少吃热量可以延缓衰老

经济学人：

In 1991 eight volunteers sealed themselves into a huge greenhouse in the desert near Tucson, Arizona. They were part of an experiment seeking to discover whether a carefully curated selection of plants and animals could develop into a self-sustaining ecosystem: a “Biosphere 2” independent of “Biosphere 1”, aka the outside world.

1991年，八名志愿者将自己封闭在亚利桑那州图森附近沙漠中的一个巨大温室里。他们参与了一项实验，旨在探索精心挑选的植物和动物是否可以发展成为一个自我维持的生态系统：独立于“生物圈 1”（即外部世界）的“生物圈 2”。

In terms of proving grand ecological truths the Biosphere 2 experiments were something of a bust. As an illustration of what can happen when somewhat fringe-y science meets extreme wealth they were fascinating. There were fierce fallings-out on both sides of the glass. In 1994 Ed Bass, an oil dynast who had paid for the facility, threw out the management team and handed the reins to Steve Bannon, later a key adviser to Donald Trump. At the same time, though, there was what some took to be a breakthrough in the science of human ageing.

就证明宏大的生态真理而言，生物圈二号实验是失败的。作为当边缘科学遇到极端财富时会发生什么的例证，它们非常有趣。玻璃两侧发生了激烈的争吵。 1994 年，支付该设施费用的石油大亨埃德·巴斯 (Ed Bass) 解雇了管理团队，并将权力移交给了史蒂夫·班农 (Steve Bannon)，后者后来成为唐纳德·特朗普 (Donald Trump) 的重要顾问。但与此同时，一些人认为人类衰老科学取得了突破。

One of the eight biospherians was Roy Walford, a professor of pathology at the University of California, Los Angeles (ucla). Research by Walford and others had shown that restricting what animals ate could significantly lengthen their lives. The lifespans of nematode worms, fruit flies, rodents and dogs could be extended as much as 50% by laboratory protocols which gave them a diet with all the nutrients they needed in terms of minerals, vitamins and the like but fewer calories than were seen as normal.

罗伊·沃尔福德（Roy Walford）是八位生物圈管理者之一，他是加州大学洛杉矶分校（UCLA）的病理学教授。沃尔福德和其他人的研究表明，限制动物的饮食可以显着延长它们的寿命。通过实验室方案，线虫、果蝇、啮齿动物和狗的寿命可以延长 50%，实验室方案为它们提供了含有矿物质、维生素等所需所有营养成分的饮食，但热量却比想象中要少。普通的。

Biosphere 2 allowed him to test the theory on humans in no position to sneak off for snacks. With a daily intake of 1,750-2,100 calories (7,320-8,790 kilojoules) the biospherians, trim to begin with, all slimmed down. But after eight months their weight stabilised. Gaunt as they were, their energy levels remained high. Blood tests showed physiological responses which matched those of calorie-restricted rodents with extended lifespans.

生物圈二号让他能够在没有能力偷偷溜走吃零食的人类身上测试这一理论。每天摄入 1,750-2,100 卡路里（7,320-8,790 千焦）的生物圈人，从一开始就瘦身，全部都瘦下来了。但八个月后，他们的体重稳定下来。尽管他们憔悴不堪，但他们的精力仍然很高。血液测试显示，其生理反应与限制热量的啮齿动物的生理反应相匹配，但寿命更长。

Some people have taken this as a reason to incorporate calorie restriction into their lives, as Walford did. But such diets, which go well beyond the sort of weight-restricting efforts to which any sensible person might aspire, are hard to maintain. That has provoked an interest in finding ways to get the benefits of calorie restriction without having to engage in it.

有些人将此作为将卡路里限制纳入生活的理由，就像沃尔福德所做的那样。但这种饮食方式远远超出了任何明智之人可能渴望的那种限制体重的努力，很难维持下去。这引发了人们对寻找无需参与热量限制就能获得热量限制好处的方法的兴趣。

The garden of forking paths

岔路花园

Calories are a measure of the amount of energy that cells can get from breaking food into its component chemical parts. The precise nature of that breaking down, and what happens with all the parts, is under the control of a range of signalling pathways which have the job of matching what the cell is doing with how much energy the organism needs and has available. Dysfunction in these nutrient-signalling pathways is one of the 12 hallmarks of ageing listed by Dr López-Otín and his colleagues.

