**6. Conclusions**

Currently there is no cure for DR. Modern therapies include anti-angiogenic strategies or surgery for retinal detachment, which cannot restore vision but only ameliorate further deterioration of the retina. A vast amount of literature stresses the pathogenic role of glycation and AGEs in the molecular basis of this eye-related disease. Based on this literature, lowering AGEs might be a potential therapeutic strategy against DR. Despite enormous effort to date, no AGEs inhibitors have reached clinical use. Exploiting the glyoxalase system and the discovery of compounds that enhance this detoxifying activity represent a therapeutic alternative to fight glycation-derived damage, under diabetic and non-diabetic conditions. As documented here, glyoxalase activity is highest in the retina, suggesting a significant role in eye physiology. The capacity of this detoxifying route is thought to decline with age. We propose that targeting the glyoxalase system through nutritional or pharmacological enhancers might be an alternative to fight this sight-threatening diabetic complication, aiming to reduce the economic burden caused by DR.

**Author Contributions:** G.A. carried out biochemical assays, analyzed the data, and wrote the paper; S.G.F., S.R., and W.Y. provided technical assistance for the optimization of glyoxalase activity assay, dissection of ocular tissues, and contributed to revision of the paper; J.W. edited the manuscript. E.B. and A.T. designed the experiments, analyzed the data, coordinated the study, and wrote the paper. All authors have read and agreed to the published version of the manuscript.

**Funding:** Funding was provided by NIH RO1EY028559, RO1EY026979 (to A.T.), USDA NIFA 2016–08885 (to A.T. and S.R.), USDA 8050-51000-089-01S (to A.T.), Kamada (to A.T.), Thome Memorial Foundation (to A.T.), BrightFocus Foundation (to S.R.), and a gran<sup>t</sup> from the Human Nutrition Research Center on Aging (to E.B.). This material is based upon work supported by the US Department of Agriculture—Agricultural Research Service (ARS), under Agreement No. 58-1950-4-003.

**Conflicts of Interest:** The authors declare no conflict of interest.
