Association of epigenetic markers of ageing with prevalent and incident type 2 diabetes.

Abstract

BACKGROUND: Type 2 diabetes (T2D) is characterised by elevated levels of metabolic and inflammatory markers but less is known about other molecular alterations that occur with ageing. We aimed to assess the associations of DNA methylation-based measures of ageing (epigenetic ageing) with prevalent and incident T2D in a large sample of middle-aged and older Australians. METHOD(S): We used data from 5403 participants in the Melbourne Collaborative Cohort Study (mean age=59 years). Five blood-based epigenetic ageing measures: PCPhenoAge, PCGrimAge, DNAmFitAge, bAge, and DunedinPACE were calculated. T2D status was assessed at baseline (1990-1994, Ncases=180) and two waves of follow-up (1995-1998, Ncases=134; 2003-2007, Ncases=244). Modified Poisson regression models were used to estimate risk ratios (RRs) for the associations of epigenetic age with prevalent and incident T2D. RESULT(S): A standard deviation increase in epigenetic age was associated with 1.11-fold (PCPhenoAge, 95%CI: 0.98-1.26) to 1.33-fold (bAge, 95%CI: 1.12-1.57) higher prevalence of T2D at baseline. Prospectively, DunedinPACE showed the strongest association with incident T2D at follow-up 2 (RR=1.22, 95%CI: 1.07-1.38). These estimates were slightly attenuated but consistent in sensitivity analyses reclassifying participants who reported being T2D-free but had high glucose concentrations (>7mmol/L for fasting glucose, >11.1mmol/L for non-fasting glucose). No evidence of increased epigenetic age was found for participants with pre-T2D (>5.6mmol/L for fasting glucose, >7.8mmol/L for non-fasting glucose). The positive associations between epigenetic age and fasting glucose levels appeared stronger in participants with T2D. CONCLUSION(S): In middle-aged and older Australians, epigenetic age, in particular as assessed by bAge and DunedinPACE, was positively associated with prevalent and incident T2D. Our findings may have implications for understanding of the aetiology and management of T2D.Copyright © The Author(s) 2025. Published by Oxford University Press on behalf of the Gerontological Society of America.