Iron status modulates immune cell proportions to drive epigenetic age acceleration: A 2-step Mendelian randomization study

Iron status is associated with human aging, but the underlying mechanisms are unclear. We aimed to estimate the causality of the association between iron status and human aging and to quantify the mediating effects of immune cells. Based on genome-wide association studies in European populations, we conducted a two-sample Mendelian randomization analysis to evaluate the causal relationships between 6 iron status biomarkers (iron, ferritin, transferrin saturation percentage, total iron-binding capacity, liver iron content, pancreatic iron content) and 5 types of percentage of immune cells (lymphocyte, neutrophil, monocyte, eosinophil, basophil). Next, we employed a 2-step Mendelian randomization design to investigate the potential role of immune cell proportions in mediating iron homeostasis-driven epigenetic aging. In this study, a 2-step randomization analysis demonstrated that lymphocyte percentage mediates 8.01% (mediation effect: 0.06; 95% confidence interval [CI]: 0.02 to 0.10) of ferritin's total effect on PhenoAge acceleration. Neutrophil percentage explained 4.88% (mediation effect: 0.03; 95% CI: 0.004 to 0.07) of the causal relationship between serum ferritin and PhenoAge acceleration, and 7.76% (mediation effect: 0.04; 95% CI: 0.01 to 0.07) of the causal relationship between transferrin saturation percentage and HannumAge acceleration. Lymphocyte and neutrophil proportions were found to partially mediate the causal association of iron status with epigenetic age acceleration. Interventions on changing the percentage of immune cells would be a potential strategy for regulating the pace of aging.