Systematic Analysis of C elegans Longevity Determinants

描述（由申请人提供）：生物体寿命是如何确定的知之甚少。以前的研究在C。线虫已经确定了在进化上不同的物种中起作用的控制寿命的新机制。然而，C.线虫的寿命基因还远远不够全面。我利用基因组和遗传技术的最新进展，系统地确定了影响C。elegans寿命。我的分析指出线粒体氧化磷酸化是C.研究秀丽隐杆线虫的寿命，此外还确定了100多个新的候选长寿基因，这些基因以前与秀丽隐杆线虫无关。elegans寿命。本提案旨在发展每一项成果。In C.在线虫中，线粒体通过与热量限制相同的遗传途径影响寿命，热量限制是已知的从酵母到哺乳动物延长寿命的唯一干预措施。因此，线粒体呼吸如何影响寿命的分子解剖可能会提供重要的见解，营养素的使用和能量代谢如何影响寿命跨越生殖。了解线粒体呼吸作用影响C.为了研究线虫的寿命，我在目标1中提出，确定线粒体影响寿命的细胞/组织，并研究将呼吸与寿命联系起来的生理触发因素。在目标2中，我建议阐明下游信号事件，可能介导的寿命效应的线粒体呼吸。作为第一步，我确定了大量额外的新的长寿基因的特征，我建议，在目标3中，将候选长寿基因分配到特定的遗传途径，并检查每个候选基因如何影响C中衰老特征的发生和/或进展。优雅这些新的候选长寿基因中许多都有哺乳动物同源基因，它们的分子特征可能会为了解生物衰老的分子基础提供重要见解，并可能对与年龄相关的人类疾病产生重要影响。

DESCRIPTION (provided by applicant): How organismal lifespan is determined is poorly understood. Previous investigations in C. elegans have identified novel mechanisms for longevity control that operate in evolutionarily diverse species. However, the analysis of C. elegans lifespan genes has been far from comprehensive. I have exploited recent advances in genomic and genetic technology to systematically identify new genes that affect C. elegans lifespan. My analyses point to mitochondrial oxidative phosphorylation as a major determinant of C. elegans lifespan and, additionally, identify over 100 new candidate longevity genes that previously have not been implicated in C. elegans lifespan. This proposal aims to develop each of these results. In C. elegans, mitochondria affect lifespan by acting in the same genetic pathway as caloric restriction, the only intervention known to extend lifespan from yeast to mammals. Thus, molecular dissection of how mitochondrial respiration affects lifespan may provide important insights into how nutrient usage and energy metabolism influence longevity across phylogeny. To understand the mechanism whereby mitochondrial respiration affects C. elegans longevity, I propose, in aim 1, to determine the cell(s)/tissue(s) in which mitochondria act to influence lifespan, and to investigate the physiological trigger that relates respiration to lifespan. In aim 2, I propose to elucidate the downstream signaling events that may mediate the longevity effect of mitochondrial respiration. As a first step to characterize the large number of additional new longevity genes I identified, I propose, in aim 3, to assign the candidate longevity genes to specific genetic pathways, and to examine how each candidate gene affects the onset and/or progression of aging features in C. elegans. Many of these new candidate longevity genes have mammalian homologs, and their molecular characterization will likely provide significant insights into the molecular underpinnings of organismal aging, and may have important implications for age-related human diseases.