Abstract 13855: Epigenetic Aging Markers Mediate the Association of Life’s Essential Eight With Cardiovascular Disease and All-Cause Mortality

Background: The American Heart Association recommended Life’s Essential 8 (LE8) as a simple cardiovascular health (CVH) metric. While optimal LE8 scores are associated with greater CVH and longevity, the mechanisms underlying these associations are unclear. Objective: To characterize the associations between LE8, epigenetic age scores, CVD, and all-cause mortality. Methods: LE8 scores were calculated for 5,669 participants in the Framingham Heart Study. Mixed proportional hazard models were used to evaluate the associations between LE8 score and CVD and all-cause mortality. We conducted mediation analyses to calculate the proportion of the association between LE8 score and CVD and all-cause mortality that is mediated by DNA methylation-based epigenetic age markers (GrimAge and PhenoAge). We performed stratified mediation analyses based on median-dichotomized polygenic risk score (PRS) of epigenetic age markers. Results: Higher LE8 scores, indicating better CVH, were associated with lower risk of CVD. One standard deviation (SD) increase in LE8 score was associated with a 35% decreased risk of CVD (95% CI: 27%, 41%, p =1.8E-15). One SD increase in LE8 was also associated with a 29% decreased risk of all-cause mortality (95% CI: 22%, 35%, p =7.0E-15). These associations were partly mediated by epigenetic age: the mean proportions of mediation by GrimAge and PhenoAge were 21% and 2% ( p =0.23) for CVD and 67% and 6% for all-cause mortality, respectively. In our stratified analysis, potential mediation effects of GrimAge and PhenoAge were more profound in participants with a higher PRS. For GrimAge, the proportion of mediation for the association between LE8 and CVD was 39% (95% CI: 14%, 80%, p =8.8E-04) for participants in the upper half of higher GrimAge PRS whereas there was no significant mediation for those with low GrimAge PRS values. For the association between LE8 and all-cause mortality, the proportion of mediation by GrimAge was 81% (95% CI: 48%, 100%, p <2.0E-16) in participants with the highest GrimAge PRS and not significant for those with the lowest GrimAge PRS. Conclusion: LE8 shows a strong association with CVD and all-cause mortality. Our observations suggest that these associations are mediated in part by DNA methylation-related mechanisms.