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BackgroundBiological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.ResultsLeveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.ConclusionThis study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

Background: Obesity is a heritable complex phenotype that 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 correlates with mortality. Objectives: We aimed to assess the cross‐sectional association of body mass index (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) twin pairs, 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 one‐unit BMI increase. Additionally, heavier twins in a BMI‐discordant MZ twin pair (ΔBMI >3 kg/m2) had an epigenetic age 5.2 months older than their lighter cotwin (p‐value = 0.0074). We also found a positive association between log (homeostatic model assessment of insulin resistance) and age acceleration, confirmed by a meta‐analysis of the FTC and two other Finnish cohorts (overall effect = 0.45 years, p‐value = 4.1 × 10–25) 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. [ABSTRACT FROM AUTHOR]

Background: Epigenetic clocks are composite markers developed to predict chronological age or mortality risk from DNA methylation (DNAm) data. The present study investigated the associations between 4 epigenetic clocks (Horvath's and Hannum's DNAmAge and DNAm GrimAge and PhenoAge) and physical functioning during a 3-year follow-up.Method: We studied 63- to 76-year-old women (N = 413) from the Finnish Twin Study on Aging. DNAm was measured from blood samples at baseline. Age acceleration (AgeAccel), that is, discrepancy between chronological age and DNAm age, was determined as residuals from linear model. Physical functioning was assessed under standardized laboratory conditions at baseline and at follow-up. A cross-sectional analysis was performed with path models, and a longitudinal analysis was conducted with repeated measures linear models. A nonrandom missing data analysis was performed.Results: In comparison to the other clocks, GrimAgeAccel was more strongly associated with physical functioning. At baseline, GrimAgeAccel was associated with lower performance in the Timed Up and Go (TUG) test and the 6-minute walk test. At follow-up, significant associations were observed between GrimAgeAccel and lowered performance in the TUG, 6-minute and 10-m walk tests, and knee extension and ankle plantar flexion strength tests.Conclusions: The DNAm GrimAge, a novel estimate of biological aging, associated with decline in physical functioning over the 3-year follow-up in older women. However, associations between chronological age and physical function phenotypes followed similar pattern. Current epigenetic clocks do not provide strong benefits in predicting the decline of physical functioning at least during a rather short follow-up period and restricted age range. [ABSTRACT FROM AUTHOR]