长寿老鼠揭开人类衰老的秘密
UCL（University College London）的科学家发现，缺少胰岛素受体底物（IRS）-1的老鼠对衰老抵抗力更强。这为胰岛素信号通路在哺乳动物衰老中的作用提供了新证据。
小组研究了通过基因改造后缺少IRS-1或-2的老鼠。IRS通过胰岛素激活，胰岛素负责调节葡萄糖和脂肪代谢。发表在FASEB上的结果显示，缺少IRS-1的老鼠寿命比同类长20％。在雌性老鼠中现象更明显，平均达到30％。老鼠预期寿命一般为25月左右，而其中一个缺少IRS-1的老鼠寿命达到了38月－比同类长66％。
除了寿命更长，缺少IRS-1的老鼠在老年时也更健康，它们视力更好也更警惕。而缺少IRS-2的老鼠寿命则有所减少，且表现出肥胖和2型糖尿病。来自UCL衰老研究中心的Dominic Withers教授是文章主要作者，他说：“缺少IRS-1使老鼠，特别是雌性老鼠对衰老抵抗力更强，包括皮肤、骨骼、免疫和运动等方面。这表明IRS-1是进化中产生的调节哺乳动物寿命的通路，利用它可能找到延缓人类衰老的方法。”
他还说：“我们并不完全清楚缺少IRS-1为何会延长寿命。其中一种可能解释是对胰岛素的轻微耐受不会对身体造成影响，而且能增强压力抵抗力，防止损伤并激发身体延长寿命的反应。”另一作者David Gems说：“胰岛素通路单个基因的变异能延长寿命。而我们发现这还能使老鼠变得更健康，延缓衰老疾病例如骨质疏松等发生。显然研究人类的类似机制很困难，但我们的研究提供了很关键的基础。”
UCL小组还研究过果蝇、线虫等，并于2007年6月得到了510万英镑的经费支持。UCL衰老健康研究所将于2008年建成，他们鼓励其他学者和UCL进行该领域的合作。
A longer-living, healthier mouse that could hold clues to human aging
A study by scientists at UCL (University College London) shows that mice lacking the insulin receptor substrate (IRS)-1 are more resistant to ageing than normal mice. The research adds to a growing body of work showing the importance of insulin signalling pathways as an ageing mechanism in mammals – and potentially humans.
The team studied ‘knock-out’ mice engineered to lack either insulin receptor substrate (IRS)-1 or -2. These proteins are activated by insulin, a hormone that regulates glucose and fat metabolism, informing the body’s cells when the animal is well fed.
The study, published in The FASEB Journal, shows that mice lacking IRS-1 had an average lifespan increase of 20 per cent when compared to normal mice. In female mice lacking IRS-1 this figure was even higher, averaging 30 per cent. While the expected life-span for a mouse is about 25 months, one of the IRS-1deficient mice in this research lived for 38 months – 66 per cent longer than a normal mouse.
As well as living longer, the mice without IRS-1 also experienced better health than the normal mice as they aged – they had brighter eyes, were more alert and were much healthier overall. In comparison, the mice that lacked IRS-2 were shorter-lived than the normal mice and displayed signs of obesity and type 2 diabetes.
Professor Dominic Withers, who works with the UCL Centre for Research on Ageing and is lead author of the study, said: “Our provisional results indicate that mice lacking IRS-1, particularly female mice, are more long-lived and show resistance to a range of markers that indicate ageing – including skin, bone, immune, and motor dysfunction.
“What’s more, these improvements were seen despite the fact that removing IRS-1 made the mice resistant to insulin throughout their lives. These results suggest that IRS-1 is a pathway conserved by evolution that regulates the lifespan of mammals, and it may point to methods of potentially delaying ageing in humans.
“We do not yet fully understand why lacking IRS-1 leads to longer life in mice. One possible explanation is that it makes them only mildly insulin resistant and that this, rather than having a negative effect on health, increases stress resistance, protects from damage and generally triggers other reactions in the body which extend life without compromising health.”
Dr David Gems, another of the study’s authors, added: “Other research has shown that mutations in single genes in the insulin pathway can extend the life of animals. However, our research adds new information because it shows that not only does manipulation of this pathway regulate how long animals live, it also shows that these effects allow the mice to stay healthier for longer. In these animals we see delay in the onset of age-related illnesses such as osteoporosis, diabetes and immune dysfunction. Obviously it’s much harder to study these mechanisms in humans because our life expectancy is so much longer, but this study and our other work on ageing are laying crucial scientific groundwork.”
The study follows other ageing research pioneered at the UCL Centre for Research on Ageing, led by Professor Linda Partridge. The teams at the Centre analyse the cellular and biochemical mechanisms of ageing in fruit flies, nematode worms and mice, and in particular the role of insulin signalling. Their work was recognised in June 2007 by a Strategic Award from the Wellcome Trust totalling ￡5.1 million, to support their work examining what causes human bodies to age and decay. The UCL Institute of Healthy Ageing, incorporating the existing Centre, will be established in 2008 and will encourage further collaboration between UCL scientists working in this area.
Source: University College London
