Repairing Extracellular Aging and Glycation

  • John D. Furber


Accumulating extracellular molecular modifications play major roles in the etiologies of age-associated physical declines and illnesses. The most important changes are caused by glycation, lipoxidation, cross-linking, and cleavage of the long-lasting extracellular structural proteins (LESPs): collagen, elastin, fibronectin, and laminin. A series of reactions results in several stable structures referred to as “advanced glycation endproducts” (AGEs) and “advanced lipoxidation endproducts” (ALEs). LESP modifications contribute to debilitation in several ways: stiffening and weakening tissues, inciting inflammatory damage, and creating an unhealthy environment for the body’s cells. Some amelioration and postponement of LESP aging can be achieved through dietary composition choices, fasting or calorie restriction, and ingesting foods, herbs, or substances that inhibit glycation or lipoxidation. Exercise and crosslink-breaking substances can repair some damage, thus producing partial rejuvenation. Proposals have been made to look for additional crosslink breakers and deglycators to destroy the full range of AGEs. This author anticipates that repair and rejuvenation of a wide range of extracellular aging and damage may be achieved by stimulating fibroblast-lineage cells to more rapidly turn over and regenerate the extracellular matrix.


Diastolic Heart Failure Amadori Product Extracellular Aging Crosslink Breaker Rage Signaling 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



I would like to thank George M. Martin, David A. Spiegel, Steven G. Clarke, Ulf T. Brunk, Duncan MacLaren, and especially my editor, Gregory M. Fahy, for their careful reading of earlier drafts or portions of this chapter, and for their helpful comments.


  1. Adlard PA, Cherny RA, Finkelstein DI, Gautier E, Robb E, Cortes M, Volitakis I, Liu X, Smith JP, Perez K, Laughton K, Li QX, Charman SA, Nicolazzo JA, Wilkins S, Deleva K, Lynch T, Kok G, Ritchie CW, Tanzi RE, Cappai R, Masters CL, Barnham KJ, Bush AI (2008) Rapid srestoration of cognition in Alzheimer’s transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial aβ. Neuron 59(1):43–55PubMedCrossRefGoogle Scholar
  2. Ahmad MS, Pischetsrieder M, Ahmed N (2007) Aged garlic extract and S-allyl cysteine prevent formation of advanced glycation endproducts. Eur J Pharmacol 561(1–3):32–38PubMedCrossRefGoogle Scholar
  3. Ahmed N, Thornalley PJ (2003) Quantitative screening of protein biomarkers of early glycation, advanced glycation, oxidation and nitrosation in cellular and extracellular proteins by tandem mass spectrometry multiple reaction monitoring. Biochem Soc Trans 31(Pt 6):1417–1422PubMedCrossRefGoogle Scholar
  4. Ahmed N, Mirshekar-Syahkal B, Kennish L, Karachalias N, Babaei-Jadidi R, Thornalley PJ (2005) Assay of advanced glycation endproducts in selected beverages and food by liquid chromatography with tandem mass spectrometric detection. Mol Nutr Food Res 49(7):691–699PubMedCrossRefGoogle Scholar
  5. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002) Molecular Biology of the Cell. Garland, New YorkGoogle Scholar
  6. Alderman JM, Flurkey K, Brooks NL, Naik SB, Gutierrez JM, Srinivas U, Ziara KB, Jing L, Boysen G, Bronson R, Klebanov S, Chen X, Swenberg JA, Stridsberg M, Parker CE, Harrison DE, Combs TP (2009) Neuroendocrine inhibition of glucose production and resistance to cancer in dwarf mice. Exp Gerontol 44(1–2):26–33PubMedCrossRefGoogle Scholar
