Ozone exposure, retinal microvasculature alterations, and the mediating effect of aging in diabetic population: A retrospective cohort study

Accumulating epidemiological evidence links ozone exposure with cerebrocardiovascular morbidity, yet its microvascular impact remains poorly characterized. Retinal microvasculature alterations have emerged as sensitive biomarkers of systemic endothelial dysfunction and predictors of cerebrocardiovascular events. Our study comprised 55,463 individuals diagnosed with type 2 diabetes mellitus (T2DM), recruited across 249 community health centers spanning all 17 administrative districts of Shanghai in 2017. Exposure assessment utilized satellite-derived ozone concentration estimates at 1*1 km spatial resolution, aggregating five-year (2013-2017) ozone exposure metrics. Retinal vascular phenotyping included central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), arteriole-to-venule ratio (AVR), vascular tortuosity (VT), and fractal dimension (D_f). The retinal age gap (RAG) is adopted to reflect accelerated aging, defined as the difference between deep learning-predicted retinal age and chronological age. Multivariable regression analyses using double machine learning showed that for every 10 μg/m³ increase in ozone, the decrease in the CRAE, CRVE, VT (×10⁴) and D_f (×10³) were 4.03 (95 %CI: 3.04, 5.01)μm, 8.35 (95 %CI: 6.69, 10.00)μm, 0.38 (95 %CI: 0.28, 0.48) and 13.7 (95 %CI: 11.20, 16.21), respectively, and the increase in RAG was 2.29 (95 %CI: 2.04, 2.54) years. Mediation analysis revealed an association between ozone exposure and reductions in CRAE (indirect effect, standardized coefficient=-0.08, 95 %CI -0.09∼-0.07), CRVE (-0.07, -0.08∼-0.06), and D_f (-0.11, -0.12∼-0.09) through the pathway of accelerated aging. Long-term ozone exposure correlates with accelerated retinal aging and microvascular remodeling (vessel narrowing, reduced tortuosity, fractal simplification), which provides novel biological evidence to elucidate the causal relationship between ozone exposure and cerebrocardiovascular risk.