Epigenetic clocks, which serve as biomarkers of biological age, have become increasingly popular in research. However, the biological mechanisms underlying these clocks remain poorly understood. This study, published in Genome Medicine, investigates the role of blood cell composition in determining DNA methylation age (DNAmAge) and age acceleration (AgeAccel).
What this study does not show
While the study identifies the influence of blood cell composition on DNA methylation age, it does not establish a direct causal relationship between these factors and specific health outcomes.
The researchers developed a robust principal component analysis (PCA) method to address the challenges posed by collinearity among blood cell counts. They analyzed a dataset comprising 4,058 samples, quantifying the contribution of various cell types to DNAmAge and AgeAccel as estimated by six different epigenetic clocks.
Findings revealed that up to 53% of the variation in DNAmAge could be attributed to blood cell counts, particularly the balance between naïve and memory T cells. In contrast, the association between AgeAccel and cell counts explained up to 21% of the variance, with neutrophils playing a significant role in 2nd-generation clocks.
Furthermore, the study examined the impact of blood cell composition on the relationship between AgeAccel and 176 incident health outcomes in a larger cohort of 18,859 individuals. Results indicated that while cell composition significantly attenuated the association of AgeAccel with health outcomes, this effect was modest.
Overall, the study concludes that DNAmAge and AgeAccel reflect different biological processes, with blood cell composition contributing differently to each measure. The minor role of cell composition in the association of AgeAccel with mortality and disease outcomes suggests that other factors may also be at play.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Not established
- Clinical utility: Not established
The evidence for this scorecard is based on the primary research findings presented in the study.