/10.1016/0968-0004(85)90076-3.
Given Carrel’s stature: John J. Conley, “The Strange Case of Alexis Carrel, Eugenicist,” in Life and Learning XXIII and XXIV: Proceedings of the Twenty-third (2013) and Twenty-fourth Conferences of the University Faculty for Life Conference at Marquette University, Milwaukee, Wisconsin, vol. 26, ed. Joseph W. Koterski (Milwaukee: University Faculty for Life), 281–88, https://www.uffl.org/pdfs/vol23/UFL_2013_Conley.pdf.
Titia de Lange: Titia de Lange, conversation with the author, September 10, 2021.
He realized that the train: This so-called end replication problem was first pointed out by J. D. Watson, “Origin of Concatemeric T7 DNA,” Nature New Biology 239, no. 94 (October 18, 1972): 197–201, https://doi.org/10.1038/newbio239197a0, and A. M. Olovnikov, “Telomeres, Telomerase, and Aging: Origin of the Theory,” Experimental Gerontology 31, no. 4 (July/August 1996): 443–48, https://www.sciencedirect.com/science/article/abs/pii/0531556596000058. For a good description of how it would work, see M. M. Cox, J. Doudna, and M. O’Donnell, Molecular Biology: Principles and Practice (New York: W. H. Freeman, 2012), 398–400. The Wikipedia page “DNA Replication,” last modified June 14, 2023, https://en.wikipedia.org/wiki/DNA_replication, is also quite informative.
At some point, she discovered: For a long time, McClintock was not believed, but these so-called transposable elements turned out to be a fundamental part of biology, and she was awarded the Nobel Prize for her work in 1983 at the age of eighty-one.
TTGGGG: E. H. Blackburn and J. G. Gall, “A Tandemly Repeated Sequence at the Termini of the Extrachromosomal Ribosomal RNA Genes in Tetrahymena,” Journal of Molecular Biology 120, no. 1 (March 25, 1978): 33–53, https://doi.org/10.1016/0022-2836(78)90294-2.
It worked like a charm: J. W. Szostak and E. H. Blackburn, “Cloning Yeast Telomeres on Linear Plasmid Vectors,” Cell 29, no. 1 (May 1982): 245–55, https://doi.org/10.1016/0092-8674(82)90109-x.
The two of them discovered an enzyme: C. W. Greider and E. H. Blackburn, “Identification of a Specific Telomere Terminal Transferase Activity in Tetrahymena Extracts,” Cell 43, no. 2, pt. 1 (November 1985): 405–13, https://doi.org/10.1016/0092-8674(85)90170-9; C. W. Greider and E. H. Blackburn, “The Telomere Terminal Transferase of Tetrahymena Is a Ribonucleoprotein Enzyme with Two Kinds of Primer Specificity,” Cell 51, no. 6 (December 24, 1987): 887–98, https://doi.org/10.1016/0092-8674(87)90576-9; C. W. Greider and E. H. Blackburn, “A Telomeric Sequence in the RNA of Tetrahymena Telomerase Required for Telomere Repeat Synthesis,” Nature 337, no. 6205 (January 26, 1989): 331–37, https://doi.org/10.1038/337331a0.
Without telomerase: C. B. Harley, A. B. Futcher, and C. W. Greider, “Telomeres Shorten During Ageing of Human Fibroblasts,” Nature 345, no. 5274 (May 31, 1990): 458–60, https://doi.org/10.1038/345458a0.
Even introducing telomerase: A. G. Bodnar et al., “Extension of Life-span by Introduction of Telomerase into Normal Human Cells,” Science 279, no. 5349 (January 16, 1998): 349–52, https://doi.org/10.1126/science.279.5349.349.
It turns out that the telomeric ends: The strand that extends beyond the other is called a 3’ overhang, so the reason for the loss of the ends is not exactly the reason first proposed by Olovnikov and Watson. Aficionados can look at J. Lingner, J. P. Cooper, and T. R. Cech, “Telomerase and DNA End Replication: No Longer a Lagging Strand Problem,” Science 269, no. 5230 (September 15, 1995): 1533–34, https://doi.org/10.1126/science.7545310.
This longer strand: T. de Lange, “Shelterin: The Protein Complex That Shapes and Safeguards Human Telomeres,” Genes & Development 19, no. 18 (September 15, 2005): 2100–10, https://doi.org/10.1101/gad.1346005; I. Schmutz and T. de Lange, “Shelterin,” Current Biology 26, no. 10 (May 23, 2016): R397–99, https://doi.org/10.1016/j.cub.2016.01.056.
This crucial structure is why the cell: W. Palm and T. de Lange, “How Shelterin Protects Mammalian Telomeres,” Annual Review of Genetics 42 (2008): 301–34, https://doi.org/10.1146/annurev.genet.41.110306.130350; P. Martínez and M. A. Blasco, “Role of Shelterin in Cancer and Aging,” Aging Cell 9, no. 5 (October 2010): 653–66, https://doi.org/10.1111/j.1474-9726.2010.00596.x.
The cell then sees: F. d’Adda di Fagagna et al. “A DNA Damage Checkpoint Response in Telomere-Initiated Senescence,” Nature 426, no. 6963 (November 13, 2003): 194–98, https://doi.org/10.1038/nature02118.
People with defective telomerase: M. Armanios and E. H. Blackburn, “The Telomere Syndromes,” Nature Reviews Genetics 13, no. 10 (October 2012): 693–704, https://doi.org/10.1038/nrg3246.
When we are stressed: E. S. Epel et al., “Accelerated Telomere Shortening in Response to Life Stress,” Proceedings of the National Academy of Sciences (PNAS) of the United States of America 101, no. 49 (December 1, 2004): 17312–15, https://doi.org/10.1073/pnas.0407162101; J. Choi, S. R. Fauce, and R. B. Effros, “Reduced Telomerase Activity in Human T Lymphocytes Exposed to Cortisol,” Brain, Behavior, and Immunity 22, no. 4 (May 2008): 600–605, https://doi.org/10.1016/j.bbi.2007.12.004. See also the following on stress and premature gray hair in mice: B. Zhang et al., “Hyperactivation of Sympathetic Nerves Drives Depletion of Melanocyte Stem Cells,” Nature 577, no. 792 (January 2020): 676–81, https://doi.org/10.1038/s41586-020-1935-3.
So it may be that the shortening: M. Jaskelioff et al. “Telomerase Reactivation Reverses Tissue Degeneration in Aged Telomerase-Deficient Mice,” Nature 469, no. 7328 (January 6, 2001): 102–6 (2011), https://doi.org/10.1038/nature09603.
According to a number of studies, mice engineered: M. A. Muñoz-Lorente, A. C. Cano-Martin, and M. A. Blasco, “Mice with Hyper-long Telomeres Show Less Metabolic Aging and Longer Lifespans,” Nature Communications 10, no. 1 (October 17, 2019): 4723, https://doi.org/10.1038/s41467-019-12664-x.
There seems to be a delicate balance: Titia de Lange, conversations with and email messages to the author, November and December 2021. See also Jalees Rehman, “Aging: Too Much Telomerase Can Be as Bad as Too Little,” Guest Blog, Scientific American online, last modified July 5, 2014, ttps://blogs.scientificamerican.com/guest-blog/aging-too-much-telomerase-can-be-as-bad-as-too-little/.
On the other hand, those with long telomeres: E. J. McNally, P. J. Luncsford, and M. Armanios, “Long Telomeres and Cancer Risk: The Price of Cellular Immortality,” Journal of Clinical Investigation 129, no. 9 (August 5, 2019): 3474–81, https://doi.org/10.1172/JCI120851.
5. Resetting the Biological Clock
“another great Anglo-American partnership”: The official text of the statement on the publication of the draft human genome sequence by the White House and the UK government is here: National Human Genome Research Institute online, “June 2000 White House Event,” news release, June 26, 2000, https://www.genome.gov/10001356/june-2000-white-house-event. A slightly different text was reported by the New York Times: “Text of the White House Statements on the Human Genome Project,” Science, New York Times online, June 27, 2000, https://archive.nytimes.com/www.nytimes.com/library/national/science/062700sci-genome-text.html. The sequence itself was described in two large, coordinated publications: the public consortium was published as International Human Genome Sequencing Consortium et al., “Initial Sequencing and Analysis of the Human Genome,” Nature 409, no. 6822 (February 15, 2001): 860–921, https://doi.org/10.1038/35057062, while the private Celera effort was published as J. C. Venter et al., “The Sequence of the Human Genome,” Science 291, 1304–51, https://doi.org/10.1126/science.1058040.
“Along with Bach’s music”: Quoted in G. Yamey, “Scientists Unveil First Draft of Human Genome,” BMJ 321, no. 7252 (July 1, 2000): 7, https://doi.org/10.1136/bmj.321.7252.7.
Venter was something: “Profile: Craig Venter,” BBC News online, last modified May 21, 2010, https://www.bbc.co.uk/news/10138849.
The decision by NIH: “US Patent Application Stirs Up Gene Hunters,” Nature, 353 (October 10, 1991): 485–86 (1991), https://doi.org/10.1038/353485a0; N. D. Zinder, “Patenting cDNA 1993: Efforts and Happenings” (abstract), Gene 135, nos. 1/2 (December 1993): 295–98, https://www.sciencedirect.com/science/article/abs/pii/037811199390080M.
Venter said later that he was always against them: Matthew Herper, “Craig Venter Mapped the Genome. Now He’s Trying to Decode Death,” Forbes (online), February 21, 2017, https://www.forbes.com/sites/matthewherper/2017/02/21/can-craig-venter-cheat-death/?sh=8f6fefa16456.
A particularly passionate advocate: John Sulston and Georgina Ferry, The Common Thread: A Story of Science, Politics, Ethics, and the Human Genome (New York: Random House, 2002).
In the run-up: “How Diplomacy Helped to End the Race to Sequence the Human Genome,” Nature 582, no. 7813 (June 2020): 460, https://doi.org/10.1038/d41586-020-01849-w.
The sequence was declared finished: S. Reardon, “A Complete Human Genome Sequence Is Close: How Scientists Filled in the Gaps,” Nature 594, no. 7862 (June 2021): 158–59, https://doi.org/10.1038/d41586-021-01506-w.
The study of this change: Nessa Carey’s The Epigenetics Revolution: How Modern Biology Is Rewriting Our Understanding of Genetics, Disease, and Inheritance (New York: Columbia University Press, 2012) is a great popular introduction to epigenetics. Mukherjee’s The Gene is more broadly about the nature of the gene but has a significant emphasis on epigenetics.
They are too far down: R. Briggs and T. J. King, “Transplantation of Living Nuclei from Blastula Cells into Enucleated Frogs’ Eggs,” Proceedings of the National Academy of Sciences (PNAS) of the United States of America 38, no. 5 (May 1952): 455–63, https://doi.org/10.1073/pnas.38.5.455.
He studied languages instead: “Sir John B. Gurdon: Biographical,” Nobel Prize online, accessed August 7, 2023, https://www.nobelprize.org/prizes/medicine/2012/gurdon/biographical/.
The clawed frog became: J. B. Gurdon and N. Hopwood, “The Introduction of Xenopus Laevis into Developmental Biology: Of Empire, Pregnancy Testing and Ribosomal Genes,” International Journal of Developmental Biology 44, no. 1 (2000): 43–50.
This was the first time: J. B. Gurdon, “The Developmental Capacity of Nuclei Taken from Intestinal Epithelium Cells of Feeding Tadpoles,” Development 10, no. 4 (December 1, 1962): 622–40, https://doi.org/10.1242/dev.10.4.622.
Eventually other researchers reproduced: I. Wilmut et al., “Viable Offspring Derived from Fetal and Adult Mammalian Cells,” Nature 385, no. 6619 (February 27, 1997): 810–13, https://doi.org/10.1038/385810a0.
Being able to grow ES cells: M. J. Evans and M. H. Kaufman, “Establishment in Culture of Pluripotential Cells from Mouse Embryos,” Nature 292, no. 5819 (July 9, 1981): 154–56, https://doi.org/10.1038/292154a0; G. R. Martin, “Isolation of a Pluripotent Cell Line from Early Mouse Embryos Cultured in Medium Conditioned by Teratocarcinoma Stem Cells,” Proceedings of the National Academy of Sciences (PNAS) of the United States of America 78, no. 12 (December 1, 1981): 7634–38, https://doi.org/10.1073/pnas.78.12.7634.
One of the first and simplest: The lac operator and repressor system was discovered in the 1960s by Jacques Monod and Francois Jacob, and its history, along with another genetic switch in a bacteriophage by Andre Lwoff, resulted in the Nobel Prize in 1965. For an insightful history, see M. Lewis, “A Tale of Two Repressors,” Journal of Molecular Biology 409, no. 1 (May 27, 2011): 14–27, https://doi.org/10.1016/j.jmb.2011.02.023.
You might expect that when cells divide: The British geneticist Adrian Bird showed that the methylation occurs mainly on islands with CG repeats. Because C pairs with a G, if you have a CpG island, the C and G on each strand will be directly across from a G and C on the opposite strand. Each C will then be diagonally across from the C on the other strand. When cells methylate a CpG island, they methylate the Cs on both strands. As soon as the cell divides, you have two molecules of DNA instead of one. Each of them has an original strand where the C is methylated, and a newly made strand in which it isn’t. There are special methyltransferase enzymes that will add a methyl group to a C only if the C diagonally across from it on the other strand already has one. This ensures that both strands end up methylated exactly in the same places they were before.
It is a striking example: E. W. Tobi et al., “DNA Methylation as a Mediator of the Association Between Prenatal Adversity and Risk Factors for Metabolic Disease in Adulthood,” Science Advances 4, no. 1 (January 31, 2018): eaao4364, https://doi.org/10.1126/sciadv.aao4364; described in Carl Zimmer, “The Famine Ended 70 Years Ago, But Dutch Genes Still Bear Scars,” New York Times online, January 31, 2018, https://www.nytimes.com/2018/01/31/science/dutch-famine-genes.html. See also Mukherjee, The Gene, and Carey, The Epigenetics Revolution.