  7. Alikhani Z, Alikhani M, Boyd CM, Nagao K, Trackman PC, Graves DT (2005) Advanced glycation end products enhance expression of pro-apoptotic genes and stimulate fibroblast apoptosis through cytoplasmic and mitochondrial pathways. J Biol Chem 280(13):12087–12095PubMedCrossRefGoogle Scholar
  8. Anderson MM, Requena JR, Crowley JR, Thorpe SR, Heinecke JW (1999) The myeloperoxidase system of human phagocytes generates N-ɛ-(carboxymethyl)lysine on proteins: a mechanism for producing advanced glycation end products at sites of inflammation. J Clin Invest 104(1):103–113PubMedCrossRefGoogle Scholar
  9. Araki N, Higashi T, Mori T, Shibayama R, Kawabe Y, Kodama T, Takahashi K, Shichiri M, Horiuchi S (1995) Macrophage scavenger receptor mediates the endocytic uptake and degradation of advanced glycation end products of the Maillard reaction. Eur J Biochem 1;230(2):408–415CrossRefGoogle Scholar
  10. Asif M, Egan J, Vasan S, Jyothirmayi GN, Masurekar MR, Lopez S, Williams C, Torres RL, Wagle D, Ulrich P, Cerami A, Brines M, Regan TJ (2000) An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci USA 97(6):2809–2813PubMedCrossRefGoogle Scholar
  11. Bakris GL, Bank AJ, Kass DA, Neutel JM, Preston RA, Oparil S (2004) Advanced glycation end-product cross-link breakers: A novel approach to cardiovascular pathologies related to the aging process. Am J Hypertens 17(12 Pt 2):23S–30SPubMedCrossRefGoogle Scholar
  12. Beisswenger P, Ruggiero-Lopez D (2003) Metformin inhibition of glycation processes. Diabetes Metab (4 Pt 2):6S95–103Google Scholar
  13. Benanti JA, Williams DK, Robinson KL, Ozer HL, Galloway DA (2002) Induction of extracellular matrix-remodeling genes by the senescence-associated protein APA-1. Mol Cell Biol 22(21):7385–7397PubMedCrossRefGoogle Scholar
  14. Biemel KM, Reihl O, Conrad J, Lederer MO (2001) Formation pathways for lysine-arginine cross-links derived from hexoses and pentoses by maillard processes: unraveling the structure of a pentosidine precursor. J Biol Chem 276(26):23405–12PubMedCrossRefGoogle Scholar
  15. Biemel KM, Friedl DA, Lederer MO (2002) Identification and quantification of major maillard cross-links in human serum albumin and lens protein: evidence for glucosepane as the dominant compound. J Biol Chem 277(28):24907–24915PubMedCrossRefGoogle Scholar
  16. Boudreau N, Bissell MJ (1998) Extracellular matrix signaling: integration of form and function in normal and malignant cells. Curr Opin Cell Biol 10(5):640–646PubMedCrossRefGoogle Scholar
  17. Bucala R, Tracey KJ, Cerami A (1991) Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest. 87(2):432–438PubMedCrossRefGoogle Scholar
  18. Bucala R, Cerami A (1992) Advanced glycosylation: chemistry, biology, and implications for diabetes and aging. Adv Pharmacol 23:1–34PubMedCrossRefGoogle Scholar
  19. Cai W, He JC, Zhu L, Chen X, Zheng F, Striker GE, Vlassara H (2008) Oral glycotoxins determine the effects of calorie restriction on oxidant stress, age-related diseases, and lifespan. Am J Pathol 173(2):327–336PubMedCrossRefGoogle Scholar
  20. Campisi J (2005) Aging, tumor suppression and cancer: high wire-act!. Mech Ageing Dev 126(1):51–58PubMedCrossRefGoogle Scholar
