Exposure to polycyclic aromatic hydrocarbons and aging acceleration: Unraveling the underlying mechanisms and the role of AKT1 via integrative methods

The exposure load of polycyclic aromatic hydrocarbons (PAHs) is elevating especially in the elderly population, but their impacts on biological aging remains unclear. Herein, we assessed the cross-sectional and longitudinal associations between PAHs exposure and aging acceleration via a repeated-measures study involving 7407 observations from the Wuhan-Zhuhai cohort, and explored the underlying mechanisms through network toxicology and a gene-environment interaction analysis. Urinary mono-hydroxylated PAHs (OH-PAHs) levels were measured, and the acceleration of clinical age calculated by Klemera-Doubal method (KDM_AA) and Phenotypic Age algorithm (PHE_AA) as well as methylated age proposed by Zhang et al. (Zhang_AA) and Levine et al. (Levine_AA) were constructed. Linear mixed models were used in the statistical analyses. Positive associations between several OH-PAHs and aging acceleration were observed. Each 1-unit increase in ln-transformed 3-OHPh and 1-OHPh was associated with an increase in KDM_AA of 0.456 (95% confidence interval 0.285, 0.627) and 0.198 (0.018, 0.377) years, and an annual rate of change in KDM_AA of 0.506 (0.136, 0.876) and 0.778 (0.416, 1.141) years/year, respectively. Similarly, each 1-unit increase in ln-transformed 9-OHPh and 1-OHP was associated with an increase in Zhang_AA of (0.026, 0.385) and 0.171 (0.054, 0.288) years, and an annual rate of change of 0.020 (0.003, 0.036) and 0.015 (0.002, 0.029) years/year, respectively. The reactive intermediate of phenanthrene showed binding affinity to AKT1 protein. AKT1 genetic variants exhibited interactions with OH-PAHs on aging acceleration, and individuals with high-risk genotypes and high OH-PAHs were susceptible to accelerated aging. Our study indicated that PAHs exposure was associated with aging acceleration, and AKT1 as a possible target molecule was involved.