When they looked at the methylation: For an expert popular account of Steve Horvath and epigenetic clocks, see Ingrid Wickelgren, “Epigenetic ‘Clocks’ Predict Animals’ True Biological Age,” Quanta, last modified August 17, 2022, https://www.quantamagazine.org/epigenetic-clocks-predict-animals-true-biological-age-20220817/. Some of the background on Horvath is taken from this article.
He was able to identify 513 sites: M. E. Levine et al., “An Epigenetic Biomarker of Aging for Lifespan and Healthspan,” Aging 10, no. 4 (April 2018): 573–91, https://doi.org/10.18632/aging.101414.
Methylation patterns are like a biological clock: S. Horvath and K. Raj, “DNA Methylation-Based Biomarkers and the Epigenetic Clock Theory of Ageing,” Nature Reviews Genetics 19, no. 6 (June 2018): 371–84, https://doi.org/10.1038/s41576-018-0004-3.
Many other research groups developed: For an example, see G. Hannum et al., “Genome-wide Methylation Profiles Reveal Quantitative Views of Human Aging Rates,” Molecular Cell 49, no. 2 (January 24, 2013): 359–67, https://doi.org/10.1016/j.molcel.2012.10.016.
In fact, its methylation pattern: C. Kerepesi et al., “Epigenetic Clocks Reveal a Rejuvenation Event During Embryogenesis Followed by Aging,” Science Advances 7, no. 26 (June 25, 2021): eabg6082, https://doi.org/10.1126/sciadv.abg6082; C. Kerepesi et al., “Epigenetic Aging of the Demographically Non-Aging Naked Mole-Rat,” Nature Communications 13, no. 1 (January 17, 2022): 355, https://doi.org/10.1038/s41467-022-27959-9.
Something about her diet: R. Kucharski et al., “Nutritional Control of Reproductive Status in Honeybees Via DNA Methylation,” Science 319, no. 5871 (March 28, 2008): 1827–30, https://doi.org/10.1126/science.1153069; M. Wojciechowski et al., “Phenotypically Distinct Female Castes in Honey Bees Are Defined by Alternative Chromatin States During Larval Development,” Genome Research 28, no. 10 (October 2018): 1532–42, https://doi.org/10.1101/gr.236497.118.
The first is that germ-line cells: L. Moore et al., “The Mutational Landscape of Human Somatic and Germline Cells,” Nature 597, no. 7876 (September 2021): 381–86, https://doi.org/10.1038/s41586-021-03822-7.
And even within an embryo that is developing normally overall: A recent example is A. Lima et al., “Cell Competition Acts as a Purifying Selection to Eliminate Cells with Mitochondrial Defects During Early Mouse Development,” Nature Metabolism 3, no. 8 (August 2021): 1091–108, https://doi.org/10.1038/s42255-021-00422-7, but there are many ways in which the body rejects defective embryos from developing to term.
This is because the pronuclei: Azim Surani, the scientist in Cambridge who first showed that a fertilized egg needed nuclei from both paternal and maternal germ-line cells to develop normally into a new animal, first suggested the idea of random, environmentally induced, and possibly deleterious epigenetic changes in our genome, which he called “epimutations.” Interview with the author, February 10, 2022.
There were also the lesser-known: Joanna Klein, “Dolly the Sheep’s Fellow Clones, Enjoying Their Golden Years,” New York Times online, July 26, 2016, https://www.nytimes.com/2016/07/27/science/dolly-the-sheep-clones.html, reports on K. D. Sinclair et al., “Healthy Ageing of Cloned Sheep,” Nature Communications 7 (July 26, 2016): 12359, https://doi.org/10.1038/ncomms12359. An extensive analysis of cloned animals in 2017 showed no systematically lower life span or other problems, suggesting that at least some cloned animals live just as long and healthy lives as naturally conceived ones: J. P. Burgstaller and G. Brem, “Aging of Cloned Animals: A Mini-Review,” Gerontology 63, no. 5 (August 2017): 417–25, https://doi.org/10.1159/000452444.
This route to rejuvenating: T. A. Rando and H. Y. Chang, “Aging, Rejuvenation, and Epigenetic Reprogramming: Resetting the Aging Clock,” Cell 148, no. 1/2 (January 20, 2012): 46–57, https://doi.org/10.1016/j.cell.2012.01.003; J. M. Freije and C. López-Otín, “Reprogramming Aging and Progeria,” Current Opinion in Cell Biology 24, no. 6 (December 2012): 757–64, https://doi.org/10.1016/j.ceb.2012.08.009.
6. Recycling the Garbage
Today more than fifty million people: “Dementia,” World Health Organization online, last modified March 15, 2023, https://www.who.int/news-room/fact-sheets/detail/dementia.
In England and Wales: “Dementia Now Leading Cause of Death,” BBC News online, last modified November 14, 2016, https://www.bbc.co.uk/news/health-37972141.
It is estimated: “One-Third of British People Born in 2015 ‘Will Develop Dementia,’” Guardian (US edition) online, last modified September 21, 2015, https://www.theguardian.com/society/2015/sep/21/one-third-of-people-born-in-2015-will-develop-dementia.
Over half of those with dementia: A very engaging and moving book on Alzheimer’s disease is Joseph Jebelli, In Pursuit of Memory: The Fight Against Alzheimer’s (London: John Murray, 2017). The author grew up with a grandfather who suffered from the disease.
There are many ways that the folding process: R. J. Ellis, “Assembly Chaperones: A Perspective,” Philosophical Transactions of the Royal Society of London, Series B, Biological Sciences 368, no. 1617 (March 25, 2013): 20110398, https://doi.org/10.1098/rstb.2011.0398.
But as we age: M. Fournet, F. Bonté, and A. Desmoulière, “Glycation Damage: A Possible Hub for Major Pathophysiological Disorders and Aging,” Aging and Disease 9, no. 5 (October 2018): 880–900, https://doi.org/10.14336/AD.2017.1121.
Cells have an elaborate sensor: For an accessible description of the unfolded protein response, see Evelyn Strauss, “Unfolded Protein Response: 2014 Albert Lasker Basic Medical Research Award,” Lasker Foundation online, accessed July 7, 2023, https://laskerfoundation.org/winners/unfolded-protein-response/#achievement. How exactly the sensor detects that there are too many unfolded proteins is still not entirely clear. I spoke with Dr. David Ron, a scientist at England’s Cambridge Institute for Medical Research, and one of the leaders in this area. One idea is that some chaperones—the proteins that help proteins to fold—are normally abundant and can bind to the sensors, which are then kept in a quiescent state. When the number of unfolded proteins increases, these chaperones are called to action, and they release the sensors, which then go on to trigger the unfolded protein response. S. Preissler and D. Ron, “Early Events in the Endoplasmic Reticulum Unfolded Protein Response,” Cold Spring Harbor Perspectives in Biology 11, no. 4 (April 1, 2019): a033894, https://doi.org/10.1101/cshperspect.a033894.
In extreme cases: A. Fribley, K. Zhang, and R. J. Kaufman, “Regulation of Apoptosis by the Unfolded Protein Response,” in Apoptosis: Methods and Protocols, ed. P. Erhardt and A. Toth (Totowa, NJ: Humana Press, 2009), 191–204, https://doi.org/10.1007/978-1-60327-017-5_14.
Eventually researchers discovered: K. D. Wilkinson, “The Discovery of Ubiquitin-Dependent Proteolysis,” Proceedings of the National Academy of Sciences (PNAS) of the United States of America 102, no. 43 (October 17, 2005): 15280–82, https://doi.org/10.1073/pnas.0504842102. There is a popular account of the discovery of the proteasome and the award of the Nobel Prize to Avram Hershko, Aaron Ciechanover, and Irwin Rose in “Popular Information: The Nobel Prize in Chemistry 2004,” Nobel Prize online, accessed July 4, 2023, https://www.nobelprize.org/prizes/chemistry/2004/popular-information/.
Deliberately introducing defects: I. Saez and D. Vilchez, “The Mechanistic Links Between Proteasome Activity, Aging and Age-Related Diseases,” Current Genomics 15, no. 1 (February 15, 2014): 38–51, https://doi.org/10.2174/138920291501140306113344.
By isolating strains: K. Takeshig et al., “Autophagy in Yeast Demonstrated with Proteinase-Deficient Mutants and Conditions for Its Induction,” Journal of Cell Biology 119, no. 2 (October 1992): 301–11, https://doi.org/10.1083/jcb.119.2.301; M. Tsukada and Y. Ohsumi, “Isolation and Characterization of Autophagy-Defective Mutants of Saccharomyces cerevisiae,” FEBS Letters 333, nos. 1/2 (October 25, 1993): 169–74, https://doi.org/10.1016/0014-5793(93)80398-e.
It has so many essential functions: For a very reader-friendly description of autophagy, see “The Nobel Prize in Physiology or Medicine 2016: Yoshinori Ohsumi,” press release, Nobel Prize online, October 3, 2016, https://www.nobelprize.org/prizes/medicine/2016/press-release/.
Integrated stress response or ISR: Two reviews of the integrated stress response are Harding, H. P. et al., “An integrated stress response regulates amino acid metabolism and resistance to oxidative stress,” Molecular Cell 11, no. 3 (March 2003): 619–33, https://doi.org/10.1016/s1097-2765(03)00105-9; and Pakos‐Zebrucka, K. et al. “The integrated stress response,” EMBO Reports 17, no.10 (2016): 1374–95, https://doi.org/10.15252/embr.201642195. Its discovery in amino acid starvation is described in Dever, T. E. et al., “Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast,” Cell 68. no. 3 (February 1992): 585–96, https://doi.org/10.1016/0092-8674(92)90193-g and that in the unfolded protein response in Harding, H. P. et al., “PERK is essential for translational regulation and cell survival during the unfolded protein response,” Molecular Cell 5, no. 5 (May 2000): 897-904, https://doi.org/10.1016/s1097-2765(00)80330-5.
If you delete the genes: M. Delépine et al., “EIF2AK3, Encoding Translation Initiation Factor 2-Alpha Kinase 3, Is Mutated in Patients with Wolcott-Rallison Syndrome,” Nature Genetics 25, no. 4 (August 2000): 406–9, https://doi.org/10.1038/78085; H. P. Harding et al., “Diabetes Mellitus and Exocrine Pancreatic Dysfunction in Perk-/- Mice Reveals a Role for Translational Control in Secretory Cell Survival,” Molecular Cell 7, no. 6 (June 2001): 1153–63, https://doi.org/10.1016/s1097-2765(01)00264-7.
They also extend life span: S. J. Marciniak et al., “CHOP Induces Death by Promoting Protein Synthesis and Oxidation in the Stressed Endoplasmic Reticulum,” Genes & Development 18, no. 24 (December 15, 2004): 3066–77, https://doi.org/10.1101/gad.1250704; M. D’Antonio et al., “Resetting Translational Homeostasis Restores Myelination in Charcot-Marie-Tooth Disease Type 1B Mice,” Journal of Experimental Medicine 210, no. 4 (April 8, 2013): 821–38, https://doi.org/10.1084/jem.20122005; P. Tsaytler et al., “Selective Inhibition of a Regulatory Subunit of Protein Phosphatase 1 Restores Proteostasis,” Science 332, no. 6025 (April 1, 2011): 91–94, https://doi.org/10.1126/science.1201396; H. Q. Jiang et al., “Guanabenz Delays the Onset of Disease Symptoms, Extends Lifespan, Improves Motor Performance and Attenuates Motor Neuron Loss in the SOD1 G93A Mouse Model of Amyotrophic Lateral Sclerosis,” Neuroscience 277 (March 2014): 132–38, https://doi.org/10.1016/j.neuroscience.2014.03.047; I. Das et al., “Preventing Proteostasis Diseases by Selective Inhibition of a Phosphatase Regulatory Subunit,” Science 348, no. 6231 (April 10, 2015): 239–42, https://doi.org/10.1126/science.aaa4484.
whether they even affected ISR directly: A. Crespillo-Casado et al., “PPP1R15A-Mediated Dephosphorylation of eIF2α Is Unaffected by Sephin1 or Guanabenz,” eLife 6 (April 27, 2017): e26109, https://doi.org/10.7554/eLife.26109.
According to their studies, deleting the genes: T. Ma et al., “Suppression of eIF2α Kinases Alleviates Alzheimer’s Disease–Related Plasticity and Memory Deficits,” Nature Neuroscience 16, no. 9 (September 2013): 1299–305, https://doi.org/10.1038/nn.3486.
Even more surprisingly: Adam Piore, “The Miracle Molecule That Could Treat Brain Injuries and Boost Your Fading Memory,” MIT Technology Review 124, no. 5 (September/October 2021): https://www.technologyreview.com/2021/08/25/1031783/isrib-molecule-treat-brain-injuries-memory/; C. Sidrauski et al., “Pharmacological Brake-Release of mRNA Translation Enhances Cognitive Memory,” eLife 2 (2013): e00498,https://doi.org/10.7554/eLife.00498; C. Sidrauski et al., “The Small Molecule ISRIB Reverses the Effects of Eif2α Phosphorylation on Translation and Stress Granule Assembly,” eLife 4 (2015): e05033, https://doi.org/10.7554/eLife.05033; A. Chou et al., “Inhibition of the Integrated Stress Response Reverses Cognitive Deficits After Traumatic Brain Injury,” Proceedings of the National Academy of Sciences (PNAS) of the United States of America 114, no. 31 (July 10, 2017): E6420–E6426, https://doi.org/10.1073/pnas.1707661114.
Nahum Sonenberg: Nahum Sonenberg, email message to the author, January 12, 2023.
