Systematic Analysis of C elegans Longevity Determinants

描述（由申请人提供）：生物体的寿命是如何确定的，人们知之甚少。先前对秀丽隐杆线虫的研究已经确定了在进化多样性物种中运作的长寿控制新机制。然而，对秀丽隐杆线虫寿命基因的分析还远远不够全面。我利用基因组和基因技术的最新进展，系统地识别影响秀丽隐杆线虫寿命的新基因。我的分析指出，线粒体氧化磷酸化是秀丽隐杆线虫寿命的主要决定因素，此外，确定了100多个新的候选长寿基因，这些基因以前没有涉及秀丽隐杆线虫的寿命。本提案旨在发展这些结果。在秀丽隐杆线虫中，线粒体通过与热量限制相同的遗传途径影响寿命，热量限制是从酵母到哺乳动物的唯一已知延长寿命的干预措施。因此，线粒体呼吸如何影响寿命的分子解剖可能为营养利用和能量代谢如何影响整个系统发育的寿命提供重要见解。为了理解线粒体呼吸影响秀丽隐杆线虫寿命的机制，我建议在目标1中确定线粒体影响寿命的细胞/组织，并研究呼吸与寿命相关的生理触发因素。在目标2中，我建议阐明可能介导线粒体呼吸的长寿效应的下游信号事件。作为表征我发现的大量新的长寿基因的第一步，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，并研究每个候选基因如何影响秀丽隐杆线虫衰老特征的发生和/或进展。许多这些新的候选长寿基因都有哺乳动物的同源基因，它们的分子特征可能会为生物体衰老的分子基础提供重要的见解，并可能对与年龄相关的人类疾病具有重要意义。

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.