Emerging PFAS contaminants PFNA and PFSA amplify epigenetic aging: sex- and age-stratified risks in an aging population

Emerging perfluoroalkyl substances (PFAS), such as perfluorononanoic acid (PFNA) and perfluorosulfonic acid (PFSA), are pervasive environmental contaminants that may influence human health. Their effects on aging, particularly through recently developed robust DNA methylation (DNAm) aging algorithms, remain largely unexplored. Using data from 326 U.S. adults aged ≥50 years (NHANES 1999-2000), we quantified serum PFAS via isotope-dilution tandem mass spectrometry and computed 12 DNAm aging algorithms. Weighted multivariable linear regression models assessed PFAS-DNAm aging associations, stratified by sex and age. PFNA exposure was significantly associated with DNAm algorithms via GrimAgeMortacc (β = 2.74, 95% CI: 1.04-4.44) and GrimAge2Mortacc (β = 2.45, 0.60-4.31), with stronger magnitudes in males (<i>P</i>-interaction = 0.0050) and adults aged 50-64 (<i>P</i>-interaction = 0.0270). PFSA was associated with LinAgeacc (β = 4.17, 0.60-7.74). Sex-stratified analyses revealed male-specific PFNA-HorvathAgeacc associations (β = 4.11, 0.71-7.52). These findings suggest that PFNA and PFSA may drive epigenetic aging disparities in aging populations, with males and middle-aged individuals at heightened risk. These findings underscore the need to regulate emerging PFAS and integrate epigenetic biomarkers into environmental health risk assessments.