Allostatic load associated with all-cause and cause-specific mortality: a large prospective cohort study

BACKGROUND: Allostatic load (AL) is a composite measure of cumulative physiological burden from chronic stress, quantifying multisystem dysregulation. Whether AL may alter the risk of overall, cause-specific mortality, and premature mortality remains unclear. METHODS: We analyzed UK Biobank participants aged 40-69 years (mean 56.6; 53.8% female) with complete data of AL metrics. AL was assessed by integrating 12 commonly applied metrics covering cardiovascular, metabolic, immune, and kidney systems (score range: 0-12), with higher scores indicating greater physiological dysregulation. Associations of AL scores with mortality from all cause and cause-specific mortality were examined. Stratified analyses assessed effect modification by premature mortality (< 70 years at death) and age at recruitment. RESULTS: Over a median follow-up of 15.4 years, 39,804 deaths were recorded, including 14,852 from cancer, 7118 from cardiovascular disease, 1938 from respiratory disease, and 1521 from digestive disease. Higher AL scores were significantly associated with increased risks of all-cause and cause-specific mortality in a dose-response manner (all P-trend < 0.001). Among specific causes, each one-point rise in AL score yielded stronger associations with digestive disease mortality (subdistribution hazard ratio [sHR] = 1.25, 95% confidence interval [CI]: 1.21-1.29) and cardiovascular disease mortality (sHR = 1.20, 95% CI: 1.18-1.21) than for cancer mortality (sHR = 1.08, 95% CI: 1.07-1.09) and respiratory disease mortality (sHR = 1.11, 95% CI: 1.09-1.14). Age significantly modified these associations (all P-interaction < 0.01), with higher HRs for premature mortality (age at death < 70 years) or younger individuals (age at enrollment < 50 years). CONCLUSIONS: Higher AL scores were associated with increased risks of all-cause and cause-specific mortality. Such associations were particularly pronounced for digestive and cardiovascular disease mortality, and appeared stronger for premature deaths and among younger individuals. These findings suggest that AL may serve as a marker of early physiological dysregulation and may help identify individuals at elevated risk of premature mortality.