advanced glycation end-product

Animal-derived foods that are high in fat and protein are generally AGE-rich and are prone to further AGE formation during cooking.{{cite journal |last1=Uribarri |first1=Jaime |last2=Woodruff |first2=Sandra |last3=Goodman |first3=Susan |last4=Cai |first4=Weijing |last5=Chen |first5=Xue |last6=Pyzik |first6=Renata |last7=Yong |first7=Angie |last8=Striker |first8=Gary E. |last9=Vlassara |first9=Helen |title=Advanced Glycation End Products in Foods and a Practical Guide to Their Reduction in the Diet |journal=Journal of the American Dietetic Association |date=June 2010 |volume=110 |issue=6 |pages=911–916.e12 |doi=10.1016/j.jada.2010.03.018 |pmid=20497781 |pmc=3704564 }} 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.{{cite journal |last1=Poulsen |first1=Malene W. |last2=Hedegaard |first2=Rikke V. |last3=Andersen |first3=Jeanette M. |last4=de Courten |first4=Barbora |last5=Bügel |first5=Susanne |last6=Nielsen |first6=John |last7=Skibsted |first7=Leif H. |last8=Dragsted |first8=Lars O. |title=Advanced glycation endproducts in food and their effects on health |journal=Food and Chemical Toxicology |date=October 2013 |volume=60 |pages=10–37 |doi=10.1016/j.fct.2013.06.052 |pmid=23867544 }} Therefore, it is unclear whether dietary AGEs contribute to disease and aging, or whether only endogenous AGEs (those produced in the body) matter.{{cite journal |last1=Luevano-Contreras |first1=Claudia |last2=Chapman-Novakofski |first2=Karen |title=Dietary Advanced Glycation End Products and Aging |journal=Nutrients |date=13 December 2010 |volume=2 |issue=12 |pages=1247–1265 |doi=10.3390/nu2121247 |pmid=22254007 |pmc=3257625 |doi-access=free }} 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.

File:Argpyrimidine Hydroimidazolone.png (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{{cite journal |last1=Chaudhuri |first1=Jyotiska |last2=Bains |first2=Yasmin |last3=Guha |first3=Sanjib |last4=Kahn |first4=Arnold |last5=Hall |first5=David |last6=Bose |first6=Neelanjan |last7=Gugliucci |first7=Alejandro |last8=Kapahi |first8=Pankaj |title=The role of advanced glycation end products in aging and metabolic diseases: bridging association and causality |journal=Cell Metabolism |date=4 September 2018 |volume=28 |issue=3 |pages=337–352 |doi=10.1016/j.cmet.2018.08.014 |pmid=30184484 |pmc=6355252 }} and some age-related chronic diseases.{{Cite journal| last1 = Glenn | first1 = J.| last2 = Stitt | first2 = A.| title = The role of advanced glycation end products in retinal ageing and disease| journal = Biochimica et Biophysica Acta (BBA) - General Subjects| volume = 1790| issue = 10| pages = 1109–1116| year = 2009| pmid = 19409449| doi = 10.1016/j.bbagen.2009.04.016}}{{Cite journal| doi = 10.1007/BF03325227| pmid = 19448391| year = 2009| last1 = Semba | first1 = R. D.| last2 = Ferrucci| last3 = Sun| last4 = Beck| last5 = Dalal| last6 = Varadhan| last7 = Walston| last8 = Guralnik| last9 = Fried| title = Advanced glycation end products and their circulating receptors predict cardiovascular disease mortality in older community-dwelling women| volume = 21| issue = 2| pages = 182–190| journal = Aging Clinical and Experimental Research | first2 = L. | first3 = K. | first4 = J. | first5 = M. | first6 = R. | first7 = J. | first8 = J. M. | first9 = L. P.| pmc = 2684987}}{{Cite journal| last1 = Semba | first1 = R.| last2 = Najjar | first2 = S.| last3 = Sun | first3 = K.| last4 = Lakatta | first4 = E.| last5 = Ferrucci | first5 = L.| title = Serum carboxymethyl-lysine, an advanced glycation end product, is associated with increased aortic pulse wave velocity in adults| journal = American Journal of Hypertension| volume = 22| issue = 1| pages = 74–79| year = 2009| pmid = 19023277| doi = 10.1038/ajh.2008.320| pmc = 2637811}} They are also believed to play a causative role in the vascular complications of diabetes mellitus.{{Cite journal| pmid = 18331228| year = 2007| last1 = Yan | first1 = S. F.| last2 = D'Agati| last3 = Schmidt| last4 = Ramasamy| title = Receptor for Advanced Glycation Endproducts (RAGE): a formidable force in the pathogenesis of the cardiovascular complications of diabetes & aging| volume = 7| issue = 8| pages = 699–710| journal = Current Molecular Medicine| doi = 10.2174/156652407783220732 | first2 = V. | first3 = A. M. | first4 = R.}}

