Aging is a risk factor for various human pathologies including Alzheimer’s disease, and both aging and Alzheimer’s disease are 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. Similarly, Alzheimer’s disease is characterized by extensive metabolic reprogramming. 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 manifestations, including ones associated with Alzheimer’s disease. In addition, impaired methionine flux and delayed SAH processing may have a strong effect on cellular physiology via inhibition of a broad spectrum of methyltransferases. I will be using transgenic Drosophila models relevant to Alzheimer’s disease to analyze how overexpression of human Tau affects methionine flux. I will be testing the effects of methionine restriction and methyltransferases on pathological signs of neurodegeneration in control flies and transgenic fly models relevant to Alzheimer’s disease. I will also use 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 and in fly models relevant to Alzheimer’s disease. Our studies will provide insights into how restoring of age-dependent defects related to impaired methionine metabolism can be applied to lifespan extension and to the potential treatment of Alzheimer’s disease.