TY - JOUR T1 - Chronic Glucocorticoid Stress Reveals Increased Energy Expenditure and Accelerated Aging as Cellular Features of Allostatic Load JF - bioRxiv DO - 10.1101/2022.02.22.481548 SP - 2022.02.22.481548 AU - Natalia Bobba-Alves AU - Gabriel Sturm AU - Jue Lin AU - Sarah A Ware AU - Kalpita R. Karan AU - Anna S. Monzel AU - Céline Bris AU - Vincent Procaccio AU - Guy Lenaers AU - Albert Higgins-Chen AU - Morgan Levine AU - Steve Horvath AU - Balaji S Santhanam AU - Brett A Kaufman AU - Michio Hirano AU - Elissa Epel AU - Martin Picard Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/05/07/2022.02.22.481548.abstract N2 - 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 StatementThe authors have declared no competing interest. ER -