The key person: D. M. Asher with M. A. Oldstone, Carleton Gajdusek, 1923–2008: Biographical Memoirs (Washington, DC: US National Academy of Sciences, 2013), http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/gajdusek-d-carleton.pdf; Caroline Richmond, “Obituary: Carleton Gajdusek,” Guardian (US edition) online, last modified February 25, 2009, https://www.theguardian.com/science/2009/feb/25/carleton-gajdusek-obituary.
On the strength of this: Frank Macfarlane Burnet studied how the immune system distinguishes between our own cells and foreign invaders and shared the 1960 Nobel Prize with Peter Medawar.
“had an intelligence quotient”: Jay Ingram, Fatal Flaws: How a Misfolded Protein Baffled Scientists and Changed the Way We Look at the Brain (New Haven, CT: Yale University Press, 2013), as quoted in M. Goedert, “M. Prions and the Like,” Brain 137, no. 1 (January 2014): 301–5, https://doi.org/10.1093/brain/awt179. See also J. Farquhar and D. C. Gajdusek, eds., Early Letters and Field-Notes from the Collection of D. Carleton Gajdusek (New York: Raven Press, 1981).
This was a recent practice among the Fore: J. Goodfield, “Cannibalism and Kuru,” Nature 387 (June 26, 1997): 841, https://doi.org/10.1038/43043; R. Rhodes, “Gourmet Cannibalism in New Guinea Tribe,” Nature 389 (September 4, 1997): 11, https://doi.org/10.1038/37853.
He showed no remorse: Ivin Molotsky, “Nobel Scientist Pleads Guilty to Abusing Boy,” New York Times online, February 19, 1997, https://www.nytimes.com/1997/02/19/us/nobel-scientist-pleads -guilty-to-abusing-boy.html. Two articles shed light on the sociology of Gajdusek’s extended family: C. Spark, “Family Man: The Papua New Guinean Children of D. Carleton Gajdusek,” Oceania 77, no. 3 (November 2007): 355–69, and C. Spark, “Carleton’s Kids: The Papua New Guinean Children of D. Carleton Gajdusek,” Journal of Pacific History 44, no. 1 (June 2009): 1–19.
The result is that the misfolded form: S. B. Prusiner, “Prions,” Proceedings of the National Academy of Sciences (PNAS) of the United States of America 95, no. 23 (November 10, 1998): 13363–83, https://doi.org/10.1073/pnas.95.23.13363.
Alzheimer himself autopsied: A good review of the beta-amyloid hypothesis is R. E. Tanzi and L. Bertram, “Twenty Years of the Alzheimer’s Disease Amyloid Hypothesis: A Genetic Perspective,” Cell 120, no. 4 (February 25, 2005): 545–55, https://doi.org/10.1016/j.cell.2005.02.008.
In 1984, scientists identified: G. G. Glenner and C. W. Wong, “Alzheimer’s Disease and Down’s Syndrome: Sharing of a Unique Cerebrovascular Amyloid Fibril Protein,” Biochemical and Biophysical Research Communications 122, no. 3 (August 16, 1984): 1131–35, https://doi.org/10.1016/0006-291x(84)91209-9.
They turn out to have mutations: A. Goate et al., “Segregation of a Missense Mutation in the Amyloid Precursor Protein Gene with Familial Alzheimer’s Disease,” Nature 349, no. 6311 (February 21, 1991): 704–6, https://doi.org/10.1038/349704a0; M. C. Chartier-Harlin et al., “Early-Onset Alzheimer’s Disease Caused by Mutations at Codon 717 of the Beta-amyloid Precursor Protein Gene,” Nature 353, no. 6347 (October 31, 1991): 844–46, https://doi.org/10.1038/353844a0.
Although scientists were skeptical at first: P. Poorkaj et al., “Tau Is a Candidate Gene for Chromosome 17 Frontotemporal Dementia,” Annals of Neurology 43, no. 6 (June 1998): 815–25, https://doi.org/10.1002/ana.410430617; M. Hutton et al., “Association of Missense and 5’-splice-site Mutations in Tau with the Inherited Dementia FTDP-17,” Nature 393, no. 6686 (June 18, 1998): 702–5, https://doi.org/10.1038/31508; M. G. Spillantini et al., “Mutation in the Tau Gene in Familial Multiple System Tauopathy with Presenile Dementia,” Proceedings of the National Academy of Sciences (PNAS) of the United States of America 95, no. 13 (June 23, 1998): 7737–41, https://doi.org/10.1073/pnas.95.13.7737.
Rather, the aberrant: S. H. Scheres et al., “M. Cryo-EM Structures of Tau Filaments,” Current Opinion in Structural Biology 64, 17–25 (2020). https://doi.org/10.1016/j.sbi.2020.05.011; M. Schweighauser et al., “Structures of α-synuclein Filaments from Multiple System Atrophy,” Nature 585, no. 7825 (September 2020): 464–69, https://doi.org/10.1038/s41586-020-2317-6; Y. Yang et al., “Cryo-EM Structures of Amyloid-β 42 Filaments from Human Brains,” Science 375, no. 6577 (January 13, 2022): 167–72, https://doi.org/10.1126/science.abm7285.
We do know that if you delete the genes: H. Zheng et al., “Beta-Amyloid Precursor Protein-Deficient Mice Show Reactive Gliosis and Decreased Locomotor Activity,” Cell 81, no. 4 (May 19, 1995): 525–31, https://doi.org/10.1016/0092-8674(95)90073-x.
There is a growing feeling: M. Goedert, M. Masuda-Suzukake, and B. Falcon, “Like Prions: The Propagation of Aggregated Tau and α-synuclein in Neurodegeneration,” Brain 140, no. 2 (February 2017): 266–78, https://doi.org/10.1093/brain/aww230; A. Aoyagi et al., “Aβ and Tau Prion-like Activities Decline with Longevity in the Alzheimer’s Disease Human Brain,” Science Translational Medicine 11, no. 490 (May 1, 2019): eaat8462, https://doi.org/10.1126/scitranslmed.aat8462; M. Jucker and L. C. Walker, “Self-propagation of Pathogenic Protein Aggregates in Neurodegenerative Diseases,” Nature 501, no. 7465 (September 5, 2013): 45–51, https://doi.org/10.1038/nature12481.
Very recently, therapies: C. H. van Dyck et al., “Lecanemab in Early Alzheimer’s Disease,” New England Journal of Medicine 388, no. 1 (January 5, 2023): 9–21, https://doi.org/10.1056/nejmoa2212948; M. A. Mintun et al, “Donanemab in Early Alzheimer’s Disease,” New England Journal of Medicine 384 (May 6, 2021): 1691–1704, https://doi.org/10.1056/NEJMoa2100708. See also the more recent discussion by S. Reardon, “Alzheimer’s Drug Donanemab: What Promising Trial Means for Treatments,” Nature 617 (May 4, 2023): 232–33, https://doi.org/10.1038/d41586-023-01537-5.
7. Less Is More
Now, in a time of plenty: J. V. Neel, “Diabetes Mellitus: A ‘Thrifty’ Genotype Rendered Detrimental by ‘Progress,’” American Journal of Human Genetics 14, no. 4 (December 1962): 353–62, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1932342/.
“drifty genes”: J. R. Speakman, “Thrifty Genes for Obesity and the Metabolic Syndrome—Time to Call off the Search?,” Diabetes and Vascular Disease Research 3, no. 1 (May 2006): 7–11, https://doi.org/10.3132/dvdr.2006.010; J. R. Speakman, “Evolutionary Perspectives on the Obesity Epidemic: Adaptive, Maladaptive, and Neutral Viewpoints,” Annual Review of Nutrition 33, no. 1 (July 2013): 289–317, https://doi.org/10.1146/annurev-nutr-071811-150711.
The first studies to test this: Two surveys of the field from the mid-2000s are E. J. Masoro, “Overview of Caloric Restriction and Ageing,” Mechanisms of Ageing and Development 126, no. 9 (September 2005): 913–22, https://doi.org/10.1016/j.mad.2005.03.012, and B. K. Kennedy, K. K. Steffen, and M. Kaeberlein, “Ruminations on Dietary Restriction and Aging,” Cellular and Molecular Life Sciences 64, no. 11 (June 2007): 1323–28, doi: 10.1007/s00018-007-6470-y.
Moreover, they appeared to have delayed: R. Weindruch and R. L. Walford, The Retardation of Aging and Disease by Dietary Restriction (Springfield, IL: C. C. Thomas, 1988), as quoted in Kennedy, Steffen, and Kaeberlein, “Ruminations,” 1323–28; L. Fontana and L. Partridge, “Promoting Health and Longevity Through Diet: From Model Organisms to Humans,” Cell 161, no. 1 (March 26, 2015): 106–18, https://doi.org/10.1016/j.cell.2015.02.020.
In 2009: R. J. Colman et al., “Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys,” Science 325, no. 5937 (July 10, 2009): 201–4, https://doi.org/10.1126/science.1173635.
But this was contradicted: J. A. Mattison et al., “Impact of Caloric Restriction on Health and Survival in Rhesus Monkeys from the NIA Study,” Nature 489, no. 7415 (September 13, 2012): 318–21, https://doi.org/10.1038/nature11432. See the accompanying commentary by S. N. Austad, “Aging: Mixed Results for Dieting Monkeys,” Nature 489, no. 7415 (September 13, 2012): 210–11, https://doi.org/10.1038/nature11484, and a related news article in the same journal, A. Maxmen, “Calorie Restriction Falters in the Long Run,” Nature 488, no. 7413 (August 30, 2012), 569, https://doi.org/10.1038/488569a.
Any evidence for the effect of CR: Laura A. Cassiday, “The Curious Case of Caloric Restriction,” Chemical & Engineering News online, last modified August 3, 2009, https://cen.acs.org/articles/87/i31/Curious-Case-Caloric-Restriction.html.
There is 5:2 fasting: Gideon Meyerowitz-Katz, “Intermittent Fasting Is Incredibly Popular. But Is It Any Better Than Other Diets?,” Guardian (US edition) online, last modified January 1, 2020, https://www.theguardian.com/commentisfree/2020/jan/02/intermittent-fasting-is-incredibly-popular-but-is-it-any-better-than-other-diets.
They concluded that matching: V. Acosta-Rodríguez et al., “Circadian Alignment of Early Onset Caloric Restriction Promotes Longevity in Male C57BL/6J Mice,” Science 376, no. 6598 (May 5, 2022): 1192–202, https://doi.org/10.1126/science.abk0297. See the accompanying commentary in S. Deota and S. Panda, “Aligning Mealtimes to Live Longer,” Science 376, no. 6598 (May 5, 2022): 1159–60, https://doi.org/10.1126/science.adc8824.
In particular, sleep deprivation: Matthew Walker, Why We Sleep: The New Science of Sleep and Dreams (New York: Scribner, 2017). See in particular chapter 8 for its effects on aging.
According to a recent study: A. Vaccaro et al., “Sleep Loss Can Cause Death Through Accumulation of Reactive Oxygen Species in the Gut,” Cell 181, no. 6 (June 11, 2020): 1307–28.e15, https://doi.org/10.1016/j.cell.2020.04.049. See also a popular discussion of this in Veronique Greenwood, “Why Sleep Deprivation Kills,” Quanta, last modified June 4, 2020, https://www.quantamagazine.org/why-sleep-deprivation-kills-20200604/, and Steven Strogatz, “Why Do We Die Without Sleep?,” The Joy of Why (podcast, transcription), March 22, 2022, https://www.quantamagazine.org/why-do-we-die-without-sleep-20220322/.
In one study: C.-Y Liao et al., “Genetic Variation in Murine Lifespan Response to Dietary Restriction: From Life Extension to Life Shortening,” Aging Cell 9, no. 1 (February 2010): 92–95, https://doi.org/10.1111/j.1474-9726.2009.00533.x.
He felt that animals: L. Hayflick, “Dietary Restriction: Theory Fails to Satiate,” Science 329, no. 5995 (August 27, 2010): 1014, https://www.science.org/doi/10.1126/science.329.5995.1014; L. Fontana, L. Partridge, and V. Longo, “Dietary Restriction: Theory Fails to Satiate—Response,” Science 329, no. 5995 (August 27, 2010): 1015, https://www.science.org/doi/10.1126/science.329.5995.1015.
Moreover, when scientists: Saima May Sidik, “Dietary Restriction Works in Lab Animals, But It Might Not Work in the Wild,” Scientific American online, last modified December 20, 2022, https://www.scientificamerican.com/article/dietary-restriction-works-in-lab-animals-but-it-might-not-work-in-the-wild/.
Among its other reported downsides: J. R. Speakman and S. E. Mitchell, “Caloric Restriction,” Molecular Aspects of Medicine 32, no. 3 (June 2011): 159–221, https://doi.org/10.1016/j.mam.2011.07.001.
In 1964: For an intriguing history of the discovery of rapamycin, see Bethany Halford, “Rapamycin’s Secrets Unearthed,” Chemical & Engineering News online, last modified July 18, 2016, https://cen.acs.org/articles/94/i29/Rapamycins-Secrets-Unearthed.html, which is the basis for the next few paragraphs. See also David Stipp, “A New Path to Longevity,” Scientific American online, last modified January 1, 2012), https://www.scientificamerican.com/article/a-new-path-to-longevity/.
Here our story shifts to Basel, Switzerland: U. S. Neill, “A Conversation with Michael Hall,” Journal of Clinical Investigation 127, no. 11 (November 1, 2017): 3916–17, https://doi.org/10.1172/jci97760; C. L. Williams, “Talking TOR: A Conversation with Joe Heitman and Rao Movva,” JCI Insight 3, no. 4 (February 22, 2018): e99816, https://doi.org/10.1172/jci.insight.99816.
How cell size and shape are controlled: M. B. Ginzberg, R. Kafri, and M. Kirschner, “On Being the Right (Cell) Size,” Science 348, no. 6236 (May 15, 2015): 1245075, https://doi.org/10.1126/science.1245075.
