- Advanced glycation endproducts
- Advanced glycation endproduct receptor
Aging is a dynamic process in which its rate and subsequent longevity of an organism are dependent upon the balance between the reactive intermediates of normal cellular metabolism and the ability of the body to reduce these by-products through a multifaceted antioxidant defence system. Every disturbance of this balance constitutes a clear and present danger to the macromolecular integrity of the body. When defence mechanisms become diminished or impaired, the resulting imbalance results in accumulation of endogenous agents, such as reactive oxygen and carbonyl species, and a state of increased cellular stress, which can accelerate the rate of aging. Glycation is the non-enzymatic glycosylation of proteins, nucleotides and lipids by saccharide derivatives. Glucose and other reducing sugars are important glycating agents, but the most reactive physiological relevant glycating agents, are the dicarbonyls, in particular methylglyoxal. Endogenously formed dicarbonyl compounds can react with proteins to form advanced glycation endproducts (AGEs). Experimental models have recently provided evidence that reduced detoxification of AGE precursors by the glyoxalase system, engagement of the cellular receptor RAGE and RAGE-dependent sustained activation of the pro-inflammatory transcription factor nuclear factor ĸB might significantly contribute to the rate of aging and the onset of age-related neurodegenerative, musculoskeletal and vascular diseases.
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- Balaban RS, Nemoto S, Finkel T: Mitochondria, oxidants and aging. Cell 2005;120:483–495.
- Davis KJA: Oxidative stress: the paradox of aerobic life. Biochem Soc Symp 1995;61:1–31.
- Finkel T, Holbrook NJ: Oxidants, oxidative stress and the biology of aging. Nature 2000;408:239–247.
- Murphy MP: How mitochondria produce reactive oxygen species. Biochem J 2009;417:1–13.
- Pryor WA: Oxy-radicals and related species: their formation, lifetimes, and reactions. Annu Rev Physiol 1986;48:657–667.
- Harman D: Aging: a theory based on free radical and radiation chemistry. J Gerontol 1957;2:298–300.
- Du X, Matsumara T, Edelsttein D, Rosetti L, Zsengeller Z, Szabo C, Brownlee M: Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest 2003;112:1049–1057.
- Nishikawa T, Edelstein D, Du X-L, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beede D, Oates PJ, Hammes H-P, Giardino I, Brownlee M: Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemia damage. Nature 2000;404:787–790.
- Dobler D, Ahmed N, Song LJ, Eboigbodin KE, Thornalley PJ: Increased dicarbonyl metabolism in endothelial cells in hyperglycemia induces anoikis and impairs angiogenesis by RGD and GFOGER motif modification. Diabetes 2006;55:1961–1969.
- Xue M, Qian Q, Adaikalakoteswari A, Rabbani N, Babei-Jadidi R, Thornalley PJ: Activation of NF-E2-related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease. Diabetes 2008;57:2809–2817.
- Du X-L, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu J, Brownlee M: Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA 2000;97:12222–12226.
- Chung SS, Ho EC, Lam KS, Chung SK: Contribution of polyol pathway to diabetes-induced oxidative stress. J Am Soc Nephrol 2003;14:S233–S236.
- Brownlee M: Biochemisty and molecular cell biology of diabetic complications. Nature 2001;414:813–820.
- Warburg O: On the origin of cancer cells. Science 1956;123:309–314.
- Gatenby RA, Gillies RJ: Why do cancers have high aerobic glycolysis? Nature Rev Cancer 2004;4:891–899.
- Blanchetot C, Boonstra J: The ROS-NOX connection in cancer and angiogenesis. Crit Rev Eukaryot Gene Expr 2008;18:35–45.
- Pan JS, Hong MZ, Ren JL: Reactive oxygen species: a double-edged sword in oncogenesis. World J Gastroenterol 2009;15:1702–1707.
- McCay CM, Crowell MF, Maynard LA: The effect of retarded growth upon the length of life and upon ultimate size. J Nutr 1935;10:63–79.
- Jiang J, Jaruga E, Repnevskaya M, Jazwinski S: An intervention resembling caloric restriction prolongs life span and retards aging in yeast. FASEB J 2000;14:2135–2137.
- Partridge L, Green A, Fowler K: Effects of egg-production and of exposure to males on female survival in Drosophila melanogaster. J Insect Physiol 1987;33:745–749.
- Chippindale AK, Leroi A, Kim SB, Rose MR: Phenotypic plasticity and selection in Drosophila life history evolution. I. Nutrition and the cost of reproduction. J Evol Biol 1993;6:171–193.
