The study published in Genome Medicine investigates the relationship between blood cell composition and DNA methylation age (DNAmAge) as well as age acceleration (AgeAccel). Epigenetic clocks, which are biomarkers of biological age, have been widely used, yet their biological underpinnings remain unclear. The authors previously demonstrated that the proportions of naïve and memory T cells influence epigenetic clocks, suggesting that blood cell composition could be a significant factor.
To address the complexities of analyzing cell composition due to collinearity between cell fractions, the researchers developed a principal component analysis (PCA) method that is robust to these issues. This approach provided biologically meaningful insights into the contribution of blood cell composition to DNA methylation age and age acceleration.
The study analyzed a total of 4,058 samples and quantified the impact of cell composition on DNAmAge and AgeAccel, estimated using six different first- or second-generation epigenetic clocks. The findings revealed that up to 53% of the variation in DNAmAge could be attributed to cell counts, particularly highlighting the significant 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. For the second-generation clocks, the influence primarily involved neutrophils. The researchers validated the contribution of cell counts to epigenetic clocks using artificial cell mixtures, reinforcing their findings.
Interestingly, the study also examined the relationship between age acceleration and 176 incident health outcomes in a larger cohort of 18,859 individuals. The results indicated that cell composition significantly attenuated the association between age acceleration and these health outcomes, although the effect was modest.
In conclusion, the study highlights that DNAmAge and AgeAccel reflect different biological processes, as evidenced by their distinct associations with blood cell composition. The authors noted that while blood cell composition contributes to the variation in age acceleration, it only has a minor role in 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 or mortality.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Partial
- Clinical utility: Not established
The evidence is based on primary research involving human participants.