Dietary advanced glycation end products and their role in health and disease

Abstract

Over the past 2 decades there has been increasing evidence supporting an important contribution from food-derived advanced glycation end products (AGEs) to the body pool of AGEs and therefore increased oxidative stress and inflammation, processes that play a major role in the causation of chronic diseases. A 3-d symposium (1st Latin American Symposium of AGEs) to discuss this subject took place in Guanajuato, Mexico, on 1-3 October 2014 with the participation of researchers from several countries. This review is a summary of the different presentations and subjects discussed, and it is divided into 4 sections. The first section deals with current general knowledge about AGEs. The second section dwells on mechanisms of action of AGEs, with special emphasis on the receptor for advanced glycation end products and the potential role of AGEs in neurodegenerative diseases. The third section discusses different approaches to decrease the AGE burden. The last section discusses current methodologic problems with measurement of AGEs in different samples. The subject under discussion is complex and extensive and cannot be completely covered in a short review. Therefore, some areas of interest have been left out because of space. However, we hope this review illustrates currently known facts about dietary AGEs as well as pointing out areas that require further research.

Keywords: RAGE; inflammation; insulin resistance; nutraceutical; nutrition; oxidative stress.

FIGURE 1

Different pathways of AGE formation. This figure schematically depicts the traditional Maillard reaction leading to AGE formation through the initial reaction between reducing sugars and the free amino group of a protein going through the stages of Schiff base and Amadori product formation. The figure also illustrates the many other different pathways that may lead to the formation of AGEs, even in the absence of glucose. AGE, advanced glycation end product; CML, carboxymethyllysine; MG-H1, methylglyoxal-derived hydroimidazolone 1.

FIGURE 2

RAGE, its ligands, and its main signaling pathways enhance oxidative stress. RAGE is a pattern-recognition protein belonging to the immunoglobulin superfamily of receptors. RAGE recognizes a diversity of ligands encompassing endogenous and food-derived AGEs, DNA, RNA, amyloid fibrils, HMGB1, the leukocyte integrin Mac-1, S100 calgranulins, and modified LDL. Upon activation, RAGE activates NADP oxidase and signaling with activation of NF-κB inducing oxidative stress and inflammation. RAGE increases ROS via NAD(P)H oxidase. RAGE also signals via PI-3K, Ki-Ras, and Erk1 and Erk2. These pathways stimulate the translocation of NF-κB from the cytoplasm to the nucleus in a coordinated manner. Activation produces inflammation and tissue injury sustained by a RAGE-dependent expression of proinflammatory mediators such as MCP-1 and VCAM-1. sRAGEs that bear the ligand-binding domains are present in the circulation and may act as decoy molecules or be surrogate biomarkers. ADAM10, a disintegrin and metalloprotease domain–containing protein 10; AGE, advanced glycation end product; Erk1, extracellular signal-regulated kinase 1; Erk2, extracellular signal-regulated kinase 2; HMGB1, high-mobility group box 1; Ki-Ras, Kirsten rat sarcoma viral oncogene homolog; MCP-1, monocyte chemoattractant protein 1; mDial1, mammalian diaphanous 1; MMP, matrix metalloproteases; PI-3K, phosphatidylinositol-3 kinase; RAGE, receptor for advanced glycation end products; ROS, reactive oxygen species; sRAGE, soluble receptor for advanced glycation end products; VCAM-1, vascular cell adhesion molecule 1.