BMI is positively associated with accelerated epigenetic aging in twin pairs discordant for BMI

ABSTRACT Background Obesity is a heritable complex phenotype which can increase the risk of age-related outcomes. Biological age can be estimated from DNA methylation (DNAm) using various “epigenetic clocks.” Previous work suggests individuals with elevated weight also display accelerated aging, but results vary by epigenetic clock and population. Here, we utilize the new epigenetic clock GrimAge, which closely relates with mortality. Objectives We aimed to assess the cross-sectional association of BMI with age acceleration in twins to limit confounding by genetics and shared environment. Methods and Results Participants were from the Finnish Twin Cohort (FTC; n = 1424), including monozygotic (MZ) and dizygotic (DZ) twins, and DNAm was measured using the Illumina 450k array. Multivariate linear mixed effects models including MZ and DZ twins showed an accelerated epigenetic age of 1.02 months ( p -value = 6.1 × 10 −12 ) per 1-unit BMI increase. Additionally, heavier twins in a BMI-discordant MZ twin pair (ΔBMI > 3 kg/m 2 ) had an epigenetic age 5.2 months older than their lighter co-twin ( p -value = 0.0074). We also found a positive association between log(HOMA-IR) and age acceleration, confirmed by a meta-analysis of the FTC and two other Finnish cohorts (overall effect = 0.45 years, p -value = 0.0025) from adjusted models. Conclusion We identified significant associations of BMI and insulin resistance with age acceleration based on GrimAge, which were not due to genetic effects on BMI and aging. Overall, these results support a role of BMI in aging, potentially in part due to the effects of insulin resistance.