Integrative genetic analysis to decode the causal effect of air pollution on accelerated aging

BACKGROUND: The relationships between air pollutants and aging remain poorly understood due to the limitations of observational studies. AIM: Herein, we aimed to infer the causality between air pollutants (PM2.5, NO2, NOx, PM2.5-10 and PM10) and a comprehensive set of aging phenotypes (frailty index, face aging, GrimAge, HannumAge, PhenoAge, granulocyte proportions, intrinsic epigenetic age acceleration, longevity, healthspan, parental lifespan and telomere length) using integrative genetic analysis framework. DESIGN AND METHODS: A three-phase study design was used: phase one involved univariable and multivariable Mendelian randomization (MR) analyses; phase two used two-step MR to identify potential mediators among 4596 candidate multi-omics traits; phase three performed transcriptome-wide association studies (TWAS) followed by biological pathway enrichment and Bayesian colocalization analyses to explore the underlying mechanisms. RESULTS: A robust causal association between PM2.5 exposure and frailty was found across all univariable MR analyses, which remained robust even after controlling for lifestyle factors or air pollutants in the multivariable MR analyses. The causal effect remained significant in multivariable MR analyses after adjusting for other air pollutants or potential lifestyle factors. We identified several common mediators that potentially mediate the effect, with the B cell lymphoma-2 protein 1 being the most prominent mediator. Our TWAS identified 98 genes associated with both PM2.5 and frailty, with the MMAB gene showing the most significant association. CONCLUSIONS: This study provides robust genetic evidence supporting a causal link between PM2.5 exposure and frailty, highlighting the detrimental effects of air pollution on aging.