Epigenetic clocks are increasingly recognized as biomarkers of biological age, yet 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, utilizing a robust principal component analysis (PCA) method to address the complexities of cell fraction collinearity.
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 conclusions about the clinical utility of DNA methylation age as a standalone health indicator.
The authors analyzed data from 4,058 samples to quantify how variations in blood cell composition contribute to DNA methylation age and age acceleration, measured by both first- and second-generation epigenetic clocks. Their 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. Conversely, the influence of cell composition on age acceleration is less pronounced, explaining up to 21% of the variance, with neutrophils being the primary contributors in second-generation clocks.
Furthermore, the study examined the impact of cell composition on the association between age acceleration and 176 incident health outcomes in a larger cohort of 18,859 individuals. The results suggest that while cell composition does attenuate the association of age acceleration with health outcomes, this effect is modest.
In conclusion, the study highlights that DNA methylation age and age acceleration reflect different biological processes, with blood cell composition playing a significant role in the former but a minor role in the latter’s association with mortality and disease outcomes.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Not established
- Clinical utility: Not established
The evidence is based on primary research involving human samples.