Abstract
BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.