Epigenetic clocks have emerged as significant biomarkers for assessing biological age, yet the underlying biological mechanisms remain poorly understood. Recent research has indicated that the proportions of naïve and memory T cells in blood may play a crucial role in influencing these clocks. This study, conducted by Jonkman et al., aims to clarify the relationship between blood cell composition and DNA methylation age (DNAmAge) as well as age acceleration (AgeAccel).
Methods
The researchers developed a principal component analysis (PCA) method that effectively addresses the collinearity of blood cell counts. This innovative approach allows for a more nuanced understanding of how different blood cell types contribute to the estimation of biological age. The study analyzed a substantial dataset comprising 4,058 samples to quantify the impact of cell composition on DNA methylation age and age acceleration, using six different epigenetic clocks.
Furthermore, the influence of cell composition on the relationship between age acceleration and various health outcomes was assessed in a larger cohort of 18,859 individuals. This comprehensive analysis aimed to uncover the extent to which blood cell composition could explain variations in biological aging and its associated health implications.
Results
The findings revealed that up to 53% of the variation in DNA methylation age could be attributed to blood cell counts, with a notable emphasis on the balance between naïve and memory T cells. In contrast, the associations between age acceleration and cell counts were found to be weaker, explaining up to 21% of the variance. Notably, for second-generation epigenetic clocks, neutrophil counts were primarily implicated.
Moreover, the study validated the role of cell counts in influencing epigenetic clocks through experiments involving artificial cell mixtures. Interestingly, the analysis showed that cell composition significantly attenuates the association between age acceleration and 176 incident health outcomes, although the effect was described as modest.
Conclusions
The research concludes that DNAmAge and AgeAccel reflect different biological processes, as evidenced by their distinct associations with blood cell composition. The study highlights that while blood cell composition contributes to variations in age acceleration, its impact on associations with mortality and disease outcomes remains limited.
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 modifying blood cell composition will lead to changes in biological age or health outcomes.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Not established
- Clinical utility: Not established
The evidence is based on primary research involving human samples.