Department of Cellular and Physiological Sciences, Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Cell Rep. 2017 Jul 11;20(2):451-463. doi: 10.1016/j.celrep.2017.06.048.
The causal relationships between insulin levels, insulin resistance, and longevity are not fully elucidated. Genetic downregulation of insulin/insulin-like growth factor 1 (Igf1) signaling components can extend invertebrate and mammalian lifespan, but insulin resistance, a natural form of decreased insulin signaling, is associated with greater risk of age-related disease in mammals. We compared Ins2 mice to Ins2 littermate controls, on a genetically stable Ins1 null background. Proteomic and transcriptomic analyses of livers from 25-week-old mice suggested potential for healthier aging and altered insulin sensitivity in Ins2 mice. Halving Ins2 lowered circulating insulin by 25%-34% in aged female mice, without altering Igf1 or circulating Igf1. Remarkably, decreased insulin led to lower fasting glucose and improved insulin sensitivity in aged mice. Moreover, lowered insulin caused significant lifespan extension, observed across two diverse diets. Our study indicates that elevated insulin contributes to age-dependent insulin resistance and that limiting basal insulin levels can extend lifespan.
胰岛素水平、胰岛素抵抗和长寿之间的因果关系尚未完全阐明。胰岛素/胰岛素样生长因子 1（Igf1）信号成分的遗传下调可以延长无脊椎动物和哺乳动物的寿命，但胰岛素抵抗是胰岛素信号自然减弱的一种形式，与哺乳动物与年龄相关的疾病风险增加有关。我们在遗传上稳定的 Ins1 缺失背景下，将 Ins2 小鼠与 Ins2 同窝对照进行了比较。来自 25 周龄小鼠的肝脏的蛋白质组学和转录组学分析表明，Ins2 小鼠可能具有更健康的衰老和改变的胰岛素敏感性。在老年雌性小鼠中，Ins2 的减半将循环胰岛素降低了 25%-34%，而 Igf1 或循环 Igf1 没有改变。值得注意的是，降低胰岛素可降低空腹血糖并改善老年小鼠的胰岛素敏感性。此外，降低胰岛素水平可显著延长两种不同饮食的寿命。我们的研究表明，升高的胰岛素导致与年龄相关的胰岛素抵抗，并且限制基础胰岛素水平可以延长寿命。
