Advanced Glycation End Products: From Pathogenesis to Treatment

Advanced glycation end products (AGEs) are chemically heterogeneous modifications generated through nonenzymatic glycation, glycoxidation, and carbonyl stress. Their accumulation increases during aging and is accelerated by hyperglycemia, oxidative stress, inflammation, exogenous exposure, and impaired renal clearance. Although AGE biology has often been framed around the AGE-RAGE-oxidative stress axis, current evidence supports a broader systems-level model in which AGE burden reflects the balance among formation, detoxification, tissue retention, and clearance. This review summarizes AGE chemistry, endogenous and exogenous sources, detoxification pathways, receptor systems, and mechanisms of AGE-mediated tissue injury. We distinguish two complementary pathogenic routes: receptor-independent structural damage, including protein dysfunction, proteostatic stress, extracellular matrix crosslinking, and altered tissue mechanics; and receptor-dependent signaling, mainly through RAGE-mediated redox-inflammatory amplification. We then examine the clinical relevance of AGEs in diabetes, cardiovascular disease, chronic kidney disease, neurovascular and retinal dysfunction, fibrosis, and aging-related tissue decline. Particular attention is given to compartment-specific biomarker interpretation, because circulating free adducts, protein-bound AGEs, tissue autofluorescence, dietary AGE estimates, and dicarbonyl stress markers are not interchangeable. Finally, we evaluate therapeutic strategies and propose a framework that matches each intervention to the relevant mechanism and can be tested clinically. In doing so, the review clarifies major conceptual and methodological uncertainties in AGE research and provides a foundation for more rigorous biomarker interpretation, study design, and clinical translation.