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

Urinary 3-hydroxyphenanthrene (3-OHPh) was positively associated with clinical aging acceleration as measured by the KDM algorithm.

• Each 1-unit increase in ln-transformed 3-OHPh was associated with an increase in KDM_AA of 0.456 years (95% CI: 0.285, 0.627).
• Each 1-unit increase in ln-transformed 3-OHPh was associated with an annual rate of change in KDM_AA of 0.506 years/year (95% CI: 0.136, 0.876).
• The study used linear mixed models and included 7407 observations from the Wuhan-Zhuhai cohort.
• The study design was a repeated-measures cross-sectional and longitudinal analysis.

Urinary 1-hydroxyphenanthrene (1-OHPh) was positively associated with clinical aging acceleration as measured by the KDM algorithm.

• Each 1-unit increase in ln-transformed 1-OHPh was associated with an increase in KDM_AA of 0.198 years (95% CI: 0.018, 0.377).
• Each 1-unit increase in ln-transformed 1-OHPh was associated with an annual rate of change in KDM_AA of 0.778 years/year (95% CI: 0.416, 1.141).
• These associations were observed in cross-sectional and longitudinal analyses using linear mixed models.

Urinary 9-hydroxyphenanthrene (9-OHPh) was positively associated with epigenetic aging acceleration as measured by the Zhang algorithm.

• Each 1-unit increase in ln-transformed 9-OHPh was associated with an increase in Zhang_AA (95% CI: 0.026, 0.385).
• Each 1-unit increase in ln-transformed 9-OHPh was associated with an annual rate of change in Zhang_AA of 0.020 years/year (95% CI: 0.003, 0.036).
• The Zhang_AA is a methylated age acceleration measure proposed by Zhang et al.

Urinary 1-hydroxypyrene (1-OHP) was positively associated with epigenetic aging acceleration as measured by the Zhang algorithm.

• Each 1-unit increase in ln-transformed 1-OHP was associated with an increase in Zhang_AA of 0.171 years (95% CI: 0.054, 0.288).
• Each 1-unit increase in ln-transformed 1-OHP was associated with an annual rate of change in Zhang_AA of 0.015 years/year (95% CI: 0.002, 0.029).
• 1-OHP is a urinary metabolite of pyrene, a polycyclic aromatic hydrocarbon.

The reactive intermediate of phenanthrene showed binding affinity to the AKT1 protein, identified through network toxicology analysis.

• Network toxicology was used to explore underlying mechanisms linking PAHs exposure to aging acceleration.
• AKT1 was identified as a possible target molecule involved in the pathway from PAHs exposure to aging acceleration.
• This finding was derived from integrative methods combining network toxicology and gene-environment interaction analysis.

AKT1 genetic variants interacted with OH-PAHs exposure on aging acceleration, with individuals carrying high-risk genotypes and high OH-PAHs exposure being most susceptible.

• Gene-environment interaction analysis was used to assess interactions between AKT1 genetic variants and OH-PAHs.
• Individuals with both high-risk AKT1 genotypes and high OH-PAHs exposure were identified as susceptible to accelerated aging.
• The study used an integrative approach combining network toxicology with gene-environment interaction analysis.
• This finding supports AKT1 as a mechanistic link between PAHs exposure and biological aging acceleration.

The study assessed both clinical and epigenetic aging acceleration using four distinct aging acceleration measures across a repeated-measures cohort of 7407 observations.

• Clinical aging acceleration was calculated using the Klemera-Doubal method (KDM_AA) and Phenotypic Age algorithm (PHE_AA).
• Epigenetic aging acceleration was calculated using methylated age measures proposed by Zhang et al. (Zhang_AA) and Levine et al. (Levine_AA).
• The study involved 7407 observations from the Wuhan-Zhuhai cohort.
• Urinary mono-hydroxylated PAHs (OH-PAHs) were used as biomarkers of PAHs exposure.
• Linear mixed models were used to analyze both cross-sectional and longitudinal associations.