卡路里是细胞将食物分解成其化学成分所获得的能量的量度。这种分解的确切性质，以及所有部分发生的情况，受到一系列信号通路的控制，这些信号通路的作用是将细胞正在做的事情与生物体需要和可用的能量相匹配。这些营养信号通路的功能障碍是 López-Otín 博士及其同事列出的 12 个衰老标志之一。

If there is a general truth behind the success of calorie restriction, it is that when energy is on the scarce side, the nutrient signalling pathways in cells pay greater attention to what is going on and keep the cell in better shape. What is necessary if the same pathways are to be recruited without the calorie reduction is an understanding of what other cues can have the same effect.

如果热量限制的成功背后有一个普遍的事实的话，那就是当能量稀缺时，细胞中的营养信号通路会更加关注正在发生的事情，并使细胞保持更好的状态。如果要在不减少卡路里的情况下招募相同的途径，那么有必要了解哪些其他线索可以产生相同的效果。

The research would be both easier to do and easier to understand if these pathways all had distinct, clearly understood functions. Alas, this is not the case. Pathways frequently regulate more than one function, functions are frequently regulated by more than one pathway and the farthest-flung parts of pathways are often obscure. To make things yet less comprehensible, the proteins involved in the pathways have incredibly opaque names.

如果这些通路都具有独特的、清晰易懂的功能，那么研究就会更容易进行，也更容易理解。可惜，事实并非如此。通路经常调节不止一种功能，功能经常由不止一种通路调节，并且通路最远的部分通常是模糊的。为了让事情更难以理解，参与这些途径的蛋白质的名称非常不透明。

Take the mtorc1 pathway. The complex of proteins which gives it its name first came to attention because an immune suppressant called rapamycin has a strong effect on it: hence “mechanistic target of rapamycin complex 1”. That gives no real clue, however, to the fact that the signalling pathway in which mtorc1 sits is a complex set of controls and feedbacks designed to regulate metabolism in response both to the availability of nutrients (for example, glucose, which provides energy, and amino acids, from which proteins are made) and impediments to their use (for example, low oxygen levels).

采用 mtorc1 途径。这种蛋白质复合物之所以得名，首先引起人们的关注是因为一种名为雷帕霉素的免疫抑制剂对其具有很强的作用：因此“雷帕霉素复合物 1 的机械靶标”。然而，这并没有提供真正的线索，表明 mtorc1 所在的信号通路是一组复杂的控制和反馈，旨在调节新陈代谢以响应营养物质的可用性（例如，提供能量的葡萄糖，和氨基酸（制造蛋白质的原料）及其使用的障碍（例如，低氧水平）。

The ambit of this regulatory power is broad; it influences the rate at which cells break down damaged internal structures (“autophagy”), the balance of their protein content (“proteostasis”) and the reproduction of their mitochondria, components responsible for turning the calories it receives into a form of energy its proteins can use. Autophagy, proteostasis and mitochondrial reproduction are three more of the 12 hallmarks of ageing.

这种监管权力的范围很广泛；它影响细胞分解受损内部结构的速度（“自噬”）、蛋白质含量的平衡（“蛋白质稳态”）以及线粒体的繁殖，线粒体是负责将接收到的卡路里转化为能量形式的成分。蛋白质可以使用。自噬、蛋白质稳态和线粒体繁殖是 12 个衰老标志中的另外三个。

Rap of ages 年代说唱

What is more, rapamycin, the effects of which give mtorc1 its name, turns out to lengthen the lives of lab animals even though it curbs their immune responses. This has led some longevity enthusiasts to seek off-label prescriptions for it. But its side-effects, including anaemia and an insensitivity to insulin, make rapamycin ill-suited for widespread use. There is thus a search for “rapalogs” which provide the benefits of a tuned-up mtorc1 pathway without so many costs.

