Aging is associated with changes to DNA methylation patterns at CpG sites, and a variety of epigenetic clocks use these patterns to predict lifespan or chronological age. Although chronological age is known to be an important risk factor for atherosclerosis, the links between subclinical atherosclerosis (SA) and lifespan remain unknown. In a recent study, Sánchez-Cabo et al. investigated the association between SA and accelerated epigenetic aging in 391 participants of the Progression of Early Subclinical Atherosclerosis (PESA) study.
The authors focused on the Grim clock, which predicts lifespan and is made up of eight biomarkers. Using methylomics data and estimates of SA burden, they found that healthy individuals with an accelerated Grim epigenetic age had an increased coronary artery calcification score and a higher risk of a cardiovascular event within 10 years, compared with individuals with a normal epigenetic age. Hematological analyses indicated an association between accelerated epigenetic age and an increase in systemic inflammation, including increased numbers of white blood cells and platelets, higher levels of inflammatory biomarkers such as fibrinogen, and an INFLA score of low-grade chronic inflammation. Furthermore, transcriptomic and proteomic data revealed 737 differentially expressed genes between individuals with an accelerated epigenetic age versus those without. Many of these genes were related to immune responses, such as the T helper 1 and 2 activation pathways, the STAT3 pathway and the inflammasome pathway. Using mediation analysis, the authors identified several pro-inflammatory markers, such as those involved in the inflammasome pathway, as mediators between SA and accelerated epigenetic age, which suggests a key role for systemic inflammation in this association. Long-term longitudinal studies are required to further investigate the strength of these associations.
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