Accelerated biological aging and the dynamic transitions of stroke and dementia: A multi-state trajectory analysis

Accelerated biological aging has been implicated in increased vulnerability to age-related diseases. However, its role in neurovascular disease trajectories remains unclear. We aimed to investigate how biological age acceleration (BAA), estimated by two established aging algorithms, influences the sequential development of stroke, dementia, comorbidity accumulation, and death.

We used data from 220,236 participants in the UK Biobank who were free of stroke and dementia at baseline. BAA was calculated as the residual difference between biological and chronological age using the Klemera-Doubal Method-Biological Age (KDM-BA) and Phenotypic Age (PhenoAge). A multi-state Cox model was employed to evaluate the associations between BAA and eight disease transitions across five states: baseline, stroke, dementia, comorbidity, and death. We further evaluated nonlinear exposure-response patterns and time-interval-specific associations.

Over a median follow-up of 15.31 years, 4436 participants experienced stroke, 3101 developed dementia, 291 accumulated comorbidities, and 17,375 died. Each standard deviation increase in BAA was significantly associated with elevated risks of initial events. PhenoAge acceleration was associated with higher risks of stroke 1.16 (95% CI: 1.14-1.19), dementia 1.10 (95% CI: 1.06-1.13), and death 1.24 (95% CI: 1.23-1.25); similar trends were observed for KDM-BA. However, no significant associations were observed for transitions from stroke or dementia to comorbidity. These patterns were consistent across various time intervals (0-1, 1-3, and > 3 years) and demographic and clinical subgroups, with no evidence of temporal or effect modification.

BAA was associated with the initial onset of stroke, dementia, and mortality, whereas its associations with later progression to comorbidity were not evident. These findings suggest that BAA may be most informative for identifying early vulnerability, highlighting the potential value of targeting accelerated aging before clinical disease onset.