Epigenetic clocks, which serve as biomarkers of biological age, have gained significant attention in recent years. However, the biological mechanisms underlying these clocks remain largely unclear. This study, published in Genome Medicine, investigates the role of blood cell composition in influencing DNA methylation age and age acceleration.
Background
Previous research indicated that the proportions of naïve and memory T cells could affect epigenetic clocks. This study builds on that foundation, suggesting that blood cell composition may be a key factor driving variations in DNA methylation age.
Methods
The researchers developed a principal component analysis (PCA) method that effectively addresses the collinearity of blood cell counts. They analyzed a total of 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, they examined the influence of cell composition on the relationship between age acceleration and 176 health outcomes using data from 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 the balance between naïve and memory T cells playing a significant role. In contrast, associations between age acceleration and cell counts explained only up to 21% of the variance, primarily involving neutrophils for the second-generation clocks.
Moreover, the study validated the contribution of cell counts to epigenetic clocks through artificial cell mixtures. Interestingly, the analysis showed that cell composition significantly attenuates the association of age acceleration with various health outcomes, although the 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, suggesting they reflect distinct biological processes. Furthermore, the contribution of blood cell composition to age acceleration’s association with mortality and 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 provide definitive insights into the mechanisms by which these factors interact.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Not established
- Clinical utility: Not established
The evidence is based on primary research involving human samples.