DNA Methylation Age Acceleration, Type 2 Diabetes, and its Complications: Cross-Sectional and Longitudinal Data from the Berlin Aging Study II (BASE-II)

Patients with diabetes mellitus are at risk for micro- and macrovascular complications that are responsible for a substantial part of the individual health burden and socio-economic costs. Therefore, implementable risk scores are needed to improve targeted prevention for patients that are particularly susceptible to complications. The "epigenetic clock" estimates an individuals biological age using DNA methylation profiles and was previously shown to be associated with morbidity and mortality. In this study, we examine older adults of the BASE-II study that were reexamined on average 7.4 years after baseline assessment as part of the GendAge study. For DNA methylation age (DNAmA) estimation we used the 7-CpG clock which was available for two timepoints (n=1,071 at follow-up). In addition, we determined epigenetic age using Horvaths clock, Hannums clock, PhenoAge and GrimAge which were available at follow-up only (n=1,067). The deviation of DNAmA from chronological age, DNA methylation age acceleration (DNAmAA), was calculated as residuals of a leukocyte cell count adjusted linear regression analysis. Diabetes associated complications were assessed with the Diabetes Complications Severity Index (DCSI). Cross-sectionally, a statistically significant association between oral glucose tolerance test results and Hannum ({beta}=0.8, SE=0.3, p=0.02, n=762) and PhenoAge DNAmAA ({beta}=0.8, SE=0.3, p=0.003, n=762) was found. PhenoAge was also associated with fasting glucose ({beta}=0.3, SE=0.1, p=0.013, n=966). In contrast, we observed no cross-sectional association after covariate adjustment between DNAmAA and a diagnosis of diabetes mellitus with any of the five clocks employed. This was true for longitudinal analyses with the 7-CpG clock as well. However, longitudinal analyses showed that every year in the 7-CpG-based DNAmAA estimate at baseline increased the risk for developing of one or more additional complications or worsening of an already existing complication during the follow-up period by 11% in male participants with diabetes mellitus type 2. This association persisted after adjustment for DCSI at baseline, chronological age, smoking, alcohol, diabetes medication, and BMI (OR =1.11, p=0.045, n=56). No statistically significant association was found in the subgroup of women or when the whole dataset was analyzed (p>0.05). Although our findings still need to be independently validated, the 7-CpG clock appears to be a promising biomarker which is informative about the individual risk for diabetic complications independent of age, sex, lifestyle factors, or complications at baseline.