Biology:Advanced glycation end-product

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Short description: Proteins or lipids that become glycated as a result of exposure to sugars

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]

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.

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]

  • 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.
  • Hemoglobin-AGE levels are elevated in diabetic individuals[24] and other AGE proteins have been shown in experimental models to accumulate with time, increasing from 5-50 fold over periods of 5–20 weeks in the retina, lens and renal cortex of diabetic rats. The inhibition of AGE formation reduced the extent of nephropathy in diabetic rats.[25] Therefore, substances that inhibit AGE formation may limit the progression of disease and may offer new tools for therapeutic interventions in the therapy of AGE-mediated disease.[26][27]
  • AGEs have specific cellular receptors; the best-characterized are those called RAGE. The activation of cellular RAGE on endothelium, mononuclear phagocytes, and lymphocytes triggers the generation of free radicals and the expression of inflammatory gene mediators.[28] Such increases in oxidative stress lead to the activation of the transcription factor NF-κB and promote the expression of NF-κB regulated genes that have been associated with atherosclerosis.[26]

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

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

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

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

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

References

  1. ↑ Goldin, Alison; Beckman, Joshua A.; Schmidt, Ann Marie; Creager, Mark A. (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. 
  2. ↑ Vistoli, G; De Maddis, D; Cipak, A; Zarkovic, N; Carini, M; Aldini, G (Aug 2013). "Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation.". Free Radic Res. 47: Suppl 1:3–27. doi:10.3109/10715762.2013.815348. PMID 23767955. http://fulir.irb.hr/3540/1/Advanced_glycoxidation_lipoxidation_2013_zarkovic_cipak.pdf. 
  3. ↑ Uribarri, Jaime; Woodruff, Sandra; Goodman, Susan; Cai, Weijing; Chen, Xue; Pyzik, Renata; Yong, Angie; Striker, Gary E. et al. (June 2010). "Advanced Glycation End Products in Foods and a Practical Guide to Their Reduction in the Diet". Journal of the American Dietetic Association 110 (6): 911–916.e12. doi:10.1016/j.jada.2010.03.018. PMID 20497781. 
  4. ↑ 4.0 4.1 Poulsen, Malene W.; Hedegaard, Rikke V.; Andersen, Jeanette M.; de Courten, Barbora; Bügel, Susanne; Nielsen, John; Skibsted, Leif H.; Dragsted, Lars O. (October 2013). "Advanced glycation endproducts in food and their effects on health". Food and Chemical Toxicology 60: 10–37. doi:10.1016/j.fct.2013.06.052. PMID 23867544. 
  5. ↑ 5.0 5.1 Luevano-Contreras, Claudia; Chapman-Novakofski, Karen (13 December 2010). "Dietary Advanced Glycation End Products and Aging". Nutrients 2 (12): 1247–1265. doi:10.3390/nu2121247. PMID 22254007. 
  6. ↑ Chaudhuri, Jyotiska; Bains, Yasmin; Guha, Sanjib; Kahn, Arnold; Hall, David; Bose, Neelanjan; Gugliucci, Alejandro; Kapahi, Pankaj (4 September 2018). "The role of advanced glycation end products in aging and metabolic diseases: bridging association and causality". Cell Metabolism 28 (3): 337–352. doi:10.1016/j.cmet.2018.08.014. PMID 30184484. 
  7. ↑ Glenn, J.; Stitt, A. (2009). "The role of advanced glycation end products in retinal ageing and disease". Biochimica et Biophysica Acta (BBA) - General Subjects 1790 (10): 1109–1116. doi:10.1016/j.bbagen.2009.04.016. PMID 19409449. 
  8. ↑ 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. doi:10.1007/BF03325227. PMID 19448391. 
