Long-term exposure to PM2.5, aging hallmarks, and age-related diseases: a nationwide prospective cohort study

Long-term exposure to fine particulate matter (PM2.5) has been linked to increased risks of morbidity and mortality, yet its association with age-related diseases (ARDs) and the underlying molecular mechanisms remains unclear. Leveraging data from 502,128 participants (mean age 56.5 years) in the UK Biobank, we systematically estimated the associations between exposure to 3-year moving-average PM2.5 and 83 ARDs and 9 recognized aging hallmarks. We additionally integrated large-scale plasma proteomics to explore potential biological pathways. Long-term exposure to PM2.5 was associated with increased risks of 12 ARDs and 6 aging hallmarks. Hazard Ratios (HRs) per 10 μg/m3 increase in PM2.5 ranged from 1.12 to 2.38 across the 12 ARDs, with the most pronounced associations observed for primary thrombocytopaenia and plasma cell cancer. Among aging hallmarks, long-term exposure to PM2.5 was linked to increased risks of loss of proteostasis (HR: 1.07, 95% CI: 1.03, 1.10), stem cell exhaustion (HR: 1.06, 95% CI: 1.03, 1.09), telomere attrition (HR: 1.06, 95% CI: 1.02, 1.09), deregulated nutrient-sensing (HR: 1.05, 95% CI: 1.02, 1.09), mitochondrial dysfunction (HR: 1.05, 95% CI: 1.02, 1.08), and cellular senescence (HR: 1.04, 95% CI: 1.01, 1.07). Compared with no intervention, a hypothetical PM2.5 reduction to the annual standards of 10 μg/m3 could substantially lower 10-year risks for most of the 12 ARDs, particularly for hypertension and cataract, and significantly attenuate all aging hallmarks. Proteomic profiling of 2923 circulating proteins identified 35 aging-related proteins that were jointly associated with both chronological age and PM2.5 exposure. These proteins were enriched in pathways involving immune regulation, epithelial integrity, vascular biology, extracellular matrix organization, and environmental responses. Mediation analyses showed that these 35 proteins collectively explained 59%-83% of the PM2.5-aging hallmark associations, with key contributors including WFDC2, TFF1, and CXCL17. Collectively, these findings provide large-scale population evidence linking long-term exposure to PM2.5 to multiple age-related diseases and aging hallmarks, and highlight candidate circulating proteins that may partially explain these associations.