FASEB：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。（教育部科技发展中心）

原文链接：http://www.physorg.com/news112279922.html

原始出处:

Published online before print October 10, 2007 as doi: 10.1096/fj.07-9261com.

Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice

Colin Selman, Steven Lingard, Agharul I. Choudhury, Rachel L. Batterham, Marc Claret, Melanie Clements, Faruk Ramadani, Klaus Okkenhaug, Eugene Schuster, Eric Blanc, Matthew D. Piper, Hind Al-Qassab, John R. Speakman, Danielle Carmignac, Iain C. A. Robinson, Janet M. Thornton, David Gems, Linda Partridge, and Dominic J. Withers

E-mail contact: d.withers@ucl.ac.uk.

Recent evidence suggests that alterations in insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) can increase mammalian life span. For example, in several mouse mutants, impairment of the growth hormone (GH)/IGF1 axis increases life span and also insulin sensitivity. However, the intracellular signaling route to altered mammalian aging remains unclear. We therefore measured the life span of mice lacking either insulin receptor substrate (IRS) 1 or 2, the major intracellular effectors of the IIS receptors. Our provisional results indicate that female Irs1-/- mice are long-lived. Furthermore, they displayed resistance to a range of age-sensitive markers of aging including skin, bone, immune, and motor dysfunction. These improvements in health were seen despite mild, lifelong insulin resistance. Thus, enhanced insulin sensitivity is not a prerequisite for IIS mutant longevity. Irs1-/- female mice also displayed normal anterior pituitary function, distinguishing them from long-lived somatotrophic axis mutants. In contrast, Irs2-/- mice were short-lived, whereas Irs1+/- and Irs2+/- mice of both sexes showed normal life spans. Our results therefore suggest that IRS1 signaling is an evolutionarily conserved pathway regulating mammalian life span and may be a point of intervention for therapies with the potential to delay age-related processes.—Selman, C., Lingard, S., Choudhury, A. I., Batterham, A. L., Claret, M., Clements, M., Ramadani, F., Okkenhaug, K., Schuster, E., Blanc, E., Piper, M. D., Al-Qassab, H., Speakman, J. R., Carmignac, D., Robinson, I. C. A., Thornton, J. M., Gems, D., Partridge, L., Withers, D. J. Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice.