Core Body Temperature as a Central Regulator of Longevity: Beyond Thermodynamics and Metabolism
In the relentless pursuit to decipher the biological determinants of aging, core body temperature (Tb) emerges as a compelling and long-established variable intersecting with lifespan across diverse species. Recent strides in aging research reveal a complex tapestry whereby lowering Tb consistently correlates with increased longevity, yet the mechanistic underpinnings defy simple thermodynamic or metabolic models traditionally posited. This evolving narrative, propelled by recent data, indicates a sophisticated biological program responding to temperature that encompasses nutrient sensing, proteostasis, epigenetic regulation, and RNA-based mechanisms, repositioning Tb from a mere thermodynamic parameter to a dynamic modulator of cellular and organismal aging.
Historically, frameworks explaining the longevity effects of lowered Tb centered on fundamental physicochemical principles. The prevailing hypothesis posited that reductions in temperature slow down nonenzymatic chemical reactions, decreasing molecular damage accrual, such as the formation of advanced glycation end products. Similarly, it was hypothesized that cooler body temperature diminishes mitochondrial generation of reactive oxygen species (ROS), thereby mitigating oxidative stress—a known contributor to cellular senescence and age-associated decline. Furthermore, models suggested that a reduced metabolic rate accompanying lower Tb conserves cellular resources, delaying the onset of aging phenotypes by minimizing energy turnover and damage from metabolic byproducts.
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Contemporary research challenges the sufficiency of these explanations, revealing that the antiaging influence of Tb extends beyond these classical thermodynamic and metabolic tenets. For instance, compelling evidence from invertebrate models demonstrates that cold exposure initiates nuanced molecular responses, involving modulation of nutrient-sensing pathways such as insulin/IGF-1 signaling and target of rapamycin (TOR) pathways—both emblematic regulators of lifespan and metabolic homeostasis. These pathways, finely attuned to environmental cues, suggest that Tb acts as a signaling vector enabling physiological recalibration for survival under cold stress, rather than just passively slowing chemical reactions.
Proteostasis—the maintenance of protein homeostasis—represents another axis through which lowered Tb exerts its survival benefits. Studies in model organisms such as Caenorhabditis elegans reveal that cold stress can enhance the capacity of cellular quality control mechanisms, promoting the folding, trafficking, and degradation of proteins. This facilitates cellular resilience against proteotoxic stressors that typically accumulate with age, mitigating aggregation-prone proteins implicated in neurodegenerative diseases. Moreover, the conformational dynamics of proteins and nucleic acids are finely sensitive to temperature changes, influencing their structural integrity and functional output. Temperature-dependent modulation of protein folding landscapes and nucleic acid stability is no longer perceived as a mere physicochemical consequence but as an active determinant in longevity pathways.
Further evidence underscores the impact of temperature on the function of thermosensitive ion channels, which mediate critical cellular processes including neuronal signaling and metabolic regulation. These channels, responsive to cold stimuli, may mediate downstream transcriptional and posttranslational effects pivotal to longevity programs. Intriguingly, genetic mutations conferring extended lifespan in invertebrates often reveal temperature sensitivity, exemplified by dauer-related mutations in nematodes, underscoring the interplay between genetic regulators of aging and thermal environment.
On the genomic level, the stability of nucleic acid structures—such as base pairing and stem-loop formations in RNA—is profoundly modulated by temperature shifts, impacting RNA metabolism, translational fidelity, and the capacity for adaptive gene expression. These thermodynamic alterations suggest that cold exposure remodels the cellular transcriptome and proteome through mechanisms extending beyond canonical gene regulation to include RNA secondary structure-driven control.
In addition to these molecular layers, epigenetic modifications emerge as a critical interface between temperature and longevity. Temperature fluctuations have been linked to alterations in DNA methylation patterns, histone modifications, and chromatin remodeling, collectively influencing gene expression landscapes that govern aging phenotypes. The modulation of inflammation—a pivotal driver of aging and age-related diseases—is also temperature-responsive, with lower Tb attenuating proinflammatory signaling pathways, thereby contributing to a systemic environment conducive to healthy aging.
On a cellular level, exposure to reduced Tb induces the expression of RNA-binding cold shock proteins which have multifaceted roles in mRNA stability, translation, and cellular stress responses. Cold-sensitive kinases activated under these conditions can orchestrate signaling cascades reprogramming cellular states toward enhanced maintenance and repair capacities. Moreover, temperature modulates RNA splicing, offering an additional layer of posttranscriptional regulation that could reshape protein isoform repertoires to favor longevity.
This compendium of insights culminates in a paradigm shift: lowering core body temperature does not merely retard metabolic or chemical reaction rates but actively engages a complex network of genetic, epigenetic, and proteomic processes tailored to extend healthspan and lifespan. These mechanisms coalesce into a refined biological response, orchestrating survival in fluctuating thermal environments and offering promising vistas for translational interventions.
Looking ahead, vital research directions include elucidating the conserved and species-specific components of temperature-responsive longevity pathways, deciphering the integrative molecular circuits linking Tb to systemic aging phenotypes, and harnessing temperature mimetics—pharmacological or genetic tools that replicate the beneficial effects of lowered Tb without necessitating actual hypothermia. Advances in thermoregulatory biology promise novel approaches to human aging management, positioning temperature modulation as a compelling frontier in geroscience.
Given the ubiquity of temperature as an environmental and physiological variable, these findings forge new frontiers in understanding the intimate dialogue between organismal physiology and aging mechanisms. The prospect of controlled Tb manipulation or mimicking its effects heralds a transformative era where longevity interventions might be engineered with precision, potentially revolutionizing healthcare paradigms for age-related decline.
In summation, the interplay between core body temperature and lifespan unfurls as a multidimensional narrative, far surpassing classical thermodynamics and metabolic intuitions. It beckons a reconceptualization of Tb from a passive modifier to an active, integrative determinant of biological aging. The emergent molecular and cellular insights lay the foundation for innovative therapeutic avenues, bridging fundamental biology with clinical aspirations to foster healthy and prolonged human life.
Subject of Research: Aging, longevity, core body temperature, molecular biology of aging
Article Title: Promoting health and survival through lowered body temperature
Article References: Conti, B., de Cabo, R. Promoting health and survival through lowered body temperature. Nat Aging 5, 740–749 (2025). https://doi.org/10.1038/s43587-025-00850-0
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s43587-025-00850-0
Keywords: core body temperature, longevity, aging, calorie restriction, nutrient sensing, proteostasis, epigenetics, RNA structure, cold shock proteins, thermosensitive ion channels
Tags: advanced glycation end productsbiological determinants of lifespancore body temperature and longevityeffects of low body temperature on agingepigenetic regulation in agingmetabolic rate and agingmitochondrial function and agingnutrient sensing and agingoxidative stress and cellular senescenceproteostasis and longevityRNA mechanisms in agingthermodynamics and metabolic processes