Association between phenotypic age acceleration and mortality in patients with chronic obstructive pulmonary disease

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. Chronological age poorly reflects biological heterogeneity in prognosis. Phenotypic age acceleration (PhenoAgeAccel), a biomarker of multisystem biological aging, may offer prognostic value beyond traditional risk factors. OBJECTIVES: We investigated whether PhenoAgeAccel predicts all-cause and cause-specific mortality in patients with COPD. METHODS: Data from 1262 COPD participants in the National Health and Nutrition Examination Survey (NHANES, 1999-2010, 2015-2018) were linked to mortality records through 2019. PhenoAgeAccel was calculated from phenotypic age residuals. Multivariable Cox models estimated hazard ratios (HRs) for all-cause, cardiovascular, cancer, and chronic lower respiratory disease (CLRD) mortality. Restricted cubic splines assessed nonlinearity, with subgroup and sensitivity analyses performed. RESULTS: Each unit increase in PhenoAgeAccel was associated with higher all-cause (HR = 1.03; 95% CI: 1.02-1.05), cardiovascular (HR = 1.03; 95% CI: 1.02-1.05), cancer (HR = 1.03; 95% CI: 1.01-1.04), and CLRD mortality (HR = 1.02; 95% CI: 1.01-1.04). Participants in the highest quartile had over a fivefold increase in all-cause mortality compared to the lowest quartile. Kaplan-Meier curves demonstrated progressively reduced survival, and associations remained consistent across subgroup and sensitivity analyses. CONCLUSION: PhenoAgeAccel is an independent predictor of mortality in COPD, providing prognostic information beyond chronological age. It may serve as a practical biomarker for risk stratification and personalized management, warranting further validation in longitudinal and interventional studies.