Sex-Specific Negative Association between Iron Intake and Cellular Aging Markers: Mediation Models Involving TNFα

Given that the dysregulation of iron homeostasis leads to genomic instability, iron has been linked to cellular aging. However, epidemiological research on dietary iron intake and cellular aging markers is scarce. The aim of this study was to explore the relationship between dietary iron intake and cellular aging markers and to investigate whether tumor necrosis factor-α (TNFα) mediated this relationship.

We conducted a cross-sectional analysis with a total of 467 subjects. Detailed dietary data were obtained using 24 h food recalls. Peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) were assessed using real-time PCR assay. The association between dietary iron intake and cellular aging markers and TNFα and superoxide dismutase (SOD) was analyzed by Pearson correlation analysis and regression models adjusted by covariates. Simple mediation models were generated to examine whether TNFα mediated the association between iron intake and cellular aging markers using PROCESS macro Version 3.3.

The study population contained more women than men, but their basic demographic and metabolic characteristics did not differ. After adjusting for age, LTL was the same for men and women, while mtDNAcn was lower in men. Multiple linear regression adjusted for confounding factors found that iron intake was negatively associated with LTL only in women and negatively associated with mtDNAcn only in men. Moreover, iron intake was positively associated with TNFα in both women and men but positively associated with SOD only in men. Path modeling showed that TNFα significantly mediated the indirect detrimental effect of iron intake on LTL only in women; in men, mediation of the indirect effect of iron intake on mtDNAcn by TNFα did not reach significance.

The study found sex-specific negative associations between dietary iron intake and cellular aging markers in that iron intake had deleterious effects on LTL attrition in women and mtDNAcn in men; only the former was partly mediated by TNFα. Consequently, when dietary iron intake and iron supplementation is recommended, the effects of iron imbalance on genomic stability and cellular aging markers must be considered.