Hypometabolism as the ultimate defence in stress response: how the comparative approach helps understanding of medically relevant questions

First conceptualized from breath‐hold diving mammals, later recognized as the ultimate cell autonomous survival strategy in anoxia‐tolerant vertebrates and burrowing or hibernating rodents, hypometabolism is typically recruited by resilient organisms to withstand and recover from otherwise life‐threatening hazards. Through the coordinated down‐regulation of biosynthetic, proliferative and electrogenic expenditures at times when little ATP can be generated, a metabolism turned ‘down to the pilot light’ allows the re‐balancing of energy demand with supply at a greatly suppressed level in response to noxious exogenous stimuli or seasonal endogenous cues. A unifying hallmark of stress‐tolerant organisms, the adaptation effectively prevents lethal depletion of ATP, thus delineating a marked contrast with susceptible species. Along with disengaged macromolecular syntheses, attenuated transmembrane ion shuttling and PO₂‐conforming respiration rates, the metabolic slowdown in tolerant species usually culminates in a non‐cycling, quiescent phenotype. However, such a reprogramming also occurs in leading human pathophysiologies. Ranging from microbial infections through ischaemia‐driven infarcts to solid malignancies, cells involved in these disorders may again invoke hypometabolism to endure conditions non‐permissive for growth. At the same time, their reduced activities underlie the frequent development of a general resistance to therapeutic interventions. On the other hand, a controlled induction of hypometabolic and/or hypothermic states by pharmacological means has recently stimulated intense research aimed at improved organ preservation and patient survival in situations requiring acutely administered critical care. The current review article therefore presents an up‐to‐date survey of concepts and applications of a coordinated and reversibly down‐regulated metabolic rate as the ultimate defence in stress responses.