Glycation (AGEs)

Advanced glycation end-products (AGEs) are a non-homogeneous, chemically diverse group of compounds formed non-enzymatically by condensation between the carbonyl groups of reducing sugars and free amine groups of nucleic acids, proteins or lipids, followed by rearrangements that yield stable, irreversible end-products. ^[1] Glycation is a protein post-translational modification that occurs on lysine and arginine residues through the non-enzymatic Maillard reaction, and because it is irreversible it can only be removed by protein degradation and replacement. ^[2] The reactive dicarbonyl compound methylglyoxal, formed mainly as a byproduct of glycolysis and detoxified by the glyoxalase system, is the major precursor of the non-enzymatic glycation of proteins and DNA that leads to AGE formation. ^[3]

AGEs are recognized by several cellular receptors and trigger many signaling pathways related to inflammation and oxidative stress. ^[1] Engagement of AGEs with their chief cellular receptor RAGE activates signaling pathways such as MAPK/ERK, TGF-beta, JNK and NF-kB, leading to enhanced oxidative stress and inflammation. ^[4] The accumulation of AGEs results from an increase in glycation reactions and oxidative stress, and by binding to RAGE they activate signaling pathways such as NF-kB that promote the release of inflammatory factors and exacerbate cell damage. ^[5] AGEs include cross-linked and non-degradable aggregates that modify proteins, lipids or nucleic acids, and their formation can activate several inflammatory signaling pathways. ^[6]

AGEs cause cellular dysfunction through the modification of intracellular molecules and accumulate in tissues with aging, and are associated with age-related diseases such as diabetes, cardiovascular disease, renal failure and Alzheimer's disease. ^[7] AGEs accumulate slowly in tissues during ageing but more rapidly and intensely in metabolic and selected inflammatory disorders such as type 2 diabetes, obesity, cardiovascular disease and chronic renal insufficiency. ^[8] Non-enzymatic glycation of dermal collagen and reducing sugars is one of the basic root causes of endogenous skin aging, with AGE accumulation resulting in wrinkles, loss of elasticity and dull yellowing that is amplified by exogenous factors such as ultraviolet radiation. ^[7] In persistent hyperglycemia the glycation reaction generates AGEs that play a central role in the pathophysiology of diabetic complications, compromising insulin signaling and perturbing metabolic homeostasis via the AGEs/RAGE axis. ^[4]

Despite correlations between glycation and disease pathogenesis, uncertainties remain because recurrent intervention failures have prevented apparently promising animal models from being translated into clinically useful anti-AGE strategies. ^[9] Reducing protein glycation has been an active area of drug development, but multiple clinical trials have had mixed results and these compounds have not been translated to the clinic, highlighting the challenge of modulating glycation therapeutically. ^[2] Several strategies to lower methylglyoxal have been developed, including glyoxalase inducers and methylglyoxal scavengers, as a way to target the dicarbonyl stress that drives AGE formation, though such interventions are not yet available in the clinical setting. ^[3] AGEs have been proposed as biomarkers, but they remain confined to clinical research without being used in daily practice because assay methods are not standardized and comparisons between studies are difficult. ^[10]