Causal associations of education, lifestyle behaviors, and cardiometabolic traits with epigenetic age acceleration: a Mendelian randomization study

BackgroundGrimAge acceleration (GrimAgeAccel) and PhenoAge acceleration (PhenoAgeAccel) are DNA methylation-based markers of accelerated biological ageing, standing out in predicting mortality and age-related cardiometabolic morbidities. Causal risk factors for GrimAgeAccel and PhenoAgeAccel are unclear. ObjectiveTo evaluate causal associations of 18 common modifiable socioeconomic, lifestyle, and cardiometabolic factors with GrimAgeAccel and PhenoAgeAccel. MethodsWe performed two-sample univariable and multivariable Mendelian randomization (MR), using summary-level data for GrimAgeAccel and PhenoAgeAccel derived from a genome-wide association study of 34,710 European participants. We used the inverse-variance weighted method as the main analysis, supplemented by three sensitivity analyses. ResultsEleven and eight factors were causally associated with GrimAgeAccel and PhenoAgeAccel, respectively. Smoking initiation was the strongest risk factor ({beta} [SE]: 1.299 [0.107] years) for GrimAgeAccel, followed by higher alcohol intake, higher waist circumference, daytime napping, higher body fat percentage, higher BMI, higher C-reactive protein, higher triglycerides, childhood obesity, and type 2 diabetes; whereas education was the strongest protective factor ({beta} [SE] per 1-SD increase in years of schooling: -1.143 [0.121] years). Higher waist circumference ({beta} [SE]: 0.850 [0.269] years) and education ({beta} [SE]: -0.718 [0.151] years) were the leading causal risk and protective factors for PhenoAgeAccel, respectively. Sensitivity analyses strengthened the robustness of these causal associations, and the multivariable MR analyses demonstrated independent direct effects of the strongest risk and protective factors on GrimAgeAccel and PhenoAgeAccel, respectively. ConclusionOur findings provide novel quantitative evidence on modifiable causal risk factors for epigenetic ageing, and hint at underlying contributors and intervention targets to the ageing process. Key PointsO_LIGenetically predicted higher educational attainment is the strongest protective factor for both GrimAgeAccel and PhenoAgeAccel, independent of causal lifestyle and cardiometabolic risk factors. C_LIO_LISmoking is the leading causal lifestyle risk factor for GrimAgeAccel or PhenoAgeAccel, followed by alcohol intake and daytime napping. Adiposity traits are the leading causal cardiometabolic risk factors for GrimAgeAccel and PhenoAgeAccel, followed by type 2 diabetes, triglycerides, and C-reactive protein. C_LIO_LIThis study provides novel quantitative evidence on modifiable causal risk factors for accelerated epigenetic ageing, indicating underlying contributors to the ageing process and promising intervention targets to promote healthy longevity. C_LI