更重要的是，雷帕霉素（mtorc1 的名字来源于雷帕霉素）被证明可以延长实验动物的寿命，尽管它会抑制实验动物的免疫反应。这导致一些长寿爱好者寻求标签外处方。但其副作用，包括贫血和对胰岛素不敏感，使得雷帕霉素不适合广泛使用。因此，人们正在寻找“rapalogs”，它可以提供经过调整的 mtorc1 通路的好处，而无需花费太多成本。

Another pathway which calorie-restriction studies have marked out as promising is named after a protein called ampk (don’t ask). This regulates the production of atp, a small energy-carrying molecule produced in mitochondria. When atp levels fall, the ampk pathway increases a cell’s sensitivity to insulin.

热量限制研究表明有希望的另一条途径以一种名为 ampk 的蛋白质命名（别问）。它调节 atp 的产生，atp 是线粒体中产生的一种携带能量的小分子。当 atp 水平下降时，ampk 通路会增加细胞对胰岛素的敏感性。

Metformin, a drug used to treat type-2 diabetes, does so by activating the ampk pathway. Like rapamycin, it extends the lifespans of healthy mice. It does the same for diabetic humans. A study published in 2014 showed that diabetes patients treated with metformin enjoyed a decreased mortality rate, not just compared with patients who were not treated with it, but also with healthy controls who were not given the drug.

二甲双胍是一种用于治疗 2 型糖尿病的药物，通过激活 ampk 通路来实现这一目的。与雷帕霉素一样，它可以延长健康小鼠的寿命。它对糖尿病人也有同样的作用。 2014 年发表的一项研究表明，接受二甲双胍治疗的糖尿病患者的死亡率不仅与未接受二甲双胍治疗的患者相比，而且与未接受该药物的健康对照组相比也有所降低。

Not surprisingly, metformin is also used off-label, probably more widely than rapamycin. The American Federation for Ageing Research, a not-for-profit organisation, hopes soon to start a six-year, 3,000-person clinical trial to measure its effects in people from 65- to 79-years-old. The Targeting Ageing with Metformin (tame) trial will see if metformin helps prevent cardiovascular disease, cancer and cognitive decline; it will also test the hypothesis that it reduces all-cause mortality.

毫不奇怪，二甲双胍也被用于标签外，可能比雷帕霉素更广泛。非营利组织美国老龄化研究联合会希望很快启动一项为期六年、有 3,000 人参与的临床试验，以衡量其对 65 岁至 79 岁人群的影响。二甲双胍（tame）靶向衰老试验将观察二甲双胍是否有助于预防心血管疾病、癌症和认知能力下降；它还将检验它降低全因死亡率的假设。

A further set of medicines developed to treat diabetes but now used more widely are the glp-1 receptor agonists. The best known, semaglutide (sold as Wegovy), has been specifically licensed in various places for use in people without diabetes who nevertheless need to lose weight. Whether they might live longer than someone of the same final weight who does not take one of the drugs is an open question. There are no published studies that show the drugs to have an effect on the lifespans of laboratory animals.

另一套用于治疗糖尿病但现在使用更广泛的药物是 glp-1 受体激动剂。最著名的是索马鲁肽（以 Wegovy 出售），已在多个地方获得特别许可，可用于没有糖尿病但需要减肥的人。他们是否会比最终体重相同但不服用其中一种药物的人活得更长，这是一个悬而未决的问题。没有已发表的研究表明这些药物对实验动物的寿命有影响。

One thing that does do the job for lab animals is taurine, an amino acid widely used as a dietary supplement. According to a recent paper by Parminder Singh of the Buck Institute for Research on Ageing in Novato, California, and colleagues, in mice taurine increases lifespan by 10%; some of this seems to be due to nutrient signalling. But there are effects on four or five other hallmarks of ageing, too. Taurine levels drop with age in humans but, in those who live to be over 100, levels stay significantly higher.

