Effects of iron homeostasis on epigenetic age acceleration: a two-sample Mendelian randomization study

Epigenetic clocks constructed from DNA methylation patterns have emerged as excellent predictors of aging and aging-related health outcomes. Iron, a crucial element, is meticulously regulated within organisms, a phenomenon referred as iron homeostasis. Previous researches have demonstrated the sophisticated connection between aging and iron homeostasis. However, their causal relationship remains relatively unexplored.

Through two-sample Mendelian randomization (MR) utilizing the random effect inverse variance weighted (IVW) method, each standard deviation (SD) increase in serum iron was associated with increased GrimAge acceleration (GrimAA, Beta_IVW = 0.27, P = 8.54E-03 in 2014 datasets; Beta_IVW = 0.31, P = 1.25E-02 in 2021 datasets), HannumAge acceleration (HannumAA, Beta_IVW = 0.32, P = 4.50E-03 in 2014 datasets; Beta_IVW = 0.32, P = 8.03E-03 in 2021 datasets) and Intrinsic epigenetic age acceleration (IEAA, Beta_IVW = 0.34, P = 5.33E-04 in 2014 datasets; Beta_IVW = 0.49, P = 9.94E-04 in 2021 datasets). Similar results were also observed in transferrin saturation. While transferrin manifested a negative association with epigenetic age accelerations (EAAs) sensitivity analyses. Besides, lack of solid evidence to support a causal relationship from EAAs to iron-related biomarkers.

The results of present investigation unveiled the causality of iron overload on acceleration of epigenetic clocks. Researches are warranted to illuminate the underlying mechanisms and formulate strategies for potential interventions.