AGEs arise under certain pathologic conditions, such as oxidative stress due to hyperglycemia in patients with diabetes.{{cite journal|last=Brownlee|first=M|title=The pathobiology of diabetic complications: a unifying mechanism.|journal=Diabetes|date=June 2005|volume=54|issue=6|pages=1615–25|pmid=15919781|doi=10.2337/diabetes.54.6.1615|doi-access=free}} AGEs play a role as proinflammatory mediators in gestational diabetes as well.{{cite journal |last1=Pertyńska-Marczewska |first1=Magdalena |last2=Głowacka |first2=Ewa |last3=Sobczak |first3=Małgorzata |last4=Cypryk |first4=Katarzyna |last5=Wilczyński |first5=Jan |title=Glycation Endproducts, Soluble Receptor for Advanced Glycation Endproducts and Cytokines in Diabetic and Non-diabetic Pregnancies |journal=American Journal of Reproductive Immunology |date=11 January 2009 |volume=61 |issue=2 |pages=175–182 |doi=10.1111/j.1600-0897.2008.00679.x |pmid=19143681 |s2cid=3186554 }}

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.{{cite journal |last1=Prasad |first1=Anand |last2=Bekker |first2=Peter |last3=Tsimikas |first3=Sotirios |title=Advanced Glycation End Products and Diabetic Cardiovascular Disease |journal=Cardiology in Review |date=2012 |volume=20 |issue=4 |pages=177–183 |doi=10.1097/CRD.0b013e318244e57c |pmid=22314141 |s2cid=8471652 }} Oxidized LDL is one of the major factors in the development of atherosclerosis.{{cite journal |last1=Di Marco |first1=Elyse |last2=Gray |first2=Stephen P. |last3=Jandeleit-Dahm |first3=Karin |title=Diabetes Alters Activation and Repression of Pro- and Anti-Inflammatory Signaling Pathways in the Vasculature |journal=Frontiers in Endocrinology |date=2013 |volume=4 |pages=68 |doi=10.3389/fendo.2013.00068 |pmid=23761786 |pmc=3672854 |doi-access=free }} 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.

