Advanced glycation end products (AGEs)

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Advanced glycation end products (AGEs), sometimes referred to as glycotoxins, are harmful oxidant compounds that result from glycation reactions during the metabolism of macromolecules in the bloodstream. Glycation (also known as the Maillard reaction or advanced glycation) is a non-enzymatic reaction that attaches a sugar (glucose or fructose) to proteins or lipids. The end-products of these reactions are implicated in diseases such as diabetes type-2,[1] cardiovascular diseases,[2] retinal disease[3] or neurodegenerative diseases.[4][5] They are also believed to play a causative role in normal aging.[1]

Dietary AGEs (dAGEs)

Highly processed foods found abundantly in western diets are rich in AGEs, which is worrisome given that dietary AGEs (dAGEs) have been shown to contribute to increased inflammation and oxidative stress, both precursor states for disease.[6] The cooking method also has a high impact in the formation of AGEs from the diet: dry heat was found to increase AGE formation by 10 to 100 fold more than uncooked food, especially in animal-derived food.[6] Vegetarian, carbohydrate-rich diets based on vegetables, milk and fruits lead to very few AGE formation even after being heat-processed.

Due to the impact of diet, conditions such as obesity or post-menopausal changes in body weight also lead to an increase in AGEs formation and therefore increased risk of cardiovascular disease.[7]

AGEs in disease

The formation of AGEs occurs during normal metabolism, however high levels might lead to disease due to protein-protein crosslinking in the bloodstream.[8] AGE processes particularly affect long-lived proteins with high turnover rates, such as structural collagen or other components of the extracellular matrix, which usually become pathogenic targets. When crosslinking of collagen occurs in the walls of the vasculature, this can be extremely deleterious. Damage to the micro- or macro-vasculature can lead to the formation of plaques, impair vascular elasticity and increase the risk for atherosclerosis and cardiovascular disease.[2]

One of the most common types of AGEs is glucosepane, which forms an irreversible, covalent cross-link molecule in collagen that might last decades before the body is able to fully remove it. It is also believed that glucosepane has a causal effect in the wrinkling of the skin over time and in the thickening of basement membranes in the vasculature.[9] It is also found in high levels in conditions of diabetes type-2.[10]

There is extensive evidence that AGEs develops more quickly in patients with diabetes, which negatively contributes to the state of their vascular system.[11] AGEs also build over time in the heart muscle and might lead to a decreased respiratory capacity.[12] Other diseases that might be highly impacted by AGEs formation are retinal disease or neurodegenerative diseases such as Alzheimer's.[3][4][5]

AGE receptors

AGEs contribute to disease by engaging with the receptor for advanced glycation endproducts (RAGE), which is believed to result in pro-inflammatory gene activation.[13] RAGE is found up-regulated in diabetes and Alzheimer's disease, and in turn activates NF-κB signalling which might mediate the inflammatory components of these diseases.[14][15] Interestingly, RAGE is down-regulated in pulmonary fibrosis and other conditions such as lung cancer.[16] However, expression of RAGE in the lungs differs significantly from the rest of the body, and is normally highly expressed in lung cells in the absence of disease.[17]

Other receptors exist, such as AGE-R1/3 which are able to recognise and bind to AGE molecules, however they don't appear to transduce cellular signals and might instead play a role in the removal and detoxification of AGE from the bloodstream.[18]

AGEs inhibitors

Several AGEs inhibitors have been developed to remove these harmful compounds from the body. One approach is the carbonyl reagent aminoguanidine hydrochloride, which targets the reactive carbonyl groups believed to be required for AGEs formation.[19] Studies have shown that aminoguanidine (Pimagedine) is able to improve the symptoms and progression of AGEs-related diseases such as diabetes type-2 and aging.[20]

Another class of agents, 4,5-dimethyl-3-phenacylthiazolium chloride (DPTC) showed able to break down the protein-protein crosslinks formed by AGEs and was proposed to revert the vascular damage in animals.[21][22]

Newer types of drugs based on anti-glucosepane antibodies aim to remove the most abundant form of AGE in the body and appeared to be successful in detecting glucosepane in the retina.[23] However, no AGE inhibitors are currently approved for humans by the FDA.

