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In human nutrition and biology, advanced glycation end products, known as AGEs, are substances that can be a factor in the development or worsening of many degenerative diseases, such as diabetes, atherosclerosis, chronic renal failure and Alzheimer's disease.
These harmful compounds can affect nearly every type of cell and molecule in the body and are thought to be one factor in aging and in some age-related chronic diseases. They are also believed to play a causative role in the blood-vessel complications of diabetes mellitus. AGEs are seen as speeding up oxidative damage to cells and in altering their normal behavior.
AGEs are formed both outside and inside the body. Specifically, they stem from glycation reaction, which refers to the addition of a carbohydrate to a protein without the involvement of an enzyme. Glucose can bind with proteins in a process called glycation, making cells stiffer, less pliable and more subject to damage and premature aging. This process is involved in the aging of the skin.
Intermediate products in the formation of an AGE are known as Amadori, Schiff base, and Maillard products, named after the researchers who first described them.
Smoking is known to elevate the level of AGEs. AGEs are formed when tobacco leaves are dried in the presence of sugars. During inhalation, these AGEs are absorbed in the lungs. Both serum AGEs and AGEs in skin (measured with skin autofluorescence) are higher in smokers, compared to non-smokers.
Barbecued foods are high in AGEs
Dietary AGEs (dAGEs) can be present in some foods (particularly meat, also butter and some other vegetable products), and can form in food during cooking, particularly in dry cooking such as frying, roasting and baking, far less so in boiling, stewing and microwaving.
In addition some foods promote glycation within the body. The total state of oxidative and peroxidative stress on the healthy body, with the AGE-related damage to it, is proportional to the dietary intake of exogenous (preformed) AGEs and the consumption of sugars with a propensity towards glycation such as fructose and galactose.
In diabetes, in cells unable to reduce glucose intake (e.g., endothelial cells), hyperglycemia results in higher intracellular glucose levels. Higher intracellular glucose levels result in increased levels of NADH and FADH, increasing the proton gradient beyond a particular threshold at which the complex III prevents further increase by stopping the electron transport chain. This results in mitochondrial production of reactive oxygen species, activating PARP1 by damaging DNA. PARP1, in turn, induces ADP-ribosylation of GAPDH, a protein involved in glucose metabolism, leading to its inactivation and an accumulation of metabolites earlier in the metabolism pathway. These metabolites activate multiple pathogenic mechanisms,[which?] one of which includes increased production of AGEs.
Examples of AGE-modified sites are carboxymethyllysine (CML), carboxyethyllysine (CEL), and argpyrimidine, which is the most common.
AGEs affect nearly every type of cell and molecule in the body and are thought to be one factor in aging and some age-related chronic diseases. They are also believed to play a causative role in the vascular complications of diabetes mellitus.
The animal and human evidence is that significant amounts of dAGEs are absorbed, and that dAGEs contribute to the body's burden of AGE, and are associated with diseases such as atherosclerosis and kidney disease.
In other diseases
The formation and accumulation of advanced glycation endproducts (AGEs) has been implicated in the progression of age-related diseases. AGEs have been implicated in Alzheimer's Disease, cardiovascular disease, and stroke. The mechanism by which AGEs induce damage is through a process called cross-linking that causes intracellular damage and apoptosis. They form photosensitizers in the crystalline lens, which has implications for cataract development. Reduced muscle function is also associated with AGEs.
In biochemistry, a receptor is a molecule usually found on the surface of a cell which receives chemical signals from outside the cell. When an external substance binds to a receptor, it directs the cell to do something, such as divide, die, or allow specific substances to enter or exit the cell.
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. While the AGE free adducts are released directly into the urine, AGE peptides are endocytosed by the epithelial cells of the proximal tubule and then degraded by the endolysosomal system to produce AGE amino acids. It is thought that these acids are then returned to the kidney's inside space, or lumen, for excretion.  AGE free adducts are the major form through which AGEs are excreted in urine, with AGE-peptides occurring to a lesser extent but accumulating in the plasma of patients with chronic kidney failure.
Although the only form suitable for urinary excretion, the breakdown products of AGE—that is, peptides and free adducts—are more aggressive than the AGE proteins from which they are derived, and they can perpetuate related pathology in diabetic patients, even after hyperglycemia has been brought under control.
Some AGEs have innate catalytic oxidative capacity, while activation of NAD(P)H oxidase through activation of RAGE and damage to mitochondrial proteins leading to mitochondrial dysfunction can also induce oxidative stress. Because perpetuation can result through AGEs' oxidative effects, concurrent treatment with antioxidants might help halt the cycle. In the end, effective clearance is necessary, and those suffering AGE increases because of kidney dysfunction might require a kidney transplant.
In diabetics who have an increased production of an AGE, kidney damage reduces the subsequent urinary removal of AGEs, forming a positive feedback loop that increases the rate of damage. A 1997 study concluded that adding sugar to egg whites causes diabetics to be 200 times more AGE immunoreactive.[clarification needed]
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