Methionine Cycle as a Mechanistic Hub for the Hallmarks of Aging

Summary (NIH) Age-dependent changes in Drosophila represent the key Hallmarks of Aging. While the progression of these Hallmarks is delayed by intervention within the nutrient sensing axis, there is no consensus for how nutrient sensing mechanistically coordinates Hallmarks or how retarded Hallmarks coordinate to regulate lifespan. We will address this issue with new genotypes of the Drosophila insulin/IGF receptor (dInr) that differentially affect nutrient sensing where each extends lifespan. Canonical long-lived dInr mutants are insulin-resistant. Remarkably, a new dInr mutation within the kinase insert domain (KID) strongly increases lifespan but retains insulin sensitivity. We conducted RNA, metabolomic and methionine-isotope labeling analyses to gain insight on how nutrient sensing regulates aging hallmarks. We found insulin-resistant dInr increases cellular methionine cycle flux, whereas insulin-sensitive dInr decreases this flux. Notably, the methionine cycle is a control hub for epigenetics, proteostasis, stress resistance, and stem cell regulation – underlying processes of aging hallmarks. We therefore hypothesize the methionine cycle provides a central mechanism to control multiple Hallmarks of Aging in response to nutrient sensing. This proposal will establish how nutrient regulation of the methionine cycle integrates Hallmarks of Aging.