Inositol signaling in C. elegans Senescence and Diapause

描述（由申请人提供）：胰岛素样信号通路是秀丽隐杆线虫中最有效的寿命调节因子。该通路在秀丽隐杆线虫、果蝇和哺乳动物中介导代谢和衰老的功能是保守的。由于许多胰岛素信号通路是保守的，我们在秀丽隐杆线虫中发现的新成分将与哺乳动物胰岛素信号传导和长寿控制具有广泛的相关性。对秀丽隐杆线虫的遗传分析继续确定可能揭示人类胰岛素样信号变异的途径成分，这对糖尿病和理解胰岛素如何发挥作用具有医学意义

DESCRIPTION (provided by applicant): An insulin-like signaling pathway is the most potent regulator of lifespan in C. elegans. The function of this pathway in mediating metabolism and aging is conserved in C. elegans, Drosophila, and mammals. Because so much of the insulin signaling pathway is conserved, the new components we discover in C. elegans will have broad relevance to mammalian insulin signaling and longevity control. Genetic analysis in C. elegans continues to identify components of the pathway that are likely to reveal human variation in insulin-like signaling, with medical significance for diabetes and the understanding of how insulin signaling and analogous hormonal pathways couple chronological age to many late onset diseases. Using RNAi to screen for defects in daf-2 pathway mediated longevity regulation, we identified a comprehensive genetic network necessary for the longevity response to low daf-2 insulin/IGF1 signaling (9). Similarly, our proteomic analysis of insulin signaling components in Aim 2 has identified other new and unstudied candidate genes to act in insulin signaling. The use of RNAi screens and proteomics in C. elegans is opportune for two reasons: first, the tissues where insulin signaling is key for metabolic control has changed dramatically over the past decade. No longer is an exploration of insulin signaling only in the liver or muscle or even pancreas definitive. Neural and adipose centers of insulin signaling have emerged (7). We have identified new protein components of insulin signaling from whole animal extracts, and our RNAi screens are done in the whole animal, so insulin signaling across tissues is surveyed. This is unlike mammalian insulin signaling functional genomics which may assay for insulin responses in tissue culture, but not in the physiological context of a whole organism. Aging and diabetes may be more physiological and endocrine, not easily modeled in cell culture. In this way, the C. elegans insulin signaling genetic system is better model system for human aging and human diabetes than human cell culture. Our full genome screens for lifespan regulatory processes have also revealed that the second most potent axis of longevity regulation surveys core components of cells, the ribosome, the mitochondrion, the cytoskeleton, and if deficits are detected, the pathway couples to an endocrine system of longevity control that is distinct from the insulin-like pathway. Our exploration of the endocrine system for surveillance and signaling of deficits in core cellular components promises to illuminate an entirely new axis of eukaryotic lifespan regulation. Variation in both these endocrine systems may underlie human lifespan variation as well as variation in metabolism and drug sensitivities.