Role of autophagy and lipid metabolism in organismal aging

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DESCRIPTION (provided by applicant): Autophagy is a key process by which cellular components are degraded and recycled, and this process plays important roles in several organismal responses, most recently in aging. For example, we and others have shown that autophagy is upregulated in several C. elegans mutants with extended longevity, including insulin/IGF-1 receptor daf-2 mutants. Intriguingly, such mutants require autophagy genes, e.g. bec-1/beclin 1, to live long (Melendez et al., Science, 2003, Hansen et al., PLoS Genetics, 2008). Removal of germline stem cells in C. elegans also extends lifespan, potentially in a conserved fashion as signals from the reproductive system can extend the lifespan of flies and mice. Germ line ablation can be mimicked genetically in C. elegans by mutation of the Notch receptor glp-1; accordingly, glp-1 mutants are long-lived. Interestingly, the intestine appears to play a key role in mediating the longevity response observed in germ line-less animals, possibly via hormonal signaling. While several genes with roles in hormonal signaling have been found to be required for glp-1 mutants to live long, the cellular mechanisms by which glp-1 mutations and/or signals from the gonad extend lifespan remains unclear. We have observed that autophagy is induced in glp-1 mutants, and our preliminary data indicate that genes that regulate autophagy are required for the extended longevity of glp-1 mutants. Interestingly, autophagy was recently linked to fat metabolism, and glp-1 mutants have increased fat levels. Moreover, a lipase has been reported to be required for glp-1 mutants to live long, suggesting an important role for nutrient partitioning in glp-1 animals. Importantly, our preliminary data indicate that autophagy genes are required for both the increase in fat seen in glp-1 mutants as well as the extended longevity observed in lipase-overexpressing animals, suggesting a novel role for autophagy in regulating fat metabolism and for the effects of lipolysis on C. elegans longevity. In this proposal, we propose to investigate the mechanisms by which autophagy is regulated in response to germ line removal. Specifically, we hypothesize that autophagy plays a role in mediating lifespan extension of glp-1 animals, at least in part by regulating fat metabolism. To this end, we will address three specific aims using genetic, cytological, and biochemical approaches in C. elegans: 1) assay in which tissues autophagy is induced and required for germline-mediated longevity, 2) test whether known longevity genes, including those involved in hormonal signaling in glp-1 mutants, regulate autophagy, and 3) determine how the processes of autophagy and fat metabolism are coordinately regulated in long-lived glp-1 mutants. Autophagy has been implicated in many disorders, including cancer, whereas deregulated fat metabolism results in obesity. Understanding the molecular mechanisms by which autophagy and fat metabolism are co- regulated in long-lived, germ line-less animals could provide important new insights into organismal aging and facilitate development of therapies for age-related diseases, including obesity. PUBLIC HEALTH RELEVANCE: The human population is rapidly aging and age-related diseases constitute a major health issue in our society; however, the genetic basis of aging and age-related diseases is poorly understood. This study aims to explore the role of autophagy - a cellular pathway by which cytoplasmic components are recycled - in aging by examining links between autophagy, metabolism, and the extended longevity observed in nematodes with no germline stem cells. The proposed research has relevance to public health, because the mechanisms to be investigated are evolutionary conserved and the findings might ultimately provide therapies to treat aging-related diseases.