In government laboratories and elsewhere, scientists are seeking a drug able to prolong life and youthful vigor. Studies of caloric restriction are showing the way

在国家实验室和其他相关机构，科学家们正着力寻找能够延长生命和保持年轻活力的药物。热量限制的研究正使此种药物的研发初显端倪

As researchers on aging noted recently, no treatment on the market today has been proved to slow human aging - the build-up of molecular and cellular damage that increases vulnerability to infirmity as we grow older. But one intervention, consumption of a low-calorie* yet nutritionally balanced diet, works incredibly well in a broad range of animals, increasing longevity and prolonging good health. Those findings suggest that caloric restriction could delay aging and increase longevity in humans, too.

研究衰老的研究人员最近公布说，目前市场上仍无药物疗法被证明可以减缓衰老进程。所谓衰老就是，随着我们年龄的增长，体内分子和细胞不断受损使得身体越来越趋向虚弱的过程。但一项在多种动物身上做的实验表明，低热量而营养均衡的饮食在增加寿命、延长身体健康状态方面效果显著。那些发现指出，热量限制用在人类身上也可以延缓衰老延长寿命。

遗憾的是，为了最有利于健康，人类不得不减少大概30％的热量摄取，也就是从每日摄取2 500卡减少到每日摄取1 750卡。很少有人能够严格遵循这一苛刻的养生法，更别说要连续坚持多年了。但是否真有人能制造出一种药片，企图模仿节食带来的生理反应而实际上并不强迫人节食?这样一种“热量限制模仿品”，姑且这么称呼它，真的能让人类长保健康，延缓衰老引起的疾病(如糖尿病、动脉硬化、心脏病、癌症)直至长命百岁吗?在有研究人员制造出一种取自啮齿科动物的可以再生热量限制产生的益处的化学药剂之后，科学家在20世纪中期首先提出了这个问题。至今仍没发现任何一种化合物能够安全地在人类身上达到相同功效，不过大量的研究结果显示，已经有希望最终能真正研制成功热量限制食物(CR)的模仿品。

Unfortunately, for maximum benefit, people would probably have to reduce their caloric intake by roughly thirty per cent, equivalent to dropping from 2,500 calories a day to 1,750. Few mortals could stick to that harsh a regimen, especially for years on end. But what if someone could create a pill that mimicked the physiological effects of eating less without actually forcing people to eat less? Could such a 'caloric-restriction mimetic', as we call it, enable people to stay healthy longer, postponing age-related disorders (such as diabetes, arteriosclerosis, heart disease and cancer) until very late in life? Scientists first posed this question in the mid-1990s, after researchers came upon a chemical agent that in rodents seemed to reproduce many of caloric restriction's benefits. No compound that would safely achieve the same feat in people has been found yet, but the search has been informative and has fanned hope that caloric-restriction (CR)mimetics can indeed be developed eventually.

热量限制的好处

人们对热量限制模仿品的追求出于更好地理解热量限制对人体的诸多影响的愿望。科学家早在60多年前就首先认识到了这项研究的价值，当时他们发现喂食低热量食物的小白鼠要比不控制饮食热量的小白鼠活得长，而且到了老年也更少出现越来越普遍的老年疾病。此外，在受控制组里，一些喂食低热量食物的动物比原来生命最长的同类还要长寿。这意味着不只是生命的平均寿命在增加，而且是生命的最长寿命也在增加。不同的外在因素，比如传染病防治药物，能够延长人的平均存活时间，但只限于减缓人体衰老速度以增加人类的最大寿命期限的方法。

The benefits of caloric restriction

小白鼠的实验结果反复进行了很多次，实验后来延伸到从酵母到果蝇、蠕虫、鱼、蜘蛛、老鼠和仓鼠等很多生物身上。直到最近，研究对象还局限于存活时间较短且基因结构同人类有较大差异的动物。但是，在进行中的热量限制研究项目里，恒河猴和松鼠两种动物的基因构造比较接近人类。这一发现让科学家们喜出望外，热量限制模仿品可能用于帮助人类。

关于猴子的研究项目表明，相对于饮食正常的接受控制的动物，热量受限制的猴子的体温更低，胰岛素分泌水平也低，并且保留更多的使得身体年轻的荷尔蒙，而这种荷尔蒙之前恰会随着年龄的增长而减少。

The hunt for CR mimetics grew out of a desire to better understand caloric restriction's many effects on the body. Scientists first recognized the value of the practice more than 60 years ago, when they found that rats fed a low-calorie diet lived longer on average than free-feeding rats and also had a reduced incidence of conditions that become increasingly common in old age. What is more, some of the treated animals survived longer than the oldest-living animals in the control group, which means that the maximum lifespan (the oldest attainable age), not merely the normal lifespan, increased. Various interventions, such as infection-fighting drugs, can increase a population's average survival time, but only approaches that slow the body's rate of aging will increase the maximum lifespan.