  9. ↑ 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. PMID 19023277. 
  10. ↑ 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. 
  11. ↑ Brownlee, M (June 2005). "The pathobiology of diabetic complications: a unifying mechanism.". Diabetes 54 (6): 1615–25. doi:10.2337/diabetes.54.6.1615. PMID 15919781. 
  12. ↑ Pertyńska-Marczewska, Magdalena; Głowacka, Ewa; Sobczak, Małgorzata; Cypryk, Katarzyna; Wilczyński, Jan (11 January 2009). "Glycation Endproducts, Soluble Receptor for Advanced Glycation Endproducts and Cytokines in Diabetic and Non-diabetic Pregnancies". American Journal of Reproductive Immunology 61 (2): 175–182. doi:10.1111/j.1600-0897.2008.00679.x. PMID 19143681. 
  13. ↑ 13.0 13.1 Prasad, Anand; Bekker, Peter; Tsimikas, Sotirios (2012). "Advanced Glycation End Products and Diabetic Cardiovascular Disease". Cardiology in Review 20 (4): 177–183. doi:10.1097/CRD.0b013e318244e57c. PMID 22314141. 
  14. ↑ 14.0 14.1 Di Marco, Elyse; Gray, Stephen P.; Jandeleit-Dahm, Karin (2013). "Diabetes Alters Activation and Repression of Pro- and Anti-Inflammatory Signaling Pathways in the Vasculature". Frontiers in Endocrinology 4: 68. doi:10.3389/fendo.2013.00068. PMID 23761786. 
  15. ↑ Srikanth, Velandai; Maczurek, Annette; Phan, Thanh; Steele, Megan; Westcott, Bernadette; Juskiw, Damian; Münch, Gerald (May 2011). "Advanced glycation endproducts and their receptor RAGE in Alzheimer's disease". Neurobiology of Aging 32 (5): 763–777. doi:10.1016/j.neurobiolaging.2009.04.016. PMID 19464758. 
  16. ↑ Simm, A.; Wagner, J.; Gursinsky, T.; Nass, N.; Friedrich, I.; Schinzel, R.; Czeslik, E.; Silber, R.E. et al. (July 2007). "Advanced glycation endproducts: A biomarker for age as an outcome predictor after cardiac surgery?". Experimental Gerontology 42 (7): 668–675. doi:10.1016/j.exger.2007.03.006. PMID 17482402. 
  17. ↑ Zimmerman, G A; Meistrell, M; Bloom, O; Cockroft, K M; Bianchi, M; Risucci, D; Broome, J; Farmer, P et al. (25 April 1995). "Neurotoxicity of advanced glycation endproducts during focal stroke and neuroprotective effects of aminoguanidine.". Proceedings of the National Academy of Sciences of the United States of America 92 (9): 3744–3748. doi:10.1073/pnas.92.9.3744. PMID 7731977. Bibcode: 1995PNAS...92.3744Z. 
  18. ↑ Shaikh, Shamim; Nicholson, Louise F.B. (July 2008). "Advanced glycation end products induce in vitro cross‐linking of α‐synuclein and accelerate the process of intracellular inclusion body formation". Journal of Neuroscience Research 86 (9): 2071–2082. doi:10.1002/jnr.21644. PMID 18335520. 
  19. ↑ Fuentealba, Denis; Friguet, Bertrand; Silva, Eduardo (January 2009). "Advanced Glycation Endproducts Induce Photocrosslinking and Oxidation of Bovine Lens Proteins Through Type-I Mechanism". Photochemistry and Photobiology 85 (1): 185–194. doi:10.1111/j.1751-1097.2008.00415.x. PMID 18673320. 
  20. ↑ Gul, Anjuman; Rahman, M. Ataur; Hasnain, Syed Nazrul (6 February 2009). "Role of fructose concentration on cataractogenesis in senile diabetic and non-diabetic patients". Graefe's Archive for Clinical and Experimental Ophthalmology 247 (6): 809–814. doi:10.1007/s00417-008-1027-9. PMID 19198870. 
  21. ↑ Haus, Jacob M.; Carrithers, John A.; Trappe, Scott W.; Trappe, Todd A. (December 2007). "Collagen, cross-linking, and advanced glycation end products in aging human skeletal muscle". Journal of Applied Physiology 103 (6): 2068–2076. doi:10.1152/japplphysiol.00670.2007. PMID 17901242. 
  22. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 22.6 "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. 1996. doi:10.1007/BF00403957. PMID 8635666. 
