Associations between persistent organic pollutants exposure and DNA methylation aging biomarkers: insights from a nationally representative study

Persistent organic pollutants (POPs) are environmental contaminants linked to adverse health outcomes, but their impact on epigenetic aging remains incompletely characterized. This study investigated associations between serum concentrations of POPs and DNA methylation (DNAm)-based age acceleration using twelve established epigenetic clocks in 815 U.S. adults aged ≥50 years from NHANES 1999-2002. POPs, including polychlorinated biphenyls (PCBs), dioxins, furans, and organochlorine pesticides (OCPs), were quantified using high-resolution gas chromatography/ isotope- dilution high-resolution mass spectrometry (HRGS/ID-HRMS), and age acceleration was estimated using multiple DNAm algorithms. The findings revealed bidirectional associations: while most PCBs exhibited inverse correlations with epigenetic age acceleration (e.g. PCB74 with HorvathAgeAcc: β = -1.08, 95% CI: -1.69, -0.46), certain furans and OCPs demonstrated positive associations with HorvathTelo acceleration (e.g. 2,3,4,7,8-PeCDF: β = 0.04, <i>P</i> = 0.0306). Sex-stratified analyses revealed significant effect modification, with positive associations between several OCPs (e.g. trans-nonachlor) and mortality-related clocks (GrimAge2Mortacc) being significantly stronger in females (<i>P</i>-interaction <0.0001). Age-specific patterns also emerged, where inverse associations between certain PCBs (e.g. PCB74) and epigenetic age acceleration were substantially amplified in or exclusively present among older adults (≥65 years) (<i>P</i>- interaction < 0.0001). These findings suggest that POP exposures differentially modulate epigenetic aging trajectories in a compound-dependent manner, highlighting the need for tailored risk assessment approaches for vulnerable populations.