In recent years, epigenetic clocks have emerged as significant biomarkers for assessing biological age. However, the biological mechanisms underlying these clocks remain largely unexplored. This study, published in Genome Medicine, investigates the influence of blood cell composition on DNA methylation age and age acceleration, providing insights into their biological interpretations.
Background
The research builds on previous findings that suggested the proportions of naïve and memory T cells could affect epigenetic clocks. The authors developed a principal component analysis (PCA) method to address the challenges posed by collinearity in blood cell counts, allowing for a more accurate assessment of how cell composition contributes to DNA methylation age.
Methods
The study analyzed a substantial dataset comprising 4,058 samples to quantify the contribution of cell composition to DNA methylation age and age acceleration, as estimated by six different epigenetic clocks. Additionally, the researchers examined the relationship between age acceleration and 176 incident health outcomes in a larger cohort of 18,859 individuals.
Results
The findings indicate that up to 53% of the variation in DNA methylation age can be attributed to blood cell counts, particularly highlighting 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 playing a significant role in 2nd-generation clocks.
Moreover, the study validated the influence of cell counts on epigenetic clocks using artificial cell mixtures. Notably, the research revealed that blood cell composition significantly attenuates the association between age acceleration and various health outcomes, although the effect was modest.
Conclusions
The study concludes that DNA methylation age (DNAmAge) and age acceleration (AgeAccel) reflect different biological processes, as evidenced by their distinct associations with blood cell composition. Furthermore, the contribution of blood cell composition to the association of age acceleration with mortality and incident disease outcomes appears 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, nor does it imply that changes in cell composition will lead to changes in DNA methylation age or age acceleration.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Not established
- Clinical utility: Not established
The evidence is based on primary research involving human samples.