AGEs in aging

AGEs accumulate during normal aging and have been proposed as a hallmark of aging.[24] They are believed to accelerate all other hallmarks of aging by, for instance, increasing cellular senescence, inflammation, oxidative stress, telomere attrition and mitochondrial dysfunction, as well as altering intracellular communication.[8][25][26] Additionally, AGEs can increase the occurrence of DNA damage and lead to transcriptional stress, a hallmark of wild-type aging and accelerated aging models.[27][28]

Diets low in animal-derived fat and high in carbohydrates, such as vegetarian diets, are thought to decrease the rate of AGEs accumulation.[6] Raw, boiled or steamed food also decreases the formation of AGEs when carbohydrate-rich diets are not possible.[6] Studies in rats have shown that caloric restriction benefits the rate of serum AGE accumulation.[29] Exercise is also able to decrease the levels of AGE formation in both healthy and diabetic patients.[30][31]

See also: Extracellular matrix

References

  1. ↑ 1.0 1.1 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
  2. ↑ 2.0 2.1 Semba, R. D.; Ferrucci, L.; Sun, K.; Beck, J.; Dalal, M.; Varadhan, R.; Walston, J.; Guralnik, J. M.; Fried, L. P. (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
  3. ↑ 3.0 3.1 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
  4. ↑ 4.0 4.1 Munch, G; Deuther-Conrad W; Gasic-Milenkovic J. (2002). "Glycoxidative stress creates a vicious cycle of neurodegeneration in Alzheimer's disease--a target for neuroprotective treatment strategies?". J Neural Transm Suppl. 62 (62): 303–307. doi: 10.1007/978-3-7091-6139-5_28
  5. ↑ 5.0 5.1 Münch, Gerald; et al. (27 February 1997). "Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of β-amyloid peptide". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1360 (1): 17–29. doi: 10.1016/S0925-4439(96)00062-2
  6. ↑ 6.0 6.1 6.2 6.3 Uribarri, J., Woodruff, S., Goodman, S., Cai, W., Chen, X. U. E., Pyzik, R., ... & Vlassara, H. (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.
  7. ↑ Pertynska-Marczewska, M., & Merhi, Z. (2015). Relationship of advanced glycation end products with cardiovascular disease in menopausal women. Reproductive Sciences, 22, 774-782.
  8. ↑ 8.0 8.1 Ulrich P, Cerami A. Protein glycation, diabetes, and aging. Recent Prog Horm Res. 2001;56:1–21.
  9. ↑ Sell, D. R., Biemel, K. M., Reihl, O., Lederer, M. O., Strauch, C. M., & Monnier, V. M. (2005). "Glucosepane is a major protein cross-link of the senescent human extracellular matrix: Relationship with diabetes". Journal of Biological Chemistry. 280 (13): 12310–12315. doi: 10.1074/jbc.M500733200
  10. ↑ Monnier, V. M., Mustata, G. T., Biemel, K. L., Reihl, O., Lederer, M. O., Zhenyu, D.; et al. (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: 533–544.
  11. ↑ Singh, V. P., Bali, A., Singh, N., & Jaggi, A. S. (2014). Advanced glycation end products and diabetic complications. The Korean journal of physiology & pharmacology: official journal of the Korean Physiological Society and the Korean Society of Pharmacology, 18(1), 1.
  12. ↑ Zieman, S. J., & Kass, D. A. (2004). Advanced glycation end product cross‐linking: pathophysiologic role and therapeutic target in cardiovascular disease. Congestive Heart Failure, 10(3), 144-151.
  13. ↑ Gasparotto, J; Ribeiro, CT; da Rosa-Silva, HT; Bortolin, RC; Rabelo, TK; Peixoto, DO; Moreira, JCF; Gelain, DP (May 2019). "Systemic Inflammation Changes the Site of RAGE Expression from Endothelial Cells to Neurons in Different Brain Areas". Mol Neurobiol. 56 (5): 3079–3089. doi: 10.1007/s12035-018-1291-6
  14. ↑ Gasparotto, J; Girardi, CS; Somensi, N; Ribeiro, CT; Moreira, JCF; Michels, M; Sonai, B; Rocha, M; Steckert, AV; Barichello, T; Quevedo, J; Dal-Pizzol, F; Gelain, DP (Nov 2017). "Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment". J Biol Chem. 293 (1): 226–244. doi: 10.1074/jbc.M117.786756
