Advanced glycation end-product

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

Contents

Dietary sources

Animal-derived foods that are high in fat and protein are generally AGE-rich and are prone to further AGE formation during cooking. [3] However, only low molecular weight AGEs are absorbed through diet, and vegetarians have been found to have higher concentrations of overall AGEs compared to non-vegetarians. [4] Therefore, it is unclear whether dietary AGEs contribute to disease and aging, or whether only endogenous AGEs (those produced in the body) matter. [5] This does not free diet from potentially negatively influencing AGE, but potentially implies that dietary AGE may deserve less attention than other aspects of diet that lead to elevated blood sugar levels and formation of AGEs. [4] [5]

Effects

Glycation often entails the modification of the guanidine group of arginine residues with glyoxal (R = H), methylglyoxal (R = Me), and 3-deoxyglucosone, which arise from the metabolism of high-carbohydrate diets. Thus modified, these proteins contribute to complications from diabetes. Argpyrimidine Hydroimidazolone.png
Glycation often entails the modification of the guanidine group of arginine residues with glyoxal (R = H), methylglyoxal (R = Me), and 3-deoxyglucosone, which arise from the metabolism of high-carbohydrate diets. Thus modified, these proteins contribute to complications from diabetes.

AGEs affect nearly every type of cell and molecule in the body and are thought to be one factor in aging [6] and some age-related chronic diseases. [7] [8] [9] They are also believed to play a causative role in the vascular complications of diabetes mellitus. [10]

AGEs arise under certain pathologic conditions, such as oxidative stress due to hyperglycemia in patients with diabetes. [11] AGEs play a role as proinflammatory mediators in gestational diabetes as well. [12]

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. [13] Oxidized LDL is one of the major factors in the development of atherosclerosis. [14] 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. [13] [14]

In other diseases

AGEs have been implicated in Alzheimer's Disease, [15] cardiovascular disease, [16] and stroke. [17] The mechanism by which AGEs induce damage is through a process called cross-linking that causes intracellular damage and apoptosis. [18] They form photosensitizers in the crystalline lens, [19] which has implications for cataract development. [20] Reduced muscle function is also associated with AGEs. [21]

Pathology

AGEs have a range of pathological effects, such as: [22] [23]

Reactivity

Proteins are usually glycated through their lysine residues. [29] In humans, histones in the cell nucleus are richest in lysine, and therefore form the glycated protein N(6)-Carboxymethyllysine (CML). [29]

A receptor nicknamed RAGE, from 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.[ clarification needed ][ which? ] 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. [30] The pathogenesis of this process hypothesized to activation of the nuclear factor kappa B (NF-κB) following AGE binding. [31] NF-κB controls several genes which are involved in inflammation. [32] AGEs can be detected and quantified using bioanalytical and immunological methods. [33]

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. [34]

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 KidneyStructures PioM.svg
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. [34] 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. [22] AGE free adducts are the major form through which AGEs are excreted in urine, with AGE-peptides occurring to a lesser extent [22] but accumulating in the plasma of patients with chronic kidney failure. [34]

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 [22] as well as liver sinusoidal endothelial cells and Kupffer cells [35] have been implicated in this process, although the real-life involvement of the liver has been disputed. [36]

Endothelial cell Endotelijalna celija.jpg
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. [22] 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 [23] 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. [22]

Some AGEs have an 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. A 2007 in vitro study found that AGEs could significantly increase expression of TGF-β1, CTGF, Fn mRNA in NRK-49F cells through enhancement of oxidative stress, and suggested that inhibition of oxidative stress might underlie the effect of ginkgo biloba extract in diabetic nephropathy. The authors suggested that antioxidant therapy might help prevent the accumulation of AGEs and induced damage. [23] In the end, effective clearance is necessary, and those suffering AGE increases because of kidney dysfunction might require a kidney transplant. [22]

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. In a 1997 study, diabetic and healthy subjects were given a single meal of egg white (56 g protein), cooked with or without 100 g of fructose; there was a greater than 200-fold increase in AGE immunoreactivity from the meal with fructose. [37]

Potential therapy

Diagram of a resveratrol molecule 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, Agmatine, benfotiamine, pyridoxamine, alpha-lipoic acid, [38] [39] taurine, [40] pimagedine, [41] aspirin, [42] [43] carnosine, [44] metformin, [45] pioglitazone, [45] and pentoxifylline. [45] Activation of the TRPA-1 receptor by lipoic acid or podocarpic acid has been shown to reduce the levels of AGES by enhancing the detoxification of methylglyoxal, a major precursor of several AGEs. [38]

