Heavy metals, epigenetic aging, and mortality: A cohort study

BACKGROUND: Aging is a multifaceted biological process modulated by interplay of genetic determinants and environmental influences. However, the role of epigenetic aging in the association between environmental exposures and mortality risk in human populations remains incompletely understood. OBJECTIVE: Investigate the associations between urinary metal exposure, epigenetic-age acceleration markers (EAMs), and mortality risk. METHODS: Utilizing data from 807 participants from the National Health and Nutrition Examination Survey, six EAMs (HorvathAge-Resid, HannumAge-Resid, PhenoAge-Resid, GrimAge-Resid, GrimAge2-Resid, DunedinPoAm) were derived from DNA methylation residuals. The relationships between metal exposure, EAMs and mortality risk were evaluated using multiple-linear regression, Cox regression, and weighted quantile sum (WQS) models, while the mediating role of EAMs in these associations was assessed through mediation analysis. RESULT: Elevated urinary levels of cadmium, barium, antimony, and tungsten were associated with increased risk of mortality. The WQS models indicated that metal exposure accelerated epigenetic aging, with cadmium, lead, and tungsten showing the highest weights for GrimAge-Resid, GrimAge2-Resid, and DunedinPoAm, respectively. Each interquartile range unit increase in urinary cadmium was associated with increases of 1.617, 1.874, and 0.023 units in GrimAge-Resid, GrimAge2-Resid, and DunedinPoAm, respectively. Furthermore, GrimAge2-Resid, GrimAge-Resid, and DunedinPoAm accounted for 46.42 %, 43.39 %, and 21.75 % of the relationship between cadmium and mortality risk; while DunedinPoAm accounted for 16.10 % for the relationship between barium and mortality risk. CONCLUSIONS: This study suggests that exposure to urinary metals is associated with an increased risk of mortality, with epigenetic aging playing a partial mediating role in this relationship.