His paper was rejected: N. C. Barbet et al., “TOR Controls Translation Initiation and Early G1 Progression in Yeast,” Molecular Biology of the Cell 7, no. 1 (January 1, 1996): 25–42, https://doi.org/10.1091/mbc.7.1.25. For Hall’s recollections about the early days and the difficulty of getting the scientific community to accept that cell growth was actively controlled, see M. N. Hall, “TOR and Paradigm Change: Cell Growth Is Controlled,” Molecular Biology of the Cell 27, no. 18 (September 15, 2016): 2804–6, https://doi.org/10.1091/mbc.E15-05-0311.
We can now see: D. Papadopoli et al., “mTOR as a Central Regulator of Lifespan and Aging,” F1000 Research 8 (July 2, 2019): 998, https://doi.org/10.12688/f1000research.17196.1; G. Y. Liu and D. M. Sabatini, “mTOR at the Nexus of Nutrition, Growth, Ageing and Disease,” Nature Reviews Molecular Biology 21, no. 4 (April 2020): 183–203, https://doi.org/10.1038/s41580-019-0199-y.
It turns out that both a defective TOR: L. Partridge, M. Fuentealba, and B. K. Kennedy, “The Quest to Slow Ageing Through Drug Discovery,” Nature Reviews Drug Discovery 19, no. 8 (August 2020): 513–32, https://doi.org/10.1038/s41573-020-0067-7.
Strikingly, even short courses: D. E. Harrison et al., “Rapamycin Fed Late in Life Extends Lifespan in Genetically Heterogeneous Mice,” Nature 460, no. 7253 (July 16, 2009): 392–95, https://doi.org/10.1038/nature08221; see the accompanying commentary by M. Kaeberlein and R. K. Kennedy, “Ageing: A Midlife Longevity Drug?,” Nature 460, no. 7253 (July 16, 2009): 331–32, https://doi.org/10.1038/460331a.
Rapamycin also delayed: F. M. Menzies and D. C. Rubinsztein, “Broadening the Therapeutic Scope for Rapamycin Treatment,” Autophagy 6, no. 2 (February 2010): 286–87, https://doi.org/10.4161/auto.6.2.11078.
While rapamycin inhibits: K. Araki et al., “mTOR Regulates Memory CD8 T-cell Differentiation,” Nature 460, no. 7251 (July 2, 2009): 108–12, https://doi.org/10.1038/nature08155.
Another study, from 2009, showed that administering rapamycin: C. Chen et al. “mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells,” Science Signaling 2, no. 98 (November 24, 2009): ra75, https://doi.org/10.1126/scisignal.2000559.
As one might expect: A. M. Eiden, “Molecular Pathways: Increased Susceptibility to Infection Is a Complication of mTOR Inhibitor Use in Cancer Therapy,” Clinical Cancer Research 22, no. 2 (January 15, 2016): 277–83, https://doi.org/10.1158/1078-0432.ccr-14-3239.
“warrants caution”: A. J. Pagán et al., “mTOR-Regulated Mitochondrial Metabolism Limits Mycobacterium-Induced Cytotoxicity, Cell 185, no. 20 (September 29, 2022): 3720–38, e13, https://doi.org/10.1016/j.cell.2022.08.018.
The consortium will analyze: K. E. Creevy et al., “An Open Science Study of Ageing in Companion Dogs,” Nature 602, no. 7895 (February 2022): 51–57, https://doi.org/10.1038/s41586-021-04282-9.
They go on to suggest: M. V. Blagosklonny and M. N. Hall, “Growth and Aging: A Common Molecular Mechanism,” Aging 1, no. 4 (April 20, 2009): 357–62, https://doi.org/10.18632/aging.100040.
8. Lessons from a Lowly Worm
A study of 2,700 Danish twins: A. M. Herskind et al., “The Heritability of Human Longevity: A Population-Based Study of 2,872 Danish Twin Pairs Born 1870–1900,” Human Genetics 97, no. 3 (March 1996): 319–23, https://doi.org/10.1007/BF02185763.
Once he and Crick: Their views and plans are outlined in a 1971 report by Francis Crick and Sydney Brenner. See F. H. C. Crick and S. Brenner, Report to the Medical Research Council: On the Work of the Division of Molecular Genetics, Now the Division of Cell Biology, from 1961–1971 (Cambridge, UK: MRC Laboratory of Molecular Biology, November 1971), https://profiles.nlm.nih.gov/spotlight/sc/catalog/nlm:nlmuid-101584582X71-doc.
Scientists went on to identify: For this work, Brenner was awarded the 2002 Nobel Prize in Physiology or Medicine, along with two of his former colleagues, John Sulston and Robert Horvitz. “The Nobel Prize in Physiology or Medicine 2002,” Nobel Prize online, accessed July 22, 2023, https://www.nobelprize.org/prizes/medicine/2002/summary/.
As Hirsh recalled: David Hirsh, email message to the author, August 1, 2022.
Instead, it turned out: D. B. Friedman and T. E. Johnson, “A Mutation in the age-1 Gene in Caenorhabditis elegans Lengthens Life and Reduces Hermaphrodite Fertility,” Genetics 118, no. 1 (January 1, 1988): 75–86, https://doi.org/10.1093/genetics/118.1.75.
Johnson went on to show: T. E. Johnson, “Increased Life-Span of age-1 Mutants in Caenorhabditis elegans and Lower Gompertz Rate of Aging,” Science 249, no. 4971 (August 24, 1990): 908–12, https://doi.org/10.1126/science.2392681.
Even after it finally appeared in the prestigious journal Science in 1990: David Stipp’s book The Youth Pill: Scientists at the Brink of an Anti-Aging Revolution (New York: Penguin, 2010) contains an engaging and detailed account of the history, personalities, and science behind the discovery of aging mutants.
she felt inspired: Two firsthand accounts by Kenyon and Johnson of their discoveries are C. Kenyon, “The First Long-Lived Mutants: Discovery of the Insulin/IGF-1 Pathway for Ageing,” Philosophical Transactions of the Royal Society B: Biological Sciences 366, no. 1561 (January 12, 2001): 9–16, https://doi.org/10.1098/rstb.2010.0276, and T. E. Johnson, “25 Years After age-1: Genes, Interventions and the Revolution in Aging Research,” Experimental Gerontology 48, no. 7 (July 2013): 640–43, https://doi.org/10.1016/j.exger.2013.02.023.
her 1993 paper: C. Kenyon et al., “A C. elegans Mutant That Lives Twice as Long as Wild Type,” Nature 366, no. 6454 (December 2, 1993): 461–64, https://doi.org/10.1038/366461a0.
As it turns out, the age-1 gene originally identified: The key papers for the identity of some of the key genes are (daf-2) K. D. Kimura, H. A. Tissenbaum, and G. Ruvkun, “daf-2, an Insulin Receptor-Like Gene That Regulates Longevity and Diapause in Caenorhabditis elegans,” Science 277, no. 5328 (August 15, 1997): 942–46, https://doi.org/10.1126/science.277.5328.942; (age-1, which turned out to be the same as daf-23), J. Z. Morris, H. A. Tissenbaum, and G. Ruvkun, “A Phosphatidylinositol-3-OH Kinase Family Member Regulating Longevity and Diapause in Caenorhabditis elegans, Nature 382, no. 6591 (August 8, 1996): 536–39, https://doi.org/10.1038/382536a0; (daf-16), S. Ogg et al., “The Fork Head Transcription Factor DAF-16 Transduces Insulin-like Metabolic and Longevity Signals in C. elegans,” Nature 389, no. 6654 (October 30, 1997): 994–99, https://doi.org/10.1038/40194, and K. Lin et al., “daf-16: An HNF-3/Forkhead Family Member That Can Function to Double the Life-Span of Caenorhabditis elegans,” Science 278, no. 5341 (November 14, 1997): 1319–22, https://doi.org/10.1126/science.278.5341.1319.
“constitute a treasure trove”: C. J. Kenyon, “The Genetics of Ageing,” Nature 464, no. 7288 (March 25, 2010): 504–12, https://doi.org/10.1038/nature08980.
Among the many reasons for this: H. Yan et al., “Insulin Signaling in the Long-Lived Reproductive Caste of Ants,” Science 377, no. 6610 (September 1, 2022): 1092–99, https://doi.org/10.1126/science.abm8767.
Deleting the gene that codes for a protein: D. J. Clancy et al., “Extension of Life-span by Loss of CHICO, a Drosophila Insulin Receptor Substrate Protein,” Science 292, no. 5514 (April 6, 2001): 104–6, https://doi.org/10.1126/science.1057991.
The IGF-1 receptor is essential: M. Holzenberger et al., “IGF-1 Receptor Regulates Lifespan and Resistance to Oxidative Stress in Mice,” Nature 421, no. 6919 (January 9, 2003): 182–87, https://doi.org/10.1038/nature01298; G. J. Lithgow and M. S. Gill, “Physiology: Cost-Free Longevity in Mice,” Nature 421, no. 6919 (January 9, 2003): 125–26, https://doi.org/10.1038/421125a.
An analysis of subjects: D. A. Bulger et al., “Caenorhabditis elegans DAF-2 as a Model for Human Insulin Receptoropathies,” G3 Genes|Genomes|Genetics 7, no. 1 (January 1, 2017): 257–68, https://doi.org/10.1534/g3.116.037184.
Mutations known to impair IGF-1: Y. Suh et al., “Functionally Significant Insulin-like Growth Factor I Receptor Mutations in Centenarians,” Proceedings of the National Academy of Sciences (PNAS) of the United States of America 105, no. 9 (March 4, 2008): 3438–42, https://doi.org/10.1073/pnas.0705467105; T. Kojima et al., “Association Analysis Between Longevity in the Japanese Population and Polymorphic Variants of Genes Involved in Insulin and Insulin-like Growth Factor 1 Signaling Pathways,” Experimental Gerontology 39, nos. 11/12 (November/December 2004): 1595–98, https://doi.org/10.1016/j.exger.2004.05.007.
Exactly as you might predict: S. Honjoh et al., “Signalling Through RHEB-1 Mediates Intermittent Fasting-Induced Longevity in C. elegans,” Nature 457, no. 7230 (February 5, 2009): 726–30, https://doi.org/10.1038/nature07583.
This means that caloric restriction: B. Lakowski and S. Hekimi, “The Genetics of Caloric Restriction in Caenorhabditis elegans,” Proceedings of the National Academy of Sciences (PNAS) of the United States of America 95, no. 22 (October 27, 1998): 13091–96, https://doi.org/10.1073/pnas.95.22.13091.
When worms were subjected: D. W. Walker et al., “Evolution of Lifespan in C. elegans,” Nature 405, no. 6784 (May 18, 2000): 296–97, https://doi.org/10.1038/35012693.
Because of recent advances: H. R. Bridges et al., “Structural Basis of Mammalian Respiratory Complex I Inhibition by Medicinal Biguanides,” Science 379, no. 6630 (January 26, 2023): 351–57, https://www.science.org/doi/10.1126/science.ade3332.
Disrupting our ability to utilize glucose: G. Rena, D. G. Hardie, and E. R. Pearson, “The Mechanisms of Action of Metformin,” Diabetologia 60, no. 9 (September 2017): 1577–85, https://doi.org/10.1007/s00125-017-4342-z; T. E. LaMoia and G. I. Shulman, “Cellular and Molecular Mechanisms of Metformin Action,” Endocrine Reviews 42, no. 1 (February 2021): 77–96, https://doi.org/10.1210/endrev/bnaa023.
Although some studies have claimed: L. C. Gormsen et al., “Metformin Increases Endogenous Glucose Production in Non-Diabetic Individuals and Individuals with Recent-Onset Type 2 Diabetes,” Diabetologia 62, no. 7 (July 2019): 1251–56, https://doi.org/10.1007/s00125-019-4872-7.
According to another study, the drug alters: H. Wu et al., “Metformin Alters the Gut Microbiome of Individuals with Treatment-Naive Type 2 Diabetes, Contributing to the Therapeutic Effects of the Drug,” Nature Medicine 23, no. 7 (July 2017): 850–58, https://doi.org/10.1038/nm.4345.
Steve O’Rahilly’s work demonstrates: A. P. Coll et al., “GDF15 Mediates the Effects of Metformin on Body Weight and Energy Balance,” Nature 578, no. 7795 (February 2020): 444–48, https://doi.org/10.1038/s41586-019-1911-y.
A second study, in humans: C. A. Bannister et al., “Can People with Type 2 Diabetes Live Longer Than Those Without? A Comparison of Mortality in People Initiated with Metformin or Sulphonylurea Monotherapy and Matched, Non-Diabetic Controls,” Diabetes, Obesity and Metabolism 16, no. 11 (November 2014): 1165–73, https://doi.org/10.1111/dom.12354.
One, from 2016, concluded that metformin: M. Claesen et al., “Mortality in Individuals Treated with Glucose-Lowering Agents: A Large, Controlled Cohort Study,” Journal of Clinical Endocrinology & Metabolism 101, no. 2 (February 1, 2016): 461–69, https://doi.org/10.1210/jc.2015-3184.
Curiously, some of the toxicity: L. Espada et al., “Loss of Metabolic Plasticity Underlies Metformin Toxicity in Aged Caenorhabditis Elegans,” Nature Metabolism 2, no. 11 (November 2020): 1316–31, https://doi.org/10.1038/s42255-020-00307-1.
Metformin also undermined: A. R. Konopka et al., “Metformin Inhibits Mitochondrial Adaptations to Aerobic Exercise Training in Older Adults,” Aging Cell 18, no. 1 (February 2019): e12880, https://doi.org/10.1111/acel.12880.
And one study claimed that diabetics: Y. C. Kuan et al., “Effects of Metformin Exposure on Neurodegenerative Diseases in Elderly Patients with Type 2 Diabetes Mellitus,” Progress in Neuropsychopharmacol and Biological Psychiatry 79, pt. B (October 3, 2017): 1777–83 (2017), https://doi.org/10.1016/j.pnpbp.2017.06.002.
