Advancing Reproducibility in Allostatic Load Research: A Component-Level Approach Using the WHI Cohort

Abstract

Background: Allostatic load (AL) is a multisystem index of physiological dysregulation due to chronic stress. While widely applied, its operationalization remains inconsistent, limiting reproducibility and equity in population health research. Streamlined indices using common biomarkers may enhance feasibility across diverse settings. Methods: This study used data from 159,230 postmenopausal women in the Women’s Health Initiative to evaluate the construct validity of a minimal AL index. Candidate biomarkers across cardiovascular, metabolic, and immune domains were screened for predictive utility with mortality outcomes. The final three-component index included systolic blood pressure, waist circumference, and white blood cell count. Cox proportional hazards models estimated associations with all-cause, cardiovascular, and immune-related mortality, adjusting for demographic and clinical covariates. Results: Higher scores were strongly associated with mortality outcomes. Hazard ratios for all-cause mortality were 1.34 (95% CI: 1.30–1.38), 1.75 (1.69–1.81), and 2.28 (2.16–2.41) for scores of 1, 2, and 3 compared with 0 (p-trend <0.00001). Similar patterns were observed for cardiovascular and immune-related mortality. Each component remained independently predictive when modeled simultaneously. Conclusion: A minimal AL index of systolic blood pressure, waist circumference, and white blood cell count demonstrated robust associations with all-cause, cardiovascular, and immune-related mortality. While not a substitute for more comprehensive indices, this streamlined measure offers a pragmatic and reproducible approach for operationalizing AL, with potential to expand applicability in large-scale and resource-limited contexts.