Advanced glycation end-products (AGEs) are a heterogeneous group of irreversible adducts and cross-links formed by non‑enzymatic reactions between reducing sugars or reactive carbonyl species (for example, glyoxal and methylglyoxal) and macromolecules, leading to structural and functional alterations in tissues. Formation proceeds through early Schiff bases and Amadori products and culminates in chemically stable AGEs, a process classically framed as the Maillard reaction. According to biochemical and clinical reviews, AGEs accumulate with age and in hyperglycemia, contribute to oxidative stress and inflammation, and are linked to chronic disease. Diabetes Care;
Nutrition Research Reviews.
Chemistry and formation
- –Early steps involve reversible formation of Schiff bases and Amadori (ketoamine) products on lysine or arginine residues; subsequent dehydration, oxidation, fragmentation, and cyclization generate reactive dicarbonyls that drive AGE formation.
Journal of Young Investigators;
Food & Function.
- –Endogenous dicarbonyl stress arises when production of methylglyoxal and glyoxal exceeds detoxification by the glyoxalase system (GLO1/GLO2), increasing arginine-derived hydroimidazolones (e.g., MG‑H1).
Glycoconjugate Journal.
- –Representative AGEs include carboxymethyl‑lysine (CML), carboxyethyl‑lysine (CEL), methylglyoxal‑derived hydroimidazolones (MG‑H1), pentosidine, and the collagen cross‑link glucosepane. Mass spectrometric studies identify glucosepane as a dominant collagen cross‑link in aged and diabetic human tissues.
J. Biol. Chem.;
Sources and exposure
- –Endogenous formation is enhanced by chronic hyperglycemia and oxidative stress in Diabetes mellitus, with downstream modification of proteins, lipids, and DNA.
Diabetes Care;
Nucleic Acids Research.
- –Exogenous AGEs occur in heat‑processed foods; dry‑heat methods (grilling, broiling, frying) sharply increase dietary AGE content, whereas moist‑heat and acidic marinades lower it. Comprehensive food tables and kitchen studies document >10–100‑fold increases with dry heat.
Journal of the American Dietetic Association.
- –Cigarette smoke contains reactive “glycotoxins” that rapidly generate AGEs on proteins in vitro and are associated with higher serum AGE signals in smokers.
PNAS;
- –Human feeding and intervention studies indicate that a fraction (roughly 10–30%) of dietary AGEs or AGE‑precursors is absorbed and can modulate circulating AGE markers; effects vary by chemical form and renal function.
Int. J. Endocrinology.
Receptors and signaling
- –The Receptor for Advanced Glycation End Products (RAGE) is a multiligand immunoglobulin superfamily receptor that binds AGEs and other ligands (S100 proteins, HMGB1, amyloid‑β), activating NF‑κB and MAPK pathways and sustaining inflammatory gene expression.
Circulation;
- –RAGE’s cytoplasmic tail signals via the formin DIAPH1; soluble decoy forms (sRAGE, esRAGE) reflect pathway activity in humans.
- –Additional AGE‑binding receptors include AGE‑R1/OST48 (facilitates clearance and dampens signaling) and AGE‑R3/galectin‑3, which modulate cellular responses and ligand disposal.
Am. J. Physiol. Renal Physiol..
Detoxification and clearance
- –Cytosolic glyoxalase I/II metabolize methylglyoxal and related dicarbonyls, limiting AGE formation; increasing GLO1 expression reduces retinal AGE adducts and vascular lesions in diabetic models.
- –Enzymatic “deglycation” of early fructosamines by fructosamine‑3‑kinase (FN3K) is a repair route for Amadori adducts in mammals.
- –The kidney filters low‑molecular‑weight AGE adducts; proximal tubular processing degrades AGE moieties, and impaired renal function elevates systemic AGE burden.
Measurement
- –Analytical targets include CML, CEL, MG‑H1 (LC‑MS/MS), pentosidine (HPLC‑fluorescence), and collagen cross‑links such as glucosepane (targeted MS).
- –Non‑invasive skin autofluorescence correlates with tissue AGE levels and predicts microvascular outcomes in diabetes in several cohorts.
Biomedical significance
- –Diabetic complications: AGE accumulation modifies extracellular matrix, stiffens Collagen, perturbs cell signaling via RAGE, and is implicated in retinopathy, nephropathy, neuropathy, and cardiomyopathy; skin collagen AGEs predict 10‑year progression of retinopathy and nephropathy in type 1 diabetes (DCCT/EDIC).
- –Cardiovascular disease: AGEs contribute to arterial stiffening, endothelial activation, and Atherosclerosis; small trials of the cross‑link breaker alagebrium (ALT‑711) improved arterial compliance, though no therapy is approved for CVD on this basis.
- –Kidney disease: CKD reduces AGE clearance and is associated with higher skin AGE signals and vascular risk.
- –Skeletal health: Collagen AGEs (e.g., pentosidine, glucosepane) degrade bone material quality and correlate with fracture risk independent of bone mineral density.
- –Neurodegeneration: RAGE mediates amyloid‑β transport across the blood–brain barrier and contributes to neuroinflammation in Alzheimer's disease; a RAGE antagonist (azeliragon/TTP488) failed Phase 3 primary endpoints in mild AD.
Neurology Advisor.
Dietary AGEs and cooking
- –Dry‑heat cooking of animal‑derived foods yields AGE‑rich products; moist heat, shorter times, lower temperatures, and acidic ingredients (lemon, vinegar) reduce formation.
- –Controlled human studies report that short‑term low‑AGE diets can decrease circulating CML/MG and urinary AGE excretion, with variable effects on intermediate outcomes and the gut microbiota.
Interventions and therapeutics
- –Glycemic control reduces upstream drivers of endogenous AGE formation and is associated with lower long‑term complication risk, with tissue AGEs serving as independent predictors in intensively followed cohorts.
- –Pharmacologic strategies explored include carbonyl scavengers (aminoguanidine/pimagedine; clinical development halted for safety and efficacy concerns), vitamin B6 derivatives (pyridoxamine; mixed results in nephropathy), cross‑link breakers (alagebrium; improved arterial compliance in short trials), and RAGE antagonism (azeliragon; negative Phase 3).
Analytical and biomarker considerations
- –LC‑MS/MS quantification of CML, CEL, and MG‑H1 in tissues and fluids is the specificity standard; fluorescence‑based measures capture only a subset (e.g., pentosidine) and may not reflect total AGE burden.
History and nomenclature
- –The term “advanced glycation end‑products” derives from progression beyond early glycation adducts to stable end‑stage products. Biochemical identification of lipid and DNA adducts extended the concept beyond proteins, linking AGEs/ALEs to oxidative pathways.