In response to environmental stressors, living organisms mount evolutionarily conserved responses that aim to increase resilience and promote survival, a phenomenon called allostasis . However, chronic activation of these responses produces allostatic load . Allostatic load is a multisystem state that reflects the additional burden, or “cost,” imposed by the activation of biological and physiological effects caused by real or perceived stressors. Applied to humans, the allostatic load model predicts that, when chronically maintained, allostatic load can lead to a maladaptive state of allostatic overload , which disrupts normal physiological functions and reduces longevity.
For example, while regular exercise improves glucose regulation and increases overall fitness, excessive exercise without adequate recovery becomes detrimental as it disrupts glucose homeostasis and insulin secretion. Large-scale epidemiological studies also show that allostatic load, quantified by abnormal levels of stress hormones, metabolites, and cardiovascular risk parameters, predicts physical and cognitive decline, as well as earlier mortality. These findings underscore the damaging long-term health effects that arise from chronic activation of stress pathways. However, the manifestations of allostatic load and overload at the cellular level and whether they can autonomously accelerate cell aging have not been fully defined.
Summary Stress triggers anticipatory physiological responses that promote survival, a phenomenon called allostasis . However, 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 of the damaging effects of allostatic load have not been defined. By longitudinally profiling primary human fibroblasts across their lifespan, we found that chronic glucocorticoid exposure induces an ~60% increase in cellular energy expenditure and an increased reliance on mitochondrial oxidative phosphorylation (OxPhos) rather than glycolysis. We show that this state of stress-induced hypermetabolism is related to mtDNA instability, affects age-related cytokine secretion, and accelerates cellular aging based on DNA methylation clocks, telomere shortening rate and reduced useful life. Pharmacological normalization of OxPhos activity while further increasing energy expenditure exacerbates the accelerated aging phenotype. Together, our findings define bioenergetic and multi-omics recalibrations of stress adaptation, underscoring increased energy expenditure and accelerated cellular aging as interrelated features of cellular allostatic load . |
Conclusions
In summary , we have defined multiple cell-autonomous features of glucocorticoid (GC)-induced allostatic load and mapped the long-term consequences associated with cell allostatic overload in primary human fibroblasts.
- First, our work quantifies the added energetic costs of chronic anticipatory responses at the cellular level, thus defining hypermetabolism as a characteristic of allostatic load.
- Second, we describe a hypersecretory phenotype that may contribute to hypermetabolism and reflects findings from clinical studies.
- Third, we document manifestations of cellular and mitochondrial allostatic load, including elevated mtDNA copy number and mtDNA density per cell, mtDNA instability, accelerated telomere shortening, and epigenetic aging by cell division.
In particular, we report a strong and temporally specific association between hypermetabolism and premature cell death , which aligns with prospective observations in the human literature where hypermetabolism increases the risk of mortality. And finally, our experimental modulation of OxPhos and total JATP suggests that total energy expenditure, rather than flux through mitochondrial OxPhos, may have a particularly influential effect on cellular aging.
Elucidating the mechanisms linking stress exposure, hypermetabolism, and shortened cellular lifespan will require further experimental work, as well as subsequent extension to well-controlled human studies. Resolving the cellular and bioenergetic basis of allostatic load and the biology of chronic stress should reveal bioenergetic principles that can be harnessed to increase human resilience and health across the lifespan.
