Abstract
BACKGROUND: Epigenetic clocks are widely applied biomarkers of biological age, but their biological underpinnings remain unclear. We previously showed that epigenetic clocks are affected by naïve and memory T cell proportions, suggesting blood cell composition as a potential driver. METHODS: Here, we quantify the contribution of cell counts to DNA methylation age (DNAmAge) and age acceleration (AgeAccel) estimated by six 1(st)- or 2(nd)-generation epigenetic clocks. First, we present a principal component analysis (PCA) method that is robust to collinearity of blood cell counts and show this provides biologically meaningful insights. RESULTS: Applying this approach, we find strong associations between DNAmAge and cell counts, particularly with naïve and memory T cells. In contrast, associations between AgeAccel and cell counts are weaker and, particularly for 2(nd)-generation clocks, primarily involve neutrophils. We validate these findings in an external dataset of artificial cell mixtures. CONCLUSIONS: We conclude that DNAmAge and AgeAccel reflect different biological processes.