GENETIC AND MOLECULAR BASIS OF LONGEVITY

胰岛素信号通路将哺乳动物的摄食和营养状况与动物大多数组织的代谢速率和模式联系起来。我们已经证明，胰岛素样信号通路调节秀丽隐杆线虫的寿命和代谢。这是一种联想，可能与哺乳动物热量限制导致的寿命延长有机械上的联系。因此秀丽隐杆线虫胰岛素信号通路的遗传成分可能是哺乳动物寿命决定通路的关键成分。我们的遗传分析也揭示了秀丽隐杆线虫胰岛素样信号的关键输出是转录因子DAF-16的活性。该建议主要关注DAF-2胰岛素样受体信号如何转导到DAF-16转录因子，以及这些DAF-16活性的调节如何反过来调节代谢和寿命。DAF-16的三个人类同源物是人类胰岛素样信号转导的极好候选者，也可以调节寿命和代谢。我们将测试这些人类蛋白是否能在秀丽隐杆线虫胰岛素样信号通路中发挥作用，即是否具有功能同源性。除了在长寿控制中可能发挥的作用外，我们通过秀丽隐杆线虫遗传学鉴定的胰岛素信号基因可能揭示哺乳动物胰岛素信号的组成部分，这对理解和最终治疗糖尿病很重要。糖尿病是一种常见疾病，影响胰岛素的产生或反应，导致毁灭性的代谢失调。成人发病或II型糖尿病中胰岛素反应缺陷的分子基础尚不清楚。很明显，它至少部分是一种遗传疾病。秀丽隐杆线虫遗传学强烈认为，药物抑制人类DAF-16活性可能绕过了上游胰岛素信号的需要。因此，人类DAF-16可能成为糖尿病药物开发的主要靶点。

An insulin signaling pathway couples feeding and nutritional status in mammals to the rate and mode of metabolism in most tissues of the animal. We have shown that an insulin-like signaling pathway regulates longevity and metabolism in C. elegans. This is reminiscent and may be mechanistically related to the longevity increase caused by caloric restriction in mammals. Thus the genetic components of the C. elegans insulin signaling pathway may be key components of a mammalian longevity determining pathway. Our genetic analysis has also revealed that the key output of C. elegans insulin-like signaling is the activity of the transcription factor DAF-16. Much of this proposal focuses on how DAF-2 insulin-like receptor signals are transduced to the DAF-16 transcription factor, and how those modulations of DAF-16 activity in turn regulate metabolism and longevity. Three human homologues of DAF-16 are excellent candidates for transducing insulin-like signaling in humans to also regulate longevity and metabolism. We will test whether these human proteins can function in the C. elegans insulin-like signaling pathway, that is, are functional homologues. In addition to their possible roles in longevity control, the insulin signaling genes we have identified by C. elegans genetics may reveal components of insulin signaling in mammals that are important for the understanding and eventual treatment of diabetes. Diabetes is a common diseases that affects the production or response to insulin, causing devastating metabolic dysregulations. The molecular basis of the defective insulin response in the adult onset or type II diabetes is unknown. It is clear that it is at least in part a genetic disease. The C. elegans genetics strongly argues that inhibition of human DAF-16 activity by drugs may bypass the need for upstream insulin signaling. Thus human DAF-16 may become a major target for pharmaceutical development of diabetes therapies.