The study’s goal is to see: “The Tame Trial: Targeting the Biology of Aging: Ushering a New Era of Interventions,” American Federation for Aging Research (AFAR) online, accessed August 1, 2023, https://www.afar.org/tame-trial.
That was exactly the skepticism: A detailed account of how Guarente became involved in this research and his laboratory’s early discoveries is found in his book, Lenny Guarente, Ageless Quest: One Scientist’s Search for Genes That Prolong Youth (Cold Spring Harbor, NY: Cold Spring Harbor Press, 2003).
Increasing the amount of Sir2: M. Kaeberlein, M. McVey, and L. Guarente, “The SIR2/3/4 Complex and SIR2 Alone Promote Longevity in Saccharomyces cerevisiae by Two Different Mechanisms,” Genes and Development 13, no. 19, October 1, 1994, 2570–80, https://doi.org/10.1101/gad.13.19.2570.
They soon found, with mounting excitement: B. Rogina and S. L. Helfand, “Sir2 Mediates Longevity in the Fly Through a Pathway Related to Calorie Restriction,” Proceedings of the National Academy of Sciences (PNAS) of the United States of America 101, no. 45 (November 2004): 15998–6003, https://doi.org/10.1073/Pnas.040418410; H. A. Tissenbaum and L. Guarente, “Increased Dosage of a Sir-2 Gene Extends Lifespan in Caenorhabditis Elegans,” Nature 410, no. 6825 (March 8, 2001): 227–30, https://doi.org/10.1038/35065638.
Sir2 turns out to be a deacetylase: S. Imai et al., “Transcriptional Silencing and Longevity Protein Sir2 Is an NAD-Dependent Histone Deacetylase,” Nature 403, no. 6771 (February 17, 2000): 795–800, https://doi.org/10.1038/35001622; W. Dang et al., “Histone H4 Lysine 16 Acetylation Regulates Cellular Lifespan,” Nature 459, no. 7248 (June 11, 2009): 802–7, https://doi.org/10.1038/nature08085.
Sure enough, in both flies and yeast: S. J. Lin, P. A. Defossez, and L. Guarente, “Requirement of NAD and SIR2 for Life-span Extension by Calorie Restriction in Saccharomyces cerevisiae,” Science 289, no. 5487 (September 22, 2000): 2126–28, https://doi.org/10.1126/science.289.5487.2126; Rogina and Helfand, “Sir2 Mediates Longevity in the Fly,” 15998–6003.
“When single genes are changed”: L. Guarente and C. Kenyon, “Genetic Pathways That Regulate Ageing in Model Organisms,” Nature 408, no. 6809 (November 9, 2000): 255–62, https://doi.org/10.1038/35041700.
Finally, here was scientific evidence: K. T. Howitz. et al., “Small Molecule Activators of Sirtuins Extend Saccharomyces cerevisiae Lifespan,” Nature 425, no. 6809 (November 9, 2000): 191–96, https://doi.org/10.1038/nature01960.
Although the mice remained overweight: J. A. Baur et al., “Resveratrol Improves Health and Survival of Mice on a High-Calorie Diet,” Nature 444, no. 7117 (November 16, 2006): 337–42, https://doi.org/10.1038/nature05354; M. Lagouge et al., “Resveratrol Improves Mitochondrial Function and Protects Against Metabolic Disease by Activating SIRT1 and PGC-1alpha,” Cell 127, no. 6 (December 15, 2006): 1109–22, https://doi.org/10.1016/j.cell.2006.11.013.
Among other things: M. Kaeberlein et al., “Sir2-Independent Life Span Extension by Calorie Restriction in Yeast,” PLoS Biology 2, no. 9 (September 2004): E296, https://doi.org/10.1371/journal.pbio.0020296.
Not only that, but they did not find: M. Kaeberlein et al., “Substrate-Specific Activation of Sirtuins by Resveratrol,” Journal of Biological Chemistry 280, no. 17 (April 2005): 17038–45, https://doi.org/10.1074/jbc.M500655200.
Pharmaceutical companies do not usually: M. Pacholec et al., “SRT1720, SRT2183, SRT1460, and Resveratrol Are Not Direct Activators of SIRT1,” Journal of Biological Chemistry 285, no. 11 (March 2010): 8340–51, https://doi.org/10.1074/jbc.M109.088682.
Five years after the sale: John La Mattina, “Getting the Benefits of Red Wine from a Pill? Not Likely,” Forbes online, last modified March 19, 2013, https://www.forbes.com/sites/johnlamattina/2013/03/19/getting-the-benefits-of-red-wine-from-a-pill-not-likely/.
This led to another commentary: B. P. Hubbard et al., “Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators,” Science 339, no. 6124 (March 8, 2013): 1216–19, https://doi.org/10.1126/science.1231097; H. Yuan and R. Marmorstein, “Red Wine, Toast of the Town (Again),” Science 339, no. 6124 (March 8, 2013): 1156–57, https://doi.org/10.1126/science.1236463.
None of them had any significant effect: R. Strong et al., “Evaluation of Resveratrol, Green Tea Extract, Curcumin, Oxaloacetic Acid, and Medium-Chain Triglyceride Oil on Life Span of Genetically Heterogeneous Mice,” Journals of Gerontology: Series A 68, no. 1 (January 2013): 6–16, https://doi.org/10.1093/gerona/gls070.
Sir2 activation actually reduces: P. Fabrizio et al., “Sir2 Blocks Extreme Life-span Extension,” Cell 123, no. 4 (November 18, 2005): 655–67, https://doi.org/10.1016/j.cell.2005.08.042; see also commentary by B. K. Kennedy, E. D. Smith, and M. Kaeberlein, “The Enigmatic Role of Sir2 in Aging,” Cell 123, no. 4 (November 18, 2005): 548–50, https://doi.org/10.1016/j.cell.2005.11.002.
Feeling embattled: C. Burnett et al., “Absence of Effects of Sir2 Overexpression on Lifespan in C. elegans and Drosophila,” Nature 477, no. 7365 (September 21, 2011): 482–85, https://doi.org/10.1038/nature10296; K. Baumann, “Ageing: A Midlife Crisis for Sirtuins,” Nature Reviews Molecular Cell Biology 12, no. 11 (October 21, 2011): 688, https://doi.org/10.1038/nrm3218; D. B. Lombard et al., “Ageing: Longevity Hits a Roadblock,” Nature 477, no. 7365 (September 21, 2011): 410–11, https://doi.org/10.1038/477410a; M. Viswanathan and L. Guarente, “Regulation of Caenorhabditis elegans lifespan by sir-2.1 Transgenes,” Nature 477, no. 7365 (September 21, 2011): E1–2, https://doi.org/10.1038/nature10440.
The protein is also a histone: R. Mostoslavsky et al., “Genomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6,” Cell 124, no. 2 (January 24, 2006): 315–29, https://doi.org/10.1016/j.cell.2005.11.044; E. Michishita et al. “SIRT6 Is a Histone H3 Lysine 9 Deacetylase That Modulates Telomeric Chromatin,” Nature 452, no. 7186 (March 27, 2008): 492–96, https://doi.org/10.1038/nature06736; A. Roichman et al., “SIRT6 Overexpression Improves Various Aspects of Mouse Healthspan,” Journals of Gerontology: Series A 72, no. 5 (May 1, 2017): 603–15, https://doi.org/10.1093/gerona/glw152; X. Tian et al., “SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species,” Cell 177, no. 3 (April 18, 2019): 622–38.e22, https://doi.org/10.1016/j.cell.2019.03.043.
Many in the gerontology community: C. Brenner, “Sirtuins Are Not Conserved Longevity Genes,” Life Metabolism 1, no. 2 (October 2022), 122–33, https://doi.org/10.1093/lifemeta/loac025.
It is made by the body: P. Belenky, K. L. Bogan, and C. Brenner, “NAD+ Metabolism in Health and Disease,” Trends in Biochemical Sciences 32, no. 1 (January 2017): 12–19, https://doi.org/10.1016/j.tibs.2006.11.006.
It can also cause a host: H. Massudi et al., “Age-Associated Changes in Oxidative Stress and NAD+ Metabolism in Human Tissue,” PLoS One 7, no. 7 (2012): e42357, https://doi.org/10.1371/journal.pone.0042357; X. H. Zhu et al., “In Vivo NAD Assay Reveals the Intracellular NAD Contents and Redox State in Healthy Human Brain and Their Age Dependences,” Proceedings of the National Academy of Sciences (PNAS) of the United States of America 112, no. 9 (February 17, 2015): 2876–81, https://doi.org/10.1073/pnas.1417921112; A. J. Covarrubias et al., “NAD+ Metabolism and Its Roles in Cellular Processes During Ageing,” Nature Reviews Molecular Cell Biology 22, no. 2 (February 2021): 119–41, https://doi.org/10.1038/s41580-020-00313-x.
Increasing NAD levels: H. Zhang et al., “NAD+ Repletion Improves Mitochondrial and Stem Cell Function and Enhances Life Span in Mice,” Science 352, no. 6292 (April 28, 2016): 1436–43, https://doi.org/10.1126/science.aaf2693; see also the commentary on this report by L. Guarente, “The Resurgence of NAD+,” Science 352, no. 6292 (April 28, 2016): 1396–97, https://doi.org/10.1126/science.aag1718; K. F. Mills et al., “Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice,” Cell Metabolism 24, no. 6 (December 13, 2016): 795–806, https://doi.org/10.1016/j.cmet.2016.09.013.
The results of taking: Partridge, Fuentealba, and Kennedy, “Quest to Slow Ageing,” 513–32.
Global sales of NMN: Global News Wire, “Nicotinamide Mononucleotide (NMN) Market Will Turn Over USD 251.2 to Revenue to Cross USD 953 Million in 2022 to 2028 Research by Business Opportunities, Top Companies, Opportunities Planning, Market-Specific Challenges,” August 19, 2022, https://www.globenewswire.com/en/news-release/2022/08/19/2501489/0/en/Nicotinamide-Mono nucleotide-NMN-Market-will-Turn-over-USD-251-2-to-Revenue-to-Cross-USD-953-million-in-2022-to-2028-Research-by-Business-Opportunities-Top-Companies-opportunities-p.html.
9. The Stowaway Within Us
“I quit my job”: Martin Weil, “Lynn Margulis, Leading Evolutionary Biologist, Dies at 73,” Washington Post online, November 26, 2011, https://www.washingtonpost.com/local/obituaries/lynn-margulis-leading-evolutionary-biologist-dies-at-73/2011/11/26/gIQAQ 5dezN_story.html.
Margulis wrote an essay: Lynn Margulis, “Two Hit, Three Down—The Biggest Lie: David Ray Griffin’s Work Exposing 9/11,” in Dorion Sagan, ed., Lynn Margulis: The Life and Legacy of a Scientific Rebel (White River Junction, VT: Chelsea Green, 2012), 150–55.
You could think of Margulis’s idea: L. Sagan, “On the Origin of Mitosing Cells,” Journal of Theoretical Biology 14, no. 3 (March 14, 1967): 255–74, https://doi.org/10.1016/0022-5193(67)90079-3.
In the same way that water: The idea that ATP is made by using a proton gradient across a membrane was proposed by Peter Mitchell and highly controversial initially. He went on to receive the 1978 Nobel Prize. See: Royal Swedish Academy of Sciences, “The Nobel Prize in Chemistry 1978: Peter Mitchell,” press release, October 17, 1978, available at Nobel Prize online, https://www.nobelprize.org/prizes/chemis try/1978/press-release/. Part of the 1997 Chemistry Nobel Prize was awarded to Paul Boyer and John Walker for their work on the molecular turbine that actually makes the ATP. The Nobel press release has an excellent description of it: Royal Swedish Academy of Sciences, “The Nobel Prize in Chemistry 1997: Paul D. Boyer, John E. Walker, Jens C. Skou,” press release, October 15, 1997, available at Nobel Prize online, https://www.nobelprize.org/prizes/chemistry/1997/press-release/.
The human body has to generate: F. Du et al., “Tightly Coupled Brain Activity and Cerebral ATP Metabolic Rate,” Proceedings of the National Academy of Sciences (PNAS) of the United States of America 105, no. 17 (April 29, 2008): 6409–14, https://doi.org/10.1073/pnas.0710766105. For a popular account of this article, see N. Swaminathan, “Why Does the Brain Need So Much Power?,” Scientific American online, April 29, 2008, https://www.scientificamerican.com/article/why-does-the-brain-need-s/.
The child will carry mostly: Ian Sample, “UK Doctors Select First Women to Have ‘Three-Person Babies,’” Guardian (US edition) online, last modified February 1, 2018, https://www.theguardian.com/science/2018/feb/01/permission-given-to-create-britains-first-three-person-babies.
Excessive contacts: J. Valades et al, “ER Lipid Defects in Neuropeptidergic Neurons Impair Sleep Patterns in Parkinson’s Diseases,” Neuron 98, no. 6 (June 27, 2018): 1155–69, https://doi.org/10.1016/j.neuron.2018.05.022.
Perhaps no other structure: N. Sun, R. J. Youle, and T. Finkel, “The Mitochondrial Basis of Aging,” Molecular Cell 61, no. 5 (March 3, 2016): 654–66, https://doi.org/10.1016/j.molcel.2016.01.028.
In 1954: D. Harman, “Origin and Evolution of the Free Radical Theory of Aging: A Brief Personal History, 1954–2009,” Biogerontology 10, no. 6 (December 2009): 773–81, https://doi.org/10.1007/s10522-009-9234-2.
Harman’s idea: R. S. Sohal and R. Weindruch, “Oxidative Stress, Caloric Restriction, and Aging,” Science 273, no. 5271 (July 5, 1996): 59–63, https://doi.org/10.1126/science.273.5271.59.