- Chapman T, Partridge L: Female fitness in Drosophila melanogaster: an interaction between the effect of nutrition and of encounter rate with males. Proc R Soc Lond B 1996;263:755–759.
- Weindruch R, Walford R, Fligiel S, Guthrie D: The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr 1986;116:641–654.
- Bartke A, Wright JC, Mattison JA, Ingram DK, Miller RA, Roth GS: Extending the life-span of long-lived mice. Nature 2001;414:412.
- Kealy R, Lawler D, Ballam J, Mantz S, Biery D, Greeley E, Lust G, Segre M, Smith G, Stowe H: Effects of diet restriction on life span and age-related changes in dogs. J Am Vet Med Assoc 2002;220:1315–1320.
- Lane M, Mattison J, Ingram D, Roth G: Caloric restriction and aging in primates: relevance to humans and possible CR mimetics. Microsc Res Tech 2002;59:335–338.
- Lane M, Mattison J, Roth G, Brant L, Ingram D: Effects of long-term diet restriction on aging and longevity in primates remain uncertain. J Gerontol A Biol Sci Med Sci 2004;59:405–407.
- Guarente L, Kenyon C: Genetic pathways that regulate ageing in model organisms. Nature 2000;408:255–262.
- Houthoofd K, Braeckman BP, Johnson TE, Vanfleteren JR: Extending life-span in C. elegans. Science 2004;305:1238–1239.
- Lee SS, Lee RYN, Fraser AG, Kamath RS, Ahringer J, Ruvkun G: A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet 2003;33:40–48.
- Turrens JF: Mitochondrial formation of reactive oxygen species. J Physiol 2003;552:335–344.
- Hartman P, Ponder R, Lo HH, Ishii N: Mitochondrial oxidative stress can lead to nuclear hypermutability. Mech Ageing Dev 2004;125:417–420.
- Nakai D, Shimizu T, Nojiri H, Uchiyama S, Koike H, Takahashi M, Hirokawa K, Shirasawa T: coq7/clk-1 regulates mitochondrial respiration and the generation of reactive oxygen species via coenzyme Q. Aging Cell 2004;3:273–281.
- Panowski SH, Wolff S, Aguilaniu H, Durieux J, Dillin A: PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans. Nature 2007;447:550–555.
- O’Brien PJ, Siraki AG, Shangari N: Aldehyde sources, metabolism, molecular toxicity, and possible effects on human health. Crit Rev Toxicol 2005;35:609–662.
- Thornalley PJ: Dicarbonyl intermediates in the Maillard reaction. Ann NY Acad Sci 2005;1043:111–117.
- Thornalley PJ: Clinical significance of glycation. Clin Lab 1999;45:263–273.
- Thornalley PJ: Protein and nucleotide damage by glyoxal and methylglyoxal in physiological systems – role in ageing and disease. Drug Metabol Drug Interact 2008;23:125–150.
- Thornalley PJ: Modification of the glyoxalase system in human red blood cells by glucose in vitro. Biochem J 1988;254:751–755.
- Phillips SA, Thornalley PJ: The formation of methylglyoxal from triose phosphates: investigation using a specific assay for methylglyoxal. Eur J Biochem 1993;212:101–105.
- Beisswenger PJ, Howell S, Nelson RG, Mauer M, Szwergold BS: α-Oxoaldehyde metabolism and diabetic complications. Biochem Soc Trans 2003;31:1358–1363.
- Thornalley PJ: Glyoxalase I – structure, function and a critical role in the enzymatic defence against glycation. Biochem Soc Trans 2003;31:1343–1348.
- Ahmed N, Dobler D, Dean M, Thornalley PJ: Peptide mapping identifies hotspot sites of modification in human serum albumin by methylglyoxal involved in ligand binding and esterase activity. J Biol Chem 2005;280:5724–5732
- Morcos M, Du X, Pfisterer F, et al: Glyoxalase I prevents mitchondrial protein modification and enhances lifespan in Caenorhabditis elegans. Aging Cell 2008;7:260–269.
- Schlotter A, Kukudov G, Bozorgmehr F, et al: C. elegans as model for the study of high glucose-mediated life span reduction. Diabetes 2009;58:2450–2456.
- Sell DR, Kleinman NR, Monnier VM: Longitudinal determination of skin collagen glycation and glycoxidation rates predicts early death in C57BL/6NNIA mice. FASEB J 2000;14:145–146.
