In recent years, epigenetic clocks have emerged as important biomarkers for assessing biological age, primarily through the analysis of DNA methylation patterns. However, the biological mechanisms underlying 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 highlight that previous research indicated a relationship between epigenetic clocks and the proportions of naïve and memory T cells in the blood. This suggests that variations in blood cell composition could significantly affect the readings of epigenetic clocks. However, analyzing these cell compositions is complicated due to collinearity among different cell types.
Methods
The researchers developed a principal component analysis (PCA) method that addresses the collinearity issue in blood cell counts. They applied this method to a dataset comprising 4,058 samples to quantify how much cell composition contributes to DNA methylation age and age acceleration, as estimated by various epigenetic clocks. Additionally, they explored 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 reveal that up to 53% of the variation in DNA methylation age can be attributed to blood cell counts, particularly influenced by the balance between naïve and memory T cells. In contrast, the association between age acceleration and cell counts explained a maximum of 21% of the variance, with neutrophils being the primary contributors for 2nd-generation clocks.
Furthermore, the study validated the role of cell counts in epigenetic clocks through experiments involving artificial cell mixtures. Notably, the analysis indicated that blood cell composition significantly attenuates the association between age acceleration and various health outcomes, although this effect was described as modest.
Conclusions
The authors conclude that DNA methylation age (DNAmAge) and age acceleration (AgeAccel) reflect different biological processes, as evidenced by their distinct associations with blood cell composition. They also note that the contribution of blood cell composition to age acceleration has a limited impact on its association with mortality and incident disease outcomes.
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 provide evidence that modifying blood cell composition will affect 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 involving human participants.