Chronic psychological stress

Chronic psychological stress is a sustained state of perceived threat or demand that persistently activates the hypothalamic–pituitary–adrenal (HPA) axis, resulting in prolonged elevation of the glucocorticoid cortisol. Unlike acute stress responses, chronic stress keeps cortisol tonically elevated; immune cells eventually develop glucocorticoid receptor resistance, losing sensitivity to its anti-inflammatory signalling and leaving pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) unrestrained — a state termed inflammaging. Excess cortisol and reactive oxygen species (ROS) also accelerate telomere attrition: Epel et al. (2004, PNAS) found 39 mothers of chronically ill children had telomeres roughly 550 base pairs shorter than 19 controls — roughly one decade of added biological aging — with 48% lower telomerase activity and an inverse correlation with caregiver years (r = −0.40). Converging evidence links chronic stress to epigenetic clock acceleration and increased all-cause mortality, though most studies are cross-sectional; causal direction has not been established in intervention trials. The HPA–telomere–inflammaging triad is regarded as a biologically plausible, empirically supported mechanism of stress-driven healthspan compression, not a fully proven causal pathway.