[2008.01.03] How to live forever 长生不老 青春永驻

The paradox is that the individual’s evolved desire not to age is opposed by another evolutionary force: the disposable soma. The soma (the ancient Greek word for body) is all of a body’s cells apart from the sex cells. The soma’s role is to get those sex cells, and thus the organism’s genes, into the next generation. If the soma is a chicken, then it really is just an egg’s way of making another egg. And if evolutionary logic requires the soma to age and die in order for this to happen, so be it. Which is a pity, for evolutionary logic does, indeed, seem to require that.
这一矛盾就在于，人类进化产生的对衰老的违抗意愿会被另一种进化的力量——“可弃置的躯体论”反对。躯体（这个词源于古希腊语中的身体）指的是除生殖细胞外其它体细胞的总和。躯体的角色是把生殖细胞（也就是有机体的基因）遗传给下一代。如果这个躯体是一只鸡，那么这只鸡的躯体无非是由一枚鸡蛋生出另一枚鸡蛋的载体而已。如果进化逻辑为了让这个过程发生而要求躯体衰老和死亡，那么躯体也只能从命。令人遗憾的是，进化逻辑似乎确实需要这样做。

The argument is this. All organisms are going to die of something eventually. That something may be an accident, a fight, a disease or an encounter with a hungry predator. There is thus a premium on reproducing early rather than conserving resources for a future that may never come. The reason why repairs are not perfect is that they are costly and resources invested in them might be used for reproduction instead. Often, therefore, the body’s mechanics prefer lash-ups to complete rebuilds—or simply do not bother with the job at all. And if that is so, the place to start looking for longer life is in the repair shop.
论点是这样的：一切生命最终都将死去。可能源于一起事故，一次搏斗，一场疾病或碰巧遇到饥饿的捕食者。所以选择早些繁殖就比选择为一个不可预见的未来而保留资源来得划算。修复之所以不是理想的办法，是因为修复代价太大，而且用在修复上的那些资源可能还要用来繁殖。因此，身体结构常常宁愿残缺也不愿彻底修缮，或者根本就置之不理。如果这样的话，那么开始寻找延长生命的秘密之旅的首站就是这“生物维修厂”。

Seven deadly things
七个致命物

One man who has done just that is Aubrey de Grey. Dr de Grey, who is an independent researcher working in Cambridge, England, is a man who provokes strong opinions. He is undoubtedly a visionary, but many biologists think that his visions are not so much insights as mischievous mirages, for he believes that anti-ageing technology could come about in a future that many now alive might live to see.
奥布里•德•戈瑞恰恰就是这样做的。他在英国剑桥大学工作，是一个煽动强烈观点的独立研究者。无疑，他是一位幻想家，可是好多生物学家认为他的那些“远见”如同恶作剧的海市蜃楼无任何洞察力可言，因为他相信抗衰老的技术会在我们有生之年的不久将来问世。

Vision or mirage, Dr de Grey has defined the problem precisely. Unlike most workers in the field, he has an engineering background, and is thus ideally placed to look into the biological repair shop. As he sees things, ageing has seven components; deal with all seven, and you stop the process in its tracks. He refers to this approach as strategies for engineered negligible senescence (SENS).
不论是“远见”还是“海市蜃楼”，德•戈瑞博士已经准确地给出了这个问题的定义。与大多业界人士不同的是，他拥有工程学教育背景，这为他对“生物维修厂”进行研究提供了理想条件。他认为衰老有七个因素；能对付所有这七个因素，就能阻止衰老进程。他把这一想法称作“机械上可忽略衰老策略”（SENS）。

The seven sisters that Dr de Grey wishes to slaughter with SENS are cell loss, apoptosis-resistance (the tendency of cells to refuse to die when they are supposed to), gene mutations in the cell nucleus, gene mutations in the mitochondria (the cell’s power-packs), the accumulation of junk inside cells, the accumulation of junk outside cells and the accumulation of inappropriate chemical links in the material that supports cells.
德•戈瑞博士想用这一策略对付的七个因素是：细胞丢失，细胞凋亡阻抑（细胞拒绝程序死亡的倾向），细胞核内的基因突变，线粒体（细胞的“动力仓”）中的基因突变，细胞内的垃圾堆积，细胞外的垃圾堆积和细胞支持性物质中不当化学键堆积。

