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Principal Investigator: Armen I Yerevanian
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $169,240
Funding agency: National Institute on Aging
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.
Terms: <Active Oxygen><Address><Adipocytes><Adipose Cell><Advisory Committees><Aging><Animal Model><Animal Models and Related Studies><Animals><Area><Assay><Automobile Driving><Bioassay><Bioavailability><Biological Assay><Biological Availability><Biology><Biology of Aging><Body Composition><Body Tissues><C elegans><C. elegans><C.elegans><Caenorhabditis elegans><Caloric Restriction><Career Counseling><Career Guidance><Cell Body><Cell Communication and Signaling><Cell Line><Cell Signaling><CellLine><Cells><Cellular biology><Characteristics><Data><Degenerative Neurologic Disorders><Disease><Disorder><Doctor of Philosophy><Dose><Down-Regulation><Dysfunction><Environment><Enzyme Gene><Enzymes><FKHR><FMN><FOXO1><FOXO1A><FOXO1A gene><Fat Cells><Five-Year Plans><Flavin Mononucleotide><Flavin-Adenine Dinucleotide><Flavins><Forkhead Box O1A><Forkhead in Rhabdomyosarcoma><Fumarate Reductase><Functional disorder><Funding><General Hospitals><Goals><Health Benefit><Hepatic><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Human><Increase lifespan><Insulin Resistance><Intermediary Metabolism><Intracellular Communication and Signaling><Investigators><Length of Life><Lipids><Lipocytes><Liver Cells><Longevity><Mammalia><Mammals><Massachusetts><Mature Lipocyte><Mature fat cell><Mediating><Medicine><Mentors><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Pathway><Metabolic Processes><Metabolism><Mice><Mice Mammals><Micronutrients><Mitochondria><Modeling><Modern Man><Molecular><Murine><Mus><Nematoda><Nematodes><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Obesity><Occupational Guidance><Organism><Ortholog><Orthologous Gene><Oxidases><Oxidation-Reduction><Oxygen Radicals><Pathway interactions><Ph.D.><PhD><Pharmacology><Phenotype><Physicians><Physiologic><Physiologic Availability><Physiological><Physiology><Physiopathology><Pro-Oxidants><Process><Production><Reactive Oxygen Species><Redox><Regulation><Research><Research Personnel><Researchers><Respiration><Riboflavin><Riboflavin 5'-(dihydrogen phosphate)><Riboflavin 5'-Monophosphate><Riboflavin 5'-Phosphate><Riboflavin Mononucleotide><Role><Scientist><Signal Transduction><Signal Transduction Systems><Signaling><Strains Cell Lines><Succinate Dehydrogenase><Succinic Dehydrogenase><Succinic Oxidase><Task Forces><Therapeutic><Thesaurismosis><Time><Tissues><Training><Vitamin B 2><Vitamin B2><Vitamin G><Vocational Counseling><Vocational Guidance><Work><Yeasts><adiposity><advisory team><aging associated><aging associated disease><aging related><aging related disease><anti aging based therapeutic><anti aging therapeutic><anti-aging property therapeutic><associate faculty><associate professor><biological adaptation to stress><biological signal transduction><caloric restricted><calorically restricted><calorie restricted><calorie restriction><career counselor><career development><cell biology><cofactor><corpulence><cultured cell line><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><disease of aging><disorder of aging><driving><elongating the lifespan><executive coaching><extend life span><extend lifespan><fat metabolism><fumarate hydrogenase><functional genomics><geroscience therapeutic><gerotherapeutic><health-span><healthspan><healthy aging><healthy human aging><healthy life span><insight><insulin resistant><insulin tolerance><knock-down><knockdown><life span><lifespan><lifespan extension><lipid metabolism><living system><medical college><medical schools><member><metabolism disorder><mid-career faculty><midcareer faculty><mimetics><mitochondrial><model of animal><mouse model><murine model><neurodegenerative illness><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><oxidation><oxidation reduction reaction><pathophysiology><pathway><professor><programs><protective effect><reaction; crisis><respiratory mechanism><response><roundworm><school of medicine><skills><social role><stress response><stress; reaction><therapeutic against aging><therapeutic interventions against aging><therapeutic strategies for aging><therapeutic strategies targeting aging><therapeutic target><therapeutic target for anti-aging><therapeutic targeting aging><therapeutic targets to reverse aging><therapeutic to prevent aging><therapeutics impacts on aging><therapeutics that slow aging><tool><translational model><translational opportunities><translational potential><uptake>