Advanced glycation end-product

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).[1] "Glycosylation" is sometimes used for "glycation" in the literature, usually as 'non-enzymatic glycosylation.'

Contents

AGE formation

AGEs may be formed external to the body (exogenously) by heating (e.g., cooking);[2] or inside the body (endogenously) 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.[3]

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).[4][5][6] This, in turn, results in increased levels of nicotinamide adenine dinucleotide (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.[7] 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.

AGE formation in other diseases

The formation and accumulation of advanced glycation endproducts (AGEs) has been implicated in the progression of age-related diseases.[8] AGEs have been implicated in Alzheimer's Disease,[9] cardiovascular disease,[10] and stroke.[11] The mechanism by which AGEs induce damage is through a process called cross-linking that causes intracellular damage and apoptosis.[12] They form photosensitizers in the crystalline lens,[13] which has implications for cataract development.[14] Reduced muscle function is also associated with AGEs.[15]

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 cells, 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.[16]

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[17] and galactose.[18]

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.[19][20][21] They are also believed to play a causative role in the vascular complications of diabetes mellitus.[22]

They have a range of pathological effects, including increasing vascular permeability, inhibition of vascular dilation by interfering with nitric oxide, oxidising LDL,[23] binding cells including macrophage, endothelial, and mesangial cells to induce the secretion of a variety of cytokines and enhancing oxidative stress.[23][24]

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.[25] The resistance of extracellular matrix proteins to proteolysis renders AGEs of these proteins less conducive to elimination.[25] 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. [23] AGE free adducts are the major form through which AGEs are excreted in urine, with AGE-peptides occurring to a lesser extent,[23] but accumulate in the plasma of patients with chronic renal failure.[25]

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[23] as well as liver sinusoidal endothelial cells and Kupffer cells [26] have been implicated in this process, although the real-life involvement of the liver has been disputed. [27]

Clearance in diabetes and kidney dysfunction

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.[23] 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[24] 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.[23] 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.[24] 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.[23]

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.[2]

Therapeutic intervention

AGEs are the subject of ongoing research. Glycation inhibitors include benfotiamine, pyridoxamine, pimagedine, alpha-lipoic acid,[28] taurine,[29] aminoguanidine,[30] aspirin,[31] carnosine,[32] resveratrol,[33] and Alagebrium.