  15. ↑ Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen J, Hong M, Luther T, Henle T, Klöting I, Morcos M, Hofmann M, Tritschler H, Weigle B, Kasper M, Smith M, Perry G, Schmidt AM, Stern DM, Häring HU, Schleicher E, Nawroth PP (December 2001). "Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB". Diabetes. 50 (12): 2792–808. doi: 10.2337/diabetes.50.12.2792
  16. ↑ Oczypok, EA; Perkins, TN; Oury, TD (June 2017). "All the "RAGE" in lung disease: The receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses". Paediatric Respiratory Reviews. 23: 40–49. doi: 10.1016/j.prrv.2017.03.012
  17. ↑ Queisser MA, Kouri FM, Königshoff M, Wygrecka M, Schubert U, Eickelberg O, Preissner KT (September 2008). "Loss of RAGE in pulmonary fibrosis: molecular relations to functional changes in pulmonary cell types". American Journal of Respiratory Cell and Molecular Biology. 39 (3): 337–45. doi: 10.1165/rcmb.2007-0244OC
  18. ↑ Bucciarelli LG, Wendt T, Rong L, Lalla E, Hofmann MA, Goova MT, Taguchi A, Yan SF, Yan SD, Stern DM, Schmidt AM. RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease. Cell Mol Life Sci. 2002;  59: 1117–1128.
  19. ↑ Hou, F. F., Boyce, J., Chertow, G. M., Kay, J., & Owen Jr, W. F. (1998). Aminoguanidine inhibits advanced glycation end products formation on beta2-microglobulin. Journal of the American Society of Nephrology, 9(2), 277-283.
  20. ↑ Thornalley, P. J. (2003). Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation endproducts. Archives of biochemistry and biophysics, 419(1), 31-40.
  21. ↑ Asif, M., Egan,J.,Vasan,S.,Jyothirmayi,G.N., Masurekar,M.R., Lopez,S.,Williams, C.,Torres,R.L., Wagle, D., Ulrich, P., Cerami, A., Brines, M., and Regan,T.J. (2000). Proc. Nat/. Acad. Sci. U.S.A.97,2809-2813.
  22. ↑ Wolffenbuttel, B.H., Boulanger, C.M., Crijns, F.R., Huijberts, M.S., Poitevin, P., Swennen, G.N., Vasan, S., Egan, J.J., Ulrich, P., Cerami, A , and Levy, B.I. (1998). Proc. Nat!. Acad. Sci. U.S.A. 95,4630-4634
  23. ↑ M. D. Streeter et al., “Generation and Characterization of Anti-Glucosepane Antibodies Enabling Direct Detection of Glucosepane in Retinal Tissue,” ACS Chem. Biol., vol. 15, no. 10, pp. 2655–2661, 2020
  24. ↑ A. Fedintsev and A. Moskalev, “Stochastic non-enzymatic modification of long-lived macromolecules – a missing hallmark of aging” Aging Research Reviews” 2020
  25. ↑ C. Correia-Melo, G. Hewitt, and J. F. Passos, “Telomeres, oxidative stress and inflammatory factors: partners in cellular senescence?,” Longev. Heal., vol. 3, no. 1, p. 1, 2014
  26. ↑ J. Zhao, “Molecular mechanisms of AGE/RAGE-mediated fibrosis in the diabetic heart,” World J. Diabetes, vol. 5, no. 6, p. 860, 2014
  27. ↑ Tamae, D., Lim, P., Wuenschell, G. E. & Termini, J. Mutagenesis and repair induced by the DNA advanced glycation end product N2-1-(carboxyethyl)-2′-deoxyguanosine in human cells. Biochemistry 50, 2321–2329 (2011).
  28. ↑ Gyenis, A., Chang, J., Demmers, J.J.P.G. et al. Genome-wide RNA polymerase stalling shapes the transcriptome during aging. Nat Genet 55, 268–279 (2023). https://doi.org/10.1038/s41588-022-01279-6
  29. ↑ W. T. Cefalu et al., “Caloric Restriction Decreases Age-Dependent Accumulation of the Glycoxidation Products, N?-(Carboxymethyl)lysine and Pentosidine, in Rat Skin Collagen,” Journals Gerontol. Ser. A, vol. 50A, no. 6, pp. B337–B341, 1995
  30. ↑ M. H. Macías-Cervantes, J. M. D. Rodríguez-Soto, J. Uribarri, F. J. Díaz-Cisneros, W. Cai, and M. E. Garay-Sevilla, “Effect of an advanced glycation end product-restricted diet and exercise on metabolic parameters in adult overweight men,” Nutrition, vol. 31, no. 3, pp. 446–451, 2015
  31. ↑ P. M. Magalhães, H. J. Appell, and J. A. Duarte, “Involvement of advanced glycation end products in the pathogenesis of diabetic complications: the protective role of regular physical activity,” Eur. Rev. Aging Phys. Act., vol. 5, no. 1, pp. 17–29, 2008
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