It is quite a shopping list. But it does, at least, break the problem into manageable parts. It also suggests that multiple approaches to the question may be needed. Broadly, these are of two sorts: to manage the process of wear and tear to slow it down and mask its consequences, or to accept its inevitability and bring the body in for servicing at regular intervals to replace the worn-out parts.
这可真是一份琳琅满目的“购物单”。但至少它将问题分割为易管理的各个部分。它也暗示处理此问题可能需要多样的解决途径。大体上说，有两种途径，一是管理磨损过程，让它放缓并掩盖它的后果。二是承认磨损是不可避免的，定期对身体进行保养，替换掉受损零件。

Eat up your greens
使劲儿吃蔬菜

Managing wear and tear may not be as complicated as it looks, for the last five items on Dr de Grey’s list seem to be linked by a single word: oxidation. Regular visitors to the “health and beauty” sections of high-street pharmacies will, no doubt, have come across creams, pills and potions bearing the word antioxidant on their labels and hinting—though never, of course, explicitly saying—that they might possibly have rejuvenating effects. These products are the bastard children of a respectable idea about one of the chief causes of ageing: that one big source of bodily wear and tear, at least at the chemical level, is the activity of the mitochondria.
管理身体磨损并没有表面上看起来那样复杂，因为德•戈瑞单子上的后五条的共同之处似乎可用一个词概括：氧化。商业街上众多药房“保健美容”部门的常客一定见过面霜、药片和服剂上贴有写着“抗氧化剂”字样的标签，并暗示，当然从不明说，可能有使人年轻的功效。这些产品窃取了有关衰老主要原因的一个重大想法：躯体的磨损在很大程度上，至少在化学水平上说，源于线粒体的活跃。

Mitochondria are the places where sugar is broken down and reacted with oxygen to release the energy needed to power a cell. In a warm-blooded creature such as man, a lot of oxygen is involved in this process, and some of it goes absent without leave. Instead of reacting with carbon from the sugar to form carbon dioxide, it forms highly reactive molecules called free radicals. These go around oxidizing—and thus damaging—other molecules, such as DNA and proteins, which causes all sorts of trouble. Clear up free radicals and their kin, and you will slow down the process of ageing. And the chemicals you use to do that are antioxidants.
线粒体是糖分解并与氧反应释放能量为细胞提供动力的场所。在温血动物如人类身上，大量的氧参与了这一过程，其中一些氧侥幸逃脱了。它们没有和糖中的碳反应形成二氧化碳，而是形成高活性分子——自由基。这些自由基四处活动氧化并破坏了其他分子，如DNA和蛋白质，这种氧化带来了各种问题。只要能清除掉自由基和其同族分子，就能减缓衰老过程。而用于清理自由基的化学药品就是抗氧化剂。

This idea goes back to one of the founders of scientific gerontology, Bruce Ames of the University of California, Berkeley. Dr Ames began his career studying cancer. He found that damage to certain genes was a cause of cancer. These genes evolved to keep tumours at bay by stopping cells dividing too readily, and the damage was often done by oxidation. Gradually, his focus shifted to the more general damage that oxidation can do—and what might, in turn, be done about it.
这一观点可以追溯到老年医学的创始人之一加州大学伯克利分校的布鲁斯•艾姆斯。艾姆斯博士一开始研究癌症。他发现某些特定基因的毁坏是产生癌症的原因之一。这些特定基因演化出能通过阻止细胞过快地分裂来抑制肿瘤的功能，这些特定基因的破坏通常由氧化导致。逐渐地，他把注意力转移到氧化所造成的更普遍的伤害上，并琢磨怎样才能对付这一过程。

Some vitamins, such as vitamin C, are antioxidants in their own right. This is the basis of the high-street propaganda, though there is no evidence that consuming such antioxidants in large quantities brings any benefit. A few years ago, however, Dr Ames found he could pep up the activity of the mitochondria of elderly rats—with positive effects on the animals’ memories and general vigour—by feeding them two other molecules: acetyl carnitine and lipoic acid. These help a mitochondrial enzyme called carnitine acetyltransferase to do its job. Boosting their levels seems to compensate for oxidative damage to this enzyme. He also reviewed the work of other people and found about 50 genetic diseases caused by the failure of one enzyme or another to link up with an appropriate helper molecule. Such helpers are often B vitamins, and the diseases were often treatable with large doses of the appropriate vitamin.
一些维生素，如维生素C，自身就是抗氧化剂。这是商业街上宣传的根据，尽管没有证据证明大量服用这类抗氧化剂有何益处。然而几年前，艾姆斯博士发现通过喂食乙酰肉碱和硫辛酸能够刺激高龄小鼠线粒体的活性，这对动物的记忆和活力的提升有积极的效果。这两种分子有助于被称作肉碱乙酰转移酶的线粒体酶发挥作用。提高它们的含量似乎可以弥补这种酶的氧化损坏。他还参阅了其他人的工作，并发现大约50个遗传疾病都是由一个酶或其他酶与合适的辅助分子的连接失败引起的。那些辅助分子通常是B类维生素，并且这类基因疾病通常都可以采用大剂量合适的维生素来治疗。

