Determining the role of flavin-containing monooxygenase-2 in longevity regulation

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Project summary. Aging is the greatest risk factor for multiple leading causes of death, such as heart diseases, multiple types of cancer, and Alzheimer’s disease. Aging is thus a growing economic and health concern worldwide as the number of people over the age of 65 continues to increase. Multiple genetic and environmental pathways that slow aging, such as dietary restriction (DR) and hypoxic response, have been discovered using animal models. However, the mechanisms by which these pathways extend lifespan remain largely unclear. This project focuses on a member of the family of xenobiotic metabolizing enzymes, flavin-containing monooxygenases, called fmo-2, that is induced downstream of DR and hypoxic response and was recently reported to be both necessary and sufficient to increase health and longevity in the nematode C. elegans. Interestingly, previous studies also report induction of FMO homologs in mammalian systems under DR and other longevity- increasing conditions. These results, combined with the knowledge that FMOs are well-conserved across taxa, make understanding the mechanisms of FMO-2-mediated life extension a crucial next step. This project will investigate the endogenous substrates and downstream processes of FMO-2 that are necessary for its longevity benefits. To this end, I will determine the key substrate(s) of FMO-2 protein that are required for its longevity benefits by first identifying potential substrates using untargeted metabolomics approach, validating the substrates using enzymatic assay, and testing the necessity of these substrates using RNAi lifespan analysis (Aim 1). Concurrently, I will determine the downstream metabolic processes that are required for fmo- 2-mediated longevity benefits by generating and improving on my current computational model, and testing the model prediction using isotope tracer flux analysis and RNAi lifespan screen (Aim 2). To ensure their success, these assays will be performed under the guidance of experts in nematode biology and aging, metabolomics profiling and data analysis, in silico modeling, and in vitro biochemistry. Collectively, these aims will further our mechanistic understanding of a highly conserved enzyme family whose member serves as a critical convergence point for multiple longevity pathways. This knowledge will allow us to identify potential therapeutic targets in the form of small molecules, genes, or proteins that can be utilized to improve human health.