Epigenetic age of the male and female heart: insights into cardiovascular risk assessment across sexes

Abstract Introduction Men and women show notable differences in symptoms/course and treatment of cardiovascular disease, suggesting the need for sex-specific biomarkers of cardiovascular damage. Chronological age is an established cardiovascular risk factor. However, people age differently, which matured the concept of "epi-genetic age determined by DNA metilation (DNAmAge)". The DNAmAge of a tissue provides information on its biological age and it can differ from the chronological age. Gathering information on the biological age of the heart could provide hints on premature cardiac aging and risk stratification. The discrepancy between chronological age and DNAmAge is defined as DeltaAge (= chronological years – DNAmAge years) and it has shown to predict mortality in humans. In this study, we assess sex-related differences in cardiac epigenetic age. Materials and Methods DNA was isolated from whole blood and heart specimens from women (N=92) and men (N=272) who underwent elective cardiac surgery for valve replacement or coronary artery bypass. After isolation, DNA was processed to convert the un-methylated cytosines to uracile. PCR reaction was used to amplify the target sequences followed by pyrosequencing to determine the methylation level of age-related CpGs. Results Women were chronologically older than men (69.9±7 vs 64.6±9 years, p0.05), while the 2 groups were comparable for cardiovascular risk factors. DeltaAge assessed in whole blood samples showed comparable values of chronological and epigenetic age in women and men. By contrast, DeltaAge assessed in cardiac specimens showed that 15.1% of women were biologically older (as compared to their chronological age) while a much higher rate (34.5%) was observed for men (Figure). Conclusions We show that men’s heart is at least 2 times older than the female heart. Our study could set the stage for larger studies leveraging the epigenetic clock as a molecular marker of premature aging and clinical outcome in men and women.