Epigenetic age acceleration mediates the association between phthalate exposure and higher mortality risk in U.S. older adults

Phthalates have been linked to increased mortality, but evidence on their relationship with epigenetic aging remains limited, particularly among older adults. We investigated associations between urinary phthalate metabolites and DNA methylation (DNAm)-derived epigenetic age acceleration (EAA) and examined EAA as a potential mediator for the phthalate-mortality association. We analyzed 611 U.S. adults aged ≥ 50 years without baseline cardiovascular diseases (CVD) or cancer from the 1999-2002 U.S. National Health and Nutrition Examination Survey (NHANES), followed for mortality through 2019. Baseline urinary concentrations of four phthalate metabolites and EAA derived from four DNAm clocks were analyzed using survey-weighted linear regression, Bayesian Kernel Machine Regression, and quantile-based g-computation for individual and mixture effects. Higher monobenzyl phthalate (MBzP) was associated with accelerated HannumAge (0.60 years per log-unit increase) and was positively associated with all-cause, cancer, and CVD mortality. Mixture analyses suggest MBzP as the primary contributor to accelerated HannumAge, PhenoAge, and GrimAge, despite no significant overall mixture effects. Mediation analyses indicated that EAA partially explained these associations, with the largest proportion mediated for cancer mortality (3.9%-9.2% across clocks). These findings suggest that among older U.S. adults, urinary MBzP was associated with accelerated epigenetic aging, which partially mediated the MBzP-mortality association, highlighting the need to reduce phthalate exposure and supporting DNAm clocks as sensitive biomarkers of environmental toxicity.