Do epigenetic clocks provide explanations for sex differences in lifespan? A cross-sectional twin study

ABSTRACT Background The sex gap in life expectancy has been narrowing in Finland over the past four to five decades; however, on average, women still live longer than men. Epigenetic clocks are markers for biological aging that predict lifespan. In this study, we examined the mediating role of lifestyle factors on the association between sex and biological aging in younger and older adults. Methods Our sample included same-sex younger and older twins (21-42-y, n = 1110; 50-76-y, n = 763) and younger opposite-sex twins (21-30-y, n = 302). Blood-based DNA methylation (DNAm) was used to compute epigenetic age acceleration by four epigenetic clocks as a measure of biological aging. Path modelling was used to study whether the association between sex and biological aging is mediated through lifestyle-related factors, i.e. education, body mass index, smoking, alcohol use, and physical activity. Findings In comparison to women, men were biologically older and, in general, they had unhealthier life habits. The effect of sex on biological aging was partly mediated by smoking, but only in older twins. Sex was directly associated with biological aging and the association was stronger in older twins. Interpretation Previously reported sex differences in lifespan are also evident in biological aging. Declining smoking prevalence among men is a plausible explanation for the narrowing of the difference in life expectancy between the sexes. Data generated by the epigenetic clocks may help in estimating the effects of lifestyle and environmental factors on aging and in predicting aging in future generations.