Epigenetics-Based Age Acceleration Associated with 2,3,7,8 TCDD Exposure in Older Americans.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is highly toxic with potential impacts on aging. While previous studies have linked TCDD exposure to reduced telomere length and altered sperm DNA methylation (DNAm) age, its relationship with epigenetic aging remains unclear. This study investigated the association between serum TCDD levels and epigenetic clocks derived from DNAm in whole blood in older adults. Using data from the 1999-2002 National Health and Nutrition Examination Survey, we analyzed 589 participants aged 50 to 79 years with available blood TCDD and DNA methylation measures. Blood TCDD levels were measured by high-resolution gas chromatography/isotope-dilution high-resolution mass spectrometry. The six DNAm-based epigenetic clocks included Horvath Age, Hannum Age, SkinBlood Age, Pheno Age, Grim Age, and Grim Age2. Multivariable regression analysis showed significant associations between TCDD levels and Horvath Age, Hannum Age, Pheno Age, Grim Age, and Grim Age2. However, when using lipid-adjusted TCDD levels, significant associations remained only for PhenoAge (β = 0.73; SE, 0.31; p = 0.0258) and Grim Age2 (β = 0.44; SE, 0.21; p = 0.0472). The strongest non-linear trends were observed for PhenoAge, Grim Age, and Grim Age2, suggesting a threshold-dependent impact of TCDD on DNAm aging processes. Our findings suggest that TCDD exposure is associated with accelerated epigenetic aging, particularly in mortality-related clocks, with a dose-dependent and non-linear pattern.