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Previously developed epigenetic clocks are mainly based on DNA methylation in heterogeneous cell types, which provide limited knowledge on the impacts of alcohol consumption at the individual cellular level. Evidence shows that monocytes play an important role in both alcohol\u2010induced pathophysiology and the aging process. In this study, we developed a novel monocyte\u2010based DNA methylation clock (MonoDNAmAge) to assess the impact of alcohol consumption on monocyte age.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A machine learning method was applied to select a set of chronological age\u2010associated DNA methylation CpG sites from 1202 monocyte methylomes. Pearson correlation was tested between MonoDNAmAge and chronological age in three independent cohorts (<jats:italic>N<\/jats:italic><jats:sub>total<\/jats:sub>\u00a0=\u00a02242). Using the MonoDNAmAge clock and four established clocks (i.e., HorvathDNAmAge, HannumDNAmAge, PhenoDNAmAge, GrimDNAmAge), we then evaluated the effect of alcohol consumption on epigenetic aging in the three cohorts [i.e., Yale Stress Center Community Study (YSCCS), Veteran Aging Cohort Study (VACS), Women's Interagency HIV Study (WIHS)] using linear and quadratic models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The MonoDNAmAge, comprised of 186 CpG sites, was moderately to strongly correlated with chronological age in the three cohorts (<jats:italic>r<\/jats:italic>\u00a0=\u00a00.90, <jats:italic>p<\/jats:italic>\u00a0=\u00a03.12E\u2212181 in YSCCS; <jats:italic>r<\/jats:italic>\u00a0=\u00a00.54, <jats:italic>p<\/jats:italic>\u00a0=\u00a01.75E\u221296 in VACS; <jats:italic>r<\/jats:italic>\u00a0=\u00a00.66, <jats:italic>p<\/jats:italic>\u00a0=\u00a01.50E\u221260 in WIHS). More importantly, we found a nonlinear association between MonoDNAmAge and alcohol consumption (<jats:italic>p<\/jats:italic><jats:sub>model<\/jats:sub>\u00a0=\u00a04.55E\u221208, \u00a0=\u00a07.80E\u221208 in YSCCS; <jats:italic>p<\/jats:italic><jats:sub>model<\/jats:sub>\u00a0=\u00a01.85E\u221202, \u00a0=\u00a03.46E\u221202 in VACS). Heavy alcohol consumption increased EAA<jats:sub>MonoDNAmAge<\/jats:sub> up to 1.60\u00a0years while light alcohol consumption decreased EAA<jats:sub>MonoDNAmAge<\/jats:sub> up to 2.66\u00a0years. These results were corroborated by the four established epigenetic clocks (i.e., HorvathDNAmAge, HannumDNAmAge, PhenoDNAmAge, GrimDNAmAge).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The results suggest a nonlinear relationship between alcohol consumption and its effects on epigenetic age. Considering adverse effects of alcohol consumption on health, nonlinear effects of alcohol use should be interpreted with caution. The findings, for the first time, highlight the complex effects of alcohol consumption on biological aging.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.14803","type":"journal-article","created":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T05:34:57Z","timestamp":1646717697000},"page":"736-748","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A new monocyte epigenetic clock reveals nonlinear effects of alcohol consumption on biological aging in three independent cohorts (<i>N<\/i>\u00a0=\u00a02242)"],"prefix":"10.1111","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7796-2441","authenticated-orcid":false,"given":"Xiaoyu","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Psychiatry Yale School of Medicine  New Haven Connecticut USA"},{"name":"VA Connecticut Healthcare System  West Haven Connecticut USA"},{"name":"Department of Preventive Medicine University of Tennessee 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