AGEs have been implicated in Alzheimer's Disease,{{cite journal |last1=Srikanth |first1=Velandai |last2=Maczurek |first2=Annette |last3=Phan |first3=Thanh |last4=Steele |first4=Megan |last5=Westcott |first5=Bernadette |last6=Juskiw |first6=Damian |last7=Münch |first7=Gerald |title=Advanced glycation endproducts and their receptor RAGE in Alzheimer's disease |journal=Neurobiology of Aging |date=May 2011 |volume=32 |issue=5 |pages=763–777 |doi=10.1016/j.neurobiolaging.2009.04.016 |pmid=19464758 |s2cid=207158367 }} cardiovascular disease,{{cite journal |last1=Simm |first1=A. |last2=Wagner |first2=J. |last3=Gursinsky |first3=T. |last4=Nass |first4=N. |last5=Friedrich |first5=I. |last6=Schinzel |first6=R. |last7=Czeslik |first7=E. |last8=Silber |first8=R.E. |last9=Scheubel |first9=R.J. |title=Advanced glycation endproducts: A biomarker for age as an outcome predictor after cardiac surgery? |journal=Experimental Gerontology |date=July 2007 |volume=42 |issue=7 |pages=668–675 |doi=10.1016/j.exger.2007.03.006 |pmid=17482402 |s2cid=30264495 }} and stroke.{{cite journal |last1=Zimmerman |first1=G A |last2=Meistrell |first2=M |last3=Bloom |first3=O |last4=Cockroft |first4=K M |last5=Bianchi |first5=M |last6=Risucci |first6=D |last7=Broome |first7=J |last8=Farmer |first8=P |last9=Cerami |first9=A |last10=Vlassara |first10=H |title=Neurotoxicity of advanced glycation endproducts during focal stroke and neuroprotective effects of aminoguanidine. |journal=Proceedings of the National Academy of Sciences of the United States of America |date=25 April 1995 |volume=92 |issue=9 |pages=3744–3748 |doi=10.1073/pnas.92.9.3744 |pmid=7731977 |pmc=42038 |bibcode=1995PNAS...92.3744Z |doi-access=free }} The mechanism by which AGEs induce damage is through a process called cross-linking that causes intracellular damage and apoptosis.{{cite journal |last1=Shaikh |first1=Shamim |last2=Nicholson |first2=Louise F.B. |title=Advanced glycation end products induce in vitro cross-linking of α-synuclein and accelerate the process of intracellular inclusion body formation |journal=Journal of Neuroscience Research |date=July 2008 |volume=86 |issue=9 |pages=2071–2082 |doi=10.1002/jnr.21644 |pmid=18335520 |s2cid=37510479 }} They form photosensitizers in the crystalline lens,{{cite journal |last1=Fuentealba |first1=Denis |last2=Friguet |first2=Bertrand |last3=Silva |first3=Eduardo |title=Advanced Glycation Endproducts Induce Photocrosslinking and Oxidation of Bovine Lens Proteins Through Type-I Mechanism |journal=Photochemistry and Photobiology |date=January 2009 |volume=85 |issue=1 |pages=185–194 |doi=10.1111/j.1751-1097.2008.00415.x |pmid=18673320 |doi-access=free }} which has implications for cataract development.{{cite journal |last1=Gul |first1=Anjuman |last2=Rahman |first2=M. Ataur |last3=Hasnain |first3=Syed Nazrul |title=Role of fructose concentration on cataractogenesis in senile diabetic and non-diabetic patients |journal=Graefe's Archive for Clinical and Experimental Ophthalmology |date=6 February 2009 |volume=247 |issue=6 |pages=809–814 |doi=10.1007/s00417-008-1027-9 |pmid=19198870 |s2cid=9260375 }} Reduced muscle function is also associated with AGEs.{{cite journal |last1=Haus |first1=Jacob M. |last2=Carrithers |first2=John A. |last3=Trappe |first3=Scott W. |last4=Trappe |first4=Todd A. |title=Collagen, cross-linking, and advanced glycation end products in aging human skeletal muscle |journal=Journal of Applied Physiology |date=December 2007 |volume=103 |issue=6 |pages=2068–2076 |doi=10.1152/japplphysiol.00670.2007 |pmid=17901242 }}

AGEs have a range of pathological effects, such as:

