出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/11/13 10:18:19」(JST)
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An advanced glycation end-product (AGE) is the end result of a chain of chemical reactions most well-known for involvement in diabetes. These end products are the result of a chain of chemical reactions after an initial glycation reaction, which refers to the addition of a carbohydrate to a protein without the involvement of an enzyme.
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. AGES accelerating oxidative damage to cells, and altering cellular mechanics.
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.[1]
AGES are often incorrectly described as "Advanced Glycosylation end products", which is incorrect as there is no enzymatic involvement.[citation needed] The literature is also inconsistent in applying terms to describe intermediate products. 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).[1]
Outside of the body (exogenously), AGEs may be formed by heating (e.g., cooking);.[2][3] Inside the body (endogenously) AGEs may be formed as a result of normal metabolism and aging.
Under certain pathologic conditions, such as oxidative stress due to hyperglycemia in patients with diabetes,[4] and hyperlipidemia[citation needed], AGE formation can be increased beyond normal levels. AGEs are now known to play a role as proinflammatory mediators in gestational diabetes as well.[5]
In diabetes, in cells unable to reduce glucose intake (e.g., endothelial cells), hyperglycemia results in higher intracellular glucose levels.[4] [6][7] 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.[8] 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.
The formation and accumulation of advanced glycation endproducts (AGEs) has been implicated in the progression of age-related diseases.[9] AGEs have been implicated in Alzheimer's Disease,[10] cardiovascular disease,[11] and stroke.[12] The mechanism by which AGEs induce damage is through a process called cross-linking that causes intracellular damage and apoptosis.[13] They form photosensitizers in the crystalline lens,[14] which has implications for cataract development.[15] Reduced muscle function is also associated with AGEs.[16]
AGEs have a different reactivity from the sugars they were formed from.
RAGE. The RAGE receptor (Receptor for Advanced Glycation End-products) is found on many cells, including endothelial cells, smooth muscle, cells of the immune system[which?] from tissue such as lung, liver, and kidney.[which?] The RAGE receptor that, when binding AGEs, contributes to age- and diabetes-related chronic inflammatory diseases such as atherosclerosis, asthma, arthritis, myocardial infarction, nephropathy, retinopathy, periodontitis and neuropathy. There may be some chemicals, such as aminoguanidine, that limit the formation of AGEs by reacting with 3-deoxyglucosone.[17] The pathogenesis of this process hypothesized to activation of the nuclear factor kappa B (NF-κB) following AGE binding. NF-κB controls several genes which are involved in inflammation.[citation needed]
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[18] and galactose.[19]
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.[20][21][22] They are also believed to play a causative role in the vascular complications of diabetes mellitus.[23]
They have a range of pathological effects, including increasing vascular permeability, inhibition of vascular dilation by interfering with nitric oxide, oxidising LDL, binding cells including macrophage, endothelial, and mesangial cells to induce the secretion of a variety of cytokines and enhancing oxidative stress.[24][25]
They are absorbed by the body during digestion with about 30% efficiency.[citation needed]
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.[26] The resistance of extracellular matrix proteins to proteolysis renders AGEs of these proteins less conducive to elimination.[26] 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. It is hypothesized that the AGE-amino acids are then exported back into the lumen of the nephron for subsequent excretion. [24] AGE free adducts are the major form through which AGEs are excreted in urine, with AGE-peptides occurring to a lesser extent,[24] but accumulate in the plasma of patients with chronic renal failure.[26]
Larger, extracellularly-derived AGE proteins cannot pass through the basement membrane of the renal corpuscle and must first be degraded into AGE-peptides and AGE free adducts. Peripheral macrophage[24] as well as liver sinusoidal endothelial cells and Kupffer cells [27] have been implicated in this process, although the real-life involvement of the liver has been disputed. [28]
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.[24] 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[25] 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.[24] 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.[25] In the end, 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.[24]
In diabetics suffering from increase AGE production, kidney damage (as a result of AGE production in the glomerulus) reduces the subsequent urinary removal of AGEs, forming a positive feedback loop which increases the rate of damage. A 1997 study concluded that adding sugar to egg whites causes diabetics to be 200 times more AGE immunoreactive.[3]
AGEs are the subject of ongoing research. There are three therapeutic approaches: preventing the formation of AGEs, breaking AGE crosslinks after they are formed, and preventing negative effects of AGEs.
Compounds that are thought to inhibit AGE formation, at least in vitro, include Vitamin C,[29] benfotiamine, pyridoxamine, alpha-lipoic acid,[30] taurine,[31] pimagedine,[32] aspirin,[33][34] carnosine,[35] metformin,[36] pioglitazone,[36] and pentoxifylline.[36]
Compounds that may prevent negative effects of AGEs, at least in vitro, include resveratrol.[37]
Compounds that are thought to break some existing AGE crosslinks include Alagebrium (and related compounds ALT-462; ALT-486; ALT-946)[38] and N-phenacyl thiazolium bromide.[39]
However, there is no agent known that can break down the most common AGE, glucosepane, which appears 10 to 1000 times more commonly in human tissue than any other cross-linking AGE.[40][41]
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