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在对抗衰老和死亡的禁忌之路上,人类掌握了这些武器 | 双语阅读

原标题:在对抗衰老和死亡的禁忌之路上,人类掌握了这些武器 | 双语阅读

编者按:衰老和死亡是人类一生的终点,这一法则从未改变过。科幻电影中,总是有人试图获得永生,虽然只是艺术作品,但这也表现出了人类对于增加寿命的强烈渴求。其实,随着医疗条件和饮食条件的进步,现在人类的平均寿命已经比以往长了很多;可是人类似乎并不满足于此,总幻想着使用某种药物来更直接地延缓衰老。很多科研人员正在进行这一领域的研究。近日,Lindsay Wu 在 The Conversation上撰写了题为”The search to extend lifespan is gaining ground, but can we truly reverse the biology of ageing?“的文章,分析了目前有希望实现延缓衰老的各种研究,是对这一领域科学进展的一个详细综述。文章较长,但值得仔细阅读。

衰老研究

The search to extend lifespan is gaining ground, but can we truly reverse the biology of ageing?

寻求延长寿命的研究正在取得进展,但是我们是否能够真正扭转衰老的生物规律呢?

It was once a fringe topic for scientists and a pseudo-religious dream for others. But research into the biology of ageing, and consequently extending the lifespan of humans and animals, has become a serious endeavour.

延长寿命曾经是科学家的一个边缘话题,也是其他一些人的伪宗教梦想。 但是,研究衰老生物学、进而进一步延长人类和动物的寿命,已经成为一个严肃的课题。

Ageing research is often promoted as the key to the “eternal fountain of youth”, or an “elixir of immortality”. But the true promise of ageing research is that rather than tackling individual diseases one at a time, a single drug would treat all the diseases that arise in old age, at once.

衰老研究经常被推广成“永恒的青春之泉”或“不朽药剂”之关键。 但是,该研究的真正承诺是,用一种药物,一次性就可以治疗所有衰老所带来的疾病,而并非处理某个单独疾病。

There would be cost savings from keeping elderly patients out of specialist appointments for each condition. And a single health-maintaining pill would avoid the problem of drug overuse and interactions common in older people who have to medicate each condition individually.

如果内一次性治疗所有衰老所带来的疾病,老年患者不需要针对各种疾病去跑专家门诊,这可以节省很多成本。 另一方面,只服用一种药物,可以避免老年人用药过度以及药物之间的相互作用。当老年人为了治疗每种病症而需服用各种不同药物时,这种问题尤其普遍。

Antibiotics have increased life expectancy - can they be considered ‘anti-ageing’? from shutterstock.com

抗生素可以延长预期寿命——它们可以被认为是”抗衰老”的妙方吗? 图片选自shutterstock.com

The idea of extending human life makes some uneasy, as preventing death seems unnatural. Certainly, were lifespan to be drastically increased, there would be challenges in funding the old age pension, among other issues.

延长寿命的想法让人不安,因为对抗死亡似乎不符合自然现象。 当然,寿命大大增加,老年养老金等资金问题也将面临挑战。

But this is already happening. Drugs and interventions developed over the past century that have almost doubled human lifespan could be considered as anti-ageing. Think of antibiotics, which have added anywhere between two and ten years to human life expectancy. There is no debate that they are an essential part of modern medicine.

但这种情况已经在发生了。 过去一个世纪以来,在新开发的药物和其他措施的帮助下,人类的寿命几乎被翻了一倍,这也可被视为抗衰老的手段之一。 想想抗生素吧,它增加了人类两到十年的预期寿命。 毫无悬念,他们已经是现代医学的重要组成部分。

But when we talk about an anti-ageing pill, we mean one that targets the process of ageing itself. There is already a list of such drugs shown to extend the lives of lab animals. Many of these work through mimicking the effects of a near starvation diet.

