What Are Advanced Glycation End Products and Why They Matter

Introduction
Endogenous vs. exogenous AGEs
Biological impact
Dietary intervention
Clinical and public health perspectives
References
Further reading

Advanced glycation end products quietly reshape metabolism, stiffen vessels, and amplify inflammation, making diet, cooking methods, and clinical screening essential levers for protecting long-term metabolic and vascular health.

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Introduction

Advanced glycation end products (AGEs) are irreversible adducts formed when reducing sugars react nonenzymatically with the amino groups lysine and arginine on proteins. Schiff bases and Amadori products, under oxidative stress, undergo glycoxidation, a process also known as the Maillard reaction, which leads to the generation of reactive dicarbonyls and inter- and intraprotein crosslinks, including well-characterized compounds such as CML, CEL, pentosidine, glucosepane, and argpyrimidine.¹

AGEs alter protein structure, deactivate enzymes, and, by binding the receptor for AGEs (RAGE), induce nuclear factor kappa B (NF kappa B) signaling, oxidative stress, and inflammation. AGEs are also endogenously present in the diet, contributing to diabetes complications, atherosclerosis, neurodegeneration, and endothelial dysfunction, and are additionally generated through lipid peroxidation pathways involving glyoxal and methylglyoxal.¹

Reducing the AGE burden or interrupting AGE-RAGE signaling is a promising approach to protect metabolic and vascular health, as well as longevity.¹ This article examines how AGEs, the Maillard glycation, and RAGE signaling are involved in inflammation, while also discussing cooking, dietary, and screening approaches that can be adopted to reduce the risk of diabetes, cardiovascular, and neurodegenerative complications.

Endogenous vs. exogenous AGEs

Endogenous AGEs form when circulating reducing sugars nonenzymatically glycate amino groups on proteins, such as collagen, leading to the transition from Schiff bases to Amadori products and, ultimately, cross-linked AGEs. These reactions are promoted by physiological conditions and oxidative stress, with accumulated AGEs implicated across metabolic and vascular disease biology and accelerated under chronic hyperglycemia and elevated reactive oxygen or nitrogen species.¹

Although a small percentage of dietary AGEs are absorbed, notable species like pyrraline and pentosidine exhibit relatively high uptake. Absorbed moieties include free amino acids and low-molecular-weight peptides, with Nε-carboxymethyl lysine (CML) entering partly by diffusion and pyrraline through peptide transport. Experimental tracer work indicates transient accumulation in the liver and kidneys following exposure. Dietary AGE load is generally higher than endogenous production in many modern dietary patterns, particularly in ultra-processed or high-temperature cooked foods.²

Exogenous AGEs are primarily acquired through the diet, especially from processed foods or those cooked using dry heat methods. High-temperature techniques, such as grilling, roasting, baking, and deep frying, significantly increase AGE content compared to moist heat or lower-temperature methods. This is a consequence of the Maillard reaction, which also contributes to browning and flavor, and prominently raises levels of CML, CEL, and methylglyoxal-derived adducts.²

Additional reactive dicarbonyls, such as glyoxal, methylglyoxal (MG), and 3-deoxyglucosone, have also been detected in baked goods and beverages, including products with high fructose corn syrup. Certain dry heat processes can also accompany contaminants like acrylamide and furan. Infants can be exposed to AGEs from formula processing steps that involve high temperatures, with CML reported at higher levels than in cow’s milk. These exposures have been shown to transiently increase circulating glycation markers in infants.²

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Biological impact

AGEs bind to RAGE on endothelial cells, macrophages, and neurons, thereby amplifying NF-κB-driven transcription of cytokines, chemokines, and adhesion molecules. This signaling recruits mitogen-activated protein kinases (MAPKs) and the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways, contributing to persistent inflammatory priming in vascular and neural tissues.¹

AGEs also increase the production of reactive oxygen species (ROS) through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondrial leakage. ROS overproduction further promotes glycoxidation, generating additional dicarbonyl intermediates that accelerate the formation of AGEs.¹ This leads to the depletion of glutathione, which weakens endogenous antioxidant defenses like superoxide dismutase and catalase, ultimately contributing to chronic low-grade inflammation with sustained oxidative stress.³

AGEs form covalent crosslinks with extracellular matrix proteins, especially collagen and elastin. Crosslinking stiffens arteries, thickens basement membranes, and impairs tissue compliance, thereby raising pulse pressure and compromising organ perfusion, which contributes to the structural changes observed in diabetic and hypertensive vasculopathy.⁵

Endothelial RAGE activation reduces nitric oxide bioavailability, promotes endothelial dysfunction, and enhances leukocyte adhesion. Glycation of low-density lipoprotein (LDL) increases its susceptibility to oxidation and uptake by scavenger receptors, thereby accelerating foam cell formation and atherogenesis. CML-modified LDL is strongly associated with plaque instability.¹

In parenchymal tissues, protein misfolding, endoplasmic reticulum stress, and apoptosis impair the repair processes, thereby delaying wound healing and remodeling. Decoy sequestration by soluble RAGE (sRAGE) may buffer some ligands but is often insufficient in disease states.³ sRAGE and esRAGE concentrations frequently decline in advanced cardiometabolic disease, limiting protective signaling.¹

In diabetes mellitus, hyperglycemia accelerates AGE formation, which intensifies insulin resistance, beta cell stress, and classic microvascular complications like nephropathy, retinopathy, and neuropathy, with glucosepane being a predominant AGE crosslink in diabetic tissues.¹ In cardiovascular disease, endothelial dysfunction, vascular stiffening, and prothrombotic signaling are directly implicated in atherosclerosis, plaque instability, heart failure remodeling, and impaired collateral growth.

