Epigenetic clocks, which are biomarkers of biological age, have gained popularity in recent years for their potential to provide insights into aging and health. 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 DNA methylation age and age acceleration.
Background
Previous research indicated that the proportions of naïve and memory T cells could influence epigenetic clocks. The authors aimed to clarify how blood cell composition contributes to variations in DNA methylation age and age acceleration.
Methods
The researchers developed a principal component analysis (PCA) method that addresses the collinearity of blood cell counts. They analyzed data from 4,058 samples to quantify the contribution of cell composition to DNA methylation age and age acceleration, using six different epigenetic clocks. Additionally, they examined the relationship between age acceleration and 176 incident health outcomes in a larger cohort of 18,859 individuals.
Results
The findings revealed that up to 53% of the variation in DNA methylation age could be attributed to blood cell counts, particularly 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 playing a significant role in the second-generation clocks.
Moreover, the study found that cell composition significantly attenuated the association between age acceleration and health outcomes, although this effect was modest. The authors validated their findings using artificial mixtures of cells.
Conclusions
The study concludes that DNA methylation age and age acceleration reflect different biological processes, as evidenced by their distinct associations with blood cell composition. Notably, the contribution of blood cell composition to age acceleration’s association with mortality and disease outcomes was found to be minor.
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 imply that modifying blood cell composition will influence DNA methylation age or age acceleration.
Evidence scorecard
- Analytic validity: established
- Clinical validity: partial
- Clinical utility: not established
The evidence is based on primary research involving human samples.