See also

References

  1. ^ Miyata T, Oda O, Inagi R, Iida Y, Araki N, Yamada N, Horiuchi S, Taniguchi N, Maeda K, Kinoshita T (September 1993). "beta 2-Microglobulin modified with advanced glycation end products is a major component of hemodialysis-associated amyloidosis". The Journal of Clinical Investigation 92 (3): 1243–52. doi:10.1172/JCI116696. PMC 288264. PMID 8376584. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=288264. 
  2. ^ a b Koschinsky T, He CJ, Mitsuhashi T, Bucala R, Liu C, Buenting C, Heitmann K, Vlassara H (1997). "Orally absorbed reactive glycation products (glycotoxins): an environmental risk factor in diabetic nephropathy". Proceedings of the National Academy of Sciences 94 (12): 6474–9. doi:10.1073/pnas.94.12.6474. PMC 21074. PMID 9177242. http://www.pnas.org/cgi/content/full/94/12/6474. 
  3. ^ Pertyńska-Marczewska M, Głowacka E, Sobczak M, Cypryk K, Wilczyński J. Am J Reprod Immunol. 2009 Feb;61(2):175-82
  4. ^ Dominiczak MH (2003). "Obesity, glucose intolerance and diabetes and their links to cardiovascular disease. Implications for laboratory medicine". Clin. Chem. Lab. Med. 41 (9): 1266–78. doi:10.1515/CCLM.2003.194. PMID 14598880. 
  5. ^ Brownlee M (2005). "The pathobiology of diabetic complications: a unifying mechanism". Diabetes 54 (6): 1615–25. doi:10.2337/diabetes.54.6.1615. PMID 15919781. http://diabetes.diabetesjournals.org/cgi/content/full/54/6/1615. 
  6. ^ Gugliucci, A. (2000). "Glycation as the glucose link to diabetic complications". The Journal of the American Osteopathic Association 100 (10): 621–634. PMID 11105451.  edit
  7. ^ Topol, Eric J.; Robert M. Califf (2006). Textbook of Cardiovascular Medicine. Lippincott Williams & Wilkins. p. 42. ISBN 0-7817-7012-2. 
  8. ^ Tan, K. C.; Chow; Lam; Lam; Bucala; Betteridge; Ip (2006). "Advanced glycation endproducts in nondiabetic patients with obstructive sleep apnea". Sleep 29 (3): 329–333. PMID 16553018.  edit
  9. ^ Srikanth V, Maczurek A, Phan T, Steele M, Westcott B, Juskiw D, Münch G. Advanced glycation endproducts and their receptor RAGE in Alzheimer's disease. Neurobiol Aging. 2009 May 21.
  10. ^ Simm A, Wagner J, Gursinsky T, Nass N, Friedrich I, Schinzel R, Czeslik E, Silber RE, Scheubel RJ. Advanced glycation endproducts: a biomarker for age as an outcome predictor after cardiac surgery? Exp Gerontol. 2007 Jul;42(7):668-75.
  11. ^ Zimmerman GA, Meistrell M 3rd, Bloom O, Cockroft KM, Bianchi M, Risucci D, Broome J, Farmer P, Cerami A, Vlassara H, et al. Neurotoxicity of advanced glycation endproducts during focal stroke and neuroprotective effects of aminoguanidine. Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3744-8.
  12. ^ Shaikh S, Nicholson LF. Advanced glycation end products induce in vitro cross-linking of alpha-synuclein and accelerate the process of intracellular inclusion body formation. J Neurosci Res. 2008 Jul;86(9):2071-82.
  13. ^ Fuentealba D, Friguet B, Silva E. Advanced glycation endproducts induce photocrosslinking and oxidation of bovine lens proteins through type-I mechanism. Photochem Photobiol. 2009 Jan-Feb;85(1):185-94.
  14. ^ Gul A, Rahman MA, Hasnain SN. Role of fructose concentration on cataractogenesis in senile diabetic and non-diabetic patients. Graefes Arch Clin Exp Ophthalmol. 2009 Jun;247(6):809-14.
  15. ^ Haus, J.; Carrithers, J.; Trappe, S.; Trappe, T. (2007). "Collagen, cross-linking, and advanced glycation end products in aging human skeletal muscle". Journal of applied physiology (Bethesda, Md. : 1985) 103 (6): 2068–2076. doi:10.1152/japplphysiol.00670.2007. PMID 17901242.  edit
  16. ^ Wells-Knecht KJ, Zyzak DV, Litchfield JE, Thorpe SR, Baynes JW (1995). "Mechanism of autoxidative glycosylation: identification of glyoxal and arabinose as intermediates in the autoxidative modification of proteins by glucose". Biochemistry 34 (11): 3702–9. doi:10.1021/bi00011a027. PMID 7893666. 
  17. ^ Goldin A, Beckman JA, Schmidt AM, Creager MA (2006). "Advanced glycation end products: sparking the development of diabetic vascular injury". Circulation 114 (6): 597–605. doi:10.1161/CIRCULATIONAHA.106.621854. PMID 16894049. 
  18. ^ Song X, Bao M, Li D, Li YM (1999). "Advanced glycation in D-galactose induced mouse aging model". Mech Ageing Dev 108 (3): 239–51. doi:10.1016/S0047-6374(99)00022-6. PMID 10405984. 