Studies in rats and mice have found that natural phenols such as resveratrol and curcumin can prevent the negative effects of the AGEs. [46] [47]

Compounds that are thought to break some existing AGE crosslinks include Alagebrium (and related ALT-462, ALT-486, and ALT-946) [48] and N-phenacyl thiazolium bromide. [49] One in vitro study shows that rosmarinic acid out performs the AGE breaking potential of ALT-711. [50]

Diagram of a glucosepane molecule 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. [51] [52]

Some chemicals, on the other hand, like aminoguanidine, might limit the formation of AGEs by reacting with 3-deoxyglucosone. [30]

See also

Related Research Articles

Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule in order to form a glycoconjugate. In biology, glycosylation usually refers to an enzyme-catalysed reaction, whereas glycation may refer to a non-enzymatic reaction.

<span class="mw-page-title-main">Pyridoxamine</span> Chemical compound

Pyridoxamine (PM) is one form of vitamin B6. Chemically it is based on a pyridine ring structure, with hydroxyl, methyl, aminomethyl, and hydroxymethyl substituents. It differs from pyridoxine by the substituent at the 4-position. The hydroxyl at position 3 and aminomethyl group at position 4 of its ring endow pyridoxamine with a variety of chemical properties, including the scavenging of free radical species and carbonyl species formed in sugar and lipid degradation and chelation of metal ions that catalyze Amadori reactions.

Glycated hemoglobin is a form of hemoglobin (Hb) that is chemically linked to a sugar. 'Glycosylated haemoglobin' is a misnomer, as glycation and glycosylation are different processes, of which only the former is relevant in this case.

Glycation is the covalent attachment of a sugar to a protein, lipid or nucleic acid molecule. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is the non-enzymatic process responsible for many complications in diabetes mellitus and is implicated in some diseases and in aging. Glycation end products are believed to play a causative role in the vascular complications of diabetes mellitus.

<span class="mw-page-title-main">Erythrulose</span> Chemical compound

D-Erythrulose (also known as erythrulose) is a tetrose carbohydrate with the chemical formula C4H8O4. It has one ketone group and so is part of the ketose family. It is used in some self-tanning cosmetics, in general, combined with dihydroxyacetone (DHA).

<span class="mw-page-title-main">Diabetic nephropathy</span> Chronic loss of kidney function

Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. The triad of protein leaking into the urine, rising blood pressure with hypertension and then falling renal function is common to many forms of CKD. Protein loss in the urine due to damage of the glomeruli may become massive, and cause a low serum albumin with resulting generalized body swelling (edema) so called nephrotic syndrome. Likewise, the estimated glomerular filtration rate (eGFR) may progressively fall from a normal of over 90 ml/min/1.73m2 to less than 15, at which point the patient is said to have end-stage renal disease. It usually is slowly progressive over years.

<span class="mw-page-title-main">Methylglyoxal</span> Chemical compound

Methylglyoxal (MGO) is the organic compound with the formula CH3C(O)CHO. It is a reduced derivative of pyruvic acid. It is a reactive compound that is implicated in the biology of diabetes. Methylglyoxal is produced industrially by degradation of carbohydrates using overexpressed methylglyoxal synthase.

<span class="mw-page-title-main">Alagebrium</span> Chemical compound

Alagebrium was a drug candidate developed by Alteon, Inc. It was the first drug candidate to be clinically tested for the purpose of breaking the crosslinks caused by advanced glycation endproducts (AGEs), thereby reversing one of the main mechanisms of aging. Through this effect Alagebrium is designed to reverse the stiffening of blood vessel walls that contributes to hypertension and cardiovascular disease, as well as many other forms of degradation associated with protein crosslinking. Alagebrium has proven effective in reducing systolic blood pressure and providing therapeutic benefit for patients with diastolic heart failure.

<span class="mw-page-title-main">Human serum albumin</span> Albumin found in human blood

Human serum albumin is the serum albumin found in human blood. It is the most abundant protein in human blood plasma; it constitutes about half of serum protein. It is produced in the liver. It is soluble in water, and it is monomeric.

The polyol pathway is a two-step process that converts glucose to fructose. In this pathway glucose is reduced to sorbitol, which is subsequently oxidized to fructose. It is also called the sorbitol-aldose reductase pathway.

