Better Lifestyle Choices Correlate with a Lower Epigenetic Age

The more that researchers correlate epigenetic clock results with mortality in the context of specific interventions and lifestyle choices, the more useful those epigenetic clocks become. At present the challenge in using clocks to assess the results of any novel therapy is that it is entirely unclear as to whether the results are accurate, useful, or actionable, since there is no established connection between the epigenetic marks measured and specific underlying processes of aging. Only when someone has calibrated a clock against the use of a therapy or intervention across a large study population does it become trustworthy for that therapy or intervention. At present it is fair to say that the more modern epigenetic clocks are trustworthy when it comes to the benefits of common lifestyle choices. One interesting outcome of the study noted here is that people with high genetic risk for age-related disease benefit more from a healthy lifestyle than those with low genetic risk.

Life's Essential 8 (LE8) is an enhanced metric for cardiovascular health. The interrelations among LE8, biomarkers of aging, and disease risks are unclear. LE8 score was calculated for 5,682 Framingham Heart Study participants. We implemented 4 DNA methylation-based epigenetic age biomarkers, with older epigenetic age hypothesized to represent faster biological aging, and examined whether these biomarkers mediated the associations between the LE8 score and cardiovascular disease (CVD), CVD-specific mortality, and all-cause mortality.

We found that a 1 standard deviation increase in the LE8 score was associated with a 35% lower risk of incident CVD, a 36% lower risk of CVD-specific mortality, and a 29% lower risk of all-cause mortality. These associations were partly mediated by epigenetic age biomarkers, particularly the GrimAge and the DunedinPACE scores. The potential mediation effects by epigenetic age biomarkers tended to be more profound in participants with higher genetic risk for older epigenetic age, compared with those with lower genetic risk. For example, in participants with higher GrimAge polygenic scores (greater than median), the mean proportion of mediation was 39%, 39%, and 78% for the association of the LE8 score with incident CVD, CVD-specific mortality, and all-cause mortality, respectively. No significant mediation was observed in participants with lower GrimAge polygenic score.

DNA methylation-based epigenetic age scores mediate the associations between the LE8 score and incident CVD, CVD-specific mortality, and all-cause mortality, particularly in individuals with higher genetic predisposition for older epigenetic age.