Systematic Analysis of C elegans Longevity Determinants

描述(由申请人提供)：生物寿命是如何确定的，人们知之甚少。之前对线虫的研究已经确定了控制寿命的新机制，这些机制在进化上不同的物种中运作。然而，对线虫寿命基因的分析还远远不全面。我利用基因组和基因技术的最新进展，系统地识别了影响线虫寿命的新基因。我的分析指出线粒体氧化磷酸化是线虫寿命的主要决定因素，此外，我还发现了100多个新的候选长寿基因，这些基因以前没有与线虫的寿命有关。该提案旨在发展这些成果中的每一个。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，这是已知的唯一将寿命从酵母延长到哺乳动物的干预措施。因此，对线粒体呼吸如何影响寿命的分子解剖可能会为营养利用和能量代谢如何影响整个系统发展史上的寿命提供重要的见解。为了了解线粒体呼吸影响线虫寿命的机制，在目标1中，我建议确定线粒体影响寿命的细胞(S)/组织(S)，并研究与呼吸有关的生理触发因素。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，在目标3中，我建议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线虫衰老特征的开始和/或进展。这些新的候选长寿基因中有许多与哺乳动物同源，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的见解，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.