Biological age acceleration, plasma proteomics, and incident arrhythmias in type 2 diabetes

To examine associations of biological age acceleration with incident arrhythmias in adults with type 2 diabetes and explore proteomic signatures and candidate mediators. We included 19,313 UK Biobank participants with type 2 diabetes and no recorded history of arrhythmia at baseline (mean age, 59.46 years; 60.49% men). Phenotypic age (PhenoAge) and the Klemera-Doubal method biological age (KDMAge) acceleration were derived as residuals from regression of biological age on chronological age. Incident arrhythmias were identified from linked hospital records. Multivariable Cox models estimated hazard ratios (HR) for incident arrhythmias and arrhythmia subtypes. In 1807 participants with proteomic data, protein-wide associations, enrichment analyses, LASSO selection, and mediation analyses were performed. During a median follow-up of 13.74 years, 2652 participants developed incident arrhythmia. Each 1-SD increase in PhenoAge acceleration was associated with higher arrhythmia risk (HR 1.20; 95% CI 1.14–1.27); the corresponding HR for KDMAge acceleration was 1.09 (95% CI 1.05–1.14). Compared with Q1, Q4 of PhenoAge and KDMAge acceleration had HRs of 1.57 (95% CI 1.39–1.76) and 1.24 (95% CI 1.11–1.38), respectively. PhenoAge acceleration showed consistent associations across arrhythmia subtypes. In a subset of 1807 participants with Olink plasma proteomic data, 2918 proteins were included in exploratory proteome-wide analyses. Proteomic analyses identified 1085 proteins associated with PhenoAge acceleration and 486 with KDMAge acceleration, enriched in immune, cell-adhesion, extracellular remodeling, complement, and coagulation pathways. Candidate statistical mediators included WFDC2, RELT, EFNA1, PLAUR, HAVCR1, and CHGB. Biological age acceleration, particularly PhenoAge acceleration, was associated with a higher risk of incident arrhythmia in adults with type 2 diabetes. Exploratory proteomic analyses identified associated proteins, enriched biological pathways, and candidate mediators, providing hypothesis-generating biological context for the observed associations.