- Verzijl N, De Groot J, Thorpe SR, et al: Effect of collagen turnover on the accumulation of advanced glycation endproducts. J Biol Chem 2000;275:39027–39031.
- Ahmed MU, Brinkmann FE, Degenhardt TP, et al: Nε-(carboxyethyl)lysine, a product of chemical modification of proteins by methylglyoxal, increases with age in human lens proteins. Biochem J 1997;324:565–570.
- Monnier VM: Towards a Maillard reaction theory of aging. Prog Clin Biol Res 1989;304:1–22.
- Ulrich P, Cerami A: Protein glycation, diabetes and aging. Rec Prog Horm Res 2001;56:1–21.
- Baynes JW: The role of AGEs in aging: causation or correlation. Exp Gerontol 2001;36:1527–1537.
- Li YM, Steffes M, Donnelly T, et al: Prevention of cardiovascular and renal pathology of aging by the advanced glycation inhibitor aminoguanidine. Proc Natl Acad Sci USA 1996;93:3902–3907.
- Vlassara H, et al: Identifying advanced glycation end products as a major source of oxidants in aging: implications for the management and/or prevention of reduced renal function in elderly persons. Semin Nephrol 2009;29:594–603.
- Semba RD, Nicklett EJ, Ferrucci L: Does accumulation of advanced glycation end products contribute to the aging phenotype? J Gerontol A Biol Sci Med Sci 2010;65:963–975.
- Bierhaus A, et al: Understanding RAGE, the receptor for advanced glycation endproducts. J Mol Med 2005;83:876–886.
- Bierhaus A, Nawroth PP: Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications. Diabetologia 2009;52:2251–2263.
- Xie J, Reverdatto S, Frolov A, Hoffmann R, Burz DS, Shekhtman A: Structural basis for pattern recognition by the receptor for advanced glycation endproducts (RAGE). J Biol Chem 2008;283:27255–27269.
- Kislinger T, Fu C, Huber B, Qu W, Taguchi A, Du Yan S, Hofmann M, Yan SF, Pischetsrieder M, Stern D, Schmidt AM: Nε-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation endproducts that activate cell signalling pathways and modulate gene expression. J Biol Chem 1999;274:31740–31749.
- Bierhaus A, et al: Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB. Diabetes 2001;50:2792–2808.
- Li J, Schmidt AM: Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products. J Biol Chem 1997;272:16498–16506.
- Brett J, Schmidt AM, Yan SD, et al: Survey of the distribution of a newly characterized receptor for advanced glycation endproducts in tissues. Am J Pathol 1993;143:1699–1712.
- Coughlan MT, Thornburn DR, Penfold SA, et. al: RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. J Am Soc Nephrol 2009;20:742–752.
- Abordo EA, Minhas HS, Thornalley PJ: Accumulation of alpha-oxoaldehydes during oxidative stress: a role in cytotoxicity. Biochem Pharmacol 1999;58:641–648.
- Bierhaus A, Stoyanov S, Haag GM, Konrade I, et al: RAGE-deficiency reduced diabetes-associated impairment of glyoxalase-1 in neuronal cells. Diabetes 2006;55:A511.
- Gravina S, Vijg J: Epigentic factors in aging and longevity. Pflugers Arch 2010;459:247–258.
- Calvanese V, Lara E, Kahn A, Fraga MF: The role of epigenetics in aging and age-related diseases. Ageing Res Rev 2009;8:268–276.
- Fraga MF: Genetic and epigenetic regulation of aging. Curr Opin Immunol 2009;21:446–453.
- Perrone L, et al: Thioredoxin interacting protein induced inflammation through chromatin modification in retinal capillary cells under diabetic conditions. J Cell Physiol 2009;221;262–272.
- Brasacchio D, Okabe J, Tikellis C, et al: Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail. Diabetes 2009;58:1229–1236.
Angelika Bierhaus, PhD
Department of Medicine I and Clinical Chemistry
Im Neuenheimer Feld 410, DE–69120 Heidelberg (Germany)
Tel. +49 6221 564 752, Fax +49 6221 564 754
Received: January 27, 2010
Accepted: August 2, 2010
Published online: October 21, 2010
Number of Print Pages : 9
Number of Figures : 1, Number of Tables : 0, Number of References : 69
Gerontology (International Journal of Experimental, Clinical, Behavioural and Technological Gerontology)
Vol. 57, No. 5, Year 2011 (Cover Date: August 2011)
Journal Editor: Wick G. (Innsbruck)
ISSN: 0304-324X (Print), eISSN: 1423-0003 (Online)
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