Cellular allostatic load is linked to increased energy expenditure and accelerated biological aging

Stress triggers anticipatory physiological responses that promote survival , a phenomenon termed allostasis. However, the chronic activation of energy-dependent allostatic responses results in allostatic load, a dysregu-lated state that predicts functional decline, accelerates aging, and increases mortality in humans. The energetic cost and cellular basis for the damaging effects of allostatic load have not been defined . Here, by longitudinally profiling three unrelated primary human fibroblast lines across their lifespan, we find that chronic glucocorticoid exposure increases cellular energy expenditure by similar to 60%, along with a metabolic shi f t from glycolysis to mitochondrial oxidative phosphorylation (OxPhos). This state of stress-induced hypermetabolism is linked to mtDNA instability, non-linearly affects age-related cytokines secretion, and accelerates cellular aging based on DNA methylation clocks, telomere shortening rate, and reduced lifespan. Pharmacologically normalizin g OxPhos activity while further increasing energy expenditure exacerbates the accelerated aging phenotype, pointin g to total energy expenditure as a potential driver of aging dynamics. Together, ou r findings define bioenergetic and multi-omic recalibrations of stress adaptation, underscoring increased ener g y expenditu r e and accelerated cellular aging as interrelated features of cellular allostatic load.

Automated summary

Stress triggers physiological responses that promote survival, but chronic activation of energy-dependent responses leads to a dysregulated state called allostatic load, which predicts functional decline, accelerates aging, and increases mortality in humans. A study on primary human fibroblast lines found that chronic exposure to glucocorticoids increases cellular energy expenditure and shifts metabolism from glycolysis to mitochondrial oxidative phosphorylation. This stress-induced hypermetabolism is associated with mtDNA instability, affects age-related cytokine secretion, and accelerates cellular aging, suggesting that increased energy expenditure is a potential driver of aging dynamics.