• 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{{cite journal | vauthors = Kostolanská J, Jakus V, Barák L | title = 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 = Journal of Pediatric Endocrinology & Metabolism | volume = 22 | issue = 5 | pages = 433–42 | date = May 2009 | pmid = 19618662 | doi = 10.1515/JPEM.2009.22.5.433 | s2cid = 23150519 }} 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.{{cite journal | journal = Diabetes | volume = 50 Suppl. (2) | pages = A178–179 | title = A novel AGE production inhibitor, prevents progression of diabetic nephropathy in STZ-induced rats | author = Ninomiya, T. | year =2001 |display-authors=etal}} 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.{{cite journal | vauthors = Bierhaus A, Hofmann MA, Ziegler R, Nawroth PP | title = AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept | journal = Cardiovascular Research | volume = 37 | issue = 3 | pages = 586–600 | date = March 1998 | pmid = 9659442 | doi = 10.1016/S0008-6363(97)00233-2 | doi-access = free }}{{cite journal | journal = Endocrinol. Metab | volume = 3 | pages = 149–166 | title = Advanced glycation and the development of diabetic complications. Unifying the involvement of glucose, methylglyoxal and oxidative stress | author = Thornalley, P.J. | year =1996 }}
• 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.{{cite journal | vauthors = Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Stern D, Schmidt AM | title = RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides | journal = Cell | volume = 97 | issue = 7 | pages = 889–901 | date = June 1999 | pmid = 10399917 | doi = 10.1016/S0092-8674(00)80801-6 | s2cid = 7208198 | doi-access = free }} 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.

Proteins are usually glycated through their lysine residues.{{cite journal | vauthors=Ansari NA, Moinuddin, Ali R | title=Glycated lysine residues: a marker for non-enzymatic protein glycation in age-related diseases | journal=Disease Markers | volume=30 | issue=6 | year=2011 | pages=317–324 | doi= 10.1155/2011/718694| pmc= 3825483 | pmid=21725160| doi-access=free }} In humans, histones in the cell nucleus are richest in lysine, and therefore form the glycated protein N(6)-Carboxymethyllysine (CML).

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|date=August 2013}} from tissue such as lung, liver, and kidney.{{clarify|date=November 2013}}{{which|date=August 2013}} 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.{{cite journal

|vauthors=Wells-Knecht KJ, Zyzak DV, Litchfield JE, Thorpe SR, Baynes JW | title=Mechanism of autoxidative glycosylation: identification of glyoxal and arabinose as intermediates in the autoxidative modification of proteins by glucose

| journal = Biochemistry

| volume=34

| issue=11

| year=1995

| pages=3702–9

| pmid=7893666

| doi=10.1021/bi00011a027

}} The pathogenesis of this process hypothesized to activation of the nuclear factor kappa B (NF-κB) following AGE binding.{{cite journal |last1=Huttunen |first1=Henri J. |last2=Fages |first2=Carole |last3=Rauvala |first3=Heikki |title=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=Journal of Biological Chemistry |date=July 1999 |volume=274 |issue=28 |pages=19919–19924 |doi=10.1074/jbc.274.28.19919|doi-access=free |pmid=10391939 }} NF-κB controls several genes which are involved in inflammation.{{cite journal |last1=Liu |first1=Ting |last2=Zhang |first2=Lingyun |last3=Joo |first3=Donghyun |last4=Sun |first4=Shao-Cong |title=NF-κB signaling in inflammation |journal=Signal Transduction and Targeted Therapy |date=December 2017 |volume=2 |issue=1 |pages=17023– |doi=10.1038/sigtrans.2017.23|doi-access=free |pmid=29158945 |pmc=5661633 }} AGEs can be detected and quantified using bioanalytical and immunological methods.{{Cite journal |last1=Ashraf |first1=Jalaluddin Mohd. |last2=Ahmad |first2=Saheem |last3=Choi |first3=Inho |last4=Ahmad |first4=Nashrah |last5=Farhan |first5=Mohd. |last6=Tatyana |first6=Godovikova |last7=Shahab |first7=Uzma |date=November 2015 |title=Recent advances in detection of AGEs: Immunochemical, bioanalytical and biochemical approaches: Technological Progress in Age Detection |journal=IUBMB Life |language=en |volume=67 |issue=12 |pages=897–913 |doi=10.1002/iub.1450|doi-access=free |pmid=26597014 }}

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.{{cite journal |vauthors=Gugliucci A, Mehlhaff K, Kinugasa E |title=Paraoxonase-1 concentrations in end-stage renal disease patients increase after hemodialysis: correlation with low molecular AGE adduct clearance |journal=Clin. Chim. Acta |volume=377 |issue=1–2 |pages=213–20 |year=2007 |pmid=17118352 |doi=10.1016/j.cca.2006.09.028|display-authors=etal}}

[[File:KidneyStructures PioM.svg|thumb|250px|left|

{{center|

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. 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.

