Advanced glycation endproduct
Encyclopedia
An advanced glycation end-product (AGE) is 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.'
ly) by heating (e.g., cooking); or inside the body (endogenous
ly) 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. AGEs are now known to play a role as proinflammatory mediators in gestational diabetes as well.
(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 AGE-modified sites are carboxymethyllysine
(CML), carboxyethyllysine (CEL), and Argpyrimidine, which is the most common epitope.
, smooth muscle, and cells of the immune system
) from tissue such as lung, liver, kidney, and 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
, periodontitis and neuropathy. There may be some chemicals, such as aminoguanidine, that limit the formation of AGEs by reacting with 3-deoxyglucosone
.
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, 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
.
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 cell
s to induce the secretion of a variety of cytokine
s and enhancing oxidative stress.
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.
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 of 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-peptides and AGE free adducts. Peripheral macrophage
as well as liver sinusoidal endothelial cells
and Kupffer cell
s
have been implicated in this process, although the real-life involvement of the liver has been disputed.
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. 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.
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. A 1997 study concluded that adding sugar to egg whites causes diabetics to be 200 times more AGE immunoreactive.
, pyridoxamine
, pimagedine
, alpha-lipoic acid, taurine, aminoguanidine, aspirin
, carnosine
, resveratrol
, and Alagebrium
.
Glycation
Glycation is the result of the bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose, without the controlling action of an enzyme. All blood sugars are reducing molecules. Glycation may occur either inside the body or outside the body...
reaction. The intermediate products are known, variously, as Amadori, Schiff base
Schiff base
A Schiff base, named after Hugo Schiff, is a compound with a functional group that contains a carbon-nitrogen double bond with the nitrogen atom connected to an aryl or alkyl group, not hydrogen....
and Maillard
Maillard reaction
The Maillard reaction is a form of nonenzymatic browning similar to caramelization. It results from a chemical reaction between an amino acid and a reducing sugar, usually requiring heat....
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
Glycosylation
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 biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
" is sometimes used for "glycation
Glycation
Glycation is the result of the bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose, without the controlling action of an enzyme. All blood sugars are reducing molecules. Glycation may occur either inside the body or outside the body...
" in the literature, usually as 'non-enzymatic glycosylation.'
AGE formation
AGEs may be formed external to the body (exogenousExogenous
Exogenous refers to an action or object coming from outside a system. It is the opposite of endogenous, something generated from within the system....
ly) by heating (e.g., cooking); or inside the body (endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
ly) through normal metabolism and aging. Under certain pathologic conditions (e.g., oxidative stress due to hyperglycemia
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
in patients with diabetes), AGE formation can be increased beyond normal levels. AGEs are now known to play a role as proinflammatory mediators in gestational diabetes as well.
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 nicotinamide adenine dinucleotideNicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...
(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
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
. This results in mitochondrial production of reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
, activating PARP1
PARP1
Poly [ADP-ribose] polymerase 1 also known as NAD+ ADP-ribosyltransferase 1 or poly[ADP-ribose] synthase 1 is an enzyme that in humans is encoded by the PARP1 gene.- Function :PARP1 works:...
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 AGE-modified sites are carboxymethyllysine
N(6)-carboxymethyllysine
N-Carboxymethyllysine , also known as N-lysine, is an advanced glycation endproduct . CML has been the most used marker for AGEs in food analysis....
(CML), carboxyethyllysine (CEL), and Argpyrimidine, which is the most common epitope.
AGE formation 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.Effects
AGEs may be less, or more, reactive than the initial sugars they were formed from. They are absorbed by the body during digestion with about 30% efficiency. Many cells in the body (for example, endothelial cellsEndothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
, smooth muscle, and cells of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
) from tissue such as lung, liver, kidney, and peripheral blood bear the Receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
for Advanced Glycation End-products (RAGE) that, when binding AGEs, contributes to age- and diabetes-related chronic inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
diseases such as atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
, arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
, myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
, nephropathy
Nephropathy
Nephropathy refers to damage to or disease of the kidney. An older term for this is nephrosis.-Causes:Causes of nephropathy include administration of analgesics, xanthine oxidase deficiency, and long-term exposure to lead or its salts...
, retinopathy
Retinopathy
Retinopathy is a general term that refers to some form of non-inflammatory damage to the retina of the eye. Frequently, retinopathy is an ocular manifestation of systemic disease.-Pathophysiology:Causes of retinopathy are varied:...
, periodontitis and neuropathy. There may be some chemicals, such as aminoguanidine, that limit the formation of AGEs by reacting with 3-deoxyglucosone
3-deoxyglucosone
3-Deoxyglucosone is a dicarbonyl sugar that is synthesized through the Maillard reaction, and is detoxified to 3-deoxyfructose and 2-keto-3-deoxygluconic acid. 3DG is a precursor for the formation of advanced glycation end-products : 3DG rapidly reacts with protein amino groups to form AGEs such...
