Sex-specific and generational effects of alcohol and tobacco use on epigenetic age acceleration in the Michigan longitudinal study

Background: Excessive alcohol and tobacco use are risk factors for poor health in both men and women, but use patterns and relationships with diseases and mortality differ between sexes. The impact of substance use on the epigenome, including DNA methylation profiles, may also differ by sex. It is also unknown whether parental substance use during childhood is associated with epigenetic changes that persist into adulthood. This study assessed the sex-specific effects of individuals' alcohol and tobacco use, as well as paternal alcohol and paternal/maternal tobacco use, on offspring's cellular aging as measured by epigenetic age acceleration.Methods: Four measures of epigenetic age acceleration (HorvathAA, HannumAA, PhenoAA, and GrimAA), the difference between chronological age and inferred age based on DNA methylation, were estimated from saliva samples. Linear mixed models tested associations between alcohol/tobacco use and epigenetic age acceleration in parents and offspring.Results: Current tobacco smoking was associated with a 4.61-year increase in GrimAA, and former tobacco smoking was associated with a 3.60-year increase in HannumAA after accounting for multiple testing ( p < 0.0125). In males only, current tobacco smoking was nominally associated with a 2.19-year increase in HannumAA ( p < 0.05), and this effect was significantly different than the female-specific effect ( p < 0.0125). Paternal heavy alcohol use when the offspring was 12 or younger was associated with a 4.43-year increase in GrimAA among offspring ( p < 0.0125).Conclusions: This study found evidence of sex-specific effects of alcohol and tobacco use, as well as paternal heavy alcohol use, on epigenetic age acceleration.