  23. ↑ 23.0 23.1 23.2 Yan, Hai-dong; Li, Xue-zhu; Xie, Jun-mei; Li, Man (May 2007). "Effects of advanced glycation end products on renal fibrosis and oxidative stress in cultured NRK-49F cells". Chinese Medical Journal 120 (9): 787–793. doi:10.1097/00029330-200705010-00010. PMID 17531120. 
  24. ↑ "HbA1c and serum levels of advanced glycation and oxidation protein products in poorly and well controlled children and adolescents with type 1 diabetes mellitus". Journal of Pediatric Endocrinology & Metabolism 22 (5): 433–42. May 2009. doi:10.1515/JPEM.2009.22.5.433. PMID 19618662. 
  25. ↑ Ninomiya, T. (2001). "A novel AGE production inhibitor, prevents progression of diabetic nephropathy in STZ-induced rats". Diabetes 50 Suppl. (2): A178–179. 
  26. ↑ 26.0 26.1 "AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept". Cardiovascular Research 37 (3): 586–600. March 1998. doi:10.1016/S0008-6363(97)00233-2. PMID 9659442. 
  27. ↑ Thornalley, P.J. (1996). "Advanced glycation and the development of diabetic complications. Unifying the involvement of glucose, methylglyoxal and oxidative stress". Endocrinol. Metab 3: 149–166. 
  28. ↑ "RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides". Cell 97 (7): 889–901. June 1999. doi:10.1016/S0092-8674(00)80801-6. PMID 10399917. 
  29. ↑ 29.0 29.1 "Glycated lysine residues: a marker for non-enzymatic protein glycation in age-related diseases". Disease Markers 30 (6): 317–324. 2011. doi:10.1155/2011/718694. PMID 21725160. 
  30. ↑ 30.0 30.1 "Mechanism of autoxidative glycosylation: identification of glyoxal and arabinose as intermediates in the autoxidative modification of proteins by glucose". Biochemistry 34 (11): 3702–9. 1995. doi:10.1021/bi00011a027. PMID 7893666. 
  31. ↑ Huttunen, Henri J.; Fages, Carole; Rauvala, Heikki (July 1999). "Receptor for Advanced Glycation End Products (RAGE)-mediated Neurite Outgrowth and Activation of NF-κB Require the Cytoplasmic Domain of the Receptor but Different Downstream Signaling Pathways". Journal of Biological Chemistry 274 (28): 19919–19924. doi:10.1074/jbc.274.28.19919. 
  32. ↑ Liu, Ting; Zhang, Lingyun; Joo, Donghyun; Sun, Shao-Cong (December 2017). "NF-κB signaling in inflammation". Signal Transduction and Targeted Therapy 2 (1): 17023. doi:10.1038/sigtrans.2017.23. 
  33. ↑ Ashraf, Jalaluddin Mohd.; Ahmad, Saheem; Choi, Inho; Ahmad, Nashrah; Farhan, Mohd.; Tatyana, Godovikova; Shahab, Uzma (November 2015). "Recent advances in detection of AGEs: Immunochemical, bioanalytical and biochemical approaches: Technological Progress in Age Detection" (in en). IUBMB Life 67 (12): 897–913. doi:10.1002/iub.1450. https://onlinelibrary.wiley.com/doi/10.1002/iub.1450. 
  34. ↑ 34.0 34.1 34.2 "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. 2007. doi:10.1016/j.cca.2006.09.028. PMID 17118352. 
  35. ↑ "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. 1997. doi:10.1042/bj3220567. PMID 9065778. 
  36. ↑ "Hepatic clearance of advanced glycation end products (AGEs)—myth or truth?". J. Hepatol. 41 (6): 1038–40. 2004. doi:10.1016/j.jhep.2004.10.004. PMID 15582139. 
  37. ↑ Koschinsky, Theodore; He, Ci-Jiang; Mitsuhashi, Tomoko; Bucala, Richard; Liu, Cecilia; Buenting, Christina; Heitmann, Kirsten; Vlassara, Helen (10 June 1997). "Orally absorbed reactive glycation products (glycotoxins): An environmental risk factor in diabetic nephropathy". Proceedings of the National Academy of Sciences of the United States of America 94 (12): 6474–6479. doi:10.1073/pnas.94.12.6474. PMID 9177242. Bibcode: 1997PNAS...94.6474K. 
  38. ↑ 38.0 38.1 Chaudhuri, Jyotiska; Bose, Neelanjan; Gong, Jianke; Hall, David; Rifkind, Alexander; Bhaumik, Dipa; Peiris, T. Harshani; Chamoli, Manish et al. (21 November 2016). "A Caenorhabditis elegans Model Elucidates a Conserved Role for TRPA1-Nrf Signaling in Reactive Alpha-dicarbonyl Detoxification". Current Biology 26 (22): 3014–3025. doi:10.1016/j.cub.2016.09.024. PMID 27773573. 
