Life in the cold: links between mammalian hibernation and longevity

Abstract

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.

Dietary restriction and insulin‐like signalling pathways as adaptive plasticity: A synthesis and re‐evaluation

“…This is of fundamental importance to overwintering mammals and insects, who change their physiology dramatically through hibernation, torpor, or diapause to survive challenging conditions, and who must also reverse metabolic depression in readiness to reproduce as conditions improve (Hut, Dardente, & Riede, 2014). There is growing evidence in insects that the IIS pathway is sensitive to photoperiod changes and is involved in regulating downstream physiological responses (reviewed in Flatt et al, 2013;Sim & Denlinger, 2013;Wu & Storey, 2016). In Drosophila, IIS controls the entry into adult diapause (essentially a reversible state of reproductive arrest, also referred to as reproductive dormancy) in concert with the steroid juvenile hormone (JH).…”

Warming the mouse to model human diseases

“…Since a stable core temperature is critical for the survival of endotherms, endothermic animals go to great lengths to defend their core temperature in colder environments, a trait that has profound effects on their metabolic, cardiovascular, and immunologic responses. However, when defense of the core temperature is not possible, such as during food scarcity or seasonal cold, many endotherms, including mice, will abandon homeothermy and engage in daily torpor or seasonal hibernation to conserve energy 6,7 .…”

Hibernation impacts lysine methylation dynamics in the 13‐lined ground squirrel, Ictidomys tridecemlineatus

“…Regulated inhibition of the ribosomal initiation and elongation phases of translation, reduced rates of mRNA turnover, and increased protein stability allow for a strong reduction in overall cellular energy usage via reducing levels of transcription, translation, and proteolysiswhile preserving pre‐existing proteins (Tessier & Storey, ; van Breukelen & Martin, ; van Breukelen, Sonenberg, & Martin, ). However, reductions in gene expression and protein synthesis are not global over the entire genome; the expression of certain genes necessary for regulating and maintaining the hibernation state is maintained or upregulated (Grabek, Martin, & Hindle, ; Wu & Storey, ). For example, some cytoprotective pathways are upregulated during torpor, such as to prevent muscle atrophy, or enhance antioxidant defenses (Rouble, Tessier, & Storey, ).…”