Over time, they damage: E. R. Stadtman, “Protein Oxidation and Aging,” Free Radical Research 40, no. 12 (December, 2006): 1250–58, https://doi.org/10.1080/10715760600918142.
Strains of mice that made: S. E. Schriner et al., “Extension of Murine Life Span by Overexpression of Catalase Targeted to Mitochondria,” Science 308, no. 5730 (June 24, 2005): 1909–11, https://doi.org/10.1126/science.1106653.
As recently as 2022: J. Hartke et al., “What Doesn’t Kill You Makes You Live Longer—Longevity of a Social Host Linked to Parasite Proteins,” bioRxiv (2022): https://doi.org/10.1101/2022.12.23.521666.
One way they may minimize: A. Rodríguez-Nuevo et al., “Oocytes Maintain ROS-free Mitochondrial Metabolism by Suppressing Complex I,” Nature 607, no. 7920 (July 2022): 756–61, https://doi.org/10.1038/s41586-022-04979-5.
Alas, although there were isolated reports: G. Bjelakovic et al., “Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-analysis,” Journal of the American Medical Association (JAMA) 297, no. 8 (2007): (February 28, 2007): 842–57, https://doi.org/10.1001/jama.297.8.842.
But over the last ten to fifteen years: S. Hekimi, J. Lapointe, and Y. Wen, “Taking a ‘Good’ Look at Free Radicals in the Aging Process,” Trends in Cell Biology 21, no. 10 (October 2011): 569–76, https://doi.org/10.1016/j.tcb.2011.06.008. There are also first-rate discussions of the evidence in López-Otín et al., “Hallmarks of Aging,” 1194–217, and A. Bratic and N. G. Larsson, “The Role of Mitochondria in Aging,” Journal of Clinical Investigation 123, no. 3 (March 2013): 951–57, https://doi.org/10.1172/JCI64125.
In fact, contrary to the report: V. I. Pérez et al., “The Overexpression of Major Antioxidant Enzymes Does Not Extend the Lifespan of Mice,” Aging Cell 8, no. 1 (February 2009): 73–75, https://doi.org/10.1111/j.1474-9726.2008.00449.x.
Giving them a herbicide: W. Yang and S. Hekimi, “A Mitochondrial Superoxide Signal Triggers Increased Longevity in Caenorhabditis elegans,” PLoS Biology 8, no. 12 (December 2010): e1000556, https://doi.org/10.1371/journal.pbio.1000556.
The naked mole rat lives: B. Andziak et al., “High Oxidative Damage Levels in the Longest-Living Rodent, the Naked Mole-Rat,” Aging Cell 5, no. 6 (December 2006): 463–71, https://doi.org/10.1111/j.1474-9726.2006.00237.x; F. Saldmann et al., “The Naked Mole Rat: A Unique Example of Positive Oxidative Stress,” Oxidative Medicine and Cellular Longevity 2019 (February 7, 2019): 4502819, https://doi.org/10.1155/2019/450281.9.
This may be an example of something called hormesis: V. Calabrese et al., “Hormesis, Cellular Stress Response and Vitagenes as Critical Determinants in Aging and Longevity,” Molecular Aspects of Medicine 32, nos. 4–6 (August–December 2011): 279–304, https://doi.org/10.1016/j.mam.2011.10.007.
At the age of about sixty weeks: A. Trifunovic et al., “Premature Ageing in Mice Expressing Defective Mitochondrial DNA Polymerase,” Nature 429, no. 6990 (May 27, 2004): 417–23, https://doi.org/10.1038/nature02517. This and several other papers published the following year are reviewed in L. A. Loeb, D. C. Wallace, and G. M. Martin, “The Mitochondrial Theory of Aging and Its Relationship to Reactive Oxygen Species Damage and Somatic MtDNA Mutations,” Proceedings of the National Academy of Sciences (PNAS) of the United States of America 102, no. 52 (December 19, 2005): 18769–70, https://doi.org/10.1073/pnas.0509776102.
There are reports of a complicated interplay: E. F. Fang et al., “Nuclear DNA Damage Signalling to Mitochondria in Ageing,” Nature Reviews Molecular Cell Biology 17, no. 5 (May 2016): 308–21, https://doi.org/10.1038/nrm.2016.14; R. H. Hämäläinen et al., “Defects in mtDNA Replication Challenge Nuclear Genome Stability Through Nucleotide Depletion and Provide a Unifying Mechanism for Mouse Progerias,” Nature Metabolism 1, no. 10 (October 2019): 958–65, https://doi.org/10.1038/s42255-019-0120-1.
In these cases, clones: T. E. S. Kauppila, J. H. K. Kauppila, and N. G. Larsson, “Mammalian Mitochondria and Aging: An Update,” Cell Metabolism 25, no. 1 (January 10, 2017): 57–71, https://doi.org/10.1016/j.cmet.2016.09.017.
The effect is most pronounced: N. Sun, R. J. Youle, and T. Finkel, “The Mitochondrial Basis of Aging,” Molecular Cell 61, no. 5 (March 3, 2016): 654–66, https://doi.org/10.1016/j.molcel.2016.01.028.
One characteristic of aging: C. Franceschi et al., “Inflamm-aging. An Evolutionary Perspective on Immunosenescence,” Annals of the New York Academy of Sciences 908, no. 1 (June 2000): 244–54, https://doi.org/10.1111/j.1749-6632.2000.tb06651.x.
Some proteins can sense: N. P. Kandul et al., “Selective Removal of Deletion-Bearing Mitochondrial DNA in Heteroplasmic Drosophila,” Nature Communications 7 (November 14, 2016): art. 13100, https://doi.org/10.1038/ncomms13100.
The inhibition of TOR: M. Morita et al., “mTORC1 Controls Mitochondrial Activity and Biogenesis Through 4E-BP-Dependent Translational Regulation,” Cell Metabolism 18, no. 5 (November 5, 2013): 698–711, https://doi.org/10.1016/j.cmet.2013.10.001.
In studies, the increased mitochondrial activity: B. M. Zid et al., “4E-BP Extends Lifespan upon Dietary Restriction by Enhancing Mitochondrial Activity in Drosophila,” Cell 139, no. 1 (October 2, 2009): 149–60, https://doi.org/10.1016/j.cell.2009.07.034.
Besides TOR, other signals: C. Cantó and J. Auwerx, “PGC-1α, SIRT1 and AMPK, an Energy Sensing Network That Controls Energy Expenditure,” Current Opinion in Lipidology 20, no. 2 (April 2009): 98–105, https://doi.org/10.1097/mol.0b013e328328d0a4.
Sometimes, though, this effort is futile: C. Cantó and J. Auwerx, “PGC-1α, SIRT1 and AMPK, an Energy Sensing Network That Controls Energy Expenditure,” Current Opinion in Lipidology 20, no. 2 (April 2009): 98–105, https://doi.org/10.1097/mol.0b013e328328d0a4.
Physical activity turns on: See Sun, Youle, and Finkel, “Mitochondrial Basis of Aging,” 654–66; J. L. Steiner et al., “Exercise Training Increases Mitochondrial Biogenesis in the Brain,” Journal of Applied Physiology 111, no. 4 (October 2011): 1066–71, https://doi.org/10.1152/japplphysiol.00343.2011.
One way it spurs mitochondrial function: Z. Radak, H. Y. Chung, and S. Goto, “Exercise and Hormesis: Oxidative Stress-Related Adaptation for Successful Aging,” Biogerontology 6, no. 1 (2005): 71–75, https://doi.org/10.1007/s10522-004-7386-7.
Of course, exercise does far more: G. C. Rowe, A. Safdar, and Z. Arany, “Running Forward: New Frontiers in Endurance Exercise Biology,” Circulation 129, no. 7 (February 18, 2014): 798–810, https://doi.org/10.1161/circulationaha.113.001590.
But it is better repaired: J. B. Stewart and N. G. Larsson, “Keeping mtDNA in Shape Between Generations,” PLoS Genetics 10, no. 10 (October 9, 2014): e1004670, https://doi.org/10.1371/journal.pgen.1004670.
Nevertheless, selection is not perfect: Y. Bentov et al., “The Contribution of Mitochondrial Function to Reproductive Aging,” Journal of Assistive Reproduction and Genetics 28, no. 9 (September 2011): 773–83, https://doi.org/10.1007/s10815-011-9588-7.
10. Aches, Pains, and Vampire Blood
These tumor suppressor genes: M. Serrano et al., “Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a,” Cell 88, no. 5 (March 7, 1997): 593–602, https://doi.org/10.1016/s0092-8674(00)81902-9; M. Narita and S. W. Lowe, “Senescence Comes of Age,” Nature Medicine 11, no. 9 (September 2005): 920–22, https://doi.org/10.1038/nm0905-920.
Senescent cells are often produced: M. Demaria et al., “An Essential Role for Senescent Cells in Optimal Wound Healing Through Secretion of PDGF-AA,” Developmental Cell 31, no. 6 (December 22, 2014): 722–33, https://doi.org/10.1016/j.devcel.2014.11.012; M. Serrano, “Senescence Helps Regeneration,” Developmental Cell 31, no. 6 (December 22, 2014): 671–72, https://doi.org/10.1016/j.devcel.2014.12.007.
As damage to our DNA accumulates: These reviews offer a comprehensive view of senescent cells’ role in aging: J. Campisi and F. d’Adda di Fagagna, “Cellular Senescence: When Bad Things Happen to Good Cells,” Nature Reviews Molecular Cell Biology 8, no. 9 (September 2007): 729–40, https://doi.org/10.1038/nrm2233; J. M. van Deursen, “The Role of Senescent Cells in Ageing,” Nature 509, no. 7501 (May 22, 2014): 439–46, https://doi.org/10.1038/nature13193; J. Gil, “Cellular Senescence Causes Ageing,” Nature Reviews Molecular Cell Biology 20 (July 2019): 388, https://doi.org/10.1038/s41580-019-0128-0.
They also lived: D. J. Baker et al., “Clearance of p16Ink4a-Positive Senescent Cells Delays Ageing-Associated Disorders,” Nature 479, no. 7372 (November 2, 2011): 232–36, https://doi.org/10.1038/nature10600; D. J. Baker et al., “Naturally Occurring p16(Ink4a)-Positive Cells Shorten Healthy Lifespan,” Nature 530, no. 7589 (February 11, 2016): 184–89, https://doi.org/10.1038/nature16932; see also the commentary by E. Callaway, “Destroying Worn-out Cells Makes Mice Live Longer,” Nature (February 3, 2016): https://doi.org/10.1038/nature.2016.19287.
When researchers used an oral cocktail: M. Xu et al., “Senolytics Improve Physical Function and Increase Lifespan in Old Age,” Nature Medicine 24, no. 8 (August 2018): 1246–56, https://doi.org/10.1038/s41591-018-0092-9.
But this isn’t strictly true: Donavyn Coffey, “Does the Human Body Replace Itself Every 7 Years?,” Live Science, last modified July 22, 2022, https://www.livescience.com/33179-does-human-body-replace-cells-seven-years.html; P. Heinke et al., “Diploid Hepatocytes Drive Physiological Liver Renewal in Adult Humans,” Cell Systems 13, no. 6 (June 15, 2022): 499–507.e12, https://doi.org/10.1016/j.cels.2022.05.001; K. L. Spalding et al., “Dynamics of Hippocampal Neurogenesis in Adult Humans,” Cell 153, no. 6 (June 6, 2013): 1219–27, https://doi.org/10.1016/j.cell.2013.05.002; A. Ernst et al., “Neurogenesis in the Striatum of the Adult Human Brain,” Cell 156, no. 5 (February 27, 2014): 1072–83, https://doi.org/10.1016/j.cell.2014.01.044.
This leads to immune system decline: For a comprehensive discussion of stem cell depletion, see López-Otín et al., “Hallmarks of Aging,” 1194–217, https://doi.org/10.1016/j.cell.2013.05.039.
After six weeks, the mice: A. Ocampo et al., “In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming,” Cell 167, no. 7 (December 15, 2016): 1719–33.e12, https://doi.org/10.1016/j.cell.2016.11.052.
Not only did the animals: K. C. Browder et al., “In Vivo Partial Reprogramming Alters Age-Associated Molecular Changes During Physiological Aging in Mice,” Nature Aging 2, no. 3 (March 2022): 243–53, https://doi.org/10.1038/s43587-022-00183-2; D. Chondronasiou et al., “Multi-omic Rejuvenation of Naturally Aged Tissues by a Single Cycle of Transient Reprogramming,” Aging Cell 21, no. 3 (March 2022): e13578, https://doi.org/10.1111/acel.13578; D. Gill et al., “Multi-omic Rejuvenation of Human Cells by Maturation Phase Transient Reprogramming,” eLife 11 (April 8, 2022): e71624, https://doi.org/10.7554/eLife.71624.
Their DNA methylation: Y. Lu et al., “Reprogramming to Recover Youthful Epigenetic Information and Restore Vision,” Nature 588, no. 7836 (December 2020): 124–29, https://doi.org/10.1038/s41586-020-2975-4; see also the news item K. Servick, “Researchers Restore Lost Sight in Mice, Offering Clues to Reversing Aging,” Science online, last modified December 2, 2020, https://doi.org/10.1126/science.abf9827.
These effects could be reversed: J.-H. Yang et al., “Loss of Epigenetic Information as a Cause of Mammalian Aging,” Cell 186, no. 2 (January 19, 2023), https://doi.org/10.1016/j.cell.2022.12.027.
He not only connected two rats: R. B. S. Harris, “Contribution Made by Parabiosis to the Understanding of Energy Balance Regulation,” Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease 1832, no. 9 (September 2013): 1449–55, https://doi.org/10.1016/j.bbadis.2013.02.021.
