The AGE-RAGE-oxidative stress axis: A paradigm shift in understanding diabetic retinopathy

Diabetic retinopathy (DR) represents a vision-threatening complication of diabetes, characterized by progressive damage to the retinal neurovascular network in both type 1 and type 2 diabetes. This condition disrupts the delicate cellular interactions within the neurovascular unit (NVU), where advanced glycation end products (AGEs) emerge as key contributors to this dysfunction. While the precise mechanisms of AGE-induced damage remain under investigation, current evidence implicates multiple pathways: the AGE-RAGE signaling axis, oxidative stress generation, inflammatory cascades, and activation of cell death programs. Notably, the irreversible loss of retinal neurons directly correlates with vision decline in diabetic patients, highlighting the urgent need for neuroprotective strategies. Among potential therapeutic targets, AGEs present a promising focus for intervention, given their central role in NVU deterioration. This review helps us in the current knowledge about AGE-mediated neurovascular dysfunction, and it also explores emerging treatment approaches, particularly antiglycation therapies aimed at preserving NVU integrity in DR. It also examines promising preclinical and clinical therapies and identifies critical research gaps-such as the need for better biomarkers of AGE activity and personalized treatment approaches.