Advanced glycation end-product

AGEs formation is initiated with the Maillard reaction which forms a reversible Schiff base between the carbonyl group of a reducing sugar — or its metabolites such as methylglyoxal — and a free amino group on a protein. This Schiff base undergoes oxidation and rearrangements to form Amadori products, which eventually lead to the formation of AGEs. AGEs affect nearly every type of cell and molecule in the body, are thought to be key contributors to the aging process, Notably, AGEs are believed to play a causative role in the vascular complications of diabetes mellitus and age related macular degeneration (AMD). == Dietary sources of AGEs ==

Animal-derived foods that are high in fat and protein are generally rich in AGEs, and are especially prone to further AGE formation during cooking. This raises uncertainty about the role of dietary AGEs in disease and aging, whether they significantly contribute, or if only endogenously produced AGEs (those formed within the body) are relevant. Most endogenous AGEs are produced intracellularly, and their rates of production and accumulation increase in response to high glycemic index diets, extended exposure to glycating moieties in vitro, and aging in laboratory animals and humans- even in non-diabetics. AGEs also accumulate upon aging, which is explained in more detail below. ==Pathology==

and HELA cells exposed to methyglyoxal. In the context of cardiovascular disease, AGEs can induce crosslinking of collagen, which can cause vascular stiffening and entrapment of low-density lipoprotein particles (LDL) in the artery walls. Oxidized LDL is one of the major factors in the development of atherosclerosis. AGEs can bind to RAGE receptors and cause oxidative stress as well as activation of inflammatory pathways in vascular endothelial cells. This receptor, when binding AGEs, is under preliminary research to determine if it contributes to age- and diabetes-related chronic inflammatory diseases. AGEs can be detected and quantified using bioanalytical and immunological methods. ==Effects==

(R = H), methylglyoxal (R = Me), and 3-deoxyglucosone, which arise from the metabolism of high-carbohydrate diets. Thus modified, these proteins contribute to complications from diabetes. AGEs can be produced in the body and in manufactured foods. and some age-related chronic diseases. They are also believed to play a causative role in the vascular complications of diabetes mellitus. AGEs may arise under certain pathological conditions, such as oxidative stress due to hyperglycemia in patients with diabetes. AGEs may have a role as proinflammatory mediators in gestational diabetes. In other diseases AGEs have been implicated in Alzheimer's disease and cardiovascular diseases. Pathology In laboratory studies, AGEs have a range of pathological effects, such as: Therefore, substances that inhibit AGE formation may limit the progression of disease and may offer new tools for therapeutic interventions in the therapy of AGE-mediated disease • AGEs have specific cellular receptors; the best-characterized are those called RAGE. Such increases in oxidative stress lead to the activation of the transcription factor NF-κB and promote the expression of NF-κB regulated genes that have been associated with atherosclerosis. As of 2024, there is no conclusive clinical evidence for AGEs having a pathological role in aging diseases, and no causality has been demonstrated between processed foods, AGEs, and onset of aging or age-related diseases. ==Clearance==

In clearance, or the rate at which a substance is removed or cleared from the body, it has been found that the cellular proteolysis of AGEs—the breakdown of proteins—produces AGE peptides and "AGE free adducts" (AGE adducts bound to single amino acids). These latter, after being released into the plasma, can be excreted in the urine. Nevertheless, the resistance of extracellular matrix proteins to proteolysis renders their advanced glycation end products less conducive to being eliminated. AGE free adducts are the major form through which AGEs are excreted in urine, with AGE-peptides occurring to a lesser extent have been implicated in this process, although the real-life involvement of the liver has been disputed. Large AGE proteins unable to enter the Bowman's capsule are capable of binding to receptors on endothelial and mesangial cells and to the mesangial matrix. and decreasing kidney function in patients with unusually high AGE levels. Peptides and free adducts, the only breakdown products of AGE that are suitable for urinary excretion, are more aggressive than the AGE proteins from which they are derived, and they can perpetuate related pathology in people with diabetes, even after hyperglycemia has been brought under control. ==Research==

Ongoing studies are performed to specify mechanisms that selectively inhibit the glycation process, and to understand how glycated molecules could be protected from further deterioration, possibly by manipulating the glyoxalase enzyme system to detoxify AGEs. Development of candidate drugs by the pharmaceutical industry includes compounds whose mechanism of action is to inhibit or revert the glycation process. ==See also==