A torpor-like state in mice slows blood epigenetic aging and prolongs healthspan [ET0301]

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 decelerating effect of torpor-like states on aging is mediated by decreased Tb. Taken together, our findings provide novel mechanistic insight into the decelerating effects of torpor and hibernation on aging and support the growing body of evidence that Tb is an important mediator of aging processes. Samples beginning with CR are from the caloric restriction experiment in figure 4 of the paper. Samples beginning with C (experimental) or F (control) (date added to the end) are from long-term experiments in figure 3 of the paper. The title of each sample explains what treatment group the sample is from.

蛰伏（torpor）与冬眠（hibernation）是恒温动物（homeotherms）的极端生理适应策略，且与延寿效应相关。然而，蛰伏影响衰老的潜在机制，以及能否通过诱导低体温与低代谢状态来延缓衰老、延长健康寿命，目前仍不明晰。本研究证实，avMLPA中空间定位明确的神经元集群（该脑区此前被鉴定为调控蛰伏的脑区）的活动足以在小鼠体内诱导类蛰伏状态（torpor-like state, TLS）。长期诱导类蛰伏状态可延缓多组织的表观遗传衰老（epigenetic aging），并延长健康寿命。本研究分别探究了代谢率降低、长期热量限制（caloric restriction）与核心体温（core body temperature, Tb）降低对血液表观遗传衰老的影响，发现类蛰伏状态延缓衰老的效应由Tb降低所介导。综上，本研究结果为蛰伏与冬眠延缓衰老的潜在机制提供了全新的认知，并进一步佐证了日益增多的研究证据：Tb是衰老进程的重要调控介质。以CR开头的样本来自本文图4中的热量限制实验；以C（实验组）或F（对照组）开头（末尾标注日期）的样本来自本文图3中的长期实验。每个样本的命名均说明其所属的处理组。