Epigenetic clocks, which are biomarkers of biological age, have gained attention in recent years for their potential to provide insights into aging and health. However, the underlying biological mechanisms that drive these clocks remain poorly understood. This study, published in Genome Medicine, investigates the role of blood cell composition in influencing DNA methylation age and age acceleration.
Background
The authors of this study previously identified that the proportions of naïve and memory T cells could affect epigenetic clocks. This led to the hypothesis that blood cell composition might be a significant factor in determining biological age as measured by DNA methylation. However, analyzing cell composition is challenging due to collinearity between different cell types.
Methods
To address these challenges, the researchers developed a principal component analysis (PCA) method that is robust against collinearity. They applied this method to a dataset of 4,058 samples to quantify how much cell composition contributes to DNA methylation age and age acceleration, which were estimated using six different epigenetic clocks. Furthermore, they examined the influence of cell composition on the relationship between age acceleration and 176 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 highlighting the role of the balance between naïve and memory T cells. In contrast, the associations between age acceleration and cell counts were weaker, explaining up to 21% of the variance, with neutrophils being the primary contributors for 2nd-generation clocks. The study also validated these contributions through artificial cell mixtures.
Interestingly, the analysis showed that blood cell composition significantly attenuates the association between age acceleration and the 176 health outcomes investigated, although this effect was described as modest.
Conclusions
The results indicate that DNA methylation age (DNAmAge) and age acceleration (AgeAccel) reflect different biological processes, as evidenced by their distinct associations with blood cell composition. Moreover, the contribution of blood cell composition to age acceleration’s association with mortality and incident 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 biological age or health outcomes.
Evidence scorecard
- Analytic validity: established
- Clinical validity: not established
- Clinical utility: not established
The evidence is based on primary research with human status unclassified.