FGF21, Insulin Action and Longevity

项目摘要 抑制生长激素（GH）-胰岛素样生长因子-1（IGF-1）信号传导 通过饮食或遗传操纵的途径延长了一系列物种的寿命， 可能包括人类然而，实现这一效果， 证明困难。FGF21是一种激素，它是从肝脏释放的，以响应 禁食和饥饿的适应性饥饿反应的不同方面。之间 在小鼠的代谢作用中，FGF21引起GH抵抗，因此显著降低了GH的表达。 循环IGF-1浓度降低。值得注意的是，转基因小鼠 从出生起过度表达FGF21的小鼠比野生型小鼠寿命长30 - 40%。在 在本申请中提出的研究中，我们将测试FGF21是否会导致 小鼠健康寿命的相应增加， 力量、免疫系统和认知功能。我们将进一步确定 在成年期开始接触FGF21也可以延长寿命和健康寿命。 最后，我们将测试FGF21是否通过诱导GH-IGF-1通路而抑制GH-IGF-1通路。 细胞因子信号传导蛋白2的抑制因子，其具有良好的抗GH 方面的影响.由于几家制药公司已经将FGF21用于临床， 在治疗肥胖和2型糖尿病的临床试验中，FGF21给药可能是一种可行的 延长人类健康和寿命的方法。

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.