但是当我们谈论抗衰老药物时,我们指的是指针对衰老进程本身的药物。 现在已经有了这样一份清单, 列出了可以延长实验室动物生命的药物。

Calorie restriction 限制卡路里摄入量

Calorie restriction has for over 80 years been the most well-studied intervention known to delay ageing.

限制卡路里摄入量是近80年来最为广为人知的抗衰老手段。

The willpower required to maintain a near starvation diet for an entire lifetime is beyond most. But regular, short term calorie restriction (such as the “5:2” diet of eating normally for five days and reducing calorie intake for two) has strong benefits for metabolic health, which helps control obesity and diabetes.

对大多数人来说,在一生中维持接近饥饿饮食的意志是渴望而不可及的。但通常上,短期内对卡路里摄入量的限制(比如“5:2”的轻断食法,一周内的5天正常进食,其余两天限制卡路里摄取量)将对人体的新陈代谢有很大的益处,它有助于控制肥胖和糖尿病。

Animal studies show a reliable extension in lifespan during intermittent fasting. Other studies have shown genetically altering the body’s ability to respond to insulin, which is released when we eat a meal, doubles lifespan in worms. A similar experiment in mice revealed a less dramatic, but a still significant, increase in lifespan of 18%.

通过对动物的研究显示,间歇性禁食有助于延长寿命。其他研究证明,从基因上改变身体对胰岛素的反应能力(当我们吃饭时会释放胰岛素),能使蠕虫的寿命延长一倍。虽然对小白鼠的类似实验没有得出如此戏剧性的结果,但该发现仍然意义重大。节食大约可以延长18%的寿命。

Early on, the effectiveness of restricting calories led scientists to hunt for genes that mediated these effects. In the late 1990s and early 2000s, scientists became interested in sirtuins – a class of enzymes that turn on defence mechanisms during starvation.

早些时候,限制卡路里摄入的显著效果使得科学家开始寻找调节这些效果的基因。在二十世纪九十年代末和二十世纪初期,科学家对去乙酰化酶颇感兴趣 ——这是一类在饥饿期间开启防御机制的酶。

Resveratrol is a compound found in red wine and considered a candidate for anti-ageing. from shutterstock.com

白藜芦醇是一种在红葡萄酒中发现的化合物,被认为是抗衰老的候选物。图片选自shutterstock.com

Drugs such as the now infamous compound resveratrol, present in red wine, can activate one member of the sirtuins, called SIRT1, to extend lifespan in mice and slow markers of ageing. The SIRT1 enzyme requires a fuel for its activity, called NAD+, the levels of which decline with old age.

某些药物,譬如现在声明狼藉的、存在于红葡萄酒中的化合物白藜芦醇,可以激活去乙酰化酶中的一个元素,称为SIRT1,它可以延长老鼠的寿命并减缓衰老(生物)标记。 SIRT1酶需要一种被称为NAD +的活性燃料,其水平随着年龄的增长而下降。

Given the importance of NAD+ to SIRT1, the idea of raising NAD+ levels has attracted attention. But NAD+ is used by other cell processes that could be involved in ageing. For example, Dr. Jun Li recently showed NAD+ levels are essential to turning on DNA repair machinery, which wanes as we age. These findings could also be used to reduce DNA damage caused by radiation exposure – such as in childhood cancer survivors – and cosmic radiation encountered by astronauts in outer space.

鉴于NAD + SIRT1的重要性,提高NAD +水平的观念引起了人们的关注。 但NAD +被其他可能参与老化的细胞过程所使用。 例如,Li Jun博士最近表明,NAD +水平对于开发DNA修复机制至关重要,一般来说,随着年龄的增长,DNA修复机制逐渐消失。 这些发现也可用于减少暴露于辐射下所引起的DNA损伤,如儿童癌症幸存者以及宇宙航天员在外太空遇到的宇宙辐射等。

The long-term effects of restricting calories on ageing in humans have yet to be fully characterised, and such a study in humans would be difficult to perform.