.
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
Fructose
Fructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...
and galactose.
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
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
.
They have a range of pathological effects, including increasing vascular permeability, inhibition of vascular dilation by interfering with nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
, oxidising LDL, binding cells including macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
, endothelial, and mesangial cell
Mesangial cell
Mesangial cells are specialized cells around blood vessels in the kidneys, at the mesangium. They are specialized smooth muscle cells that function to regulate blood flow through the capillaries, usually divided into two types, each having a very distinct function and location:* Extraglomerular...
s to induce the secretion of a variety of cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s 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 systemLysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
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.
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 of patients with chronic renal failure.
Larger, extracellularly-derived AGE proteins cannot pass through the basement membrane of the renal corpuscle
Renal corpuscle
In the kidney, a renal corpuscle is the initial blood-filtering component of a nephron. It consists of two structures: a glomerulus and a Bowman's capsule. The glomerulus is a small tuft of capillaries containing two cell types. Endothelial cells, which have large fenestrae, are not covered by...
and must first be degraded into AGE-peptides and AGE free adducts. Peripheral macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
as well as liver sinusoidal endothelial cells
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
and Kupffer cell
Kupffer cell
Kupffer cells, also known as Browicz-Kupffer cells and stellate macrophages, are specialized macrophages located in the liver lining the walls of the sinusoids that form part of the reticuloendothelial system .-History:The cells were first observed by Karl Wilhelm von Kupffer in 1876...
s
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 capsuleBowman's capsule
The Bowman's capsule is a cup-like sac at the beginning of the tubular component of a nephron in the mammalian kidney that performs the first step in the filtration of blood to form urine. A glomerulus is enclosed in the sac...
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
Metalloproteinase
Metalloproteinases constitute a family of enzymes from the group of proteases, classified by the nature of the most prominent functional group in their active site. These are proteolytic enzymes whose catalytic mechanism involves a metal. Most metalloproteases are zinc-dependent, but some use...
and increases production of mesangial matrix, leading to glomerulosclerosis
Glomerulosclerosis
Glomerulosclerosis refers to a hardening of the glomerulus in the kidney. It is a general term to describe scarring of the kidneys' tiny blood vessels, the glomeruli, the functional units in the kidney that filter urine from the blood....
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. 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.
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. A 1997 study concluded that adding sugar to egg whites causes diabetics to be 200 times more AGE immunoreactive.
Therapeutic intervention
AGEs are the subject of ongoing research. Glycation inhibitors include benfotiamineBenfotiamine
Benfotiamine is a synthetic S-acyl derivative of thiamine . After absorption, benfotiamine can be dephosphorylated by cells bearing an ecto-alkaline phosphatase to the lipid-soluble S-benzoylthiamine...
, pyridoxamine
Pyridoxamine
Pyridoxamine is a vitamer in the vitamin B6 family, which includes pyridoxal and pyridoxine. Pyridoxamine is converted to the biologically active form of vitamin B6, pyridoxal 5-phosphate, via the vitamin B6 salvage pathway. Vitamin B6 acts as an enzyme cofactor in a variety of metabolic processes...
, pimagedine
Pimagedine
Pimagedine, also known as aminoguanidine, is an investigational drug for the treatment of diabetic nephropathy. Pimagedine is a diamine oxidase and nitric oxide synthase inhibitor...
, alpha-lipoic acid, taurine, aminoguanidine, aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
, carnosine
Carnosine
Carnosine is a dipeptide of the amino acids beta-alanine and histidine. It is highly concentrated in muscle and brain tissues....
, resveratrol
Resveratrol
Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
, and Alagebrium
Alagebrium
Alagebrium is a failed drug candidate developed by Alteon Corporation. It was the first drug to be clinically tested for the purpose of breaking the crosslinks caused by advanced glycation endproducts , thereby reversing one of the main mechanisms of aging...
.
See also
- GlucosepaneGlucosepaneGlucosepane is a lysine-arginine protein cross-linking product and advanced glycation end product derived from D-glucose. It is an irreversible, covalent cross-link product that has been found to make intermolecular and intramolecular cross-links in the collagen of the extracellular matrix and...
- GlycosylationGlycosylationGlycosylation 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 biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
- Glyoxalase systemGlyoxalase systemThe 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...
- MethylglyoxalMethylglyoxalMethylglyoxal, also called pyruvaldehyde or 2-oxopropanal is the aldehyde form of pyruvic acid. It has two carbonyl groups, so it is a dicarbonyl compound. Methylglyoxal is both an aldehyde and a ketone....
- Raw foodismRaw foodismRaw foodism is the practice of consuming uncooked, unprocessed, and often organic foods as a large percentage of the diet....
External links
- "Food Preparation May Play A Bigger Role In Chronic Disease Than Was Previously Thought", Medical News Today, 26 April 2007
- "How and Why to Prevent AGE Damage", Life Enhancement Website