In recent years, epigenetic clocks have emerged as significant biomarkers for biological age, with DNA methylation age and age acceleration being key metrics. However, the biological mechanisms underlying these clocks remain poorly understood. This study, published in Genome Medicine, investigates the role of blood cell composition in interpreting these epigenetic markers.
What this study does not show
While the research highlights the influence of blood cell composition on DNA methylation age and age acceleration, it does not establish a direct causal relationship between these factors and specific health outcomes.
The authors developed a principal component analysis (PCA) method that is robust against collinearity among blood cell counts. This innovative approach allowed them to derive biologically meaningful insights from the data. The study analyzed a total of 4,058 samples to quantify the impact of cell composition on DNA methylation age and age acceleration, estimated by six different 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 weaker, explaining up to 21% of the variance, with neutrophils being the primary contributors for 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 significantly attenuated the association between age acceleration and health outcomes, this effect was modest.
In conclusion, the study suggests that DNA methylation age and age acceleration reflect different biological processes, as evidenced by their distinct associations with blood cell composition. Despite the notable contributions of cell composition to these epigenetic markers, the variation in age acceleration attributed to blood cell composition has only a minor impact on its association with mortality and incident disease outcomes.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Partial
- Clinical utility: Not established
The evidence is based on primary research involving human samples.