Epigenetic clocks, which are biomarkers of biological age, have been widely utilized in research and clinical settings. However, the biological mechanisms underlying these clocks remain poorly understood. This study, published in Genome Medicine, investigates the role of blood cell composition in interpreting DNA methylation age and age acceleration.
Background
Previous research indicated that the proportions of naïve and memory T cells could influence epigenetic clocks. The authors aimed to clarify how blood cell composition contributes to the variability in DNA methylation age and age acceleration.
Methods
The researchers developed a principal component analysis (PCA) method that accounts for collinearity among blood cell counts. They analyzed a dataset comprising 4,058 samples to quantify the impact of cell composition on DNA methylation age and age acceleration, as estimated by six different epigenetic clocks. Additionally, they examined the relationship between age acceleration and 176 incident health outcomes in a larger cohort of 18,859 individuals.
Results
The findings revealed that up to 53% of the variation in DNA methylation age could be attributed to blood cell counts, particularly influenced by the balance of naïve and memory T cells. In contrast, the association between age acceleration and cell counts explained up to 21% of the variance, with neutrophils playing a significant role in 2nd-generation clocks.
Furthermore, the study validated the contribution of cell counts to epigenetic clocks using artificial mixtures of cells. Notably, the influence of cell composition on the relationship between age acceleration and health outcomes was significant but modest.
Conclusions
The research indicates that DNA methylation age and age acceleration reflect different biological processes, as evidenced by their distinct associations with blood cell composition. While blood cell composition does affect age acceleration, its contribution to associations with mortality and disease outcomes appears limited.
What this study does not show
This study does not establish a direct causal relationship between blood cell composition and health outcomes, nor does it provide definitive evidence for the clinical utility of epigenetic clocks in predicting health risks.
Evidence scorecard
- Analytic validity: established
- Clinical validity: not established
- Clinical utility: not established
The evidence is based on primary research involving human samples.