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

Lymphocyte percentage mediates a significant portion of ferritin's total effect on PhenoAge acceleration.

• Lymphocyte percentage mediated 8.01% of ferritin's total effect on PhenoAge acceleration.
• Mediation effect estimate: 0.06 (95% CI: 0.02 to 0.10).
• Analysis was based on genome-wide association studies in European populations using a 2-step Mendelian randomization design.
• PhenoAge acceleration was used as the epigenetic aging outcome measure.

Neutrophil percentage mediates a portion of the causal relationship between serum ferritin and PhenoAge acceleration.

• Neutrophil percentage explained 4.88% of the causal relationship between serum ferritin and PhenoAge acceleration.
• Mediation effect estimate: 0.03 (95% CI: 0.004 to 0.07).
• This finding was obtained using a 2-step Mendelian randomization framework.

Neutrophil percentage mediates a portion of the causal relationship between transferrin saturation percentage and HannumAge acceleration.

• Neutrophil percentage explained 7.76% of the causal relationship between transferrin saturation percentage and HannumAge acceleration.
• Mediation effect estimate: 0.04 (95% CI: 0.01 to 0.07).
• HannumAge acceleration was used as a separate epigenetic aging outcome measure distinct from PhenoAge.

The study evaluated causal relationships between six iron status biomarkers and five types of immune cell proportions.

• Iron status biomarkers included: iron, ferritin, transferrin saturation percentage, total iron-binding capacity, liver iron content, and pancreatic iron content.
• Immune cell proportions examined were: lymphocyte, neutrophil, monocyte, eosinophil, and basophil percentages.
• Two-sample Mendelian randomization analysis was used to evaluate causal relationships between iron biomarkers and immune cell proportions.
• All GWAS data were drawn from European populations.

Interventions targeting immune cell proportions are proposed as a potential strategy for regulating the pace of aging.

• Both lymphocyte and neutrophil proportions were found to partially mediate the causal association of iron status with epigenetic age acceleration.
• The authors conclude that 'interventions on changing the percentage of immune cells would be a potential strategy for regulating the pace of aging.'
• The mediation analyses suggest immune cell modulation as a mechanistic pathway linking iron homeostasis to epigenetic aging.