Selman Colin, Lingard Steven, Choudhury Agharul I, Batterham Rachel L, Claret Marc, Clements Melanie, Ramadani Faruk, Okkenhaug Klaus, Schuster Eugene, Blanc Eric, Piper Matthew D, Al-Qassab Hind, Speakman John R, Carmignac Danielle, Robinson Iain C A, Thornton Janet M, Gems David, Partridge Linda, Withers Dominic J
Centre for Diabetes and Endocrinology, Department of Medicine, Rayne Institute, University College London, University St., London, UK.
FASEB J. 2008 Mar;22(3):807-18. doi: 10.1096/fj.07-9261com. Epub 2007 Oct 10.
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.
最近的证据表明，胰岛素/胰岛素样生长因子1（IGF1）信号传导（IIS）的改变可以延长哺乳动物的寿命。例如，在几种小鼠突变体中，生长激素（GH）/IGF1轴的损伤会延长寿命并提高胰岛素敏感性。然而，导致哺乳动物衰老改变的细胞内信号传导途径仍不清楚。因此，我们测量了缺乏胰岛素受体底物（IRS）1或2（IIS受体的主要细胞内效应器）的小鼠的寿命。我们的初步结果表明，雌性Irs1-/-小鼠寿命较长。此外，它们对一系列与年龄相关的衰老标志物具有抵抗力，包括皮肤、骨骼、免疫和运动功能障碍。尽管存在轻度的终身胰岛素抵抗，但仍观察到这些健康方面的改善。因此，增强胰岛素敏感性不是IIS突变体长寿的先决条件。Irs1-/-雌性小鼠的垂体前叶功能也正常，这使它们与长寿的生长激素轴突变体有所不同。相比之下，Irs2-/-小鼠寿命较短，而Irs1+/-和Irs2+/-雌雄小鼠的寿命均正常。因此，我们的结果表明，IRS1信号传导是调节哺乳动物寿命的进化保守途径，可能是具有延缓年龄相关进程潜力的治疗干预点。
