Longevity
Eat less, live more少食,长寿
Apr 20th 2006
From The Economist print edition
How to live longer—maybe
如何长寿－可能的话
DIETING, according to an old joke, may not actually make you live longer, but it sure feels that way. Nevertheless, evidence has been accumulating since the 1930s that calorie restriction—reducing an animal's energy intake below its energy expenditure—extends lifespan and delays the onset of age－related diseases in rats, dogs, fish and monkeys. Such results have inspired thousands of people to put up with constant hunger in the hope of living longer, healthier lives.They have also led to a search for drugs that mimic the effects of calorie restriction without the pain of going on an actual diet.
据一则古老的笑话所说,节食并不一定能使人长寿,但是它常常会让人感觉如此.然而,二十世纪三十年代以来,层出不穷的证据证明:限制卡路里的摄入量－减少动物的能量摄取到低于其能量消耗－可以延长老鼠,狗,鱼和猴子的寿命,并延缓与年龄相关的疾病.这些结论鼓励那些渴望长寿和健康的人去忍受饥饿.也使得人们开始研制此类药物－它们能模拟限制卡路里摄入量的效果,但是(食用此类药物)人们无需真正节食.
Amid the hype, it is easy to forget that no one has until now shown that calorie restriction works in humans. That omission, however, changed this month, with the publication of the initial results of the first systematic investigation into the matter. This study, known as CALERIE(Comprehensive Assessment of Long－term Effects of Reducing Intake of Energy), was sponsored by America's National Institutes of Health. It took 48 men and women aged between 25 and 50 and assigned them randomly to either a control group or a calorie－restriction regime. Those in the second group were required to cut their calorie intake for six months to 75% of that needed to maintain their weight.
在天花乱坠的宣传中,人们很容易忘记这样一点:至今,仍然没有人能够证明限制卡路里的摄入量对人类同样有效.然而在本月,随着对此进行的第一次系统研究初步结果的公布,填补了这项空白.该研究－称为CALERIE(对减少能量摄取的长期效果的综合评定)－由美国国家健康署资助,它调查了48位年龄在25－50岁的男性和女性,并将其随机分为控制组或者卡路里限制组.卡路里限制组被要求减少其卡路里摄入量至维持体重所需量的75%,坚持六个月.
The CALERIE study is a landmark in the history of the field, because its subjects were either of normal weight or only slightly overweight. Previous projects have used individuals who were clinically obese, thus confusing the unquestionable benefits to health of reducing obesity with the possible advantages of calorie restriction to the otherwise healthy.
CALERIE研究成为该领域历史上的一个里程碑,因为它的研究对象处于正常体重或者只是稍微偏重.由于以往的研究对象都是临床肥胖者,因此,人们会把减肥对健康勿庸置疑的益处与限制卡路里摄入量对健康人群可能带来的好处混淆在一起.
At a molecular level, CALERIE suggests these advantages are real. For example, those on restricted diets had lower insulin resistance (high resistance is a risk factor for type 2 diabetes) and lower levels of low－density lipoprotein cholesterol (high levels are a risk factor for heart disease). They showed drops in body temperature and blood－insulin levels—both phenomena that have been seen in long－lived, calorie－restricted animals. They also suffered less oxidative damage to their DNA.
在分子层面上,CALERIE得出的结论是,:限制卡路里摄入确实会对健康有好处.比如:节食者的胰岛素阻抗性更低(高阻抗性是导致Ⅱ型糖尿病的危险因素)和较少的低密度脂蛋白质胆固醇(较多的低密度脂蛋白质胆固醇会是导致心脏病的危险因素).他们表现出:体温下降和血液－胰岛素量减少－这两种现象在长寿并限制卡路里量的动物身上一直存在.节食者同样有较少的DNA氧化损伤.
Eric Ravussin, of Louisiana State University in Baton Rouge, who is one of the study's authors, says that such results provide support for the theory that calorie restriction produces a metabolic adaptation over and above that which would be expected from weight loss alone. (He also points out that it will be a long time before such work reveals whether calorie restriction actually extends life.) Nevertheless, such metabolic adaptation could be the reason why calorie restriction is associated with longer lifespans in other animals—and that is certainly the hope of those who, for the past 15 years, have been searching for ways of triggering that metabolic adaptation by means other than semi－starvation.
来自路易斯安那州立大学(位于巴吞鲁日)的Eric Ravussin是该研究报告的作者之一,他认为这些结果可以证明:限制卡路里可以产生新陈代谢调节,其水平高于单纯减肥产生的新陈代谢调节.(他同时指出,要揭示限制卡路里是否能够真正延长寿命需要很长的时间).然而,这种新陈代谢调节可以解释其他动物中卡路里限制与长寿有关的原因－这当然是一些人所希望的,这些人在过去的15年一直寻找如何通过其他方法而非半饥饿状态来引发这种调节.
The search for a drug that will stave off old age is itself as old as the hills—as is the wishful thinking of the suckers who finance such efforts. Those who hope to find it by mimicking the effect of calorie restriction are not, however, complete snake－oil salesmen, for there is known to be a family of enzymes called sirtuins, which act both as sensors of nutrient availability and as regulators of metabolic rate. These might provide the necessary biochemical link between starving and living longer.
对抗衰老药物的研究可谓年深日久－同样资助此研究的轻信者们一直对此都怀有美好愿望.他们希望通过模拟限制卡路里的作用来研制药物,然而他们并非完全只是些江湖郎中,因为人类已经发现名为”去乙酰化酶”的酶家族,它既是有效营养量的传感器又是新陈代谢速率的调节器.这些酶也许能建立饥饿和长寿之间必然的生化联系.
An elixir of life?
长生不老药?
Boosting the activity of sirtuins in yeast, nematode worms and fruitflies (three rapidly reproducing stalwarts of biological laboratories) does indeed result in longer lifespans. In 2003 a team led by David Sinclair of Harvard Medical School described 19 plant－derived molecules that activate sirtuins in yeast. One of these molecules, resveratrol, is found in red wine—which created excitement among those who think that a wine－rich diet is part of the explanation for the healthy old age apparently enjoyed by many who live in southern Europe.
提高酵母,线形虫和果蝇(这三种生物在生物实验室能快速繁殖)体内去乙酰化酶的活性,确实能延长它们的寿命.2003年,在哈佛医学院David Sinclair的领导下,一个医学团队描述了19种来源于植物、能激发酵母中去乙酰化酶活性的分子.其中,白藜芦醇存在于红酒中,这一发现使得一些人非常兴奋,他们认为日常饮食多喝些酒晚年可以更健康,南欧的许多居民正是如此.
In February, a group led by Dario Valenzano of the Scuola Normale Superiore in Pisa, Italy, showed that the effect applies in vertebrates, too. Dr Valenzano's experiments with resveratrol increased the maximum lifespan of a small fish, called Nothobranchius furzeri, by 60%.(Nothobranchius furzeri was chosen because it is the shortest－lived vertebrate known, with a normal maximum lifespan of 12 weeks.)
2月，意大利比萨高级师范学校的Dario Valenzano领导的研究小组表示脊椎动物同样存在这种现象.Valenzano博士对白藜芦醇的研究延长了一种名叫非洲齿鲤的小鱼的最长寿命,延长达六成.（选择非洲齿鲤是因为它是已知的寿命最短的脊椎动物,一般最长能活12周.）
Resveratrol, however, is only a starting point. Sirtris Pharmaceuticals, a firm based in Cambridge, Massachusetts, of which Dr Sinclair is a co－founder, has identified a number of synthetic molecules whose effect on yeast is many times more potent than resveratrol's. Although there is, as yet, no published evidence that sirtuins extend life in mammals, or that resveratrol activates sirtuins in human cells, some of these molecules are already in clinical trials for safety.
然而, 白藜芦醇只是一个开始.赛特里斯制药公司(位于马萨诸塞州的剑桥,Sinclair博士是其创立者之一)已经鉴别出大量的合成分子,这些分子对酵母的作用比白藜芦醇强许多倍.尽管目前还不能证明去乙酰化酶能延长哺乳动物的寿命,也不能证明白藜芦醇能激发人体细胞中去乙酰化酶的活性,但是对其中一些分子的安全性的临床试验已经进行.
Moreover, Dr Sinclair thinks he knows why plant molecules such as resveratrol might affect longevity in animals. Resveratrol is produced when a vine is under stress—for example, due to dehydration or over－exposure to sunshine. According to Dr Sinclair's theory, which he calls xenohormesis, animals rely on such botanical stress signals to give them extra information about their own environments, in the same way that the alarm calls of one species warn others of danger. If bad things are happening to plants, he surmises, that is a reason for pre－emptive animal action. Animal bodies thus react to molecules such as resveratrol by activating their own defence mechanisms. These, in turn, protect their cells from stress－related damage.
此外,Sinclair博士认为他了解植物分子（如白藜芦醇）能影响动物寿命的原因.当葡萄树受到压力时－如脱水或在阳光下暴晒,它就能制造白藜芦醇.根据Sinclair博士的理论(他称之为外来毒物兴奋效应),动物依赖这种植物压力信号来获得有关自身环境的额外信息,这与一种物种对其他物种发出危险警告信号的方式相同.Sinclair博士猜测,植物遇到不测是动物采取先发制人行动的原因.因此,动物体通过激活自身防御机制,对诸如白藜芦醇的分子做出反应.反过来,这些防御机制也可以保护动物的细胞免受与压力有关的损伤.