限制卡路里对人类衰老的长期影响尚未得到充分表征,而对人类的这种研究将难以执行。

Protein restriction 限制蛋白质的摄入量

It may be that the anti-ageing effect of calorie restriction isn’t in overall calorie intake, but rather the intake of the protein component of diets. Researchers have measured health and lifespan in an array of diets with different ratios of protein to carbohydrate to fats. They discovered protein restriction, rather than overall calorie restriction, is more important to lifespan.

有一种可能是,限制卡路里的抗衰老效果不全是由通过限制卡路里总摄入量而实现的,它与饮食中的蛋白质成分提取量也有关。 研究人员测量了不同比例的蛋白质对碳水化合物,对脂肪的饮食序列,在健康和寿命之间的关系。 他们发现,限制蛋白质摄入量,而不是对总体热量进行限制,对于寿命来说更为重要。

Translated to human diets, this would be the exact opposite of the “paleo” diet, a high protein diet which emphasises meat and unprocessed vegetables over grains. The concept behind this diet is to mimic that of early paleolithic humans living a hunter-gatherer existence. It is worth noting, however, that paleolithic humans are thought to have had a lifespan of only 33 years.

The one population with the lowest recorded levels of heart disease in the world are the Tsimane, a tribal group leading a gatherer-horticulturalist existence in the Bolivian Amazon. This group has a high carbohydrate and low protein diet.

反映到人类饮食上,这将与“古老”饮食原则完全相反——其特点是高蛋白饮食、肉类和未加工蔬菜的比例超过谷物成分。 该饮食背后的概念是模仿早期的古石器时代的人类,通过打猎而生存。 值得注意的是,古代石器时代的人类寿命据我们所知,只有33年。

根据纪录,世界上心脏病发病率最低的一个种族是提斯曼原住民(Tsimane), 一个居住于玻利维亚亚马逊流域的采集园艺的部落。该部落食用含有高碳水化合物和低蛋白质的饮食。

Consistent with the idea that lowering protein intake extends lifespan, turning off the enzyme mTOR, which senses protein intake, with the drug rapamycin is the most powerful drug intervention we have so far to extend lifespan.

与降低蛋白质摄入量以延长寿命的观念相一致,雷帕霉素是目前为止最有效的药物,它通过切断mTOR酶对蛋白摄入量的感应来延长寿命。

Rapamycin is used in the clinic to suppress the immune system during organ transplants. It extends life in a number of animal species such as worms, fruit flies, and mice, even when delivered briefly in middle age, or late in life. The downside, of course, is that one must live with a suppressed immune system, which is a bit of a drag if you’re not living in a sterile lab environment.

雷帕霉素在临床中用于抑制器官移植期间的免疫系统。 即使是在中年或晚年才使用,它仍延长了许多动物物种的生命,如蠕虫、果蝇和小鼠。 当然,其缺点是,人们必须生活在受抑制的免疫系统中,如果你不生活在无菌的实验室环境中,这将是一个拖累。(编者注:也就是说,如果人们把雷帕霉素用来当做日常药物抗衰老,势必导致自己平日免疫力下降,无法承受有细菌和病毒的环境。)

The Bolivian Tsimane have a high carbohydrate and low protein diet. Photo RNW.org/Flickr, CC BY

玻利维亚Tsimane人食用具有高碳水化合物和低蛋白质的饮食。照片 RNW.org/Flickr, CC BY

In addition to simulating protein restriction, mTOR inhibition with rapamycin also promotes a process called autophagy. This is where the cell essentially “eats” itself, breaking down and destroying the old and damaged parts of the cell into its raw materials, which can be recycled into new structures. A compound called spermidine, discovered in semen and present in trace quantities in cheese, has been found to extend lifespan in mice by 10%. It’s thought this is due to spermidine’s ability to turn on autophagy.

