Advanced glycation end-product

A possible mechanism for formation of AGEs in vivo involves the reaction between an amino group of lysine and the carbonyl group of glucose, forming a Schiff base, which in turn forms an Amadori rearrangement. Some Amadori products are converted to AGEs, and others form reactive carbonyl species, which may react with proteins to form AGEs. In humans, histones in the cell nucleus are richest in lysine, and therefore form the glycated protein N(6)-carboxymethyllysine.

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. This receptor, when binding AGEs, is under preliminary research to determine if it contributes to age- and diabetes-related chronic inflammatory diseases.

The pathogenesis of this process is hypothesized to activation of the nuclear factor kappa B (NF-κB) following AGE binding. NF-κB controls several genes 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 }}

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 }}

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 can be produced in the body and in manufactured foods. The accumulation of AGEs may have causative roles in several age-related diseases by forming adducts with proteins and lipids. In preliminary research, AGEs affect nearly every type of cell and molecule in the body, and may be a 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}} 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 may arise under certain pathological 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 may have a role as proinflammatory mediators in gestational diabetes.{{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, a possible AGE mechanism is to 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 }} AGEs can bind to RAGE receptors and cause oxidative stress as well as activation of inflammatory pathways in vascular endothelial cells.

AGEs have been implicated in Alzheimer's disease and cardiovascular diseases.

According to in vitro research, the mechanism by which AGEs may 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 }}

In laboratory studies, 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 }} 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.

As of 2024, there is no conclusive clinical evidence for AGEs having a pathological role in aging diseases, and no causality has been demonstrated between processed foods, AGEs, and onset of aging or age-related diseases.

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

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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 — peptides and free adducts — are more aggressive than the AGE proteins from which they are derived, and they can perpetuate related pathology in people with diabetes, even after hyperglycemia has been brought under control.

Ongoing studies are performed to specify mechanisms that selectively inhibit the glycation process, and to understand how glycated molecules could be protected from further deterioration, possibly by manipulating the glyoxalase enzyme system to detoxify AGEs.

Development of candidate drugs by the pharmaceutical industry includes compounds whose mechanism of action is to inhibit or revert the glycation process.

• Glycosylation
• Methylglyoxal
• N(6)-Carboxymethyllysine
• Lipofuscin

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{{DEFAULTSORT:Advanced Glycation End Product}}

Category:Biomolecules

Category:Post-translational modification

Category:Senescence

Category:Advanced glycation end-products