Epigenetic clocks are increasingly recognized as biomarkers of biological age, yet their biological underpinnings remain a topic of investigation. This study, published in Genome Medicine, examines the role of blood cell composition in influencing DNA methylation age and age acceleration.
Background
The research builds on previous findings that indicated the proportions of naïve and memory T cells could affect epigenetic clocks. However, analyzing cell composition is complicated by collinearity between different cell fractions. To address this, the authors developed a principal component analysis (PCA) method that is robust against such collinearity, allowing for biologically meaningful insights into the relationship between blood cell composition and epigenetic measures.
Methods
The study analyzed a total of 4,058 samples to quantify the contribution of cell composition to DNA methylation age and age acceleration as estimated by six different epigenetic clocks. Furthermore, the influence of cell composition on the association between age acceleration and 176 incident health outcomes was tested using data from 18,859 individuals.
Results
The findings revealed that up to 53% of the variation in DNA methylation age 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, with neutrophils being the primary contributor for 2nd-generation clocks.
Additionally, the study validated the impact of cell counts on epigenetic clocks through experiments with artificial cell mixtures. Notably, cell composition was found to significantly attenuate the association of age acceleration with 176 incident health outcomes, although this effect was described as modest.
Conclusions
The research concludes that DNA methylation age (DNAmAge) and age acceleration (AgeAccel) reflect different biological processes, as evidenced by their distinct associations with blood cell composition. Surprisingly, the contribution of blood cell composition to the variation in age acceleration has only a minor 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 imply that altering blood cell composition will influence biological age or age acceleration.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Not established
- Clinical utility: Not established
The evidence is based on primary research with human status unclassified.