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. ? ?
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