A Torpor-Like State (TLS) in Mice Slows Blood Epigenetic Aging and Prolongs Healthspan

Torpor and hibernation are extreme physiological adaptations of homeotherms associated with pro-longevity effects. Yet the underlying mechanisms of how torpor affects aging, and whether hypothermic and hypometabolic states can be induced to slow aging and increase health span, remain unknown. We demonstrate that the activity of a spatially defined neuronal population in the avMLPA, which has previously been identified as a torpor-regulating brain region, is sufficient to induce a torpor like state (TLS) in mice. Prolonged induction of TLS slows epigenetic aging across multiple tissues and improves health span. We isolate the effects of decreased metabolic rate, long-term caloric restriction, and decreased core body temperature (Tb) on blood epigenetic aging and find that the pro-longevity effect of torpor-like states is mediated by decreased Tb. Taken together, our findings provide novel mechanistic insight into the pro-longevity effects of torpor and hibernation and support the growing body of evidence that Tb is an important mediator of aging processes.### Competing Interest StatementS. Horvath and R.T. Brooke are founders of the non-profit Epigenetic Clock Development Foun-dation, which licenses several patents from UC Regents including a patent on the mammalian methylation array platform. These patents list S.Horvath as inventor. V.G.S. serves as an advisor to and/or has equity in Branch Biosciences, Ensoma, and Cellarity, all unrelated to this work.