**2. AGEs**

### **2.1 AGE formation by glucose and its derivatives**

AGEs are proteins generated by a series of reactions termed the Maillard Reaction. Classically, AGE formation has been described by a nonenzymatic reaction between proteins and glucose 18, 19. AGEs derive from the spontaneous reaction of carbohydrates with amino group of proteins, which undergo from the formation of reversible products (Schiff base adducts) to the generation of more stable products (Amadori products). Subsequently, complex reactions occur including intermolecular crosslink formation, and cleavage through oxidation, dehydration, condensation, cyclization, and other reactions follows, with generation of AGEs through a late reaction characterized by fluorescent and brown coloration and molecular crosslinkage. Recently, it was confirmed that AGEs are also formed by non-enzymatic reaction of reactive carbonyl compounds such as 3 deoxyglucosone, methylglyoxal resulting from persisting high blood glucose level, and oxidative stress associated with the amino residues of proteins.

### **2.2 AGEs formation independent of hyperglycemia**

There is also increasing evidence that AGEs are also formed through lipid-derived intermediates, resulting in advanced lipoxidation products 20. AGEs might be formed directly by autoxidation of free glucose 21, 22. In this pathway, known as autoxidative glycosylation, such reactive oxygen species as hydrogen peroxide were identified as both products and catalysts of autoxidation of sugars. Other than diabetes mellitus patients, high plasma and tissue levels of AGEs are observed in patients with ESRD. It has been reported that no difference was noted in blood AGEs levels between those with and without diabetes mellitus among chronic renal failure patients on hemodialysis, which is believed to enhance production and accumulation of AGEs in conditions other than hyperglycemia. Local accumulation of AGEs is also observed in patients with Alzheimer disease, rheumatoid arthritis, arteriosclerosis, cancer, and other diseases, suggesting the involvement of inflammation and oxidative stress in the formation of AGEs.