  19. ^ Glenn, J.; Stitt, A. (2009). "The role of advanced glycation end products in retinal ageing and disease". Biochimica et Biophysica Acta 1790 (10): 1109–1116. doi:10.1016/j.bbagen.2009.04.016. PMID 19409449.  edit
  20. ^ Semba, R. D.; Ferrucci, L.; Sun, K.; Beck, J.; Dalal, M.; Varadhan, R.; Walston, J.; Guralnik, J. M. et al. (2009). "Advanced glycation end products and their circulating receptors predict cardiovascular disease mortality in older community-dwelling women". Aging clinical and experimental research 21 (2): 182–190. PMC 2684987. PMID 19448391. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2684987.  edit
  21. ^ Semba, R.; Najjar, S.; Sun, K.; Lakatta, E.; Ferrucci, L. (2009). "Serum carboxymethyl-lysine, an advanced glycation end product, is associated with increased aortic pulse wave velocity in adults". American journal of hypertension 22 (1): 74–79. doi:10.1038/ajh.2008.320. PMC 2637811. PMID 19023277. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2637811.  edit
  22. ^ Yan, S. F.; D'Agati, V.; Schmidt, A. M.; Ramasamy, R. (2007). "Receptor for Advanced Glycation Endproducts (RAGE): a formidable force in the pathogenesis of the cardiovascular complications of diabetes & aging". Current molecular medicine 7 (8): 699–710. doi:10.2174/156652407783220732. PMID 18331228.  edit
  23. ^ a b c d e f g h Gugliucci A, Bendayan M (1996). "Renal fate of circulating advanced glycated end products (AGE): evidence for reabsorption and catabolism of AGE-peptides by renal proximal tubular cells". Diabetologia 39 (2): 149–60. doi:10.1007/BF00403957. PMID 8635666. http://www.nature.com/ki/journal/v53/n2/full/4490049a.html. 
  24. ^ a b c Yan HD, Li XZ, Xie JM, Li M (2007). "Effects of advanced glycation end products on renal fibrosis and oxidative stress in cultured NRK-49F cells". Chin. Med. J. 120 (9): 787–93. PMID 17531120. http://www.cmj.org/Periodical/paperlist.asp?id=LW2007429414606901754&linkintype=pubmed. 
  25. ^ a b c Gugliucci A, Mehlhaff K, Kinugasa E, et al. (2007). "Paraoxonase-1 concentrations in end-stage renal disease patients increase after hemodialysis: correlation with low molecular AGE adduct clearance". Clin. Chim. Acta 377 (1-2): 213–20. doi:10.1016/j.cca.2006.09.028. PMID 17118352. 
  26. ^ Smedsrød B, Melkko J, Araki N, Sano H, Horiuchi S (1997). "Advanced glycation end products are eliminated by scavenger-receptor-mediated endocytosis in hepatic sinusoidal Kupffer and endothelial cells". Biochem. J. 322 (Pt 2): 567–73. PMC 1218227. PMID 9065778. http://www.biochemj.org/bj/322/0567/bj3220567.htm. 
  27. ^ Svistounov D, Smedsrød B (2004). "Hepatic clearance of advanced glycation end products (AGEs)—myth or truth?". J. Hepatol. 41 (6): 1038–40. doi:10.1016/j.jhep.2004.10.004. PMID 15582139. 
  28. ^ Abdul HM, Butterfield DA (2007). "Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and alpha-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease". Free Radical Biology & Medicine 42 (3): 371–384. doi:10.1016/j.freeradbiomed.2006.11.006. PMC 1808543. PMID 17210450. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1808543. 
  29. ^ Nandhini AT, Thirunavukkarasu V, Anuradha CV (August 2005). "Taurine prevents collagen abnormalities in high fructose-fed rats". Indian J. Med. Res. 122 (2): 171–7. PMID 16177476. http://www.icmr.nic.in/ijmr/2005/august/0911.pdf. 
  30. ^ A. Gugliucci, "Sour Side of Sugar, A Glycation Web Page
  31. ^ Bucala R, Cerami A (1992). "Advanced glycosylation: chemistry, biology, and implications for diabetes and aging". Adv. Pharmacol. 23: 1–34. doi:10.1016/S1054-3589(08)60961-8. PMID 1540533. 
  32. ^ Guiotto A, Calderan A, Ruzza P, Borin G (2005). "Carnosine and carnosine-related antioxidants: a review". Current Medicinal Chemistry 12 (20): 2293–2315. doi:10.2174/0929867054864796. PMID 16181134. 
  33. ^ Kenichi Mizutani, Katsumi Ikeda, Yukio Yamori (2000). "Resveratrol Inhibits AGEs-Induced Proliferation and Collagen Synthesis Activity in Vascular Smooth Muscle Cells from Stroke-Prone Spontaneously Hypertensive Rats". Biochemical and Biophysical Research Communications 274 (1): 61–67. doi:10.1006/bbrc.2000.3097. PMID 10903896. 

External links