Epigenetic clocks are increasingly recognized as valuable biomarkers for assessing biological age. However, the biological mechanisms underlying these clocks remain poorly understood. This study investigates the role of blood cell composition in influencing DNA methylation age and age acceleration, providing new insights into their biological interpretations.
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 definitive conclusions on the clinical utility of DNA methylation age as a standalone predictor of health.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Partial
- Clinical utility: Not established
The research utilized a principal component analysis (PCA) method to address the collinearity of blood cell counts, allowing for a clearer understanding of how these counts contribute to variations in DNA methylation age. The study analyzed data from 4,058 samples and found that up to 53% of the variation in DNA methylation age could be attributed to blood cell counts, particularly the balance between naïve and memory T cells.
In contrast, the association between age acceleration and blood cell composition was weaker, explaining up to 21% of the variance, with neutrophils being the primary contributors for 2nd-generation clocks. The findings suggest that while DNA methylation age and age acceleration are related to blood cell composition, they reflect different biological processes.
Furthermore, the study examined the influence of blood cell composition on the relationship between age acceleration and 176 incident health outcomes in a larger cohort of 18,859 individuals. Although cell composition significantly attenuated the association between age acceleration and health outcomes, the effect was modest. This indicates that while blood cell composition plays a role in biological aging, it may not be a major determinant of health outcomes.
Overall, the study highlights the complexity of biological aging as measured by DNA methylation and underscores the importance of considering blood cell composition in future research. The findings may have implications for understanding the biological underpinnings of aging and its relationship to health.