{{cite journal |vauthors=Gugliucci A, Bendayan M |title=Renal fate of circulating advanced glycated end products (AGE): evidence for reabsorption and catabolism of AGE peptides by renal proximal tubular cells |journal=Diabetologia |volume=39 |issue=2 |pages=149–60 |year=1996 |pmid=8635666 |doi=10.1007/BF00403957 |doi-access=free }}

AGE free adducts are the major form through which AGEs are excreted in urine, with AGE-peptides occurring to a lesser extent but accumulating in the plasma of patients with chronic kidney 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 cells

{{cite journal |vauthors=Smedsrød B, Melkko J, Araki N, Sano H, Horiuchi S |title=Advanced glycation end products are eliminated by scavenger-receptor-mediated endocytosis in hepatic sinusoidal Kupffer and endothelial cells |journal=Biochem. J. |volume=322 |issue=Pt 2 |pages=567–73 |year=1997 |pmid=9065778 |pmc=1218227 |doi=10.1042/bj3220567 }}

have been implicated in this process, although the real-life involvement of the liver has been disputed.

{{cite journal |vauthors=Svistounov D, Smedsrød B |title=Hepatic clearance of advanced glycation end products (AGEs)—myth or truth? |journal=J. Hepatol. |volume=41 |issue=6 |pages=1038–40 |year=2004 |pmid=15582139 |doi=10.1016/j.jhep.2004.10.004|doi-access=free }}

File:Endotelijalna ćelija.jpg

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. 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{{cite journal |last1=Yan |first1=Hai-dong |last2=Li |first2=Xue-zhu |last3=Xie |first3=Jun-mei |last4=Li |first4=Man |title=Effects of advanced glycation end products on renal fibrosis and oxidative stress in cultured NRK-49F cells |journal=Chinese Medical Journal |date=May 2007 |volume=120 |issue=9 |pages=787–793 |pmid=17531120 |doi=10.1097/00029330-200705010-00010 |doi-access=free }} 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.

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 {{em|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. In the end, effective clearance is necessary, and those suffering AGE increases because of kidney dysfunction might require a kidney transplant.

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.{{cite journal |last1=Koschinsky |first1=Theodore |last2=He |first2=Ci-Jiang |last3=Mitsuhashi |first3=Tomoko |last4=Bucala |first4=Richard |last5=Liu |first5=Cecilia |last6=Buenting |first6=Christina |last7=Heitmann |first7=Kirsten |last8=Vlassara |first8=Helen |title=Orally absorbed reactive glycation products (glycotoxins): An environmental risk factor in diabetic nephropathy |journal=Proceedings of the National Academy of Sciences of the United States of America |date=10 June 1997 |volume=94 |issue=12 |pages=6474–6479 |doi=10.1073/pnas.94.12.6474 |pmid=9177242 |pmc=21074 |bibcode=1997PNAS...94.6474K |doi-access=free }}

File:Resveratrol.svg 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.

