Sex-Specific Biological Aging-Related Lipidomic Profiles Mediate the Impact of Urinary Polycyclic Aromatic Hydrocarbon Exposures on Cognitive Function in Healthy Older Adults

Emerging evidence suggests that exposure to polycyclic aromatic hydrocarbons (PAHs) may exacerbate cognitive deterioration and biological aging, but the biomolecular mechanisms, particularly those driving sex-specific vulnerability, remain unclear. This 5-month longitudinal panel study, conducted among 76 healthy participants aged 60-69 in Jinan, China. Urinary concentrations of six PAHs were measured, and biological age was estimated using the Klemera and Doubal method. The associations between individual and combined PAH exposures and cognitive function were examined using linear mixed-effects model, and the mediating effect of biological aging was assessed by mediation model. Additionally, lipidomic profiling including lipidome clustering and individual lipids helped identify key biomolecular mediators. The results showed that exposure to four PAHs was significantly associated with cognitive decline, with combined exposure analysis further indicated the detrimental effects of PAH mixtures. And biological aging partially mediated the association between 2-hydroxynaphthalene (2-NAP) and cognitive function. Key lipid levels, particularly phosphatidylethanolamines (PEs)-dominated clustering pattern, emerged as pivotal molecular mediator shaping this relationship. Additionally, more lipid species, notably phosphatidylcholines (PCs), mediated PAHs-induced cognitive decline in females. These findings elucidate lipid levels as a key mechanism linking biological aging and PAHs-induced cognitive decline, with specific lipid alterations partially explaining the increased vulnerability of females to cognitive decline.