Refining Allostatic Load Measurement: Mortality Associations of an Empirically Derived Three-Component Score in the Women’s Health Initiative

Allostatic load (AL) is a multisystem index of physiological dysregulation due to chronic stress. Although widely applied, its operationalization remains inconsistent, limiting reproducibility and equity. Streamlined indices based on common biomarkers may enhance feasibility across settings. Using data from 150 293 postmenopausal women in the Women's Health Initiative, we evaluated the construct validity of a streamlined, multisystem AL index. Biomarkers across cardiovascular, metabolic, and immune domains were screened for stable associations with mortality. The final three-component AL index included systolic blood pressure, waist circumference, and white blood cell count. Cox proportional hazards models estimated associations with all-cause, cardiovascular, and immune/inflammatory mortality, adjusting for demographic and clinical covariates. Higher AL scores were strongly associated with mortality. Hazard ratios for all-cause mortality were 1.34 (95% CI, 1.30-1.38), 1.74 (1.68-1.80), and 2.27 (2.15-2.39) for scores of 1, 2, and 3 versus 0 (Ptrend < 0.001), with similar patterns observed for cardiovascular and immune/inflammatory mortality. A streamlined, multisystem AL index comprised of systolic blood pressure, waist circumference, and white blood cell count demonstrated robust associations with mortality outcomes, supporting the feasibility of such an operationalization of AL, which may enhance reproducibility and extend the applicability of AL indices in large-scale and resource-limited contexts.