The Environmental Exposome and Age-Related Macular Degeneration: Oxidative Stress as a Molecular Link

Age-related macular degeneration (AMD) is a multifactorial retinal disease in which genetic susceptibility, aging, metabolic dysfunction, and environmental factors interact to determine disease onset and progression. Although environmental exposures are increasingly recognized as modifiable risk factors for AMD, the molecular mechanisms linking cumulative environmental stress to retinal degeneration remain incompletely understood. In this review, we examine the environmental exposome relevant to AMD and propose oxidative stress as a central molecular link connecting diverse environmental exposures with retinal aging and AMD susceptibility. Epidemiological evidence linking air pollution, particulate matter, cigarette smoke, and other environmental stressors to AMD is reviewed, followed by an analysis of their effects on redox homeostasis and the retinal pigment epithelium (RPE)-Bruch's membrane-choriocapillaris complex. We further discuss how chronic oxidative stress promotes mitochondrial dysfunction, lipid peroxidation, ferroptosis, autophagy and mitophagy impairment, cellular senescence, and senescence-associated inflammation. These processes interact with complement activation, microglial activation, and chronic retinal inflammation, ultimately contributing to RPE dysfunction, choriocapillaris and Bruch's membrane abnormalities, photoreceptor degeneration, and AMD progression. Integrating these mechanisms, we propose an environmental exposome-oxidative stress-retinal aging axis in which cumulative environmental exposures progressively reduce retinal resilience and increase susceptibility to AMD. We also evaluate antioxidant and redox-modulating strategies, including the established evidence for AREDS/AREDS2 supplementation and emerging approaches targeting Nrf2 signaling, glutathione homeostasis, mitochondria, and ferroptosis. Importantly, antioxidant supplementation should not be equated with primary prevention of environmentally induced AMD. Future studies integrating individual exposure monitoring, oxidative stress biomarkers, genetic susceptibility, and retinal phenotyping may enable precision prevention and personalized redox-based interventions. This framework positions environmental exposure as a potentially modifiable driver of retinal biological aging and provides a mechanistic basis for understanding and preventing environmentally driven AMD.