Epigenetic clocks, which are biomarkers of biological age, have become increasingly popular in research. However, the biological mechanisms underlying these clocks remain poorly understood. This study investigates the role of blood cell composition in influencing DNA methylation age and age acceleration.
What this study does not show
While the study identifies associations between blood cell composition and DNA methylation metrics, it does not establish a direct causal relationship or provide insights into specific health outcomes linked to these metrics.
The researchers developed a principal component analysis (PCA) method that addresses the collinearity of blood cell counts, allowing for a more nuanced understanding of their contributions to DNA methylation age. They analyzed data from 4,058 samples to quantify how much cell composition contributes to DNA methylation age and age acceleration, using six different epigenetic clocks.
Findings indicate that up to 53% of the variation in DNA methylation age can be attributed to blood cell counts, particularly the balance between naïve and memory T cells. In contrast, the association between age acceleration and cell counts explained only up to 21% of the variance, with neutrophils being the primary contributors for the second-generation clocks.
Furthermore, the study 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. The results revealed that while cell composition significantly attenuates the association of age acceleration with these health outcomes, the effect is relatively modest.
Overall, the study concludes that DNA methylation age and age acceleration reflect different biological processes, as evidenced by their distinct associations with blood cell composition. However, the contribution of blood cell composition to age acceleration’s association with mortality and disease outcomes appears to be minor.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Not established
- Clinical utility: Not established
This evidence is based on the primary research findings presented in the study.