In the realm of biological aging, epigenetic clocks have emerged as significant biomarkers. However, the biological mechanisms underlying these clocks remain somewhat elusive. The study conducted by Jonkman et al. (2026) delves into the relationship between blood cell composition and DNA methylation age, providing new insights into how these factors interplay.
Background
Previous research indicated that epigenetic clocks could be influenced by the proportions of naïve and memory T cells. This suggests that the composition of blood cells might be a crucial driver of biological age as measured by DNA methylation. However, analyzing cell composition is often complicated due to collinearity among different cell fractions.
Methods
The researchers developed a principal component analysis (PCA) method that effectively addresses the collinearity issue associated with blood cell counts. This innovative approach allowed them to gain biologically meaningful insights into the contributions of various cell types to DNA methylation age and age acceleration.
In their analysis, they examined 4,058 samples and quantified how cell composition impacted DNA methylation age and age acceleration as estimated by six different epigenetic clocks. Furthermore, they explored the influence of cell composition on the association 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, with a notable contribution from 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, primarily involving neutrophils for the 2nd-generation clocks.
Additionally, the study validated the role of cell counts in influencing epigenetic clocks using artificial mixtures of cells. Interestingly, the composition of blood cells significantly attenuated the association between age acceleration and the 176 health outcomes investigated, although the effect was modest.
Conclusions
The study concludes that DNA methylation age (DNAmAge) and age acceleration (AgeAccel) exhibit markedly different associations with blood cell composition, suggesting they reflect distinct biological processes. Notably, the variation in age acceleration attributed to blood cell composition has only a minor contribution to its association with mortality and incident disease outcomes.
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 a comprehensive understanding of all biological factors influencing DNA methylation age.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Not established
- Clinical utility: Not established
The evidence is based on primary research involving human samples.