Xenohormesis is a variation of a more general theory, hormesis, which interests Suresh Rattan of Aarhus University in Denmark. A good example of hormesis is exercise. In theory, this should damage cells because it increases oxygen uptake, and oxidative stress is bad for things like DNA.Of course, exercise is not actually bad for cells—and the reason is that the body activates defence mechanisms which overcompensate for the stress the exercise creates, producing beneficial effects. So, while chronic stress is always bad for you, a short period of mild stress followed by a period of recovery can be good.
外来毒物兴奋效应是一种更广泛的理论－毒物兴奋效应－的变体,毒物兴奋效应吸引了丹麦奥尔胡斯大学Suresh Rattan的兴趣.毒物兴奋效应理论一个很好的例子就是锻炼.理论上,锻炼应该会损伤细胞,因为它增加氧的摄入量,而氧化应激对DNA等物质是有害的.当然事实上,锻炼对细胞并无害处,原因在于锻炼时,身体激活了防御机制,防御机制能远远补偿锻炼导致的压力,起到对身体有益的效果.因此,尽管长时间的压力对健康有害,短时间的轻微压力之后,一段时间的恢复是有益处的.
Many of the health benefits of exercise are thought to be due to the synthesis of damagecontrolling molecules called heat－shock proteins, and Dr Rattan's group has been experimenting with other ways of triggering these proteins. He has found, for example, that taken in combination with exercise, a spice called curcumin boosts the production of heat－shock proteins several－fold.
人们认为:锻炼对健康的许多益处归功于锻炼时人体合成了一种叫做热休克蛋白的损伤控制分子,Rattan博士的研究小组不断进行实验,试图用其他方法引发这些蛋白.例如,他发现,在锻炼的同时,摄入一种叫做姜黄素的香料能成倍的增加热休克蛋白的产量.
According to Dr Rattan, such interventions improve the function of a cell over time, and in doing so, may produce clinical benefits such as protection against neurodegenerative diseases. Resveratrol may also produce benefits, he says, but how it does so is not yet clear. He disagrees with Dr Sinclair over the existence of a regulatory pathway for longevity in which sirtuins play a key role. In his view, ageing is about the accumulation of damage, and is not under tight genetic control. Sirtuins will, he says, probably be but a small part of a more complicated picture.
根据Rattan博士的理论,随着时间流逝,这些影响改善了细胞的功能,同时,也可产生许多临床益处(如免受神经退化疾病). Rattan博士认为,白藜芦醇可能也是有益的,但目前它的作用机理尚不清楚.对于是否存在去乙酰化酶在其中发挥主要作用的寿命协调性代谢途径, Rattan博士与Sinclair博士持有异议.Rattan博士认为老化是损伤的不断积累,而且老化并未从基因上得到严格的控制.他说, 去乙酰化酶也许只是更纷繁复杂的情形中很小的一部分.
Dr Rattan also doubts whether calorie restriction will extend maximum human life expectancy. He argues that the concepts of ageing and longevity must be separated. It may, indeed, be possible to reduce or eliminate particular age－related diseases, and that would increase average lifespans in the way that eliminating other diseases has done in the past. But this is not the same as slowing down ageing itself, and thus increasing maximum lifespans. Longevity is a more complex trait than any individual disease, and, in his opinion, it will not be altered so easily.
Rattan博士同样怀疑限制卡路里能否延长人类的期望寿命.他认为,人们应该区分衰老和长寿这两个概念.事实上,也许确实能够减少和消除某些特定的与年龄相关的疾病,并且这将增加人类的平均寿命, 在过去,消除其他疾病也同样提高了人类的平均寿命.但这与减缓老化本身从而增加最长寿命不同.寿命比任何单一的疾病更加复杂,在Rattan博士看来,很难轻易去改变寿命.
Cynthia Kenyon, a researcher at the University of California, San Francisco, and a co－founder of Elixir Pharmaceuticals, another company looking into anti－ageing drugs, believes that molecules such as resveratrol are likely to be approved in the next five to ten years, for use as prophylactics against age－related diseases. People then will start taking them, and a huge natural experiment will get under way. If Dr Rattan is wrong, maximum lifespan as well as average lifespan will increase. If he is right, at least people will enjoy a healthier old age.
Cynthia Kenyon是加州大学旧金山校区的一名研究员,同时也是万能制药公司(另外一家研制抗衰老药物的公司)的创立者之一,他相信在以后的五到十年内,白藜芦醇等分子将有可能通过审批,用于预防与年龄相关的疾病.那时人们将开始服用这类药剂,并进行大量的自然实验.如果Rattan博士是错的,人类的最长寿命和平均寿命将会提高.如果他是对的,那么至少人们将能够享受更加健康的老年生活.
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