Epigenetic clocks have emerged as significant biomarkers for assessing biological age, yet their biological foundations remain largely unexplored. This study investigates the role of blood cell composition in influencing DNA methylation age and age acceleration, providing insights into the underlying mechanisms.
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 confirm the clinical utility of DNA methylation age as a standalone predictor of health.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Partial
- Clinical utility: Not established
The authors developed a principal component analysis (PCA) method that addresses the collinearity of blood cell counts, allowing for a clearer understanding of how these components contribute to DNA methylation age. They analyzed a substantial dataset of 4,058 samples and quantified the impact of cell composition on age acceleration across various epigenetic clocks.
Results indicated that up to 53% of the variation in DNA methylation age could be attributed to blood cell counts, particularly highlighting the balance between naïve and memory T cells. In contrast, the association between age acceleration and cell counts was less pronounced, accounting for up to 21% of the variance, with neutrophils being a significant factor in 2nd-generation clocks.
Furthermore, the study examined the influence of blood cell composition on the relationship between age acceleration and 176 incident health outcomes in a larger cohort of 18,859 individuals. The findings revealed that while cell composition does attenuate the association between age acceleration and health outcomes, the effect is relatively modest.
In conclusion, the study underscores that DNA methylation age and age acceleration reflect different biological processes, with blood cell composition playing a crucial role in these distinctions. However, the contribution of blood cell composition to the association of age acceleration with mortality and disease outcomes appears to be limited.