<span class="mw-page-title-main">RAGE (receptor)</span> Protein-coding gene in the species Homo sapiens

RAGE, also called AGER, is a 35 kilodalton transmembrane receptor of the immunoglobulin super family which was first characterized in 1992 by Neeper et al. Its name comes from its ability to bind advanced glycation endproducts (AGE), which include chiefly glycoproteins, the glycans of which have been modified non-enzymatically through the Maillard reaction. In view of its inflammatory function in innate immunity and its ability to detect a class of ligands through a common structural motif, RAGE is often referred to as a pattern recognition receptor. RAGE also has at least one other agonistic ligand: high mobility group protein B1 (HMGB1). HMGB1 is an intracellular DNA-binding protein important in chromatin remodeling which can be released by necrotic cells passively, and by active secretion from macrophages, natural killer cells, and dendritic cells.

An immunoproteasome is a type of proteasome that degrades ubiquitin-labeled proteins found in the cytoplasm in cells exposed to oxidative stress and proinflammatory stimuli. In general, proteasomes consist of a regulatory and a catalytic part. Immunoproteasomes are induced by interferon gamma and oxidative stress, which in the cell triggers the transcription of three catalytic subunits that do not occur in the classical proteasome. Another possible variation of proteasome is the thymoproteasome, which is located in the thymus and folds to present peptides to naive T cells.

The glyoxalase system is a set of enzymes that carry out the detoxification of methylglyoxal and the other reactive aldehydes that are produced as a normal part of metabolism. This system has been studied in both bacteria and eukaryotes. This detoxification is accomplished by the sequential action of two thiol-dependent enzymes; firstly glyoxalase І, which catalyzes the isomerization of the spontaneously formed hemithioacetal adduct between glutathione and 2-oxoaldehydes into S-2-hydroxyacylglutathione. Secondly, glyoxalase ІІ hydrolyses these thiolesters and in the case of methylglyoxal catabolism, produces D-lactate and GSH from S-D-lactoyl-glutathione.

<span class="mw-page-title-main">Pentosidine</span> Chemical compound

Pentosidine is a biomarker for advanced glycation endproducts, or AGEs. It is a well characterized and easily detected member of this large class of compounds.

Chronic systemic inflammation (SI) is the result of release of pro-inflammatory cytokines from immune-related cells and the chronic activation of the innate immune system. It can contribute to the development or progression of certain conditions such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease, autoimmune and neurodegenerative disorders, and coronary heart disease.

<span class="mw-page-title-main">Diabetic cardiomyopathy</span> Medical condition

Diabetic cardiomyopathy is a disorder of the heart muscle in people with diabetes. It can lead to inability of the heart to circulate blood through the body effectively, a state known as heart failure(HF), with accumulation of fluid in the lungs or legs. Most heart failure in people with diabetes results from coronary artery disease, and diabetic cardiomyopathy is only said to exist if there is no coronary artery disease to explain the heart muscle disorder.

<span class="mw-page-title-main">3-Deoxyglucosone</span> Chemical compound

3-Deoxyglucosone (3DG) is a sugar that is notable because it is a marker for diabetes. 3DG reacts with protein to form advanced glycation end-products (AGEs), which contribute to diseases such as the vascular complications of diabetes, atherosclerosis, hypertension, Alzheimer's disease, inflammation, and aging.

<span class="mw-page-title-main">Argpyrimidine</span> Chemical compound

Argpyrimidine is an organic compound with the chemical formula C11H18N4O3. It is an advanced glycation end-product formed from arginine and methylglyoxal through the Maillard reaction. Argpyrimidine has been studied for its food chemistry purposes and its potential involvement in aging diseases and diabetes mellitus.

<span class="mw-page-title-main">Reactive carbonyl species</span>

Reactive carbonyl species (RCS) are molecules with highly reactive carbonyl groups, and often known for their damaging effects on proteins, nucleic acids, and lipids. They are often generated as metabolic products. Important RCSs include 3-deoxyglucosone, glyoxal, and methylglyoxal. RCSs react with amines and thiol groups leading to advanced glycation endproducts (AGEs). AGE's are indicators of diabetes.

Azeliragon is a small-molecule RAGE inhibitor. It is developed by vTv Therapeutics for various cancers, including triple-negative breast cancer, pancreatic cancer.

References

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