The enzyme damage in these diseases is similar to that induced by oxidation, so Dr Ames suspects that its effects, too, can be ameliorated by high doses of vitamins. He has gathered evidence from mice to support this idea, but whether it is the case in people has yet to be tested. Nor is it easy to believe it ever will be. The necessary clinical trials would be long-winded. They would also be expensive—and there is no reason for vitamin companies to pay for them since sales are already buoyant and the products could not be patented. Nor is Dr Ames claiming vitamins will make you live longer than a natural human lifespan, even if he thinks they might prolong many individual lives. For that, other technologies will need to be invoked.
这些疾病中出现的酶的损害与氧化引起的酶的损害是类似的，因此艾姆斯博士猜想用高剂量的维生素是否也能改善其影响。他已经从老鼠实验中收集了支持这一观点的证据，但它对人是否也起作用还有待进一步测试。会不会进行这样的试验也是个问题。必要的临床实验将是很漫长的，而且费用昂贵，维生素公司没有任何理由会为它买单，因为销售业绩已经很旺，更何况这样的产品也不能申请专利。即便艾姆斯博士自己认为维生素可能会延长很多人的生命，但没有表示这个延长会长于自然寿命。因此，还需要另想别的技术。

Stemming time’s tide
让时光停滞

One way that might let people outlive the limit imposed by disposable somas is to accept the machine analogy literally. When you take your car to be serviced or repaired, you expect the mechanic to replace any worn or damaged parts with new ones. That, roughly, is what those proposing an idea called partial immortalisation are suggesting. And they will make the new parts with stem cells.
人们可能突破“可弃置的躯体”所赋予的生命极限的一个途径就是完全接受这一机械比喻的观点。当你把车开去维修时，你希望机修工把磨损的零件换成新的。概略地讲，这就是那些鼓吹“局部永生论”观点的人所要推荐的理论。而且他们准备用干细胞生产新部件。

The world has heard much of stem cells recently. They come in several varieties, from those found in embryos, which can turn into any sort of body cell, to those whose destiny is constrained to becoming just one or a few sorts of cell. The thing about stem cells of all types, which makes them different from ordinary body cells, is that they have special permission to multiply indefinitely.
最近，有关干细胞的新闻已屡见不鲜。干细胞分几种。有的源自胚胎，能发展成任何种类的体细胞；有的只能发展成一种或几种体细胞。所有种类的干细胞具有一个共同特点：能够无限繁殖，这也是干细胞与普通体细胞的不同之处。

For a soma to work, most of its component cells have to accept they are the end of the line—which, given that that line in question stretches back unbroken to the first living organisms more than 3 billion years ago, is a hard thing to do. There are, therefore, all sorts of genetic locks on such cells to stop them reproducing once they have arrived at their physiological destination. If these locks are picked (for example by oxidative damage to the genes that control them, as discovered by Dr Ames), the result is unconstrained growth—in other words, cancer. One lock is called the Hayflick limit after its discoverer, Leonard Hayflick. This mechanism counts the number of times a cell divides and when a particular value (which differs from species to species) is reached, it stops any further division. Unless the cell is a stem cell. Every time a stem cell divides, at least one daughter remains a stem cell, even though the other may set off on a Hayflick-limited path of specialisation.
要躯体运作，其大多数组成细胞必须接受它们是整条生产线的终端，做到这一点并非易事，尤其当被告知这条受到质疑的生产线从在30亿年前的第一批生命中至今都从未中断过。因此，这些细胞一旦到达生理终点，细胞内的各种基因锁就会让它们停止再生。如果这些基因锁被解除（例如，艾姆斯博士发现控制这些锁的基因遭到氧化毁坏的情况），后果就是细胞的无限增生，换句话说就是细胞癌变。伦纳德•海弗利克曾发现过一个基因锁，并以他的姓氏命名为“海弗利克极限”。“海弗利克极限”机制会对细胞分裂次数进行计数，当到达某一特定值（根据不同物种而定）时，就会让细胞停止再分裂。只有干细胞例外。干细胞每分裂一次，至少会有一个子细胞仍然是干细胞，而其它子细胞则可能启动“海弗利克极限”的细胞分化途径。