In the central nervous system (CNS), AGE-RAGE interactions on neurons and microglia amplify oxidative stress and cytokine release, exacerbate amyloid beta toxicity, compromise the integrity of the blood-brain barrier, and promote synaptic loss.³ AGE–RAGE interactions are also reported in traumatic brain injury, ALS, and Parkinsonian neurodegeneration.¹

Dietary intervention

Boiling and steaming operate at lower temperatures and higher humidity, which limits Maillard reactions, whereas frying, grilling, and baking use higher, drier heat that accelerates AGE formation. In a randomized crossover trial, low AGE techniques, such as boiling and steaming, reduced circulating AGE markers and were accompanied by a more favorable lipid profile. Comparatively, high AGE techniques increased fecal butyrate without improving systemic inflammatory or cardiometabolic proteomic profiles.⁴ This controlled design using identical ingredients confirms cooking method as an independent determinant of serum AGE burden.⁴

An AGE-lowering dietary pattern prioritizes moist heat methods, such as boiling, steaming, stewing, or pressure cooking. Consumers are also advised to increase their consumption of minimally processed staples, such as pulses, whole grains, vegetables, fruits, nuts, seeds, low-fat dairy or fortified alternatives, eggs, fish, and lean meats, while limiting ultra-processed foods, as they contribute substantially to dAGE intake.⁴

Simple culinary steps can also mitigate AGE generation, such as cooking with more water, incorporating acidic marinades like lemon, yogurt, and tomato into recipes, and avoiding repeated oil use. Together, these habits lower dietary AGE load and support lipid management and vascular health.⁴

Clinical and public health perspectives

Tissue-anchored AGEs, measured by skin autofluorescence (SAF), reflect the long-term glycemic burden in collagen and correlate with cardiovascular, renal, and microvascular outcomes. SAF is non-invasive and fast; however, skin pigmentation can affect readings, which require algorithmic correction, and does not capture non-fluorescent AGE species, such as glucosepane.³

AGEs can be assessed alongside hemoglobin A1c (HbA1c) levels to support risk prediction for chronic complications of diabetes mellitus. Moreover, protein-bound CML and MG can reflect glycoxidation load, whereas sRAGE may often be inversely related to inflammatory and cardiometabolic risk. A practical screening approach is to combine routine HbA1c with SAF and a small panel of plasma AGEs or sRAGE to triage patients for surveillance of retinal, renal, neuropathy, and cardiovascular conditions.⁵ No gold-standard clinical assay exists, and inter-laboratory variability remains a major barrier to standardization.³

Diets that limit AGE-dense foods and emphasize moist heat cooking methods, together with smoking cessation and regular physical activity, lower circulating CML/MG and improve SAF. Public health programs that emphasize nutrition education can provide cooking guidance for households and institutional kitchens.⁵

Pharmacological therapies have also been widely studied for their potential to interrupt the AGE-RAGE axis. Some examples include inhibitors of endogenous formation, such as metformin, benfotiamine, and pyridoxamine, as well as binders like sevelamer, which reduce dietary AGE absorption. However, most trials show biomarker improvement, but there is no consistent evidence of reduced primary clinical outcomes.⁵

RAGE pathway modulation can also be achieved through the use of thiazolidinediones, statins, and glucagon-like peptide 1 (GLP-1) analogs. Although some trials have reported improvements in biomarker levels, a lack of consistent evidence for event reduction and long-term safety data remains.⁵ Emerging AGE-breaker compounds (for example, alagebrium) show biochemical promise but lack definitive clinical validation.¹

References

1. Reddy, V. P., Aryal, P., Darkwah, E. K. (2022). Advanced Glycation End Products in Health and Disease. Microorganisms 10(9). DOI:10.3390/microorganisms10091848, https://www.mdpi.com/2076-2607/10/9/1848
2. Gill, V., Kumar, V., Singh, K., et al. (2019). Advanced Glycation End Products (AGEs) May Be a Striking Link Between Modern Diet and Health. Biomolecules 9(12). DOI:10.3390/biom9120888, https://www.mdpi.com/2218-273X/9/12/888
3. Perrone, A., Giovino, A., Benny, J., Martinelli, F. (2020). Advanced Glycation End Products (AGEs): Biochemistry, Signaling, Analytical Methods, and Epigenetic Effects. Oxidative Medicine and Cellular Longevity. DOI:10.1155/2020/3818196, https://www.hindawi.com/journals/omcl/2020/3818196
4. Wellens, J., Vissers, E., Dumoulin, A., et al. (2025). Cooking methods affect advanced glycation end products and lipid profiles: A randomized crossover study in healthy subjects. Cell Reports Medicine 6(5). DOI:10.1016/j.xcrm.2025.102091, https://www.sciencedirect.com/science/article/pii/S2666379125001648
5. Salazar, J., Navarro, C., Ortega, Á., et al. (2021). Advanced Glycation End Products: New Clinical and Molecular Perspectives. International Journal of Environmental Research and Public Health 18(14). DOI:10.3390/ijerph18147236, https://www.mdpi.com/1660-4601/18/14/7236

Further Reading

Last Updated: Nov 16, 2025