A Circulating Proteomic Signature of Allostatic Load Is Associated with Multisystem Disease and Mortality

Background: Chronic stress contributes to the development of cardiometabolic, malignant, and other chronic diseases through cumulative multisystem physiological dysregulation, conceptualized as allostatic load (AL). However, traditional AL relies on heterogeneous clinical biomarkers that are frequently unavailable or inconsistently collected in large cohorts, limiting reproducibility and translational utility. We developed and validated ProAL50, a proteomics-based measure of AL derived from 50 circulating proteins. Methods: Using high-dimensional plasma proteomic data from the UK Biobank, we constructed ProAL50 via penalized regression and stability selection and externally validated its construct in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Results: Among 37,089 UK Biobank participants, ProAL50 correlated strongly with traditional AL in the held-out test set (r = 0.72) and showed moderate external construct validity in CARDIA (r = 0.62). ProAL50 closely mirrored traditional AL in its associations with sociodemographic characteristics, lifestyle behaviors, physical and mental health, inflammation, and biological aging, supporting construct validity. In prospective analyses, ProAL50 showed associations with incident chronic disease, including type 2 diabetes, ischemic heart disease, chronic lung disease, chronic liver disease, chronic kidney disease, overall cancer, and all-cause and cause-specific mortality that were broadly comparable to traditional AL. Representative associations included incident type 2 diabetes (HR per SD = 2.72, 95% CI 2.61-2.84) and chronic liver disease (HR = 2.12, 95% CI 1.96-2.29). Conclusions: These findings support ProAL50 as a biologically informative, protein-based surrogate of AL for research use that complements traditional AL, pending further external validation and assay standardization.