Lipid metabolism plays a key role in human health and longevity. Lipid metabolism undergoes fundamental changes during aging, which attributes to the development of many age-associated diseases, such as diabetes mellitus, neurodegenerative disorder and cancer. As a major site of lipid metabolism, adipose tissue exerts crucial endocrine effects on the aging process in both invertebrate and vertebrate organisms. However, it remains poorly understood how lipid metabolism is coupled to lifespan control. Lipids are not only crucial biological molecules for cellular structure and energy consumption, but also signaling messengers actively involved in transcriptional response and signal transduction. A family of fatty acid binding proteins has been identified as chaperones of lipid messengers to facilitate their cellular effects. Lipase-induced lipolysis is a canonical metabolic process to break down fat, which is recently shown to produce lipid messengers that are essential for the regulation of energy metabolism. During the preliminary studies, we characterized LIPL-4 as a lysosomal acid lipase in Caenorhabditis elegans. Its constitute expression in the fat storage tissue induces lipolysis as well as prolongs organism lifespan, which requires the activity of nuclear hormone receptor NHR- 49 signaling. Furthermore, a lipophilic metabolite oleoylethanolamide (OEA) and a fatty acid binding protein LBP-8 were identified that play crucial roles in the regulation of the LIPL-4-mediated longevity. These studie suggest a novel longevity mechanism that lipase-induced lipolysis promotes longevity via activating specific lipid messengers and lipid signaling. This proposal seeks to dissect the novel functions of lipase-induced lipolysis in the regulation of longevity through the following specific aims: 1) characterize the effects of the lipid messenger OEA in the regulation of organism longevity. 2) Study the mechanism by which LBP-8 functions in the lipase-mediated longevity. 3) Investigate cellular bioenergetic changes that are responsible for organism longevity. We will apply cutting- edge high-throughput metabolomics and label-free chemical imaging techniques combining with genetic, biochemical and transcriptional profiling approaches to dissect the molecular mechanisms underlying this new longevity pathway. These studies will yield new insights to the molecular mechanisms by which lipid metabolism affects the aging process, and also provide novel therapeutic targets to improve metabolic health in elderly.
Results from this study are important for public health as increased incidence of diseases with age. This study will provide insight into essential roles of lipid metabolism in regulating lifespan as well as address many fundamental issues in lipid metabolism and energy homeostasis.
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