Redox Signaling and Advanced Glycation Endproducts (AGEs) in Diet-Related Diseases

Abstract

Diets are currently characterized by elevated sugar intake, mainly due to the increased consumption of processed sweetened foods and drinks during the last 40 years. Diet is the main source of advanced glycation endproducts (AGEs). These are toxic compounds formed during the Maillard reaction, which takes place both in vivo, in tissues and fluids under physiological conditions, favored by sugar intake, and ex vivo during food preparation such as baking, cooking, frying or storage. Protein glycation occurs slowly and continuously through life, driving AGE accumulation in tissues during aging. For this reason, AGEs have been proposed as a risk factor in the pathogenesis of diet-related diseases such as diabetes, insulin resistance, cardiovascular diseases, kidney injury, and age-related and neurodegenerative diseases. AGEs are associated with an increase in oxidative stress since they mediate the production of reactive oxygen species (ROS), increasing the intracellular levels of hydrogen peroxide (H₂O₂), superoxide (O₂^-), and nitric oxide (NO). The interaction of AGEs with the receptor for AGEs (RAGE) enhances oxidative stress through ROS production by NADPH oxidases inside the mitochondria. This affects mitochondrial function and ultimately influences cell metabolism under various pathological conditions. This short review will summarize all evidence that relates AGEs and ROS production, their relationship with diet-related diseases, as well as the latest research about the use of natural compounds with antioxidant properties to prevent the harmful effects of AGEs on health.

Keywords: RAGE; advanced glycation products; antioxidants; diet-related diseases.

Figure 1

Formation of advanced glycation endproducts (AGEs). During the Maillard reaction, the free amino group of a protein, aminophospholipid, or nucleic acid reacts with the carbonyl group of a reducing sugar, producing a Schiff base. This molecule, following some rearrangement, is spontaneously transformed into an Amadori product. Depending on pH, these products form 1,2-dicarbonyls as 3-deoxyglucosone (3-DG), 3-deoxygalactosone (3-DGal), or methylglyoxal (MGO) or form 2,3-dicarbonyls such as 1-deoxyglucosone (1-DG). Then, dicarbonyls following condensation produce AGEs such as Nε-(carboxyethyl)lysine (CEL), Nε-(carboxymethyl)lysine (CML) or methylglyoxal-derived hydroimidazolone 1 (MG-H1).

Figure 2

Molecular signaling pathways activated upon the interaction of advanced glycation endproducts (AGEs) with their receptor (RAGE). AGEs interact with their receptor RAGE, increasing the production of ROS by the NOX enzymes and the mitochondria, enhancing the activity of antioxidant enzymes. ROS initiate several signal transduction cascades such as RAS/MEK/ERK, IP3K/AKT or p38MAPK that lead to the activation of NF-κB that results in the activation of the NLRP-3 inflammasome and the production of several cytokines, chemokines, and other proinflammatory factors, inducing inflammation, apoptosis, and proliferation. The elevated production of O₂⁻ and NO mediated by AGEs and the upregulation of iNOS by NF-κB favor the production of ONOO⁻ that conducts the inactivation of proteins such as thioredoxin, impeding its anti-apoptotic and antioxidant functions.

Figure 3

AGEs are involved in the pathogenesis of several diet-related diseases and age-associated diseases by interfering with oxidative stress, neovascularization, inflammation, and cross-linking with the extracellular matrix.