BACKGROUND: Lead and cadmium are among the most prevalent environmental toxicants and are highly detrimental to human health. While prior studies link heavy metal exposure to reduced telomere length and increased DNA methylation age, their relationship with epigenetic age acceleration (EAA) remains understudied. This study investigates whether exposure to lead and cadmium accelerates biological aging. METHODS: This cross-sectional study analyzed data from 2201 participants aged 50 or older from the 1999-2002 NHANES. Blood lead and cadmium levels were measured using simultaneous multi-element atomic absorption spectrometry. Eight DNA-methylation-based epigenetic clocks were included in the analysis: Hannum Age, Horvath pan-tissue Age, PhenoAge, GrimAge, GrimAge version 2, Skin Blood Age, epiTOC, and DNAmTL. EAA for each individual was calculated as the residuals from the regression of estimated epigenetic age on chronological age. RESULTS: Of the 2201 American older adults, the mean (SE, standard error) chronological age was 65.75 (0.21), which was closest to the mean GrimAge (65.99
SE = 0.19). After adjusting for demographics, lifestyle factors, comorbidities, and cell type composition, multivariate linear regression analyses revealed associations of blood lead and cadmium levels with significantly higher Hannum Age, Grim Age, Grim Age2, Skin Blood Age (associated with lead only), as well as Phenotypic Age and DNAmTL (associated with cadmium only). Quartile-based analyses of blood lead and cadmium levels according to quartiles revealed consistent and strong associations between greater exposure to lead or cadmium (e.g., the fourth quartile of the metals) and EAA. Among lifestyle factors, smoking had a pronounced impact on accelerated aging, especially in the Grim Age and Grim Age2. CONCLUSIONS: We found that exposure to lead and cadmium was associated with accelerated epigenetic age. These findings suggest the potential role of lead and cadmium in EAA and propose the integration of environmental factors to refine epigenetic age prediction.