Definitions

end product

Advanced glycation end product

Advanced Glycation End products (AGEs) are the result of a chain of chemical reactions after an initial glycation reaction. The intermediate products are known, variously, as Amadori, Schiff base and Maillard products, named after the researchers who first described them. (The literature is inconsistent in applying these terms. For example, Maillard reaction products are sometimes considered intermediates and sometimes end products.) Side products generated in intermediate steps may be oxidizing agents (such as hydrogen peroxide), or not (such as beta amyloid proteins). "Glycosylation" is sometimes used for "glycation" in the literature, usually as 'non-enzymatic glycosylation.'

AGE formation

AGEs may be formed external to the body (exogenously) by heating (e.g. cooking) sugars with fats or proteins; or, inside the body (endogenously) through normal metabolism and aging. Under certain pathologic conditions (e.g. oxidative stress due to hyperglycemia in patients with diabetes), AGE formation can be increased beyond normal levels.

AGE formation in diabetes

In the pathogenesis of diabetes-related AGE formation, hyperglycemia results in higher cellular glucose levels in those cells unable to reduce glucose intake (e.g. endothelial cells). This in turn results 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, ADP-ribosylates 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, 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 epitope.

Effects

AGEs may be less, or more, reactive than the initial sugars they were formed from. Foods may be up to 200 times more immunoreactive after cooking. Many cells in the body (for example endothelial cells, smooth muscle or cells of the immune system) from tissue such as lung, liver, kidney or peripheral blood bear the Receptor for Advanced Glycation End products (RAGE) that, when binding AGEs, contributes to age- and diabetes-related chronic inflammatory diseases such as atherosclerosis, asthma, arthritis, myocardial infarction, nephropathy, retinopathy or neuropathy. There may be some chemicals, such as aminoguanidine, that limit the formation of AGEs.

The total state of oxidative and peroxidative stress on the healthy body, and the accumulation of AGE-related damage is proportional to the dietary intake of exogenous (preformed) AGEs, the consumption of sugars with a propensity towards glycation such as fructose and galactose .

AGEs affect nearly every type of cell and molecule in the body, are thought to be major factors in aging and age related chronic diseases. They are also believed to play a causative role in the vascular complications of diabetes mellitus eg. diabetic retinopathy and diabetic neuropathy.

They have a range of pathological effects, including increasing vascular permeability, inhibition of vascular dilation by interfering with nitric oxide, oxdising LDL, binding cells including macrophage, endothelial and mesangial cells to induce the secretion of a variety of cytokines and enhancing oxidative stress

Clearance

Cellular proteolysis of AGEs produces AGE peptides and "AGE free adducts" (AGE adducts bound to single amino acids) which, after being released into the plasma, can be excreted in the urine. The resistance of extracellular matrix proteins to proteolysis, renders AGEs of these proteins less conducive to elimination. While the AGE free adducts are released directly into the urine, AGE-peptides have been shown to be endocytosed by the epithelial cells of the proximal tubule and subsequently degraded by the endolysosomal system to produce AGE-amino acids. The AGE-amino acids are hypothesised to then be exported back into the lumen of the nephron for subsequent excretion. AGE free adducts are the major form through which AGEs are excreted in urine with AGE-peptides occurring to a lesser extent but accumulate in the plasma patients with chronic renal failure.

Larger, extracellularly-derived, AGE proteins cannot pass through the basement membrane of the renal corpuscle and must first be degraded into AGE-petides and AGE free adducts. Peripheral macrophage as well as liver sinusoidal endothelial cells and Kuppfer's cells have been implicated in this process although the real-life involvement of the liver has been disputed.

Clearance in diabetes and kidney dysfunction

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. Activation of RAGE induces production of a variety of cytokines, including TNFβ which mediates an inhibition of metalloproteinase and increases production of mesangial matrix, leading to glomerulosclerosis and decreasing kidney function in patients with unusually high AGE levels.

Although the only form suitable for urinary excretion, the breakdown products of AGE, AGE-peptides and AGE free adducts are more aggressive than their AGE-proteins from which they are derived, and can perpetuate related pathology in diabetic patients, even after hyperglycemia has been brought under control. Since perpetuation may result through their oxidative effects (some AGE 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) concurrent treatment with antioxidants, may help to stem the vicious cycle. Ultimately, effective clearance is necessary, and those suffering AGE increases due to kidney dysfunction (in the presence or absence of diabetes) will require a kidney transplant.

In diabetics, suffering from increase AGE production, subsequent kidney damage (by AGE production in the glomerulus) reduces the subsequent urinary removal of AGEs, forming a positive feedback loop and further increasing the rate of damage.

Therapeutic intervention

AGEs are the subject of ongoing research. AGE crosslink breaking drugs are currently being developed for the purpose breaking crosslinks between proteins. Alt-711, also called alagebrium developed by Synvista Therapeutics Inc. is the first of these to reach clinical trials.

Glycation inhibitors include benfotiamine, pyridoxamine, taurine , aminoguanidine (sold as Pimagedine), carnosine and aspirin; it is also believed that alpha-lipoic acid and acetyl-l-carnitine can also reduce glycation damage

See also

References

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