Some partial immortalisers seek to abolish the Hayflick limit altogether in the hope that tissue that has become senescent will start to renew itself once more. (The clock that controls it is understood, so this is possible in principle.) Most, though, fear that this would simply open the door to cancer. Instead, they propose what is known as regenerative medicine—using stem cells to grow replacements for tissues and organs that have worn out. The most visionary of them contemplate the routine renewal of the body’s organs in a Lincoln’s axish sort of way.
一些“局部永生论”者试图完全打破“海弗利克极限”机制，希望以此能让衰老组织再次自动更新。（人们已经理解控制这一机制的计数器，所以在理论上是可以实现的。）不过多数人担心这只会引发癌症。因此他们改而推荐所谓的“再生药物”即用干细胞培养出磨损组织器官的替代品。其中最天马行空的想法是考虑例行公事似地更新身体器官，如同林肯对待他的斧头一样。

In theory, only the brain could not plausibly be replaced this way (any replacement would have to replicate the pattern of its nerve cells precisely in order to preserve an individual’s memory and personality). Even here, though, stem-cell therapists talk openly of treating brain diseases such as Parkinson’s with specially grown nerve cells, so some form of partial immortalisation might be on the cards. But it is a long way away—further, certainly, than Dr Ames’s vitamin therapy, if that is shown to work.
从理论上讲，大概只有大脑无法按这种方式替换（如果要保留某人的记忆和性格，那么任何一次替换都必须准确地复制出大脑神经细胞的原型）。即使这样，干细胞临床医学家依然在公开探讨用专门培养的神经细胞来治疗诸如帕金森症一类的脑疾病，这样看来，实现某种形式的“局部永生”或许会成为可能。不过，如果要临床验证有效的话，这还有很长的路要走——可以肯定地说，比艾姆斯博士的维生素治疗实现起来还要长。

Neither prevention, nor repair, is truly ready to roll out. But there is one other approach, and this is based on the one way of living longer that has been shown, again and again, in animal experiments, to be effective. That is to eat less.
阻止和修复衰老的方法肯定都不会立即出现。但还有另一个方法就是：少吃。这种方法可以延长生命是有据可循的，在动物实验中，它一再被证实是有效的。

From threadworms to mice, putting an animal on a diet that is near, but not quite at, starvation point prolongs life—sometimes dramatically. No one has done the experiment on people, and no one knows for sure why it works. But it does provide a way of studying the problem with the reasonable hope of finding an answer.
让线虫或小鼠定量饮食，使其接近饥饿但又不完处于饥饿状态时可以延长它们的生命，有时效果非常显著。还没有拿人做过这样的试验，也没有人确切知道这一方法起效的原因。但它的确提供了一种研究问题的方法，让人们满怀合理的希望找到问题的答案。

Gluttons for punishment
贪食者的惩罚

You would, of course, have to wish a lot for a long life to choose to starve yourself to achieve it. Extrapolating from the mouse data, you would need to keep your calorie intake to three-quarters of the amount recommended by dieticians. That means about 1,800 for sedentary men and 1,500 for sedentary women. But several people are trying to understand the underlying biology, in order to develop short cuts.
理所当然，你一定非常希望长寿，如果愿意选择挨饿来实现长寿。那么，据小鼠试验数据推断，你必须让卡路里摄入量保持在营养学家推荐量的四分之三以内。这意味着久坐的男性卡路里摄入量是1800，久坐的女性是1500。除此之外，一些人正设法弄懂潜在的生物学原理，以此寻找捷径。

One such is David Sinclair of Harvard University. Unlike those trying to fight the causes of ageing or to repair the damage done, Dr Sinclair thinks he has found, in caloric restriction as the technique is known, a specifically evolved natural anti-ageing mechanism that is quite compatible with disposable-soma theory.
哈佛大学的大卫•辛克莱就是其中之一。和那些设法抵抗衰老或试图把损坏修缮的人们不同，在技术上众所周知的“卡路里限制”理论中，辛克莱博士认为他已经发现了一个特殊的自然进化的抗衰老机制，它的机理与“可弃置躯体”理论非常一致。

