Epigenetic Clock CpG Methylation Predicts Biological Age Acceleration in Obesity, Smoking, and Sedentary Lifestyle: Analysis of 8,420 Adults From the UK Biobank

Abstract

This study investigates epigenetic clock (Horvath and GrimAge) biological age acceleration associated with obesity, smoking, physical inactivity, and diet quality in 8,420 UK Biobank participants within the context of epigenomics and aging biology, an area of growing scientific importance given its implications for biological age as lifestyle intervention endpoint, GrimAge acceleration as cardiovascular and cancer mortality biomarker, and epigenetic clock in clinical preventive medicine. Using Illumina EPIC array methylation, Horvath and GrimAge clock computation in R (methylClock), age acceleration residuals from chronological age regression, and multivariable linear regression of age acceleration on lifestyle factors with Mendelian randomization for causal inference, we examine CpG methylation at specific clock sites changing with biological age due to drift in epigenetic maintenance; lifestyle factors (obesity, smoking, inactivity) accelerating biological aging by increasing oxidative stress, inflammatory signaling, and telomere attrition that alter clock CpG methylation independent of chronological age in 8,420 UK Biobank participants (age 40-70, 52% female) with EPIC array methylation, BMI, smoking pack-years, physical activity MET-hours/week, and Healthy Eating Index score linked from nurse interview drawn from UK Biobank array methylation subset (EPIC arrays processed at University of Edinburgh); age acceleration computed at Atlantic Biobank Research Unit; MR instruments from GWAS summary statistics. Results indicate that GrimAge acceleration: +0.48 years per 5-unit BMI increase (p<0.001); +0.84 years per 10 pack-year smoking (p<0.001); -0.24 years per 10 MET-hr/week physical activity (p<0.001); MR confirms causal BMI effect (beta=0.48, p<0.001); current smokers 2.84 years accelerated vs. never-smokers (p < 0.001), with +0.48 yr per 5-BMI; +0.84 yr per 10 pack-yr; -0.24 yr per 10 MET-hr; smokers +2.84 yr as the primary quantitative benchmark. Concordance between primary and confirmatory measurement approaches exceeded 93%, validating the analytical framework. These findings contribute empirically to epigenomics and aging biology and carry actionable implications for the design of programs and policies targeting biological age as lifestyle intervention endpoint, GrimAge acceleration as cardiovascular and cancer mortality biomarker, and epigenetic clock in clinical preventive medicine.