Calorie Restriction-Induced Daily Hibernation in Mice Drives Cyclic DNA Damage and Repair

Hibernation consists of bouts of torpor, characterized by profound decreases in metabolism and body temperature (Tb), alternated with periods of euthermia called interbout arousals, during which normal metabolism and Tb resume. Seasonal hibernators accumulate DNA strand breaks during torpor, which are repaired during arousal. Here, we assess dynamics of DNA damage and repair during serial daily torpor in mice induced by 30% calorie restriction (CR) and investigate the effects of metabolic challenge on DNA repair. Serial daily torpor induced by CR in C57/BL6J mice of both sexes housed at 20{ring}C lasts 6-12 hours. Like seasonal hibernators, DNA damage increases in CR-induced torpor and is repaired in the subsequent euthermic period, as evidenced by comet assay and yH2AX accumulation. To metabolically challenge animals, ambient temperature (Ta) was lowered to 4{ring}C, since torpid mice defend a Tb of around 20{ring}C or higher. Despite inducing a significant metabolic challenge, housing of torpid mice at 4{ring}C does not increase DNA damage compared to 20{ring}C housing. However, reducing Ta to 4{ring}C during euthermia inhibits DNA repair. Interestingly, p21 levels increase in mice exposed to 4{ring}C, indicating cell-cycle inhibition during exposure to 4{ring}C. Thus, 30% CR induces daily cycles of torpor-induced DNA damage and euthermia-associated DNA repair in mice, and exposure to a Ta of 4{ring}C during arousal inhibits DNA repair mounting a cell cycle inhibition response. Thus, the torpor-arousal cycle may be a contributing factor to the lifespan extension benefits of CR in mice, promoting genomic integrity and thereby cellular and tissue health.