A New Monocyte Epigenetic Clock Reveals Effects of Alcohol Consumption on Epigenetic Aging in Three Independent Cohorts

Abstract Background Excessive alcohol consumption increases the risk of aging-related comorbidities and mortality. Assessing the impact of alcohol consumption on biological age is important for clinical decision-making and prevention. Evidence shows that alcohol alters monocyte function, and age is associated with DNA methylome and transcriptomic changes among monocytes. However, no monocyte-based epigenetic clock(definition) is currently available. In this study, we developed a new monocyte-based DNA methylation clock (MonoDNAmAge) by using elastic net regularization. The MonoDNAmAge was validated by benchmarking using epigenetic age acceleration (EAA) in HIV infection. Using MonoDNAmAge clock as well as four established clocks (i.e., HorvathDNAmAge, HannumDNAmAge, PhenoDNAmAge, GrimDNAmAge), we then evaluated the effect of alcohol consumption on biological aging in three independent cohorts (N=2,242). Results MonoDNAmAge, comprised of 186 CpG sites, was highly correlated with chronological age (rtraining=0.96, p<2.20E-16; rtesting=0.86, p=1.55E-141). The MonoDNAmAge clock predicted an approximately 10-year age acceleration from HIV infection in two cohorts. Quadratic regression analysis showed a nonlinear relationship between MonoDNAmAge and alcohol consumption in the Yale Stress Center Community Study (YSCCS, p model =4.55E-08, p x 2 =7.80E-08) and in the Veteran Aging Cohort Study (VACS, p model =1.85E-02, p x 2 =3.46E-02). MonoDNAmAge and light alcohol consumption showed a negative linear relationship in the Women’s Interagency HIV Study (WIHS, β =-2.63, p x =2.82E-06). Heavy consumption increased EAAMonoDNAmAge up to 1.60 years in the VACS while light consumption decreased EAAMonoDNAmAge to 2.66 years in the WIHS. These results were corroborated by the four established epigenetic clocks. Conclusions We observed a nonlinear effect of alcohol consumption on epigenetic age that is estimated by a novel monocyte-based “clock” in three distinct cohorts, highlighting the complex effects of alcohol consumption on biological age.