Epigenetic clocks, which are biomarkers of biological age, have gained popularity in recent years. 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. This study aims to clarify how blood cell composition contributes to the variability in DNA methylation age and its association with health outcomes.
Methods
The researchers developed a principal component analysis (PCA) method that addresses the collinearity of blood cell counts. They analyzed data from 4,058 samples to quantify the impact of cell composition on DNA methylation age and age acceleration, using six different epigenetic clocks. Additionally, they examined the influence of cell composition on the relationship between age acceleration and 176 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 the balance between naïve and memory T cells. In contrast, the associations between age acceleration and cell counts were weaker, explaining up to 21% of the variance, with neutrophils being the primary contributors for 2nd-generation clocks.
Furthermore, the study validated the role of cell counts in epigenetic clocks using artificial cell mixtures. Notably, cell composition was found to significantly attenuate the association between age acceleration and the 176 health outcomes, although this effect was modest.
Conclusions
The study concludes that DNA methylation age and age acceleration reflect different biological processes, as indicated by their distinct associations with blood cell composition. Interestingly, the contribution of blood cell composition to age acceleration’s association with mortality and disease outcomes was found to be minor.
What this study does not show
This study does not establish a direct causal relationship between blood cell composition and health outcomes or mortality.
Evidence scorecard
- Analytic validity: established
- Clinical validity: not established
- Clinical utility: not established
The evidence is based on primary research involving human samples.