“If two rats are not adjusted”: C. M. McCay, F. Pope, and W. Lunsford, “Experimental Prolongation of the Life Span,” Journal of Chronic Diseases 4, no. 2 (August 1956): 153–58, https://www.sciencedirect.com/science/article/abs/pii/0021968156900157. Quoted in an overview of the field by M. Scudellari, “Ageing Research: Blood to Blood,” Nature 517, no. 7535 (January 22, 2015): 426–29, https://doi.org/10.1038/517426a.
By the same criteria: M. J. Conboy, I. M. Conboy, and T. A. Rando, “Heterochronic Parabiosis: Historical Perspective and Methodological Considerations for Studies of Aging and Longevity,” Aging Cell 12, no. 3 (June 2013): 525–30, https://doi.org/10.1111/acel.12065.
He showed that old blood: S. A. Villeda et al., “The Ageing Systemic Milieu Negatively Regulates Neurogenesis and Cognitive Function,” Nature 477, no. 7362 (August 31, 2011): 90–94, https://doi.org/10.1038/nature10357; S. A. Villeda et al., “Young Blood Reverses Age-Related Impairments in Cognitive Function and Synaptic Plasticity in Mice,” Nature Medicine 20, no. 6 (June 2014): 659–63, https://doi.org/10.1038/nm.3569.
that were not joined: J. Rebo et al, “A Single Heterochronic Blood Exchange Reveals Rapid Inhibition of Multiple Tissues by Old Blood,” Nature Communications 7, no. 1 (June 10, 2016): art. 13363, https://doi.org/10.1038/ncomms13363.
Such cautionary views: Rebecca Robbins, “Young-Blood Transfusions Are on the Menu at Society Gala,” Scientific American online, last modified March 2, 2018, https://www.scientificamerican.com/article/young-blood-transfusions-are-on-the-menu-at-society-gala/.
Alarmed, the US Food and Drug Administration (FDA): Scott Gottlieb, “Statement from FDA Commissioner Scott Gottlieb, M.D., and Director of FDA’s Center for Biologics Evaluation and Research Peter Marks, M.D., Ph.D., Cautioning Consumers Against Receiving Young Donor Plasma Infusions That Are Promoted as Unproven Treatment for Varying Conditions,” U.S. Food and Drug Administration, press release, February 19, 2019, https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-director-fdas-center-biologics-evaluation-and-0.
“Our patients really want”: Emily Mullin, “Exclusive: Ambrosia, the Young Blood Transfusion Startup, Is Quietly Back in Business,” OneZero, last modified November 8, 2019, https://onezero.medium.com/exclusive-ambrosia-the-young-blood-transfusion-startup-is-quietly-back-in-business-ee2b7494b417.
As for old blood, they zeroed in: J. M. Castellano et al., “Human Umbilical Cord Plasma Proteins Revitalize Hippocampal Function in Aged Mice,” Nature 544, no. 7651 (April 27, 2017): 488–92, https://doi.org/10.1038/nature22067; H. Yousef et al., “Aged Blood Impairs Hippocampal Neural Precursor Activity and Activates Microglia Via Brain Endothelial Cell VCAM1,” Nature Medicine 25, no. 6 (June 2019): 988–1000, https://doi.org/10.1038/s41591-019-0440-4.
In a second study: F. S. Loffredo et al., “Growth Differentiation Factor 11 Is a Circulating Factor That Reverses Age-Related Cardiac Hypertrophy,” Cell 153, no. 4 (May 9, 2013): 828–39, https://doi.org/10.1016/j.cell.2013.04.015; M. Sinha et al., “Restoring Systemic GDF11 Levels Reverses Age-Related Dysfunction in Mouse Skeletal Muscle,” Science 344, no. 6184 (May 9, 2014): 649–52, https://doi.org/10.1126/science.1251152; L. Katsimpardi et al., “Vascular and Neurogenic Rejuvenation of the Aging Mouse Brain by Young Systemic Factors,” Science 344, no. 6184 (May 9, 2014): 630–34, https://doi.org/10.1126/science.1251141. These findings are described in a very accessible article by Carl Zimmer, “Young Blood May Hold Key to Reversing Aging,” New York Times online, May 4, 2014, https://www.nytimes.com/2014/05/05/science/young-blood-may-hold-key-to-reversing-aging.html.
Clearing those senescent cells: O. H. Jeon et al., “Systemic Induction of Senescence in Young Mice After Single Heterochronic Blood Exchange,” Nature Metabolism 4, no. 8 (August 2022): 995–1006, https://doi.org/10.1038/s42255-022-00609-6.
It turns out that blood: A. M. Horowitz et al., “Blood Factors Transfer Beneficial Effects of Exercise on Neurogenesis and Cognition to the Aged Brain,” Science 369, no. 6500 (July 10, 2020): 167–73, https://doi.org/10.1126/science.aaw2622.
Rando and Wyss-Coray: J. O. Brett et al., “Exercise Rejuvenates Quiescent Skeletal Muscle Stem Cells in Old Mice Through Restoration of Cyclin D1,” Nature Metabolism 2, no. 4 (April 2020): 307–17, https://doi.org/10.1038/s42255-020-0190-0.
Although they both stimulated: M. T. Buckley et al., “Cell Type–Specific Aging Clocks to Quantify Aging and Rejuvenation in Regenerative Regions of the Brain,” Nature Aging 3 (January 2023): 121–37, https://www.nature.com/articles/s43587-022-00335-4.
He went to Resurgence Wellness, a Texas outfit: David Averre and Neirin Gray Desai, “Tech Billionaire, 45, Who Spends $2 Million a Year Trying to Reverse His Ageing Reveals Latest Gadget He Uses That Puts His Body Through the Equivalent of 20,000 Sit Ups in 30 Minutes,” Daily Mail (London) online, last modified April 5, 2023, https://www.dailymail.co.uk/news/article-11942581/Tech-billionaire-45-spends-2million-year-trying-reverse-ageing-reveals-latest-gadget.html; Orianna Rosa Royle, “Tech Billionaire Who Spends $2 Million a Year to Look Young Is Now Swapping Blood with His 17-Year-Old Son and 70-Year-Old Father,” Fortune online, last modified May 23, 2023, https://fortune.com/2023/05/23/bryan-johnson-tech-ceo-spends-2-million-year-young-swapping-blood-17-year-old-son-talmage-70-father/; Alexa Mikhail, “Tech CEO Bryan Johnson admits he saw ‘no benefits’ after controversially injecting his son’s plasma into his body to reverse his biological age,” Fortune, July 8, 2023, https://fortune.com/well/2023/07/08/bryan-johnson-plasma-exchange-results-anti-aging/.
11. Crackpots or Prophets?
An entire field of biology: S. Bojic et al., “Winter Is Coming: The Future of Cryopreservation,” BMC Biology 19, no. 1 (March 24, 2021): 56, https://doi.org/10.1186/s12915-021-00976-8.
The idea has been around a long time: Paul Vitello, “Robert C. W. Ettinger, a Proponent of Life After (Deep-Frozen) Death, Is Dead at 92,” New York Times online, July 29, 2011, https://www.nytimes.com/2011/07/30/us/30ettinger.html; Associated Press, “Cryonics Pioneer Robert Ettinger Dies,” Guardian (US edition) online, last modified July 26, 2011, https://www.theguardian.com/science/2011/jul/26/cryonics-pioneer-robert-ettinger-dies.
One such proponent is Elon Musk: See “Elon Musk on Cryonics,” Elon Musk, interviewed by Zach Latta, YouTube video, 2:09, uploaded by Hack Club on May 4, 2020, https://www.youtube.com/watch?v=MSIjNKssXAc.
“die on Mars”: Daniel Terdiman, “Elon Musk at SXSW: ‘I’d Like to Die on Mars, Just Not on Impact,’” CNET, last modified March 9, 2013, https://www.cnet.com/culture/elon-musk-at-sxsw-id-like-to-die-on-mars-just-not-on-impact/.
It would be like trying to deduce the entire state of a country: See a particularly cutting article that deals with this and the general issue of cryonics by the neurobiologist Michael Hendrick, “The False Science of Cryonics,” MIT Technology Review, September 15, 2015, https://www.technologyreview.com/2015/09/15/109906/the-false-science-of-cryonics.
She took the matter to court: Owen Bowcott and Amelia Hill, “14-Year-Old Girl Who Died of Cancer Wins Right to Be Cryogenically Frozen,” Guardian (US edition) online, last modified November 18, 2016, https://www.theguardian.com/science/2016/nov/18/teenage-girls-wish-for-preservation-after-death-agreed-to-by-court.
This elicited an outcry: Alexandra Topping and Hannah Devlin, “Top UK Scientist Calls for Restrictions on Marketing Cryonics,” Guardian (US edition) online, last modified November 18, 2016, https://www.theguardian.com/science/2016/nov/18/top-uk-scientist-calls-for-restrictions-on-marketing-cryonics.
In almost a mirror image: Tom Verducci, “What Really Happened to Ted Williams?,” Sports Illustrated online, last modified August 18, 2003, https://vault.si.com/vault/2003/08/18/what-really-happened-to-ted-williams-a-year-after-the-jarring-news-that-the-splendid-splinter-was-being-frozen-in-a-cryonics-lab-new-details-including-a-decapitation-suggest-that-one-of-americas-greatest-heroes-may-never-rest-in.
According to press reports: See sources cited in https://en.wikipedia.org/wiki/List_of_people_who_arranged_for_cryonics; when I wrote to Nick Bostrom, he replied, “It has been thus reported in the media. My general stance however has been not to comment on my funereal or other posthumous arrangements . . .”, email January 11, 2023.
a San Francisco company called Nectome: Antonio Regalado, “A Startup Is Pitching a Mind-Uploading Service That Is ‘100 Percent Fatal,’” MIT Technology Review online, last modified March 13, 2018, https://www.technologyreview.com/2018/03/13/144721/a-startup-is-pitching-a-mind-uploading-service-that-is-100-percent-fatal/.
In response, Robert McIntyre, the founder of Nectome said: Sharon Begley, “After Ghoulish Allegations, a Brain-Preservation Company Seeks Redemption,” Stat (online), January 30, 2019, https://www.statnews.com/2019/01/30/nectome-brain-preservation-redemption.
He began his career: Evelyn Lamb, “Decades-Old Graph Problem Yields to Amateur Mathematician,” Quanta, last modified April 17, 2018, https://www.quantamagazine.org/decades-old-graph-problem-yields-to-amateur-mathematician-20180417/.
He asserts that the first humans: Aubrey de Grey, “A Roadmap to End Aging,” TED Talk, July 2005, 22:35, https://www.ted.com/talks/aubrey_de_grey_a_roadmap_to_end_aging/.
if we crack seven key problems: A. D. de Grey et al., “Time to Talk SENS: Critiquing the Immutability of Human Aging,” Annals of the New York Academy of Sciences 959, no. 1 (April 2002): 452–62, discussion 463, https://doi.org/10.1111/j.1749–6632.2002.tb02115.x; A. D. de Grey, “The Foreseeability of Real Anti-Aging Medicine: Focusing the Debate,” Experimental Gerontology 38, no. 9 (September 1, 2013): 927–34, https://doi.org/10.1016/s0531-5565(03)00155-4.
In response to his claims: H. Warner et al., “Science Fact and the SENS Agenda: What Can We Reasonably Expect from Ageing Research,” EMBO Reports 6, no. 11 (November 2005): 1006–8, https://doi.org/10.1038/sj.embor.7400555.
Other mainstream researchers: Estep et al., “Life Extension Pseudoscience and the SENS Plan,” MIT Technology Review, 2006, http://www2.technologyreview.com/sens/docs/estepetal.pdf; Sherwin Nuland, “Do You Want to Live Forever?,” MIT Technology Review online, last modified February 1, 2005, https://www.technologyreview.com/2005/02/01/231686/do-you-want-to-live-forever/.
One of them, Richard Miller: Richard Miller, open letter to Aubrey de Grey, MIT Technology Review online, November 29, 2005, https://www.technologyreview.com/2005/11/29/274243/debating-immortality/.
He denied the allegations: Analee Armstrong, “Anti-Aging Foundation SENS Fires de Grey After Allegations He Interfered with Investigation into His Conduct,” Fierce Biotech, last modified August 23, 2021, https://www.fiercebiotech.com/biotech/anti-aging-foundation-sens-turfs-de-grey-after-allegations-he-interfered-investigation-into.
A company report: SENS Research Foundation, “Announcement from the SRF Board of Directors,” news release, March 23, 2022, https://www.sens.org/announcement-from-the-srf-board-of-directors/.
De Grey, undaunted: “Meet the Team,” LEV Foundation online, accessed August 7, 2023, https://www.levf.org/team.
For example, he has predicted: David Sinclair, quoted in Antonio Regalado, “How Scientists Want to Make You Young Again,” MIT Technology Review online, last modified October 25, 2022, https://www.technologyreview.com/2022/10/25/1061644/how-to-be-young-again/.
Such statements: Catherine Elton, “Has Harvard’s David Sinclair Found the Fountain of Youth,” Boston online, last modified October 29, 2019, https://www.bostonmagazine.com/health/2019/10/29/david-sinclair/.
I doubt whether: David Sinclair and Matthew LaPlante, Lifespan: Why We Age, and Why We Don’t Have To (New York: Atria Books, 2019). For a sharply critical review of the book, see C. A. Brenner, “A Science-Based Review of the World’s Best-Selling Book on Aging,” Archives of Gerontology and Geriatrics 104 (January 2023): art. 104825, https://doi.org/10.1016/j.archger.2022.104825.
In an essay on LinkedIn: David Sinclair, “This Is Not an Advice Article,” LinkedIn, last modified June 25, 2018, https://www.linkedin.com/pulse/advice-article-david-sinclair.
They would often make: As one of hundreds of examples, see this description of companies founded in response to findings on blood transfusions: Rebecca Robbins, “Young-Blood Transfusions Are on the Menu at Society Gala,” Scientific American online, last modified March 2, 2018, https://www.scientificamerican.com/article/young-blood-transfusions-are-on-the-menu-at-society-gala/.
