Atherosclerotic plaque epigenetic age acceleration is characterized by mesenchymal reprogramming and poor prognosis

Epigenetic age estimators (clocks) are known to be predictive of human mortality risk. However, it is not yet known whether the epigenetic age of atherosclerotic plaques can be used for predicting secondary events. Here we estimated an age adjusted measure of epigenetic age, epigenetic age acceleration (EAA), using DNA methylation of human atherosclerotic plaques and of blood. EAA of plaque, but not blood, independently predicted secondary events in a 3-year follow-up (HR=1.3, p= 0.018). Plaque EAA concurred with a high metabolic epigenetic and transcriptional state in plaques. Patients with diabetes and a high body mass index had a higher plaque EAA. EAA was lower in female plaques compared to male plaques by approximately 2 years. Single-cell RNA-seq revealed mesenchymal smooth muscle cells and endothelial cells as main drivers of EAA. Plaque-specific ageing may help identify processes that explain poor health outcomes.