Hibernation slows epigenetic aging in yellow-bellied marmots

Species that hibernate live longer than would be expected based solely on their body size. Hibernation is characterized by long periods of metabolic suppression (torpor) interspersed by short periods of increased metabolism (arousal). The torpor-arousal cycles occur multiple times during hibernation, and it has been suggested that processes controlling the transition between torpor and arousal states cause aging suppression. Metabolic rate is also a known correlate of longevity, we thus proposed the hibernation-aging hypothesis whereby aging is suspended during hibernation. We tested this hypothesis in a well-studied population of yellow-bellied marmots (Marmota flaviventer), which spend 7-8 months per year hibernating. We used two approaches to estimate epigenetic age: the epigenetic clock and the epigenetic pacemaker. Variation in epigenetic age of 149 samples collected throughout the life of 73 females were modeled using generalized additive mixed models (GAMM), where season (cyclic cubic spline) and chronological age (cubic spline) were fixed effects. As expected, the GAMM using epigenetic ages calculated from the epigenetic pacemaker was better able to detect nonlinear patterns in epigenetic age change over time. We observed a logarithmic curve of epigenetic age with time, where the epigenetic age increased at a higher rate until females reached sexual maturity (2-years old). With respect to circannual patterns, the epigenetic age increased during the summer and essentially stalled during the winter. Our enrichment analysis of age-related CpG sites revealed pathways related to development and cell differentiation, while the season-related CpGs enriched pathways related to central carbon metabolism, immune system, and circadian clock. Taken together, our results are consistent with the hibernation-aging hypothesis and may explain the enhanced longevity in hibernators.