Epigenetic clocks are increasingly recognized as biomarkers of biological age, yet their underlying biological mechanisms remain poorly understood. This study investigates the role of blood cell composition in influencing DNA methylation age and age acceleration, utilizing a robust principal component analysis (PCA) method to address the complexities of collinearity among blood cell counts.
What this study does not show
This research does not establish a direct causal relationship between blood cell composition and health outcomes, nor does it provide definitive evidence on 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 study analyzed a total of 4,058 samples to quantify how blood cell composition contributes to DNA methylation age and age acceleration as estimated by various epigenetic clocks. The findings indicate that up to 53% of the variation in DNA methylation age can 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 explained only up to 21% of the variance, with neutrophils being the primary contributors for second-generation clocks.
Furthermore, the study tested the influence of blood cell composition on the relationship between age acceleration and 176 incident health outcomes, utilizing a larger cohort of 18,859 individuals. Results showed that while cell composition does attenuate the association of age acceleration with health outcomes, the effect is modest. This suggests that DNA methylation age (DNAmAge) and age acceleration (AgeAccel) reflect different biological processes, with blood cell composition playing a significant role in the former but a lesser role in the latter’s association with mortality and disease outcomes.
Overall, this research highlights the complexity of biological aging and the potential for blood cell composition to inform our understanding of epigenetic clocks. However, the modest contribution of cell composition to health outcomes underscores the need for further research to clarify these relationships.