In a recent study published in Journal of the American Heart Associationinvestigators investigated whether deoxyribonucleic acid (DNA) methylation-based epigenetic age biomarkers mediate the associations between Life’s Essential 8 (LE8) score and cardiovascular disease (CVD) risks, CVD-specific mortality, and all-cause mortality the causes.
Study: Epigenetic age mediates association of life’s essential 8 with cardiovascular disease and mortality. Image credit: fizkes/Shutterstock.com
Record
Cardiovascular disease is the leading cause of death in the United States (US). The American Heart Association (AHA) proposed a new measure of cardiovascular health (CVH), LE8, which includes diet, physical activity, nicotine exposure, sleep health, body mass index (BMI), blood lipid levels, blood glucose levels and blood pressure. .
Optimal levels of these factors reduce the risk of cardiovascular disease and other diseases. However, ideal CVH levels are low in Americans. DNA methylation, influenced by genetics and lifestyle, is associated with cardiovascular disease and mortality.
Further research is needed to better understand the molecular mechanisms by which DNA methylation affects CVH and to develop targeted prevention and intervention strategies.
About the study
Data from participants in the Offspring and Third Generation cohorts of the Framingham Heart Study (FHS) were analyzed. Of the 6,432 participants at baseline, 5,682 had complete LE8 data, 4,130 had epigenetic age score data, and 3,693 had both.
The study was approved by the Institutional Review Boards of Boston University Medical Center and Tufts University, with written informed consent of the participants.
LE8 scores were calculated using dietary intakes, physical activity indices, hours of sleep, BMI, blood pressure, non-high-density lipoprotein cholesterol, and fasting glucose according to AHA guidelines. Smoking scores followed AHA guidelines, with adjustments for recent quitters.
DNA methylation profiles were measured using the Infinium HumanMethylation450 BeadChip, evaluating approximately 450,000 cytosine-phosphate-guanine sites (CpGs).
Four epigenetic age scores based on DNA methylation, DunedinPACE, Phenotypic age (PhenoAge), Telomere length based on DNA methylation
(DNAmTL) and GrimAge were calcd. Polygenetic scores (PGS) for PhenoAge and GrimAge were derived using Bayesian regression and genotype information.
Primary clinical outcomes included incident CVD, CVD-specific mortality, and all-cause mortality, monitored over a median follow-up of 14 years for Offspring and 11 years for Third Generation participants.
Linear mixed models examined associations between LE8 and DNA methylation scores, while mixed proportional hazard models assessed hazards of clinical outcomes. Mediation and interaction analyzes explored the roles of DNA methylation and genetic background in the relationships between LE8 and clinical outcomes.
Study results
The mean LE8 score among FHS participants was 68.7, with a range of 20.6 to 100 and a median of 68.8. Female and younger participants generally had higher LE8 scores.
The BMI component showed the highest correlation with the LE8 score (Pearson r=0.59), followed by blood pressure (r=0.55), blood glucose (r=0.52), diet (r=0.50) , blood lipids (r=0.46), physical activity (r=0.40), smoking (r=0.38) and sleep (r=0.26).
The four epigenetic age scores were moderately correlated, with pairwise Pearson r values ranging from 0.28 to 0.68.
After adjusting for various factors, a higher LE8 score was associated with lower residuals for DunedinPACE, GrimAge, and PhenoAge and higher residuals for DNAmTL. A 1 SD increase in LE8 score (13 points) corresponded to 0.39 SD lower DunedinPACE, 0.42 SD lower GrimAge, 0.15 SD lower PhenoAge, and 0.10 SD higher DNAmTL.
Higher LE8 scores were associated with lower risk of incident CVD, CVD-specific mortality, and all-cause mortality. Each 1 SD increase in LE8 score resulted in a 35% lower risk of incident CVD, a 36% lower risk of CVD-related mortality, and a 29% lower risk of all-cause mortality.
There was a dose-response relationship between LE8 scores and these outcomes. Health factors in LE8 had stronger associations with incident CVD and CVD mortality, while health behaviors were more strongly associated with all-cause mortality.
Higher DunedinPACE, GrimAge, and PhenoAge scores and lower DNAmTL scores were associated with increased risks of incident CVD, all-cause mortality, and CVD-related mortality.
Mediation analyzes showed that almost all epigenetic age scores significantly mediated associations between LE8 scores and clinical outcomes, with DunedinPACE and GrimAge scores showing the highest mediation ratios.
Stratified analyzes by PGS showed significant interactions between LE8 scores and GrimAge and PhenoAge PGS, with stronger associations in participants with higher PGS values. Stratified group mediation analyzes showed significant effects for the higher PGS groups, particularly the GrimAge groups, but not for the lower PGS groups.
conclusions
In summary, this analysis in middle-aged to older adults revealed a strong inverse relationship between CVH, as measured by the LE8 score, and CVD incidence, CVD-specific mortality, and all-cause mortality.
The study suggests that favorable CVH may reduce the risks of cardiovascular disease and mortality through epigenetic effects. The benefit of optimal CVH in reducing epigenetic burden is more apparent in those genetically predisposed to older epigenetic age.
Improving CVH appears to be a promising strategy to delay the onset of CVD and promote healthy aging. The findings highlight the importance of CVH promotion in the general population, especially for those genetically predisposed at a higher epigenetic age.
