Promoting health and survival through lowered body temperature

Core body temperature (T_b) is a long-established determinant of longevity across species. In this Perspective, we first summarize evidence demonstrating that reducing T_b increases lifespan and that lowered T_b contributes to the antiaging effects of calorie restriction. Next, we discuss recent data that diverge from prior hypotheses on the mechanisms by which T_b affects longevity, suggesting these are limited neither to the thermodynamics of nonenzymatic chemical reactions, nor reduced formation of mitochondrial reactive oxygen species nor lowered metabolic rate. Instead, recent findings in invertebrates show that cold promotes longevity via specific pathways including nutrient sensing and proteostasis, as well as modulating the thermodynamics of proteins and nucleic acids by changing their structure and function, for example, affecting temperature-sensitive ion channels, long-lived temperature-sensitive dauer mutations, base-pair stability and stem-loop RNA structures. Temperature affects the epigenetic signature and inflammation, and lowering T_b can also induce RNA-binding cold shock proteins, activate cold-sensitive kinases and differential splicing to potentially reshape the cellular environment. Finally, we reflect on important future work and the translational potential of temperature management and temperature mimetics.