  39. ↑ Mohmmad Abdul, Hafiz; Butterfield, D. Allan (February 2007). "Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and α-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: Implications for Alzheimer's disease". Free Radical Biology and Medicine 42 (3): 371–384. doi:10.1016/j.freeradbiomed.2006.11.006. PMID 17210450. 
  40. ↑ "Taurine prevents collagen abnormalities in high fructose-fed rats". Indian J. Med. Res. 122 (2): 171–7. August 2005. PMID 16177476. http://www.icmr.nic.in/ijmr/2005/august/0911.pdf. Retrieved 2009-04-16. 
  41. ↑ A. Gugliucci, "Sour Side of Sugar, A Glycation Web Page
  42. ↑ Urios, P.; Grigorova-Borsos, A.-M.; Sternberg, M. (2007). "Aspirin inhibits the formation of... preview & related info". Diabetes Research and Clinical Practice 77 (2): 337–340. doi:10.1016/j.diabres.2006.12.024. PMID 17383766. http://www.mendeley.com/research/aspirin-inhibits-formation-pentosidine-crosslinking-advanced-glycation-end-product-collagen/. Retrieved 2013-11-13. 
  43. ↑ Bucala, Richard; Cerami, Anthony (1992). Advanced Glycosylation: Chemistry, Biology, and Implications for Diabetes and Aging. Advances in Pharmacology. 23. pp. 1–34. doi:10.1016/S1054-3589(08)60961-8. ISBN 978-0-12-032923-6. 
  44. ↑ Guiotto, Andrea; Calderan, Andrea; Ruzza, Paolo; Borin, Gianfranco (1 September 2005). "Carnosine and Carnosine-Related Antioxidants: A Review". Current Medicinal Chemistry 12 (20): 2293–2315. doi:10.2174/0929867054864796. PMID 16181134. 
  45. ↑ 45.0 45.1 45.2 Rahbar, S; Figarola, JL (2013-03-25). "Novel inhibitors of advanced glycation endproducts". Arch. Biochem. Biophys. 419 (1): 63–79. doi:10.1016/j.abb.2003.08.009. PMID 14568010. 
  46. ↑ Mizutani, Kenichi; Ikeda, Katsumi; Yamori, Yukio (July 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. 
  47. ↑ Tang, Youcai; Chen, Anping (10 March 2014). "Curcumin eliminates the effect of advanced glycation end-products (AGEs) on the divergent regulation of gene expression of receptors of AGEs by interrupting leptin signaling". Laboratory Investigation 94 (5): 503–516. doi:10.1038/labinvest.2014.42. PMID 24614199. 
  48. ↑ Bakris, George L.; Bank, Alan J.; Kass, David A.; Neutel, Joel M.; Preston, Richard A.; Oparil, Suzanne (1 December 2004). "Advanced glycation end-product cross-link breakersA novel approach to cardiovascular pathologies related to the aging process". American Journal of Hypertension 17 (S3): 23S–30S. doi:10.1016/j.amjhyper.2004.08.022. PMID 15607432. 
  49. ↑ Vasan, Sara; Zhang, Xin; Zhang, Xini; Kapurniotu, Aphrodite; Bernhagen, Jürgen; Teichberg, Saul; Basgen, John; Wagle, Dilip et al. (July 1996). "An agent cleaving glucose-derived protein crosslinks in vitro and in vivo". Nature 382 (6588): 275–278. doi:10.1038/382275a0. PMID 8717046. Bibcode: 1996Natur.382..275V. 
  50. ↑ Jean, Daniel; Pouligon, Maryse; Dalle, Claude (2015). "Evaluation in vitro of AGE-crosslinks breaking ability of rosmarinic acid". Glycative Stress Research 2 (4): 204–207. doi:10.24659/gsr.2.4_204. 
  51. ↑ Monnier, Vincent M.; Mustata, Georgian T.; Biemel, Klaus L.; Reihl, Oliver; Lederer, Marcus O.; Zhenyu, Dai; Sell, David R. (June 2005). "Cross-Linking of the Extracellular Matrix by the Maillard Reaction in Aging and Diabetes: An Update on 'a Puzzle Nearing Resolution'". Annals of the New York Academy of Sciences 1043 (1): 533–544. doi:10.1196/annals.1333.061. PMID 16037276. Bibcode: 2005NYASA1043..533M. 
  52. ↑ Furber, John D. (June 2006). "Extracellular Glycation Crosslinks: Prospects for Removal". Rejuvenation Research 9 (2): 274–278. doi:10.1089/rej.2006.9.274. PMID 16706655. 



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