TORC1 integrates metabolic state transitions during aging

Abstract

Target of rapamycin complex 1 (TORC1) coordinates nutrient availability with anabolic metabolism, yet how TORC1-linked metabolic states influence cellular aging remains unclear. Using genetic, transcriptomic, metabolomic, and pharmacological analyses in prototrophic Saccharomyces cerevisiae, we identify context-dependent metabolic state transitions that uncouple cellular proliferation from long-term survival during aging. Loss of the SEACIT complex, conserved with mammalian GATOR1, establishes a low-flux metabolic state characterized by coordinated remodeling of nitrogen, nucleotide, and central carbon metabolism during stationary phase. Pharmacological restraint of nucleotide, glycolytic, or sterol metabolism converges on similar adaptive metabolic programs, whereas perturbations that impair mitochondrial respiratory capacity destabilize these states and reduce survival. Integrative analyses in human cancer and primary cells further reveal that diverse metabolic perturbations converge on mTORC1 suppression but generate distinct mitochondrial and stress responses depending on nutrient availability. Together, these findings demonstrate that TORC1 integrates metabolic state transitions in which nutrient availability and mitochondrial function determine cellular survival during aging.