Physiology of Lifespan Extension and Metabolic Hormesis with Riboflavin Depletion

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This proposal describes a five-year plan for Armen Yerevanian MD to transition to an independently-funded investigator with expertise in the metabolism of aging and the molecular physiology of riboflavin. He will be mentored by Alexander Soukas MD PhD, Associate Professor of Medicine at Harvard Medical School and an expert in both functional genomics and the biology of C. elegans. He will be co-mentored by Marcia Haigis PhD, Professor of Cell Biology at Harvard Medical School and a member of the Paul F. Glenn Center for the Biology of Aging. An advisory committee of physician-scientists with expertise in human aging, C. elegans aging, and metabolism have been assembled, including Gary Ruvkun PhD, Keith Blackwell MD PhD, Jose Florez MD PhD, and Richard Lee MD to provide scientific direction and career guidance during the transition to independence. Dr. Yerevanian will carry out the planned career development activities in the research and training environment at the Massachusetts General Hospital and Harvard Medical School. This research program utilizes the organism C. elegans, murine cell lines and mouse models to examine the physiology of riboflavin depletion and identify the core molecular mechanisms that underpin the lifespan extending effects of riboflavin depletion in C. elegans. The biology of riboflavin utilization and transport is strongly conserved through metazoans, making it an attractive area to study as a translational target. The ability to modulate cellular energetics and metabolic hormesis through riboflavin depletion may provide key therapeutic targets for the complications of aging, particularly metabolic complications including insulin resistance, changes in body composition and neurodegenerative diseases. Preliminary studies have already shown that riboflavin depletion extends lifespan in C. elegans, and utilizes canonical pathways associated with longevity including AMPK and FOXO. We hope to further elucidate the metabolic regulators of this process, including flavin co- factor synthesis, mitochondrial energetics, and lipid metabolism. The investigator will utilize functional genomics of C. elegans, metabolic assays of enzyme regulation, and novel mechanisms for altering cellular energetics to explore these aims. The ultimate goal of this work is to characterize the fundamental biology of riboflavin depletion, promote metabolic hormesis and healthy aging via riboflavin depletion in translational models, and to transition to independent investigator status.