Life in the cold: links between mammalian hibernation and longevity

The biological process of aging is the primary determinant of lifespan, but the factors that influence the rate of aging are not yet clearly understood and remain a challenging question. Mammals are characterized by >100-fold differences in maximal lifespan, influenced by relative variances in body mass and metabolic rate. Recent discoveries have identified long-lived mammalian species that deviate from the expected longevity quotient. A commonality among many long-lived species is the capacity to undergo metabolic rate depression, effectively re-programming normal metabolism in response to extreme environmental stress and enter states of torpor or hibernation. This stress tolerant phenotype often involves a reduction in overall metabolic rate to just 1-5% of the normal basal rate as well as activation of cytoprotective responses. At the cellular level, major energy savings are achieved via coordinated suppression of many ATP-expensive cell functions; e.g. global rates of protein synthesis are strongly reduced via inhibition of the insulin signaling axis. At the same time, various studies have shown activation of stress survival signaling during hibernation including up-regulation of protein chaperones, increased antioxidant defenses, and transcriptional activation of pro-survival signaling such as the FOXO and p53 pathways. Many similarities and parallels exist between hibernation phenotypes and different long-lived models, e.g. signal transduction pathways found to be commonly regulated during hibernation are also known to induce lifespan extension in animals such as Drosophila melanogaster and Caenorhabditis elegans. In this review, we highlight some of the molecular mechanisms that promote longevity in classic aging models C. elegans, Drosophila, and mice, while providing a comparative analysis to how they are regulated during mammalian hibernation.