对实验动物有效的一种物质是牛磺酸，一种广泛用作膳食补充剂的氨基酸。根据加利福尼亚州诺瓦托市巴克衰老研究所的 Parminder Singh 及其同事最近发表的一篇论文，牛磺酸可使小鼠的寿命延长 10%；其中一些似乎是由于营养信号传导所致。但它也会对其他四五个衰老标志产生影响。牛磺酸水平在人类中随着年龄的增长而下降，但在活到 100 岁以上的人中，牛磺酸水平仍显着升高。

Nutrient sensitivity may also be enhanced by a molecule called nad+. Some enzymes—proteins which catalyse chemical reactions—require the presence of a small extra molecule to do their thing. nad+ is such a “co-enzyme”. More than 300 enzymes need it to be present if they are to do their bit for the cell. And if you give mice more of it, they live longer.

一种名为 nad+ 的分子也可以增强营养敏感性。一些酶（催化化学反应的蛋白质）需要存在一个额外的小分子才能发挥作用。 nad+就是这样一种“辅酶”。超过 300 种酶需要它的存在才能为细胞发挥作用。如果你给老鼠提供更多的东西，它们就会活得更久。

Considering that nad+ is so generous with its favours it is difficult to know exactly which of the enzymes it helps are responsible for delivering this effect. But one connection which looks particularly interesting is that with a set of proteins called sirtuins.

考虑到 nad+ 如此慷慨，很难确切地知道它所帮助的哪些酶负责提供这种效果。但看起来特别有趣的一个联系是与一组称为sirtuins的蛋白质的联系。

La vie en vin rouge

红葡萄酒的生活

Sirtuins came to prominence two decades ago when David Sinclair, who is now co-director of the Centre for Biology of Ageing Research at Harvard University, showed that stimulating their production prolongs life in a variety of laboratory animals. One form of stimulation is calorie restriction. But Dr Sinclair discovered a chemical alternative: resveratrol, a molecule found, among other places, in the skins of red grapes.

二十年前，哈佛大学衰老生物学研究中心联合主任 David Sinclair 发现，刺激 Sirtuins 的产生可以延长多种实验动物的寿命，从而使 Sirtuins 声名鹊起。刺激的一种形式是限制热量。但辛克莱博士发现了一种化学替代品：白藜芦醇，一种在红葡萄皮等地方发现的分子。

Dr Sinclair is by no means publicity-shy; his discovery saw a great deal of brouhaha. He founded a company, Sirtris, to produce resveratrol derivatives suited to the human body. The work did not amount to much. Sirtris, having been bought by GlaxoSmithKline, ceased to exist as a separate entity in 2013.

辛克莱博士绝不回避公众的关注。他的发现引发了轩然大波。他创立了 Sirtris 公司，生产适合人体的白藜芦醇衍生物。工作量并不大。 Sirtris 被葛兰素史克 (GlaxoSmithKline) 收购后，于 2013 年不再作为独立实体存在。

That might seem a cautionary tale. But it can also be seen as grounds for hope. Sirtuins got a lot of attention because there had been no similarly credible claims about longevity for some time. Their story set out a blueprint for looking into such things: a mechanism looked interesting, a molecule seemed promising, investigations were carried out, conclusions were drawn. Many more mechanisms and drugs are now being scrutinised in the same way. Some scepticism is warranted. But there is no reason to believe that none of them will get results just because the few looked at so far have not. ■

这似乎是一个警示故事。但这也可以被视为希望的理由。 Sirtuins 受到了很多关注，因为一段时间以来没有类似可信的关于长寿的说法。他们的故事为研究此类事情制定了蓝图：一种机制看起来很有趣，一种分子似乎很有前途，进行了调查，得出了结论。现在正在以同样的方式审查更多的机制和药物。一些怀疑是有道理的。但我们没有理由相信，仅仅因为迄今为止所研究的少数研究还没有取得成果，他们中的任何一个都不会取得成果。