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。
The search to extend lifespan is gaining ground, but can we truly reverse the biology of ageing?
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.
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.
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.
Antibiotics have increased life expectancy – can they be considered ‘anti-ageing’? from 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.
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.
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.
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%.
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.
Resveratrol is a compound found in red wine and considered a candidate for anti-ageing. from 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.
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。
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.
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.
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.
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.
Telomeres, that cap the ends of our chromosomes, shorted as we age. from 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.
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.
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.
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.
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.
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.
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.
Metformin is likely to be the first ever anti-ageing drug to reach the market. from 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.
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.
Any such drug will instead be targeted towards specific diseases of ageing, for example, arthritis or type 2 diabetes.
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.