  21. Candido R, Forbes JM, Thomas MC, Thallas V, Dean RG, Burns WC, Tikellis C, Ritchie RH, Twigg SM, Cooper ME, Burrell LM (2003) A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes. Circ Res 92(7): 785–792PubMedCrossRefGoogle Scholar
  22. Castellani RJ, Zhu X, Lee HG, Moreira PI, Perry G, Smith MA (2007) Neuropathology and treatment of Alzheimer disease: did we lose the forest for the trees? Expert Rev Neurother 7(5):473–85PubMedCrossRefGoogle Scholar
  23. Cefalu WT, Bell-Farrow AD, Wang ZQ, Sonntag WE, Fu MX, Baynes JW, Thorpe SR (1995) Caloric restriction decreases age-dependent accumulation of the glycoxidation products, N-ɛ-(carboxymethyl)lysine and pentosidine, in rat skin collagen. J Gerontol A Biol Sci Med Sci 50(6):B337–341PubMedCrossRefGoogle Scholar
  24. Cerami A, Vlassara H, Brownlee M (1987) Glucose and aging. Sci Am 256(5):90–96PubMedCrossRefGoogle Scholar
  25. Cheng R, Feng Q, Argirov OK, Ortwerth BJ (2004) Structure elucidation of a novel yellow chromophore from human lens protein. J Biol Chem 279(44):45441–9PubMedCrossRefGoogle Scholar
  26. Cheng G, Wang LL, Long L, Liu HY, Cui H, Qu WS, Li S (2007) Beneficial effects of C36, a novel breaker of advanced glycation endproducts cross-links, on the cardiovascular system of diabetic rats. Br J Pharmacol 152(8):1196–1206PubMedCrossRefGoogle Scholar
  27. Clarke S (2003) Aging as war between chemical and biochemical processes: protein methylation and the recognition of age-damaged proteins for repair. Ageing Res Rev 2(3):263–285PubMedCrossRefGoogle Scholar
  28. Collard F, Zhang J, Nemet I, Qanungo KR, Monnier VM, Yee VC (2008) Crystal structure of the deglycating enzyme fructosamine oxidase (Amadoriase II). J Biol Chem 283(40):27007–27016Google Scholar
  29. Coughlan MT, Forbes JM, Cooper ME (2007) Role of the AGE crosslink breaker, alagebrium, as a renoprotective agent in diabetes. Kidney Int Suppl (106):S54–S60Google Scholar
  30. Creel D (1980) Inappropriate use of albino animals as models in research. Pharmacol Biochem Behav 12(6):969–977 PubMedCrossRefGoogle Scholar
  31. Culbertson SM, Vassilenko EI, Morrison LD, Ingold KU (2003) Paradoxical impact of antioxidants on post-Amadori glycoxidation: counterintuitive increase in the yields of pentosidine and N-ɛ-carboxymethyllysine using a novel multifunctional pyridoxamine derivative. J Biol Chem 278(40):38384–38394PubMedCrossRefGoogle Scholar
  32. DeGroot J, Verzijl N, Bank RA, Lafeber FP, Bijlsma JW, TeKoppele JM (1999) Age-related decrease in proteoglycan synthesis of human articular chondrocytes: the role of nonenzymatic glycation. Arthritis Rheum 42(5):1003–1009PubMedCrossRefGoogle Scholar
  33. DeGroot J, Verzijl N, Budde M, Bijlsma JW, Lafeber FP, TeKoppele JM (2001a) Accumulation of advanced glycation end products decreases collagen turnover by bovine chondrocytes. Exp Cell Res 266(2):303–310PubMedCrossRefGoogle Scholar
  34. DeGroot J, Verzijl N, Jacobs KM, Budde M, Bank RA, Bijlsma JW, TeKoppele JM, Lafeber FP (2001b) Accumulation of advanced glycation endproducts reduces chondrocyte-mediated extracellular matrix turnover in human articular cartilage. Osteoarthritis Cartilage 9(8):720–726PubMedCrossRefGoogle Scholar
  35. DeGroot J, Verzijl N, Wenting-Van Wijk MJ, Bank RA, Lafeber FP, Bijlsma JW, TeKoppele JM (2001c) Age-related decrease in susceptibility of human articular cartilage to matrix metalloproteinase-mediated degradation: the role of advanced glycation end products. Arthritis Rheum 44(11):2562–2571PubMedCrossRefGoogle Scholar
