In recent years, epigenetic clocks have emerged as significant biomarkers for assessing biological age. However, the biological mechanisms underlying these clocks remain poorly understood. This study, published in Genome Medicine, investigates the role of blood cell composition in interpreting DNA methylation age and age acceleration.
What this study does not show
While the study identifies associations between blood cell composition and DNA methylation metrics, it does not establish a direct causal relationship between these factors and health outcomes.
The researchers developed a principal component analysis (PCA) method to address the challenges posed by collinearity among blood cell counts. This innovative approach allowed them to gain biologically relevant insights into how different blood cell types contribute to DNA methylation age and age acceleration.
By analyzing a substantial dataset of 4,058 samples, the study found that up to 53% of the variation in DNA methylation age could be attributed to blood cell counts, particularly highlighting the influence of naïve and memory T cells. In contrast, the association between age acceleration and blood cell composition was weaker, explaining only up to 21% of the variance, with neutrophils being the primary contributor for 2nd-generation epigenetic clocks.
Moreover, the study examined the impact of cell composition on the relationship between age acceleration and 176 incident health outcomes in a larger cohort of 18,859 individuals. The findings indicated that while cell composition significantly attenuated the association of age acceleration with health outcomes, the effect was modest.
These results suggest that DNA methylation age (DNAmAge) and age acceleration (AgeAccel) reflect different biological processes, as evidenced by their distinct associations with blood cell composition. The study concludes that although blood cell composition contributes to the interpretation of age acceleration, its role in predicting mortality and disease outcomes is limited.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Not established
- Clinical utility: Not established
The evidence is derived from primary research involving human samples.