Advanced-glycation end products (AGEs) cause issues in two major ways. Firstly a few species of persistent AGE can cross-link molecules of the extracellular matrix, changing tissue properties in harmful ways, such as loss of elasticity in blood vessels and skin. Secondly, more prevalent short-lived AGEs can provoke chronic inflammation through their interaction with the receptor for AGEs, RAGE. This is thought to be an important contributing cause of chronic inflammation in metabolic conditions such as diabetes, but also shows up as a concern in a number of other conditions. As illustrated in this review, the research community is interested in finding ways to reduce or interfere in inflammatory AGE-RAGE signaling. There is a great deal more work taking place in this part of the field than in the search for ways to break persistent AGE cross-links.
Advanced-glycation end products (AGEs) are heterogeneous molecules derived from post-translational nonenzymatic modifications of macromolecules including proteins, lipids, and nucleic acids by glucose or other saccharides (fructose and pentose). AGEs are deleterious molecules and are found to be increased in the plasma of physiological aging and age-related diseases, diabetes mellitus, and autoimmune/inflammatory rheumatic diseases.
AGEs, by binding to receptors for AGE (RAGEs), alter innate and adaptive immune responses to induce inflammation and immunosuppression via the generation of proinflammatory cytokines, reactive oxygen species (ROS), and reactive nitrogen intermediates (RNI). These pathological molecules cause damage to vascular endothelial, smooth muscular, and connective tissue cells and renal mesangial, endothelial, and podocytic cells in AGE-related diseases. In this context, oxidative stress can disturb intracellular signals to become pathological states, particularly insulin-mediated metabolic responses and insulin resistance.
AGEs contribute to the development of physiological aging and many major chronic diseases, including diabetic pathology, and neurodegenerative, autoimmune/inflammatory, and metabolic cardiovascular diseases. Accordingly, it is valuable to search for novel therapeutic interventions for AGE-related diseases. The underlying modes of action of different AGE inhibitors are based on the attenuation of glycosylation, antioxidative stress, metal ion chelating, and scavengers of reactive 1,2-dicarbonyl compounds or ROS/RNI. Arbitrarily, these novel therapeutic AGE inhibitors can be classified into 4 categories: (1) inhibitors of AGE formation; (2) breakers of preformed AGEs; (3) blockades of AGE-RAGE axis signaling; and (4) inducers of intracellular glyoxalase, ubiquitin-proteasome, and autophagy pathways.