Chronic Glucocorticoid Stress Reveals Increased Energy Expenditure and Accelerated Aging as Cellular Features of Allostatic Load

Stress triggers energy-dependent, anticipatory responses that promote survival, a phenomenon termed allostasis. However, chronic activation of allostatic responses results in allostatic load, a dysregulated state that predicts functional decline, accelerates aging, and increases mortality in humans. The cellular basis for the damaging effects of allostatic load remains unclear. By longitudinally profiling primary human fibroblasts across their lifespan, we show that chronic glucocorticoid stress induces a ∼60% increase in cellular energy expenditure and a greater reliance on mitochondrial oxidative phosphorylation (OxPhos) for energy production. Chronic stress also causes mtDNA instability, affects age-related cytokines secretion, and accelerates cellular aging, based on DNA methylation clocks, telomere shortening rate, and reduced lifespan. Finally, pharmacologically normalizing OxPhos activity while further increasing energy expenditure induces an exacerbation of the aging phenotype. Altogether, our findings define multi-omic recalibrations of stress adaptation, underscoring increased energy expenditure and accelerated cellular aging as interrelated features of cellular allostatic load. ### Competing Interest Statement The authors have declared no competing interest.