Advanced glycation end products (AGEs)
Advanced glycation end products (AGEs), sometimes referred to as glycotoxins, are harmful oxidant compounds that result from glycation reactions during the metabolism of macromolecules in the bloodstream. Glycation (also known as the Maillard reaction or advanced glycation) is a non-enzymatic reaction that attaches a sugar (glucose or fructose) to proteins or lipids. The end-products of these reactions are implicated in diseases such as diabetes type-2, cardiovascular diseases, retinal disease or neurodegenerative diseases. They are also believed to play a causative role in normal aging.
Dietary AGEs (dAGEs)
Highly processed foods found abundantly in western diets are rich in AGEs, which is worrisome given that dietary AGEs (dAGEs) have been shown to contribute to increased inflammation and oxidative stress, both precursor states for disease. The cooking method also has a high impact in the formation of AGEs from the diet: dry heat was found to increase AGE formation by 10 to 100 fold more than uncooked food, especially in animal-derived food. Vegetarian, carbohydrate-rich diets based on vegetables, milk and fruits lead to very few AGE formation even after being heat-processed.
Due to the impact of diet, conditions such as obesity or post-menopausal changes in body weight also lead to an increase in AGEs formation and therefore increased risk of cardiovascular disease.
AGEs in disease
The formation of AGEs occurs during normal metabolism, however high levels might lead to disease due to protein-protein crosslinking in the bloodstream. AGE processes particularly affect long-lived proteins with high turnover rates, such as structural collagen or other components of the extracellular matrix, which usually become pathogenic targets. When crosslinking of collagen occurs in the walls of the vasculature, this can be extremely deleterious. Damage to the micro- or macro-vasculature can lead to the formation of plaques, impair vascular elasticity and increase the risk for atherosclerosis and cardiovascular disease.
One of the most common types of AGEs is glucosepane, which forms an irreversible, covalent cross-link molecule in collagen that might last decades before the body is able to fully remove it. It is also believed that glucosepane has a causal effect in the wrinkling of the skin over time and in the thickening of basement membranes in the vasculature. It is also found in high levels in conditions of diabetes type-2.
There is extensive evidence that AGEs develops more quickly in patients with diabetes, which negatively contributes to the state of their vascular system. AGEs also build over time in the heart muscle and might lead to a decreased respiratory capacity. Other diseases that might be highly impacted by AGEs formation are retinal disease or neurodegenerative diseases such as Alzheimer's.
AGEs contribute to disease by engaging with the receptor for advanced glycation endproducts (RAGE), which is believed to result in pro-inflammatory gene activation. RAGE is found up-regulated in diabetes and Alzheimer's disease, and in turn activates NF-κB signalling which might mediate the inflammatory components of these diseases. Interestingly, RAGE is down-regulated in pulmonary fibrosis and other conditions such as lung cancer. However, expression of RAGE in the lungs differs significantly from the rest of the body, and is normally highly expressed in lung cells in the absence of disease.
Other receptors exist, such as AGE-R1/3 which are able to recognise and bind to AGE molecules, however they don't appear to transduce cellular signals and might instead play a role in the removal and detoxification of AGE from the bloodstream.
Several AGEs inhibitors have been developed to remove these harmful compounds from the body. One approach is the carbonyl reagent aminoguanidine hydrochloride, which targets the reactive carbonyl groups believed to be required for AGEs formation. Studies have shown that aminoguanidine (Pimagedine) is able to improve the symptoms and progression of AGEs-related diseases such as diabetes type-2 and aging.
Another class of agents, 4,5-dimethyl-3-phenacylthiazolium chloride (DPTC) showed able to break down the protein-protein crosslinks formed by AGEs and was proposed to revert the vascular damage in animals.
Newer types of drugs based on anti-glucosepane antibodies aim to remove the most abundant form of AGE in the body and appeared to be successful in detecting glucosepane in the retina. However, no AGE inhibitors are currently approved for humans by the FDA.
AGEs in aging
AGEs accumulate during normal aging and have been proposed as a hallmark of aging. They are believed to accelerate all other hallmarks of aging by, for instance, increasing cellular senescence, inflammation, oxidative stress, telomere attrition and mitochondrial dysfunction, as well as altering intracellular communication. Additionally, AGEs can increase the occurrence of DNA damage and lead to transcriptional stress, a hallmark of wild-type aging and accelerated aging models.
Diets low in animal-derived fat and high in carbohydrates, such as vegetarian diets, are thought to decrease the rate of AGEs accumulation. Raw, boiled or steamed food also decreases the formation of AGEs when carbohydrate-rich diets are not possible. Studies in rats have shown that caloric restriction benefits the rate of serum AGE accumulation. Exercise is also able to decrease the levels of AGE formation in both healthy and diabetic patients.
See also: Extracellular matrix
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