Phenotypic Age Acceleration for Stratification of Mortality Risk and Survival Benefits in major chronic disease Populations: A Prospective Cohort Study

Background Biological aging reflects multisystem physiological decline and is a key driver of chronic diseases and mortality. However, integrative metrics that capture its complexity and mediate the effects of lifestyle and socioeconomic factors remain limited. We aimed to evaluate Phenotypic Age Acceleration (PhenoAgeAccel) as an indicator of multisystem aging and its utility in predicting mortality risk and residual life expectancy in individuals with chronic diseases (diabetes, dementia, cancer, and chronic respiratory diseases). Methods This prospective analysis utilized data from the UK Biobank (n = 353,619) and the Chinese cohort (n = 307,329). Multivariable-adjusted Cox regression and Royston-Parmar flexible parametric survival models were used to assess mortality risk and life expectancy. Mediation analyses quantified pathways through which lifestyle and socioeconomic factors influence outcomes via PhenoAgeAccel. Findings: In both the UK Biobank and Chinese cohorts, accelerated phenotypic aging was consistently associated with higher mortality risk and reduced life expectancy, with particularly pronounced effects among individuals with chronic diseases. Non-accelerated aging conferred substantial survival benefits, with risk reductions of 18–33% compared to severe acceleration. Life expectancy analyses revealed survival advantages of 3.87 years in Chinese cohort and 5.94 years in the the UK Biobank associated with non-accelerated versus severe aging. The association remained independent of sociodemographic, lifestyle, and both sexes, and was validated through extensive sensitivity analyses. Mediation analyses demonstrated PhenoAgeAccel partially mediated the pathways of adverse socioeconomic and poor lifestyle leading to mortality. Longitudinal cluster analysis further identified distinct aging patterns, where stable non-accelerated aging correlated with a survival advantage exceeding 12 years compared to rapidly accelerating trajectories. Finally, we developed PhenoDis-M, a digital tool to translate these insights into actionable preventive strategies, which was validated by an independent prospective Chinese cohort (n = 2789, AUC = 0.82). Interpretation: PhenoAgeAccel serves as a robust, integrative biomarker of biological aging that captures multisystem physiological decline and mediates key risk pathways. This work supports the development of targeted prevention strategies and advances the translation of geroscience into public health practice. Clinical Trial Registration Not applicable. This study is an observational, prospective cohort study and is not a clinical trial.