Even back in 2002: S. J. Olshansky, L. Hayflick, and B. A. Carnes, “Position Statement on Human Aging,” Journals of Gerontology: Series A 57, no. 8 (August 1, 2002): B292–97, https://doi.org/10.1093/gerona/57.8.b292. A total of fifty-one gerontologists cosigned the statement, and the three lead authors also published a popular summary, “Essay: No Truth to the Fountain of Youth,” Scientific American 286, no. 6 (June 2002): 92–95, https://doi.org/10.1038/scientific american0602-92.
California tech billionaires, especially: See, for example, Todd Friend, “Silicon Valley’s Quest to Live Forever,” New Yorker online, last modified March 27, 2017, https://www.newyorker.com/mag azine/2017/04/03/silicon-valleys-quest-to-live-forever; Anjana Ahuja, “Silicon Valley’s Billionaires Want to Hack the Ageing Process,” Financial Times online, last modified September 7, 2021, https://www.ft.com/content/24849908-ac4a-4a7d-b53c-847963ac1228; Anjana Ahuja, “Can We Defeat Death?,” Financial Times online, last modified October 29, 2021, https://www.ft.com/content/60d9271c-ae0a-4d44-8b11-956cd2e484a9.
When they were young, they wanted to be rich: This paraphrases an idea expressed previously by Antonio Regalado, “Meet Altos Labs, Silicon Valley’s Latest Wild Bet on Living Forever,” MIT Technology Review online, last modified September 4, 2021, https://www.technologyreview.com/2021/09/04/1034364/altos-labs-silicon-valleys-jeff-bezos-milner-bet-living-forever/.
Recently, he wrote a tract: Yuri Milner, Eureka Manifesto, available for downloading at https://yurimilnermanifesto.org/.
When news of Altos Labs: Antonia Regalado, “Meet Altos Labs, Silicon Valley’s Latest Wild Bet on Living Forever,” MIT Technology Review online, last modified September 4, 2021, https://www.technologyreview.com/2021/09/04/1034364/altos-labs-silicon-valleys-jeff-bezos-milner-bet-living-forever/.
Rick Klausner, its chief scientist: Hannah Kuchler, “Altos Labs Insists Mission Is to Improve Lives Not Cheat Death,” Financial Times online, last modified January 23, 2022, https://www.ft.com/content/f3bceaf2-0d2f-4ec7-b767-693bf01f9630.
“Our goal is for everyone”: The author was present at the launch of the Cambridge campus of Altos Labs on June 22, 2022.
“I went through a period”: Michael Hall, email message to the author, September 2, 2021.
Other drugs aim to target: A more comprehensive list of strategies and drugs that are used to combat aging is found in Partridge, Fuentealba, and Kennedy, “Quest to Slow Ageing,” 513–32.
Some of the biggest excitement: M. Eisenstein, “Rejuvenation by Controlled Reprogramming Is the Latest Gambit in Anti-Aging,” Nature Biotechnology 40, no. 2 (February 2022): 144–46, https://doi.org/10.1038/d41587-022-00002-4.
“Despite intensive study”: Olshansky, Hayflick, and Carnes, “Position Statement,” B292–97.
In addition to epigenetic changes: K. S. Kudryashova et al., “Aging Biomarkers: From Functional Tests to Multi-Omics Approaches,” Proteomics 20, nos. 5/6 (March 2020): art. E1900408, https://doi.org/10.1002/pmic.201900408; Buckley et al., “Cell Type–Specific Aging Clocks.”
This goal was termed: Kudryashova et al., “Aging Biomarkers: From Functional Tests to Multi-Omics Approaches”; Buckley et al., “Cell Type–Specific Aging Clocks.”
“forever remain quixotic”: A. D. de Grey, “The Foreseeability of Real Anti-Aging Medicine: Focusing the Debate,” Experimental Gerontology 38, no. 9 (September 1, 2003): 927–34, https://doi.org/10.1016/s0531-5565(03)00155-4.
If anything, data: “Health State Life Expectancies, UK: 2018 to 2020,” Office of National Statistics (UK) online, last modified March 4, 2022, https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/healthandlifeexpectancies/bulletins/health statelifeexpectanciesuk/latest.
A United Nations report: Jean-Marie Robine, “Aging Populations: We Are Living Longer Lives, But Are We Healthier?,” United Nations Department of Economic and Social Affairs, Population Division, online, September 2021, https://desapublications.un.org/file/653/download.
A farmer was merrily riding: Oliver Wendell Holmes, The Deacon’s Masterpiece or the Wonderful One-Hoss Shay, Cambridge, MA: Houghton, Mifflin, 1891. With illustrations by Howard Pyle. Reproduced in http://www.ibiblio.org/eldritch/owh/shay.html.
This would argue in favor: S. L. Andersen et al., “Health Span Approximates Life Span Among Many Supercentenarians: Compression of Morbidity at the Approximate Limit of Life Span,” Journals of Gerontology: Series A 67, no. 4 (April 2012): 395–405 (2012), https://doi.org/10.1093/gerona/glr223.
Similarly, a variant of a gene: P. Sebastiani et al., “A Serum Protein Signature of APOE Genotypes in Centenarians,” Aging Cell 18, no. 6 (December 2019): e13023, https://doi.org/10.1111/acel.13023; B. N. Ostendorf et al., “Common Germline Variants of the Human APOE Gene Modulate Melanoma Progression and Survival,” Nature Medicine 26, no. 7 (July 2020): 1048–53, https://doi.org/10.1038/s41591-020-0879-3; B. N. Ostendorf et al., “Common Human Genetic Variants of APOE Impact Murine COVID-19 Mortality,” Nature 611, no. 7935 (November 2022): 346–51, https://doi.org/10.1038/s41586-022-05344-2.
12. Should We Live Forever?
The share of older people: United Nations Department of Economic and Social Affairs, Population Division, World Population Prospects 2022: Summary of Results (New York: United Nations, 2022), https://www.un.org/development/desa/pd/sites/www.un.org.development.desa.pd/files/wpp2022_summary_of_results.pdf.
In both social and economic terms: David E. Boom and Leo M. Zucker, “Aging Is the Real Population Bomb,” Finance & Development online, June 2022, 58–61, https://www.imf.org/en/Publications/fandd/issues/Series/Analytical-Series/aging-is-the-real-population-bomb-bloom-zucker.
The poor not only live: Veena Raleigh, “What Is Happening to Life Expectancy in England?,” King’s Fund online, last modified August 10, 2022, https://www.kingsfund.org.uk/publications/whats-happening-life-expectancy-england.
Things are even worse in the United States: R. Chetty et al., “The Association Between Income and Life Expectancy in the United States, 2001–2014,” Journal of the American Medical Association (JAMA) 315, no. 16 (April 26, 2016): 1750–66, https://doi.org/10.1001/jama.2016.4226.
Advances in medicine: V. J. Dzau and C. A. Balatbat, “Health and Societal Implications of Medical and Technological Advances,” Science Translational Medicine 10, no. 463 (October 17, 2018): eaau4778, https://doi.org/10.1126/scitranslmed.aau4778; D. Weiss et al. “Innovative Technologies and Social Inequalities in Health: A Scoping Review of the Literature,” PLoS One 13, no. 4 (April 3, 2018): e0195447 (2018), https://doi.org/10.1371/journal.pone.0195447; Fiona McMillan, “Medical Advances Can Exacerbate Inequality,” Cosmos online, last modified October 21, 2018, https://cosmosmagazine.com/people/medical-advances-can-exacerbate-inequality/.
This is because fertility: D. R. Gwatkin and S. K. Brandel, “Life Expectancy and Population Growth in the Third World,” Scientific American 246, no. 5 (May 1982): 57–65, https://doi.org/10.1038/scientificamerican0582-57.
Elon Musk believes: Tweet by Elon Musk, August 26, 2022, https://twitter.com/elonmusk/status/1563020169160851456.
Nevertheless, as people live longer: J. R. Goldstein and W. Schlag, “Longer Life and Population Growth,” Population and Development Review 25, no. 4 (December 1999): 741–47, https://doi.org/10.1111/j.1728-4457.1999.00741.x.
Large percentages of people: Paul Root Wolpe, quoted in Jenny Kleeman, “Who Wants to Live Forever? Big Tech and the Quest for Eternal Youth,” New Statesman online, last modified October 13, 2021, https://www.newstatesman.com/long-reads/2022/12/live-forever-big-tech-search-quest-eternal-youth-long-read.
In 2023: Angelique Chrisafis, “More Than 1.2 Million March in France over Plan to Raise Pension Age to 64,” Guardian (US edition) online, last modified March 7, 2023, https://www.theguardian.com/world/2023/mar/07/nationwide-strikes-in-france-over-plan-to-raise-pension-age-to-64.
Reacting to the French protests: Annie Lowrey, “The Problem with the Retirement Age Is That It’s Too High,” Atlantic online, last modified April 15, 2023, https://www.theatlantic.com/ideas/archive/2023/04/social-security-benefits-france-pension-protests/673733/.
Most studies say our general cognitive abilities: T. A. Salthouse, “When Does Age-Related Cognitive Decline Begin?,” Neurobiology of Aging 30, no. 4 (April 2009): 507–14, https://doi.org/10.1016/j.neurobiolaging.2008.09.023; L. G. Nilsson et al., “Challenging the Notion of an Early-Onset of Cognitive Decline,” Neurobiology of Aging 30, no. 4 (April 2009): 521–24, discussion 530, https://doi.org/10.1016/j.neurobiolaging.2008.11.013; T. Hedden and J. D. Gabrieli, “Insights into the Ageing Mind: A View from Cognitive Neuroscience,” Nature Reviews Neuroscience 5, no. 2 (February 2004): 87–96, https://doi.org/10.1038/nrn1323.
The one category: A. Singh-Manoux et al., “Timing of Onset of Cognitive Decline: Results from Whitehall II Prospective Cohort Study,” BMJ 344, no. 7840 (January 5, 2012): d7622, https://doi.org/10.1136/bmj.d7622.
The latter declines steadily: D. Murman, “The Impact of Age on Cognition,” Seminars in Hearing 36, no. 3 (2015): 111–21, https://doi.org/10.1055/s-0035-1555115.
This is partly because: Household total wealth in Great Britain: April 2018 to March 2020, Office of National Statistics, January 7, 2022, https://www.ons.gov.uk/peoplepopulationandcommunity/per sonalandhouseholdfinances/incomeandwealth/bulletins/totalwealth ingreatbritain/april2018tomarch2020; Donald Hays and Briana Sullivan, The Wealth of Households:2020, United States Census Bureau, August 2022, https://www.census.gov/content/dam/Census/library/publications/2022/demo/p70br-181.pdf.
By contrast, the vast majority: D. Murman, “The Impact of Age on Cognition,” Seminars in Hearing 36, no. 3 (2015): 111–21, https://doi.org/10.1055/s-0035-1555115.
“at the peak of their careers”: “Tom Williams, “Oxford Professors ‘Forced to Retire’ Win Tribunal Case,” Times Higher Education, March 17, 2023, https://www.timeshighereducation.com/news/oxford-professors-forced-retire-win-tribunal-case.
“I had been telling”: P. B. Moore, “Neutrons, Magnets, and Photons: A Career in Structural Biology,” Journal of Biological Chemistry 287, no. 2 (January 2012): 805–18, https://doi.org/10.1074/jbc.X111.324509.
The other concluded: V. Skirbekk, “Age and Individual Productivity: A Literature Survey” (MPIDR working paper WP 2003–028, Max Planck Institute for Demographic Research, Rostock, Ger., August 2003), https://www.demogr.mpg.de/papers/working/wp-2003-028.pdf; C. A. Viviani. et al. “Productivity in Older Versus Younger Workers: A Systematic Literature Review,” Work 68, no. 3 (2021): 577–618, https://doi.org/10.3233/WOR-203396.o.
There is a lot of evidence: P. A. Boyle et al., “Effect of a Purpose in Life on Risk of Incident Alzheimer Disease and Mild Cognitive Impairment in Community-Dwelling Older Persons,” Archives of General Psychiatry 67, no. 3 (March 2010): 304–10, https://doi.org/10.1001/archgenpsychiatry.2009.208; R. Cohen, C. Bavishi, and A. Rozanski, “Purpose in Life and Its Relationship to All-Cause Mortality and Cardiovascular Events: A Meta-Analysis,” Psychosomatic Medicine 78, no. 2 (February/March 2016): 122–33, https://doi.org/10.1097/PSY.0000000000000274.
Social isolation and loneliness: A. Steptoe et al., “Social Isolation, Loneliness, and All-Cause Mortality in Older Men and Women,” Proceedings of the National Academy of Sciences (PNAS) of the United States of America 110, no. 15 (March 25, 2013): 5797–801, https://doi.org/10.1073/pnas.1219686110; J. Holt-Lunstad et al., “Loneliness and Social Isolation as Risk Factors for Mortality: A Meta-Analytic Review,” Perspectives on Psychological Science 10, no. 2 (March 2015): 227–37, https://doi.org/10.1177/1745691614568352.
Arieff believes: Allison Arieff, “Life Is Short. That’s the Point,” New York Times online, August 18, 2018, https://www.nytimes.com/2018/08/18/opinion/life-is-short-thats-the-point.html.
The clear-eyed view: Report: Living to 120 and Beyond: Americans’ Views on Aging, Medical Advances and Radical Life Extension (Washington, DC: Pew Research Center, August 6, 2013), https://www.pewresearch.org/religion/2013/08/06/living-to-120-and-beyond-americans-views-on-aging-medical-advances-and-radical-life-extension/.
Index
A specific form of pagination for this digital edition has been developed to match the print edition from which the index was created. If the application you are reading this on supports this feature, the page references noted in this index should align. At this time, however, not all digital devices support this functionality. Therefore, we encourage you to please use your device’s search capabilities to locate a specific entry.