除了模拟限制蛋白质摄入量以外,用雷帕霉素与mTOR抑制剂也会促成一种被称为自噬的进程。 即细胞自己“吃”自己,将细胞中旧的及损坏的部分破坏并转化为原材料,使其可以再循环到新的结构中。 一种被发现存在精液以及微量存在于奶酪中的,称之为精胺的复合物,已经将小鼠的寿命延长了10%。它被认为是精胺启动了自噬功能的结果。

Out with the old 除去老化部分

Another anti-ageing strategy is one called “senolysis”: that is, killing off old and damaged or “senescent” cells. These cells take up space, grow larger, and release substances that cause inflammation. When mice are genetically engineered so that it is possible to kill off senescent cells, health is drastically improved and animals live 20 to 30% longer.

另一种抗衰老策略是一种叫做“分解”的方法:就是杀死旧的损害的“衰老”细胞。这些细胞占据空间,并逐步增大,释放引起炎症的物质。当小鼠被基因编辑之后,衰老的细胞能够被毁掉,健康状况得到显着改善,动物的寿命可延长20至30%。

The hunt is now on for “senolytic” drugs, which can selectively kill off senescent cells. One company, Unity Biotech, recently raised US$116 million to achieve this.

最近,科学家正在研究一种叫做“senolytic”的药物,它可以选择性地杀死衰老细胞。一家叫做Unity Biotech的公司最近筹集了1.16亿美元来实现这一目标。

DNA changes 改变DNA

There is strong evidence that ageing is literally part of our DNA. So-called “jumping genes” are DNA parasites, caused by ancient viral infections in our evolutionary ancestors, and they make up almost half of our genetic material. These genes can actually “cut and paste” themselves so that they jump around to a different part of our DNA, and in doing so make our genomes less stable.

有强有力的证据表明,衰老是我们DNA的一部分。所谓的“跳跃基因”是DNA的寄生虫,它们是由我们进化祖先的古代病毒感染所引起的,其占我们遗传物质的近一半。这些基因实际上可以“剪切和粘贴”自身,以便它们跳转到DNA的不同部分,其结果是我们的基因变得不太稳定。

Telomeres, that cap the ends of our chromosomes, shorted as we age. from shutterstock.com

端粒,覆盖在我们染色体的末端,像我们年龄一样在缩短。来自shutterstock.com

These genes are normally turned off by another sirtuin enzyme called SIRT6, and animals genetically engineered to have an extra copy of this gene live longer and in better health.

这些基因通常被称一种称为SIRT6的去乙酰化酶所“关闭”。被基因工程改造过的动物因具有该基因的附加拷贝而活得更长、更健康。

Our DNA changes as we get older. For example, structures that cap the ends of our chromosomes (which carry our genes) called telomeres shorten with old age or stress. Lengthening telomeres has been suggested as a way to restore youth. The trouble is the gene that does this, called telomerase, is normally only turned on in adults who have cancer.

我们的DNA随着年龄的增长而变化。例如,覆盖在我们染色体(携带我们的基因)的末端的端粒,其结构随着年龄或压力而缩短。延长端粒被认为是恢复青春的一种方式。麻烦的是,这种名为称为端粒酶的基因通常只在患癌症的成年人身上开启。

Genetically engineered animals that over-produce telomerase from birth develop cancer. But to add confusion, using genetically engineered viruses to force old mice to make more telomerase results in a longer lifespan with improved late-life health, without an increased risk of cancer.

如果对动物进行基因编辑,使它们在出生时大量生产出端粒酶,它们很可能会得癌症。更令人困惑的是,使用基因工程病毒来强迫老鼠制造更多的端粒酶,结果老鼠的寿命得到了延长,并不会有增加癌症的风险。

Elizabeth Parrish, who is the CEO of Bioviva – a company working to develop anti-ageing treatments – recently travelled to Colombia to receive gene therapy to extend her telomeres.

Bioviva的伊丽莎白·帕里什(Elizabeth Parrish),是一家致力于开发抗衰老治疗公司的CEO,她最近前往哥伦比亚接受基因治疗以延长她的端粒。

Another drastic way to reverse ageing might be to turn adult cells back into youthful stem cells, which is possible by turning on so-called “Yamanaka factors”. These work through turning certain genes “on” or “off”. The problem is that turning “Yamanaka factors” on too much again causes cancer. Instead, turning these genes on briefly appears to reverse ageing and extend lifespan in short-lived mice. This could be a powerful but risky strategy for reversing ageing.

