Physiological Chemistry and Pathophysiology of Advanced Glycation End Products

Advanced glycation end products (AGEs) are a heterogenous group of compounds formed by non-enzymatic, heat-driven reactions between simple sugars and amino acids/peptides either endogenously through biological processes or exogenously via the Maillard reaction in food processing. The body possesses homeostatic mechanisms to metabolize and eliminate AGEs but over-production of endogenous AGEs and/or excess consumption of dietary AGEs (dAGEs) overwhelm these defense mechanisms creating a state of inflammation and degeneration that lead to development of chronic diseases. The Maillard reaction is a desirable culinary process that gives heat processed foods the aroma, dark color, taste and texture such as the dark color of coffee or the brown crust of bread and pastries. The end point of the Maillard reaction is the brown pigment, melanoidin, that not only contributes flavor to food but also possesses anti-inflammatory properties. At the end of cooking or heat processing, the food contains all the products of the Maillard reaction including late stage AGEs that can initiate inflammation. Glycotoxins are also produced during normal physiological processes in the body such as carbohydrate metabolism. The AGE pool of the body comprises both endogenous and dAGEs that are indistinguishable, so when the total AGE burden is high there are structural and functional changes in cells. Protein cross-linking occurs when AGEs bind to collagen, local AGE accumulation increases oxidative stress in tissues and binding to the receptor for AGEs, RAGE, on cell surfaces initiates a sustained and persistent inflammatory cascade within cells that cause either cell damage or death. Several diseases are associated with dAGEs such as diabetes mellitus Type II, cardiovascular disease and atherosclerosis and chronic kidney disease while degenerative processes contribute to cellular aging because of intake. An appreciation for the formation, chemistry and pathophysiological effects of AGEs is needed as we seek to understand their biological role and possible consequences of excessive dietary intake. The goal is to accurately determine the molecular disturbances cause by AGEs so that there can be specific, targeted therapy and management approaches to decrease the harmful effects of AGEs.