In the realm of biological age assessment, epigenetic clocks have emerged as significant biomarkers. However, the biological mechanisms underpinning these clocks are not fully understood. 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, suggesting that blood cell composition might be a crucial factor. However, analyzing cell composition is complicated by the collinearity between different cell fractions.
Methods
The researchers developed a principal component analysis (PCA) method that addresses the collinearity of blood cell counts. This robust approach enabled them to derive biologically meaningful insights. They quantified the contribution of cell composition to DNA methylation age and age acceleration using six different epigenetic clocks, analyzing a total of 4,058 samples. Additionally, they examined the influence of cell composition on the relationship between age acceleration and 176 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 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 2nd-generation clocks.
Moreover, the study validated the contribution of cell counts to epigenetic clocks through the use of artificial cell mixtures. Interestingly, the composition of blood cells significantly attenuated the association between age acceleration and the 176 health outcomes investigated, 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, suggesting they reflect distinct biological processes. Notably, the variation in age acceleration attributed to blood cell composition only minimally contributes 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 imply that modifications in blood cell composition will lead to changes in DNA methylation age or age acceleration.
Evidence scorecard
- Analytic validity: established
- Clinical validity: partial
- Clinical utility: not established
The evidence is based on primary research involving human samples.