接受热量限制实验的动物在抵御老年疾病方面也表现甚好。比如，它们的血压和甘油三酸酯偏低(这说明患心脏病的可能性减小)，血糖正常(指患糖尿病的风险减小。而通常血糖高是患糖尿病的标志)。而且，最近发现一直食用热量限制食物近15年的恒河猴患慢性病的很少。不过，它们和其他猴子还将接受更长时间的跟踪实验，才能知道低热量摄入能否延长猴子的平均和最长寿命。与众多自吹为最新研发的抗衰老长生不老药不同，热量限制替代品通过改变隐藏于老化作用背后的最根本过程而起作用。我们的目标是开发一些化合物，这些化合物可以骗取细胞积极地进行保养和修复。

热量限制替代晶如何发生作用

The rat findings have been replicated many times and extended to creatures ranging from yeast to fruit flies, worms, fish, spiders, mice and hamsters. Until fairly recently, the studies were limited to short-lived creatures genetically distant from humans. But caloric-restriction projects underway in two species more closely related to humans - rhesus and squirrel monkeys - have made scientists optimistic that CR mimetics could help people.

研究得出的最好的热量限制替代品2DG(2个脱氧D葡萄糖)通过干扰细胞处理葡萄糖的过程起作用。可是。给动物服用了一定剂量后发现有毒性，因此还不能用于人体实验。但这说明化学药物可以复制热量限制的效果，诀窍是找到合适的化学药物。

细胞利用食物中的葡萄糖生成ATP(三磷酸腺苷)，这是一种向机体许多活动提供动力来源的分子。通过控制饮食，热量限制使最少量的葡萄糖进入细胞，从而减少ATP的形成。当饮食不受控制的动物食用了2DG后，大量葡萄糖到达细胞，不过药物会阻止大部分葡萄糖参与处理过程，进而减少ATP生成物。针对为何干预葡萄糖的合成过程和ATP的生成会延缓衰老，研究人员给出了几点解释。一种可能同ATP产生的自由基的组织排泄物有关，这种物质被认为会导致衰老，并且引发相关年龄阶段的并发症，比如，通过损害正常细胞而引发癌症。退化的组织机能应该控制它们的产出物，借此降低细胞损耗。另一种假设表明，减少葡萄糖合成过程对细胞而言预示着人体内食物缺乏(即使实际食物并不缺乏)，从而促使细胞转移到抗衰老状态，在有机体生长和繁殖阶段加强对有机体的保护。

The monkey projects demonstrate that, compared with control animals that eat normally, caloric-restricted monkeys have lower body temperatures and levels of the pancreatic hormone insulin, and they retain more youthful levels of certain hormones that tend to fall with age.

The caloric-restricted animals also look better on indicators of risk for age-related diseases. For example, they have lower blood pressure and triglyceride levels (signifying a decreased likelihood of heart disease), and they have more normal blood glucose levels (pointing to a reduced risk for diabetes, which is marked by unusually high blood glucose levels). Further, it has recently been shown that rhesus monkeys kept on caloric-restricted diets for an extended time (nearly 15 years) have less chronic disease. They and the other monkeys must be followed still longer, however, to know whether low-calorie intake can increase both average and maximum lifespans in monkeys. Unlike the multitude of elixirs being touted as the latest anti-aging cure, CR mimetics would alter fundamental processes that underlie aging. We aim to develop compounds that fool cells into activating maintenance and repair.

How a prototype caloric-restriction mimetic works

The best-studied candidate for a caloric-restriction mimetic, 2DG (2-deoxy-D-glucose), works by interfering with the way cells process glucose. It has proved toxic at some doses in animals and so cannot be used in humans. But it has demonstrated that chemicals can replicate the effects of caloric restriction; the trick is finding the right one.

Cells use the glucose from food to generate ATP (adenosine triphosphate), the molecule that powers many activities in the body. By limiting food intake, caloric restriction minimizes the amount of glucose entering cells and decreases ATP generation. When 2DG is administered to animals that eat normally, glucose reaches cells in abundance but the drug prevents most of it from being processed and thus reduces ATP synthesis. Researchers have proposed several explanations for why interruption of glucose processing and ATP production might retard aging. One possibility relates to the ATP-making machinery's emission of free radicals, which are thought to contribute to aging and to such age-related diseases as cancer by damaging cells. Reduced operation of the machinery should limit their production and thereby constrain the damage. Another hypothesis suggests that decreased processing of glucose could indicate to cells that food is scarce (even if it isn't) and induce them to shift into an anti-aging mode that emphasizes preservation of the organism over such 'luxuries' as growth and reproduction.

* calorie: a measure of the energy value of food