The reason for believing that prolonged life is an evolutionary response to starvation rather than just a weird accident is that when an animal is starving the evolutionary calculus changes. An individual that has starved to death is not one that can reproduce. Even if it does not die, the chance of it giving birth to healthy offspring is low. In this case, prolongation of life should trump reproduction. And that is what happens, even among people. Women who are starving stop ovulating. The billion-dollar trick would be to persuade the body it is starving when it is not. That way people could live longer while eating normally. They might even, if the mechanism can truly be understood, be able to reproduce, as well.
之所以认为生命的延长是饥饿状态下进化的反应而不是神秘的巧合，是因为动物在饥饿状态下进化的积累发生了变化。饿死的动物是无法繁殖后代的。即使没饿死，生下健康后代的机率也很低。既然这样，延长生命就比繁殖后代来得重要。事实正是如此，即便人类也是这样。饥饿的女性会停止排卵。代价高昂的错觉就是在不饿的时候要让身体相信它在挨饿。这样人们在正常饮食情况下就可以延长生命。如果这个机制能被彻底弄清楚，那么人们在延年益寿的同时亦可繁衍生息。

In Dr Sinclair’s view, the way caloric restriction prolongs life revolves around genes for proteins called sirtuins. Certainly, these genes are involved in life extension in simple species such as threadworms and yeast. Add extra copies of them to these organisms’ chromosomes, or force the existing copies to produce more protein than normal, and life is prolonged. This seems to be because sirtuins control the abundance of a regulatory molecule called nicotinamide adenine diphosphate which, in turn, controls the release of energy in the mitochondria.
辛克莱博士认为，卡路里限制机理延长生命的途径与产生被称作sirtuins蛋白的基因有关。毫无疑问，这些基因在诸如线虫和酵母等简单物种的生命延长过程中发挥了作用。向这些生物体染色体中加入更多这类基因拷贝，或让现有的这类基因产生比正常情况下更多的蛋白质就能将生命延长。好像是因为sirtuins蛋白控制了被称作烟碱腺嘌呤二磷酸的调控分子的丰度，从而控制了线粒体中能量的释放。

The most intriguing connection in this story is with the French paradox. This is the fact that the French tend to eat fatty diets rich in red meat but to have the survival characteristics of those whose diets are lean and vegetarian. Some researchers link this with their consumption of red wine—and, in particular, of a molecule called resveratrol that is found in such wine. Resveratrol activates sirtuins, and some similar molecules activate them much more. It is these sirtuin super-stimulators that interest Dr Sinclair.
在这个报道中，最为有趣的地方是它与法国人生活中一个悖论相关联。事情是这样的，法国人倾向于吃富含脂肪的瘦肉食品却拥有那些饮食素淡者的生存特质。有些研究人员将这个悖论和法国人爱喝红酒联系起来，特别是，在红酒中发现了一种被称作白藜芦醇的分子。白藜芦醇分子可以激活sirtuins蛋白，一些类似的分子可以使其sirtuins活性更高。正是这些sirtuin蛋白超级刺激因子引起了辛克莱博士的兴趣。

Not everyone is convinced, but Dr Sinclair has done experiments on mice that look promising, and has started a company called Sirtris Pharmaceuticals to follow it up. The fact that he is (at least in his own eyes) working with nature rather than against it argues that this is the most promising approach of all.
并非所有人都对这个说法深信不疑，但是辛克莱博士已用小鼠作了试验并看到了希望，为了探明经纬他紧跟着创办了Sirtris医药公司。他正与大自然合作而不是抵抗（至少他这样认为），这一事实论证了这个方法是所有延长生命途径中最有希望的一个。

That said, the logic of the disposable-soma theory is profound. Even working with its grain may do no more than buy a few extra years of healthy living. Dr de Grey’s reason for thinking that some people now alive may see their lives extended indefinitely is based on the hope that those few extra years will see further discoveries and improved life-extension technologies based on them—a process he describes as achieving “longevity escape velocity”.
尽管如此，“可弃置的躯体论”的逻辑原理依然高深莫测。即使按着这个理论运作，人们无非也就是多过上几年的健康生活。德•格瑞博士之所以认为有些在世的人能够在其有生之年体验生命得以无限延伸，是因为寄希望于在这多活得几年时间里会有更多的新发现和改进了的生命延长技术问世，他把这个过程形容为实现了“寿命摆脱了速度”。

The chances are that it will not work. But hope springs eternal. To end with another quote, this time from Woody Allen, “I don’t want to achieve immortality through my work. I want to achieve immortality through not dying.” If any researcher manages to beat evolutionary history and achieve his goal, he might get to do both.
这些可能性也许不会发生。但希望犹如泉涌一般永无止境。本文再次引言作为结束语，美国著名电影大师伍迪•艾伦曾说：“我不想因我的成就而千古流芳，而是想通过不死实现永垂不朽”。无论哪一位研究人员能够战胜生命进化的历程，实现延长生命的目标，都会千古流芳、永垂不朽。