Epigenetic clocks are increasingly recognized as biomarkers for biological age, yet the biological mechanisms behind these clocks remain poorly understood. This study, published in Genome Medicine, investigates the role of blood cell composition in determining DNA methylation age and age acceleration.
What this study does not show
While the study identifies associations between blood cell composition and DNA methylation metrics, it does not establish a direct causal relationship or provide evidence of clinical outcomes resulting from these associations.
The researchers developed a principal component analysis (PCA) method that addresses the collinearity of blood cell counts, allowing for a clearer understanding of how different cell types contribute to biological age assessments. They analyzed a substantial dataset comprising 4,058 samples to quantify the impact of cell composition on DNA methylation age and age acceleration as estimated by various epigenetic clocks.
Results indicated that up to 53% of the variation in DNA methylation age could be attributed to blood cell counts, particularly the balance between naïve and memory T cells. In contrast, the association between age acceleration and cell counts was weaker, accounting for up to 21% of the variance, with neutrophils playing a significant role in 2nd-generation clocks.
Furthermore, the study examined the influence of blood cell composition on the relationship between age acceleration and 176 incident health outcomes in a larger cohort of 18,859 individuals. Findings revealed that while cell composition significantly attenuated the association between age acceleration and health outcomes, the effect was modest.
These results suggest that DNA methylation age (DNAmAge) and age acceleration (AgeAccel) reflect different biological processes, with distinct associations with blood cell composition. The authors conclude that the contribution of blood cell composition to age acceleration’s association with mortality and disease outcomes is relatively minor.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Not established
- Clinical utility: Not established
The evidence is based on primary research involving human samples.