Advanced glycation end-product

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.

Formation

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.

Outside the body, AGEs can be formed by heating (for example, cooking).

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

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.

Foods

Barbecued foods are high in AGEs

Dietary AGEs (dAGEs) can be present in some foods (particularly meat, also butter and some 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, steaming 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.

Glycerol produced from breaking down triglycerides does not do this though.

In diabetes

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, one of which includes increased production of AGEs.

Examples of AGEs are carboxymethyllysine (CML), carboxyethyllysine (CEL), and argpyrimidine, which is the most common.

Effects

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.

Under certain pathologic conditions, such as oxidative stress due to hyperglycemia in patients with diabetes, and hyperlipidemia, AGE formation can be increased beyond normal levels. AGEs are now known to play a role as proinflammatory mediators in gestational diabetes as well.

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.

Pathology

AGEs have a range of pathological effects, such as:

• Increased vascular permeability.
• Increased arterial stiffness
• Inhibition of vascular dilation by interfering with nitric oxide.
• Oxidizing LDL.
• Binding cells—including macrophage, endothelial, and mesangial—to induce the secretion of a variety of cytokines.
• Enhanced oxidative stress.

Reactivity

Proteins are usually glycated through their lysine residues. In humans, histones in the cell nucleus are richest in lysine, and therefore form the glycated protein N(6)-Carboxymethyllysine (CML).

A receptor (biochemistry) nicknamed RAGE, from Receptor for Advanced Glycation End products, is found on many cells, including endothelial cells, smooth muscle, cells of the immune system from tissue such as lung, liver, and kidney. This receptor, when binding AGEs, contributes to age- and diabetes-related chronic inflammatory diseases such as atherosclerosis, asthma, arthritis, myocardial infarction, nephropathy, retinopathy, periodontitis and neuropathy. 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.

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.

1. Renal pyramid • 2. Interlobular artery • 3. Renal artery • 4. Renal vein 5. Renal hilum • 6. Renal pelvis • 7. Ureter • 8. Minor calyx • 9. Renal capsule • 10. Inferior renal capsule • 11. Superior renal capsule • 12. Interlobular vein • 13. Nephron • 14. Minor calyx • 15. Major calyx • 16. Renal papilla • 17. Renal column

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.

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 as well as liver sinusoidal endothelial cells and Kupffer cells have been implicated in this process, although the real-life involvement of the liver has been disputed.

Endothelial cell

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—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.

Potential therapy

File:Resveratrol.svg

Diagram of a resveratrol molecule

AGEs are the subject of ongoing research. There are three therapeutic approaches: preventing the formation of AGEs, breaking crosslinks after they are formed and preventing their negative effects.

Compounds that have been found to inhibit AGE formation in the laboratory include Vitamin C, benfotiamine, pyridoxamine, alpha-lipoic acid, taurine, pimagedine, aspirin, carnosine, metformin, pioglitazone, and pentoxifylline.

Studies in rats and mice have found that natural phenols such as resveratrol and curcumin can prevent the negative effects of the AGEs.

Compounds that are thought to break some existing AGE crosslinks include Alagebrium (and related ALT-462, ALT-486, and ALT-946) and N-phenacyl thiazolium bromide.

File:Glucosepane.svg

Diagram of a glucosepane molecule

There is, however, no agent known that can break down the most common AGE, glucosepane, which appears 10 to 1,000 times more common in human tissue than any other cross-linking AGE.

Some chemicals, on the other hand, like aminoguanidine, might limit the formation of AGEs by reacting with 3-deoxyglucosone.

See also

• Glycosylation
• Glyoxalase system
• Methylglyoxal
• Raw foodism
• N(6)-Carboxymethyllysine

External links

• How and Why to Prevent AGE Damage, Life Enhancement Website