Advanced glycation end-product

Advanced glycation end products (AGEs) are proteins or lipids that become glycated as a result of exposure to sugars.^[1] They can be a factor in aging and in the development or worsening of many degenerative diseases, such as diabetes, atherosclerosis, chronic renal failure, and Alzheimer's disease.^[2]

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.^[3][4][5] They are also believed to play a causative role in the vascular complications of diabetes mellitus.^[6]

Under certain pathologic conditions, such as oxidative stress due to hyperglycemia in patients with diabetes,^[7] 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.^[8]

The animal and human evidence is that significant amounts of dietary advanced glycation end-products (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.^[9]

In the context of cardiovascular disease, AGEs can induce crosslinking of collagen which can cause vascular stiffening and entrapment of low-density lipoprotein particles (LDL) in the artery walls. AGEs can also cause glycation of LDL which can promote its oxidation.^[10] Oxidized LDL is one of the major factors in the development of atherosclerosis.^[11] Finally, AGEs can bind to RAGE (receptor for advanced glycation end products) and cause oxidative stress as well as activation of inflammatory pathways in vascular endothelial cells.^[10][11]

In other diseases

The formation and accumulation of advanced glycation endproducts (AGEs) has been implicated in the progression of age-related diseases.^[12] AGEs have been implicated in Alzheimer's Disease,^[13] cardiovascular disease,^[14] and stroke.^[15] The mechanism by which AGEs induce damage is through a process called cross-linking that causes intracellular damage and apoptosis.^[16] They form photosensitizers in the crystalline lens,^[17] which has implications for cataract development.^[18] Reduced muscle function is also associated with AGEs.^[19]

Pathology

AGEs have a range of pathological effects, such as:^[20][21]

• 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.^[22] In humans, histones in the cell nucleus are richest in lysine, and therefore form the glycated protein N(6)-Carboxymethyllysine (CML).^[22]

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.^[23] 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.^[24]

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.^[24] 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. ^[20] AGE free adducts are the major form through which AGEs are excreted in urine, with AGE-peptides occurring to a lesser extent^[20] but accumulating in the plasma of patients with chronic kidney failure.^[24]

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^[20] as well as liver sinusoidal endothelial cells and Kupffer cells ^[25] have been implicated in this process, although the real-life involvement of the liver has been disputed. ^[26]

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.^[20] 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^[21] 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.^[20]

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.^[21] In the end, effective clearance is necessary, and those suffering AGE increases because of kidney dysfunction might require a kidney transplant.^[20]

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.^[27]

Potential therapy

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,^[28] benfotiamine, pyridoxamine, alpha-lipoic acid,^[29] taurine,^[30] pimagedine,^[31] aspirin,^[32][33] carnosine,^[34] metformin,^[35] pioglitazone,^[35] and pentoxifylline.^[35]

Studies in rats and mice have found that natural phenols such as resveratrol and curcumin can prevent the negative effects of the AGEs.^[36][37]

Compounds that are thought to break some existing AGE crosslinks include Alagebrium (and related ALT-462, ALT-486, and ALT-946)^[38] and N-phenacyl thiazolium bromide.^[39] One in vitro study shows that rosmarinic acid out performs the AGE breaking potential of ALT-711. ^[40]

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.^[41][42]

Some chemicals, on the other hand, like aminoguanidine, might limit the formation of AGEs by reacting with 3-deoxyglucosone.^[23]

See also

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

References

External links

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