Epigenetic clocks have emerged as significant biomarkers for assessing biological age, yet their underlying biological mechanisms remain somewhat elusive. A recent study published in Genome Medicine investigates the role of blood cell composition in influencing DNA methylation age and age acceleration, providing new insights into these epigenetic markers.
Background
The research highlights that previous findings indicated a relationship between epigenetic clocks and the proportions of naïve and memory T cells. This suggests that the composition of blood cells could be a critical factor driving the variability observed in epigenetic age assessments. However, analyzing cell composition is often complicated due to collinearity among different cell fractions.
Methods
To address this issue, the researchers developed a principal component analysis (PCA) method that is robust against the collinearity of blood cell counts. This innovative approach allowed them to derive biologically meaningful insights into the contributions of various blood cell types to DNA methylation age and age acceleration.
The study analyzed a substantial dataset comprising 4,058 samples to quantify how much cell composition contributes to DNA methylation age and age acceleration as estimated by six different epigenetic clocks. Furthermore, the researchers examined the influence of cell composition on 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, with a notable impact 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 second-generation clocks.
Additionally, the study validated the contribution of cell counts to epigenetic clocks using artificial cell mixtures. Importantly, the researchers found that blood cell composition significantly attenuates the association of age acceleration with the 176 incident health outcomes, although this effect was described as modest.
Conclusions
The study concludes that DNA methylation age (DNAmAge) and age acceleration (AgeAccel) exhibit markedly different associations with blood cell composition, indicating that they may reflect distinct biological processes. Surprisingly, the contribution of blood cell composition to the variation in age acceleration has only a minor impact on 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 evidence of clinical utility for the use of epigenetic clocks in predicting health outcomes based on blood cell composition.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Partial
- Clinical utility: Not established
The evidence is based on primary research involving human participants.