Roles of Lipid Metabolism in Regulation of Longevity

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Lipid metabolism plays a key role in human health and longevity. Dysregulation of lipid metabolism has been implicated in many age-related diseases. As a major site of lipid metabolism, adipose tissue exerts crucial endocrine effects on aging in both invertebrate and vertebrate organisms. Altered fat storage has been also observed in a variety of long-lived animals. However, it remains poorly understood how lipid metabolism is coupled to lifespan control. Preliminary studies have suggested that lipases and lipid chaperones exert exquisite control over lipid metabolism and lifespan in Caenorhabditis elegans. Lipases and lipid chaperones are up-regulated in long-lived animals, and necessary for their longevity. Their functions are also pivotal for fat mobilization in wild type and long-lived mutants. Constitute expression ofthe lipase K04A8.5 in fat storage tissue promotes lipolysis as well as longevity, which is largely non-overlapping with previous known longevity mechanisms. These studies suggest novel mechanisms for lipid metabolism in the control of aging. This proposal seeks to dissect the function of lipid metabolism in the regulation of longevity through the following specific aims: 1) Study the mechanisms by which lipase overexpression extends lifespan. 2) Characterize the roles of lipid chaperones in lifespan regulation. 3) Identify lipid messengers that extend lifespan. We will apply genetic and biochemical techniques to dissect the signaling components in the regulation of lipase and lipid chaperone functions, especially their mediated longevity. Additionally, we will employ lipidomic approaches with the goal of identifying particular lipid species and human metabolites as key regulators of aging. These studies will yield insights to mechanisms by which lipid metabolism affects the aging process, and provide novel therapeutic targets to improve metabolic health in elderly.