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Background: Obesity is associated with increased risk of cardiovascular and other age-related diseases that may represent accelerated aging. As methylation levels in DNA change with aging, epigenetic age (EA), which integrates whole-genome methylation has emerged as a novel biomarker of aging and has been associated with mortality and age-related morbidity. Epigenetic age acceleration (EAA), is based on the residual value of 353 previously defined methylation markers regressed on chronologic age (CA), and is thus independent of CA. Therefore, we sought to examine the association of obesity and EAA in midlife.Methods: A subset of participants in the CARDIA cohort (n=1200) randomly selected (balanced on race and sex) underwent genome-wide DNA methylation profiling with the Illumina EPIC array from exam year 15 (2000-01 [age 33-45 years]) and 20 (2005-06 [38-50 years] for calculation of EAA. Body mass index (BMI) was measured at Y15 and Y20, respectively. We used linear regression to examine the association of obesity (independent variable) with EAA after adjusting for CA, race, sex, education, study center, smoking status, physical activity, and alcohol intake.Results: Participants were 52% female and 41% black and had mean BMI 28.5±6.2 kg/m2 at Y15 and 29.2±6.4 kg/m2at Y20. At Y15, participants who were obese had 1.04 (0.38) years higher EAA compared to normal BMI participants (p<0.01, Figure). Similar results were observed at Y20. Results were similar when evaluating the association of BMI continuously with EAA (p<0.05).Conclusions: EAA is a promising molecular biomarker of aging associated with obesity. Changes in DNA methylation may serve as an intermediate phenotype prior to the onset of age-associated pathologies related to obesity.