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Stress triggers energy-dependent, anticipatory responses that promote survival, a phenomenon termed allostasis. However, the chronic activation of allostatic responses results in allostatic load (AL) and in the maladaptive state known as allostatic overload. Epidemiological studies show that allostatic load predicts physical and cognitive decline, as well as earlier mortality; yet the manifestations of allostatic load and overload at the cellular level remain unclear. To define the energetic cost and potential detrimental effects of prolonged cellular allostatic load, we developed a longitudinal model of chronic glucocorticoid stress in primary human fibroblasts. Results replicated in three healthy donors demonstrated that chronic stress robustly increased cellular basal energy consumption by 62%. This hypermetabolic state relied on a bioenergetic shift away from glycolysis towards mitochondrial oxidative phosphorylation (OxPhos), supported by an upregulation of mitochondrial biogenesis and increased mitochondrial DNA (mtDNA) density. As in humans where chronic stress accelerates biological aging, chronic allostatic load altered extracellular cytokine and cell-free DNA, caused mtDNA instability, increased the rate of epigenetic aging based on DNA methylation clocks, accelerated telomere shortening, and reduced lifespan (i.e., Hayflick limit). Pharmacological blockade of mitochondrial nutrients uptake normalized OxPhos activity but exacerbated hypermetabolism, which further accelerated telomere shortening and reduced cellular lifespan. Together, these results highlight the increased energetic cost of cellular allostatic load and suggests a mechanism for the transduction of chronic stress into accelerated cellular aging to be examined in humans.

No abstract

The allometric theory of metabolism predicts that the rate of biological aging is proportional to an organism’s size and metabolic rate (MR). Here we test this hypothesis in humans by generating longitudinal, multi-modal signatures of aging in primary human fibroblasts. Relative to metabolic rates in the human body, isolated cells exhibit markedly elevated MR and operate closer to their maximal energy production capacity. Accordingly, per-cell division, isolated cells display accelerated telomere shortening and increased rate of DNA methylation aging. Moreover, despite a marked reduction in division rate towards the end of life, mass-specific MR increases exponentially, reflecting hypermetabolism. We develop a theoretical-mathematical model that accounts for a partitioning of energetic costs related to both growth or maintenance, quantifying the potential origins of hypermetabolism in vitro, and with advancing age. Moreover, we define genome-wide molecular rescaling factors that confirm and quantify the systematic acceleration of molecular aging kinetics in cultured fibroblasts, and use this approach to show how metabolic and pharmacological manipulations that increase or decrease MR predictably accelerate or decelerate the rates of biological aging. The interconnected speedup of energetic and molecular dynamics across the lifespan of human cells has important theoretical and clinical implications for aging biology.