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 dysregulated 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 ∼60%, along with a metabolic shift 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 normalizing OxPhos activity while further increasing energy expenditure exacerbates the accelerated aging phenotype, pointing to total energy expenditure as a potential driver of aging dynamics. Together, our findings define bioenergetic and multi-omic recalibrations of stress adaptation, underscoring increased energy expenditure and accelerated cellular aging as interrelated features of cellular allostatic load.

The energetic cost of allostasis and allostatic load.

Chronic psychosocial stress increases disease risk and mortality, but the underlying mechanisms remain largely unclear. Here we outline an energy-based model for the transduction of chronic stress into disease over time. The energetic model of allostatic load (EMAL) emphasizes the energetic cost of allostasis and allostatic load, where the "load" is the additional energetic burden required to support allostasis and stress-induced energy needs. Living organisms have a limited capacity to consume energy. Overconsumption of energy by allostatic brain-body processes leads to hypermetabolism, defined as excess energy expenditure above the organism's optimum. In turn, hypermetabolism accelerates physiological decline in cells, laboratory animals, and humans, and may drive biological aging. Therefore, we propose that the transition from adaptive allostasis to maladaptive allostatic states, allostatic load, and allostatic overload arises when the added energetic cost of stress competes with longevity-promoting growth, maintenance, and repair. Mechanistically, the energetic restriction of growth, maintenance and repair processes leads to the progressive wear-and-tear of molecular and organ systems. The proposed model makes testable predictions around the physiological, cellular, and sub-cellular energetic mechanisms that transduce chronic stress into disease risk and mortality. We also highlight new avenues to quantify allostatic load and its link to health across the lifespan, via the integration of systemic and cellular energy expenditure measurements together with classic allostatic load biomarkers.