Long-term BMI trajectories and epigenetic age acceleration: the role of genetic risk for obesity.

BACKGROUND: Previous studies reported mixed findings in the relationship between body mass index (BMI) and epigenetic age acceleration (EAA), while none considered long-term trajectory of BMI and individuals' genetic background. Therefore, we aimed to evaluate the joint effects of long-term BMI trajectory and genetic risk for obesity on EAA among older US adults. METHODS: We performed secondary analyses of panel survey data from 3312 participants of the Health and Retirement Study. BMI was assessed biennially from 1996 to 2016. Latent variable mixture modeling was used to identify distinct BMI trajectories over the 20-year period. Thirteen epigenetic clocks were used to calculate EAAs based on DNA methylation data from the 2016 Venous Blood Study (VBS). Genetic risk for obesity was quantified by a polygenic risk score (PRS) and categorized into low, moderate, and high risk based on quartile cutoffs. Multivariable linear regression models were used to test associations between BMI trajectories and EAAs overall and stratified by genetic risk, while adjusting for age, sex, ancestry, education, cigarette smoking, alcohol drinking, and physical activity. Bonferroni method was used to correct for multiple testing. RESULTS: The HRS participants demonstrated stable BMI trajectories over time and were classified into three groups: consistently normal weight, overweight, and obese. Overall, 41.0% had a BMI trajectory consistent with their genetic risk levels, 33.2% deviated to a worse trajectory, and 25.7% to a better trajectory. BMI trajectories were significantly associated with 6 of the 13 EAAs. BMI started to predict EAAs in at least 8 years ahead of EAA measurement. Consistently obese participants, but not those consistently overweight, exhibited significantly accelerated epigenetic aging compared to those with consistently normal weight. These associations were most pronounced among individuals with low or moderate genetic risk for obesity. CONCLUSIONS: Long-term obesity but not overweight was associated with EAA in older adults, particularly among individuals with low or moderate genetic risk for obesity.