Dietary iron attenuates epigenetic aging through DNA methylation remodeling and extends survival in older adults

Iron homeostasis is essential for fundamental biological processes, yet its impact on epigenetic aging and mortality remains poorly understood. This study aimed to investigate associations between dietary iron intake and DNA methylation (DNAm) aging markers and to determine whether these epigenetic signatures mediate iron's effects on mortality outcomes.

We analyzed data from 2,398 adults aged ≥ 50 years in the National Health and Nutrition Examination Survey (1999-2002) with up to 20 years of mortality follow-up. Dietary iron intake was assessed through 24-h recall interviews. DNA methylation was profiled using the Illumina Infinium MethylationEPIC BeadChip. We employed multiple linear regression to identify iron-responsive DNAm features, Cox proportional hazards models to assess mortality associations, and formal mediation analyses to quantify epigenetic pathways.

Higher dietary iron intake was significantly associated with favorable epigenetic profiles, particularly with reduced levels of mortality-predictive DNAm markers GrimAge2Mort (β = -0.079, FDR = 0.00022), CRPMort (β = -0.072, FDR = 0.0037), and B2MMort (β = -0.057, FDR = 0.042). These iron-responsive DNAm features strongly predicted all-cause mortality (HRs per SD increase: 1.34, 1.21, and 1.08, respectively; all p < 0.05) and cause-specific mortality. Higher iron intake was directly associated with reduced risk of all-cause mortality (HR = 0.93 per SD increase, 95% CI 0.87-0.99), heart disease mortality (HR = 0.87, 95% CI 0.78-0.97), and respiratory disease mortality (HR = 0.72, 95% CI 0.56-0.93). Mediation analyses revealed that GrimAge2Mort mediated 22.7% of iron's protective effect on all-cause mortality and 14.7% on heart disease mortality.

This study establishes dietary iron as a modifiable determinant of epigenetic aging and mortality risk in older adults, with epigenetic recalibration mediating a substantial proportion of iron's protective effects. These findings suggest optimizing iron intake may represent a promising nutritional strategy to promote healthy aging.