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

BackgroundEpigenetic 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.ResultsThrough 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, BetaIVW = 0.27, P = 8.54E-03 in 2014 datasets; BetaIVW = 0.31, P = 1.25E-02 in 2021 datasets), HannumAge acceleration (HannumAA, BetaIVW = 0.32, P = 4.50E-03 in 2014 datasets; BetaIVW = 0.32, P = 8.03E-03 in 2021 datasets) and Intrinsic epigenetic age acceleration (IEAA, BetaIVW = 0.34, P = 5.33E-04 in 2014 datasets; BetaIVW = 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.ConclusionsThe 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.

Automated summary

Through two-sample Mendelian randomization (MR) using the random effect inverse variance weighted (IVW) method, it was found that an increase in serum iron was positively associated with GrimAge acceleration, HannumAge acceleration, and Intrinsic epigenetic age acceleration (IEAA). Transferrin saturation showed similar results. However, there was no solid evidence to support a causal relationship from epigenetic age accelerations to iron-related biomarkers.