FGF21, Insulin Action and Longevity

项目摘要 抑制生长激素-胰岛素样生长因子-1信号转导 饮食或基因操作的途径延长了一系列物种的寿命， 可能包括人类。然而，从药理上实现这种效果 事实证明这很难。FGF21是一种从肝脏释放的荷尔蒙，对 禁食并引起适应性饥饿反应的不同方面。在ITS中 在小鼠中的代谢作用，FGF21导致生长激素抵抗，从而显著 降低循环中的IGF-1浓度。值得注意的是，转基因小鼠 出生时过量表达FGF21的小鼠比野生型小鼠活得长30-40%。在 本申请中提出的研究，我们将测试FGF21是否导致 通过测量评估小鼠的健康寿命相应增加 力量、免疫系统和认知功能。我们将进一步确定是否 在成年时开始接触FGF21也可以延长寿命和健康时间。 最后，我们将测试FGF21是否通过诱导GH-IGF-1途径抑制GH-IGF-1途径 细胞因子信号蛋白2的抑制物，它已经建立了良好的抗GH 效果。由于几家制药公司已经将FGF21投入临床 治疗肥胖症和2型糖尿病的试验，使用FGF21可能是可行的 延长人类健康寿命和寿命的方法。

Project Summary Inhibiting the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) signaling pathway by dietary or genetic manipulation extends lifespan in a range of species, including possibly humans. However, achieving this effect pharmacologically has proven difficult. FGF21 is a hormone that is released from the liver in response to fasting and elicits diverse aspects of the adaptive starvation response. Among its metabolic actions in mice, FGF21 causes GH resistance and consequently a marked reduction in circulating IGF-1 concentrations. Remarkably, transgenic mice overexpressing FGF21 from birth live 30-40% longer than wild-type mice. In the studies proposed in this application, we will test whether FGF21 causes a corresponding increase in the healthspan of mice as assessed by measuring strength, immune system and cognitive function. We will further determine whether initiating exposure to FGF21 in adulthood also extends lifespan and healthspan. Lastly, we will test whether FGF21 suppresses the GH-IGF-1 pathway by inducing suppressor of cytokine signaling protein 2, which has well established anti-GH effects. Since several pharmaceutical companies already have FGF21 in clinical trials for treating obesity and type 2 diabetes, FGF21 administration may be a viable approach for extending healthspan and lifespan in humans.