Longitudinal insights into dynamic patterns and cumulative burdens of biological age acceleration in relation to type II diabetes mellitus, all-cause mortality and glycemic traits

Background: Accelerated biological aging (BioAgeAccel) has been implicated in type II diabetes (T2D) mellitus development; however, its dynamic changes and their links to T2D incidence, mortality and glycemic traits remain unclear. Methods: Leveraging repeated measures from the UK Biobank, we first calculated two BioAgeAccel metrics (KDMAccel and PhenoAgeAccel) and derived three burdens (slope, cumulative, and relative cumulative change). We then assessed associations of BioAgeAccel transitions and these burdens with incident T2D and mortality. Secondary analyses extended the two primary outcomes by incorporating glucose, HbA1c, and six IR surrogates, which were also evaluated as potential mediators. Results: Among 13,751 included participants, 412 (3.0%) new T2D cases and 609 (4.4%) all-cause deaths were identified within a median follow-up of 9.5 years. Dynamic transition from non-accelerated to accelerated aging was markedly related to elevated T2D risk (KDMAccel: HR=1.65 [1.24~2.20]; PhenoAgeAccel: HR=1.50 [1.12~2.00]) and all-cause mortality risk (KDMAccel: HR=1.32 [1.06~1.64]; PhenoAgeAccel: HR=2.17 [1.73~2.71]). BioAgeAccel burdens demonstrated dose-response effects, with cumulative BioAgeAccel showing the greatest influence on T2D (KDMAccel: HR=1.25 [1.03~1.51]; PhenoAgeAccel: HR=1.26 [1.06~1.49]) and all-cause mortality (KDMAccel: HR=1.25 [1.07~1.47]; PhenoAgeAccel: HR=1.51 [1.31~1.74]). Similar association patterns were observed for all the eight glycemic traits. Mediation analyses revealed that these glycemic traits on average mediated 19~32% of the KDMAccel burden-T2D effect and 16~24% of the PhenoAgeAccel burden-T2D effect. Incorporating BioAgeAccel burden into FINDRISC significantly enhanced prediction accuracy, reaching up to 10.9% improvement in some specific aging transition statuses. Conclusion: Dynamic biological aging trajectories and BioAgeAccel burdens are independently related to elevated risks of T2D and all-cause mortality, partly via glycemic dysregulation, highlighting biological aging as a potential intervention target.