AGE-RAGE axis

The AGE-RAGE axis describes signalling initiated when advanced glycation end products (AGEs) and other endogenous ligands engage RAGE, a multiligand immunoglobulin-superfamily receptor encoded by the AGER gene. Besides AGEs, RAGE binds S100/calgranulin proteins, HMGB1, amyloid-beta peptides and certain beta-sheet fibrils. Ligand binding activates intracellular cascades involving NADPH oxidase, MAP kinases and NF-kB, leading to sustained pro-inflammatory and pro-oxidant gene expression in endothelial cells, vascular smooth muscle cells, macrophages and neurons. NF-kB also upregulates RAGE itself, generating a feed-forward loop. The axis is implicated in diabetic vascular complications, atherosclerosis, chronic kidney disease and neurodegeneration, and is regarded as one mechanistic bridge between hyperglycaemia, oxidative stress and chronic low-grade inflammation associated with biological ageing.