{{primary sources|date=August 2019}}

Compounds that have been found to inhibit AGE formation in the laboratory include Vitamin C, Agmatine, benfotiamine, pyridoxamine, alpha-lipoic acid,{{cite journal |last1=Chaudhuri |first1=Jyotiska |last2=Bose |first2=Neelanjan |last3=Gong |first3=Jianke |last4=Hall |first4=David |last5=Rifkind |first5=Alexander |last6=Bhaumik |first6=Dipa |last7=Peiris |first7=T. Harshani |last8=Chamoli |first8=Manish |last9=Le |first9=Catherine H. |last10=Liu |first10=Jianfeng |last11=Lithgow |first11=Gordon J. |last12=Ramanathan |first12=Arvind |last13=Shawn Xu |first13=X. Z. |last14=Kapahi |first14=Pankaj |title=A Caenorhabditis elegans Model Elucidates a Conserved Role for TRPA1-Nrf Signaling in Reactive Alpha-dicarbonyl Detoxification |journal=Current Biology |date=21 November 2016 |volume=26 |issue=22 |pages=3014–3025 |doi=10.1016/j.cub.2016.09.024 |pmid=27773573 |pmc=5135008 |bibcode=2016CBio...26.3014C }}{{cite journal |last1=Mohmmad Abdul |first1=Hafiz |last2=Butterfield |first2=D. Allan |title=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 |journal=Free Radical Biology and Medicine |date=February 2007 |volume=42 |issue=3 |pages=371–384 |doi=10.1016/j.freeradbiomed.2006.11.006 |pmid=17210450 |pmc=1808543 }} taurine,{{cite journal |vauthors=Nandhini AT, Thirunavukkarasu V, Anuradha CV |title=Taurine prevents collagen abnormalities in high fructose-fed rats |journal=Indian J. Med. Res. |volume=122 |issue=2 |pages=171–7 |date=August 2005 |pmid=16177476 |url=http://www.icmr.nic.in/ijmr/2005/august/0911.pdf |access-date=2009-04-16 |archive-url=https://web.archive.org/web/20090417033030/http://icmr.nic.in/ijmr/2005/august/0911.pdf |archive-date=2009-04-17 |url-status=dead }} pimagedine,A. Gugliucci, "[http://209.209.34.25/webdocs/Glycation%20Page/Glycation%20Page.htm Sour Side of Sugar, A Glycation Web Page] {{webarchive |url=https://web.archive.org/web/20070701161048/http://209.209.34.25/webdocs/Glycation%20Page/Glycation%20Page.htm |date=July 1, 2007 }} aspirin,{{cite journal|url=http://www.mendeley.com/research/aspirin-inhibits-formation-pentosidine-crosslinking-advanced-glycation-end-product-collagen/ |title=Aspirin inhibits the formation of... preview & related info |journal=Diabetes Research and Clinical Practice |volume=77 |issue=2 |pages=337–340 |doi=10.1016/j.diabres.2006.12.024 |pmid=17383766 |access-date=2013-11-13|year=2007 |last1=Urios |first1=P. |last2=Grigorova-Borsos |first2=A.-M. |last3=Sternberg |first3=M. }}{{cite book |doi=10.1016/S1054-3589(08)60961-8 |pmid=1540533 |isbn=978-0-12-032923-6 |title=Advanced Glycosylation: Chemistry, Biology, and Implications for Diabetes and Aging |series=Advances in Pharmacology |year=1992 |last1=Bucala |first1=Richard |last2=Cerami |first2=Anthony |volume=23 |pages=1–34 }} carnosine,{{cite journal |last1=Guiotto |first1=Andrea |last2=Calderan |first2=Andrea |last3=Ruzza |first3=Paolo |last4=Borin |first4=Gianfranco |title=Carnosine and Carnosine-Related Antioxidants: A Review |journal=Current Medicinal Chemistry |date=1 September 2005 |volume=12 |issue=20 |pages=2293–2315 |doi=10.2174/0929867054864796 |pmid=16181134 }} metformin,{{Cite journal|pmid=14568010 |title=Novel inhibitors of advanced glycation endproducts |date=2013-03-25 |volume=419 |issue=1 |journal=Arch. Biochem. Biophys. |pages=63–79|doi=10.1016/j.abb.2003.08.009 | last1 = Rahbar | first1 = S | last2 = Figarola | first2 = JL}} pioglitazone, and pentoxifylline. 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.

