PROJECT SUMMARY/ABSTRACT Aging is a risk factor for various human pathologies including neurodegenerative diseases (e.g. Alzheimer's and Parkinson's) and is characterized by extensive metabolic changes. Several studies have revealed a number of metabolic pathways for which perturbation of the pathway can extend lifespan in flies and other organisms. Using targeted high-throughput metabolite profiling in Drosophila melanogaster adults of different ages, we demonstrated that methionine metabolism changes during aging. Particularly, we showed that one of the methionine downstream metabolites, SAH, accumulates with age and further, that inhibition of SAH accumulation extends life- and healthspan. The experiments proposed in this application aim to address the fundamental questions of how methionine flux is reprogrammed at the whole-organism level and in different organs and whether organ-specific activation/suppression of methionine flux can extend lifespan and suppress different age-related pathological manifestation. It also raises the question whether inhibition of SAH accumulation can be combined with alteration of other metabolic pathways for life- and healthspan extension. I will work toward these goals under the mentorship of Dr. Norbert Perrimon, a long-standing expert in Drosophila genetics; Dr. Mel Feany, who has established and extensively characterized Drosophila models relevant to Alzheimer's and Parkinson's diseases; and Dr. Joshua Rabinowitz, who has created techniques for studying in vivo methionine flux. During my training period, I will be testing the effects of methionine restriction on age-dependent loss of muscle integrity and pathological signs of neurodegeneration in control flies and fly models relevant to Alzheimer's and Parkinson's diseases. I will also establish a genetic model of methionine restriction, which will allow me to test the tissue-specific effects of methionine restriction and examine how the distribution of labeled methionine in downstream metabolic pathways is changed with age. These tools and training will be critical to help me establish my own group focusing on metabolic mechanisms of aging and translating findings from Drosophila to develop better therapeutic options for patients with neurodegenerative diseases.