In recent years, epigenetic clocks have gained prominence as biomarkers for biological age, yet the biological mechanisms underlying these clocks remain poorly understood. This study, published in Genome Medicine, investigates the role of blood cell composition in influencing DNA methylation age and age acceleration, providing new insights into the biological interpretation of these metrics.
Background
The research builds upon previous findings that indicated a relationship between epigenetic clocks and the proportions of naïve and memory T cells. The authors propose that blood cell composition may significantly affect the readings of these epigenetic clocks. However, analyzing cell composition is complicated due to collinearity between different cell fractions, which can obscure the true relationships.
Methods
The researchers developed a principal component analysis (PCA) method that addresses the collinearity issue among blood cell counts. They applied this method to a dataset comprising 4,058 samples to quantify how cell composition contributes to DNA methylation age and age acceleration as estimated by six different epigenetic clocks. Additionally, 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, particularly highlighting the significant role of the balance between naïve and memory T cells. In contrast, the association between age acceleration and cell counts explained a maximum of 21% of the variance, with neutrophils being primarily involved in the second-generation clocks.
Furthermore, the study validated the contribution of cell counts to epigenetic clocks through experiments using artificial cell mixtures. Notably, the analysis indicated that cell composition attenuates the association of age acceleration with various health outcomes, although this effect was described as modest.
Conclusions
The research concludes that DNA methylation age (DNAmAge) and age acceleration (AgeAccel) exhibit markedly different associations with blood cell composition, suggesting they reflect distinct biological processes. Interestingly, the contribution of blood cell composition to age acceleration’s association with mortality and incident disease outcomes was found to be minimal.
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 modifying blood cell composition will influence biological age metrics.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Not established
- Clinical utility: Not established
The evidence is based on primary research involving human samples.