Significance of Advanced Glycation End Products in Aging-Related Disease

Abstract

Carbohydrates are indispensable nutrients for life. However, due to the presence of a carbonyl group, reducing sugars such as glucose react non-enzymatically with amino groups on proteins in glycation (or Maillard) reactions. This reaction is divided into early and advanced phase reactions: the former covers the reaction progression up to the Amadori rearrangement, and the latter covers the reaction through the subsequent alterations of oxidation, dehydration, condensation, and so on, eventually generating advanced glycation end products (AGEs). Among post-translational modifications, processes such as phosphorylation or acetylation are known as “post-translational modifications with order,” because the target proteins and the time of modification are controlled. However, glycation is a “post-translational modification with disorder” because post-translational modification of proteins by glucose progresses non-enzymatically, irreversibly, and at random, and because the progression depends on the existing time (aging) and the concentration of glucose, rather than the variety of proteins involved. While AGEs were initially considered simply as rust or waste matter in the body, significant attention is now afforded these compounds as a target molecule for newly-developing drugs, for the following reasons: AGEs damage the body by changing the structure and affecting the function proteins; receptors that recognizes AGEs, such as RAGE (receptor for AGE), exist in the body and mediate cellular derangements to induce morbidity; and inhibitors for AGE generation, such as aminoguanidine, pyridoxamine, and benfotiamine, delay the pathogenesis of diabetic nephropathy and retinopathy. Further, racemization proteins containing D-amino acids have been noted, along with AGEs, in drusen, which are characteristic of age-related macular degeneration (AMD). Here, we introduce current topics and future goals of AGEs research, particularly with regard to kidney disease associated with aging and diabetes mellitus, and touch on the involvement of AGEs in the progression of ocular diseases and the function of RAGE.