Understanding biological age is a complex endeavor, and epigenetic clocks have emerged as significant biomarkers in this field. This study, published in Genome Medicine, investigates the role of blood cell composition in interpreting DNA methylation age and age acceleration.
Background
Epigenetic clocks are increasingly utilized to estimate biological age, yet the biological mechanisms behind these clocks remain largely unclear. Previous research indicated that the proportions of naïve and memory T cells could influence epigenetic clocks, suggesting that blood cell composition might be a key factor.
Methods
The researchers developed a principal component analysis (PCA) method that addresses the collinearity issues inherent in blood cell counts. They analyzed a dataset comprising 4,058 samples to quantify how cell composition contributes to DNA methylation age and age acceleration, as estimated by various epigenetic clocks. Furthermore, they examined the impact of cell composition on the relationship between age acceleration and 176 health outcomes using 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 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.
Additionally, the study validated the role of cell counts in epigenetic clocks through artificial cell mixtures. Notably, cell composition was found to significantly attenuate the association between age acceleration and the 176 health outcomes, although this effect was described as modest.
Conclusions
The study concludes that DNA methylation age (DNAmAge) and age acceleration (AgeAccel) exhibit markedly different associations with blood cell composition, suggesting they reflect distinct biological processes. Importantly, the contribution of blood cell composition to age acceleration’s association with mortality and disease outcomes appears to be minimal.
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 manipulating cell composition will affect biological age or health outcomes.
Evidence scorecard
- Analytic validity: established
- Clinical validity: partial
- Clinical utility: not established
The evidence is based on primary research involving human participants.