逆转衰老的另一个激烈方式是将成年细胞转变成年轻的干细胞。它可能是通过开启所谓的“山中伸弥因子”即将某些基因“打开”或“关闭”来实现的。问题在于,打开过多的“山中伸弥因子”会导致癌症。相反,短暂地开启这些基因似乎能反转老化,并延长寿命短暂的老鼠的生命周期。这或许是逆转衰老的强有力但颇具风险的策略。

Is it already here? 它已经被实现了?

In the end, the first ever anti-ageing drug likely to reach the market will be one we’re already familiar with: metformin. It’s used to treat diabetes, has been around since the 1950s and is used by tens of millions of people.

最后,有可能进入市场的抗衰老药物是我们已经熟悉的二甲双胍。自1950年代以来,它一直被用于治疗糖尿病,并已被数千万人使用。

In animals, metformin extends lifespan and maintains health, while population-wide studies show it reduces cancer risk. Metformin is thought to work by turning on an energy sensor in cells called “AMPK”, which senses situations of low energy and alters metabolism in response.

在动物中,二甲双胍可延长寿命并保持健康,而一项全民性的医学研究显示,它可以降低癌症的风险。据认为,在一种被称为“AMPK”的细胞中,二甲双胍可以通过打开其能量传感器来感测到低能量的情形,并改变新陈代谢以进行应对。

Metformin is likely to be the first ever anti-ageing drug to reach the market. from shutterstock.com

二甲双胍将有可能是第一个被投放到市场的抗衰老药物。来自shutterstock.com

The effect of metformin on health and lifespan in older, non-diabetic individuals is currently the subject of the TAME trial in New York. If successful, this trial may lead to the first ever “gero-protective” or “anti-ageing” pill, which would be taken as a widely-used prophylactic by the older population.

目前,二甲双胍对老年非糖尿病患者的健康和寿命的影响是纽约TAME试验的主题。如果成功,这次试验可能会是首个“保护老人”或“抗衰老”的药片,它被认为是老年人可广泛使用的预防性药物。

The TAME trial is being watched keenly by the drug industry. Ageing is not yet recognised as an actual disease by regulatory authorities, which makes potential therapies that treat ageing less commercially viable.

医药行业正在密切注视TAME试验。衰老尚未被监管当局认定为是疾病,这使得治疗老年化的潜在疗法不太可商业化。

Any such drug will instead be targeted towards specific diseases of ageing, for example, arthritis or type 2 diabetes.

这种药物可以取代因衰老而产生的特定疾病的治疗药物,例如关节炎或2型糖尿病。

Regardless of whether any of the drugs above are eventually shown to be safe and effective in humans, the current advice for maintaining health in old age is predictable but effective. Exercise, a varied and moderate diet, maintaining social contact, and avoiding stress have profound health benefits, beyond anything that will ever be available in a pill.

无论上述任何药物最终是否会对对人体安全有效,目前而言,对老年人保持健康的最可靠建议仍然是锻炼、保持多样及适度的饮食、保持社交和避免压力。这些抗衰老措施效果显著,超越了任何一种药物的疗效。

重点词汇

  • genetical engineer:基因工程

  • extend lifespan:延长寿命

  • aging:衰老

  • protein:蛋白质

  • Rapamycin:雷帕霉素

  • autophagy:(细胞的)自我吞噬(作用)

  • metformin:二甲双胍

  • telomere:端粒(在染色体端位上的着丝点)

编译组出品。译者:袁艺,编辑:郝鹏程返回搜狐,查看更多

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声明:本文由入驻搜狐号的作者撰写,除搜狐官方账号外,观点仅代表作者本人,不代表搜狐立场。
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