Studies in rats and mice have found that natural phenols such as resveratrol and curcumin can prevent the negative effects of the AGEs.{{cite journal |last1=Mizutani |first1=Kenichi |last2=Ikeda |first2=Katsumi |last3=Yamori |first3=Yukio |title=Resveratrol Inhibits AGEs-Induced Proliferation and Collagen Synthesis Activity in Vascular Smooth Muscle Cells from Stroke-Prone Spontaneously Hypertensive Rats |journal=Biochemical and Biophysical Research Communications |date=July 2000 |volume=274 |issue=1 |pages=61–67 |doi=10.1006/bbrc.2000.3097 |pmid=10903896 }}{{cite journal |last1=Tang |first1=Youcai |last2=Chen |first2=Anping |title=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 |journal=Laboratory Investigation |date=10 March 2014 |volume=94 |issue=5 |pages=503–516 |doi=10.1038/labinvest.2014.42 |pmid=24614199 |pmc=4006284 }}

Compounds that are thought to break some existing AGE crosslinks include Alagebrium (and related ALT-462, ALT-486, and ALT-946){{cite journal |last1=Bakris |first1=George L. |last2=Bank |first2=Alan J. |last3=Kass |first3=David A. |last4=Neutel |first4=Joel M. |last5=Preston |first5=Richard A. |last6=Oparil |first6=Suzanne |title=Advanced glycation end-product cross-link breakersA novel approach to cardiovascular pathologies related to the aging process |journal=American Journal of Hypertension |date=1 December 2004 |volume=17 |issue=S3 |pages=23S–30S |doi=10.1016/j.amjhyper.2004.08.022 |pmid=15607432 |doi-access=free }} and N-phenacyl thiazolium bromide.{{cite journal |last1=Vasan |first1=Sara |last2=Zhang |first2=Xin |last3=Zhang |first3=Xini |last4=Kapurniotu |first4=Aphrodite |last5=Bernhagen |first5=Jürgen |last6=Teichberg |first6=Saul |last7=Basgen |first7=John |last8=Wagle |first8=Dilip |last9=Shih |first9=David |last10=Terlecky |first10=Ihor |last11=Bucala |first11=Richard |last12=Cerami |first12=Anthony |last13=Egan |first13=John |last14=Ulrich |first14=Peter |title=An agent cleaving glucose-derived protein crosslinks in vitro and in vivo |journal=Nature |date=July 1996 |volume=382 |issue=6588 |pages=275–278 |doi=10.1038/382275a0 |pmid=8717046 |bibcode=1996Natur.382..275V |s2cid=4366953 }} One in vitro study shows that rosmarinic acid out performs the AGE breaking potential of ALT-711.{{cite journal |last1=Jean |first1=Daniel |last2=Pouligon |first2=Maryse |last3=Dalle |first3=Claude |title=Evaluation in vitro of AGE-crosslinks breaking ability of rosmarinic acid |journal=Glycative Stress Research |date=2015 |volume=2 |issue=4 |pages=204–207 |doi=10.24659/gsr.2.4_204 }}

File:Glucosepane.svg

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.{{cite journal |last1=Monnier |first1=Vincent M. |last2=Mustata |first2=Georgian T. |last3=Biemel |first3=Klaus L. |last4=Reihl |first4=Oliver |last5=Lederer |first5=Marcus O. |last6=Zhenyu |first6=Dai |last7=Sell |first7=David R. |title=Cross-Linking of the Extracellular Matrix by the Maillard Reaction in Aging and Diabetes: An Update on 'a Puzzle Nearing Resolution' |journal=Annals of the New York Academy of Sciences |date=June 2005 |volume=1043 |issue=1 |pages=533–544 |doi=10.1196/annals.1333.061 |pmid=16037276 |bibcode=2005NYASA1043..533M |s2cid=27507321 }}{{cite journal |last1=Furber |first1=John D. |title=Extracellular Glycation Crosslinks: Prospects for Removal |journal=Rejuvenation Research |date=June 2006 |volume=9 |issue=2 |pages=274–278 |doi=10.1089/rej.2006.9.274 |pmid=16706655 }}Nevertheless, research is ongoing.[https://longevity.technology/news/new-spiroligomer-molecules-can-change-medicine/]

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

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

{{Reflist|30em}}

{{DEFAULTSORT:Advanced Glycation End Product}}

Category:Biomolecules

Category:Post-translational modification

Category:Senescence

Category:Advanced glycation end-products