  36. DeGroot J, Verzijl N, Wenting-van Wijk MJ, Jacobs KM, Van El B, Van Roermund PM, Bank RA, Bijlsma JW, TeKoppele JM, Lafeber FP (2004) Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis. Arthritis Rheum 50(4):1207–1215PubMedCrossRefGoogle Scholar
  37. DeVry CG, Tsai W, Clarke S (1996) Structure of the human gene encoding the protein repair L-isoaspartyl (D-aspartyl) O-methyltransferase. Arch Biochem Biophys 335(2):321–32PubMedCrossRefGoogle Scholar
  38. Dong Y, Wu Y, Wu M, Wang S, Zhang J, Xie Z, Xu J, Song P, Wilson K, Zhao Z, Lyons T, Zou MH (2008) Activation of Protease Calpain by Oxidized and Glycated LDL Increases the Degradation of Endothelial Nitric Oxide Synthase. J Cell Mol Med 13(9a):2899–2910Google Scholar
  39. Drinda S, Franke S, Rüster M, Petrow P, Pullig O, Stein G, Hein G (2005) Identification of the receptor for advanced glycation end products in synovial tissue of patients with rheumatoid arthritis. Rheumatol Int 25(6):411–413Google Scholar
  40. Eble AS, Thorpe SR, Baynes JW (1983) Nonenzymatic glucosylation and glucose-dependent cross-linking of protein. J Biol Chem 258(15):9406–9412PubMedGoogle Scholar
  41. Everts V, Van der Zee E, Creemers L, Beertsen W (1996) Phagocytosis and intracellular digestion of collagen, its role in turnover and remodeling. Histochem J 28, 229–245PubMedCrossRefGoogle Scholar
  42. Fawcett DW (1986) A Textbook of Histology, 11th edn. Saunders, PhiladelphiaGoogle Scholar
  43. Ferguson MW, Duncan J, Bond J, Bush J, Durani P, So K, Taylor L, Chantrey J,Mason T, James G, Laverty H, Occleston NL, Sattar A, Ludlow A, O’Kane S (2009) Prophylactic administration of avotermin for improvement of skin scarring: three double-blind, placebo-controlled, phase I/II studies. Lancet 373(9671):1264–1274PubMedCrossRefGoogle Scholar
  44. Figarola JL, Loera S, Weng Y, Shanmugam N, Natarajan R, Rahbar S (2008) LR-90 prevents dyslipidaemia and diabetic nephropathy in the Zucker diabetic fatty rat. Diabetologia 51(5):882–891PubMedCrossRefGoogle Scholar
  45. Finch CE (2007) The Biology of Human Longevity: Inflammation, Nutrition, and Aging in the Evolution of Life Spans. Academic, AmsterdamGoogle Scholar
  46. Flurkey K, Papaconstantinou J, Miller RA, Harrison DE (2001) Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci USA 98(12):6736–6741PubMedCrossRefGoogle Scholar
  47. Furber JD (2006)  Extracellular glycation crosslinks: prospects for removal. Rejuvenation Res 9(2):274–278PubMedCrossRefGoogle Scholar
  48. Gardiner DM (2005) Ontogenetic decline of regenerative ability and the stimulation of human regeneration. Rejuvenation Res 8(3):141–153PubMedCrossRefGoogle Scholar
  49. Gilbert SF (2000) Developmental Biology, 6th edn. Sinauer, Sunderland, MAGoogle Scholar
  50. Goldberg T, Cai W, Peppa M, Dardaine V, Baliga BS, Uribarri J, Vlassara H (2004) Advanced glycoxidation end products in commonly consumed foods. J Am Diet Assoc 104(8):1287–1291PubMedCrossRefGoogle Scholar
  51. Haimes HB (2005) Alagebrium: Intervention on the A.G.E. pathway modifies deficits caused by aging and diabetes. Paper presented at strategies for engineered negligible senescence (SENS), 2nd conference, Cambridge, England, 7–11 September 2005Google Scholar
  52. Haimes HB (2007) Hardening of the arteries: breaking the ties that bind. Paper presented at Edmonton aging symposium, Edmonton, Canada, 30–31 March 2007Google Scholar
  53. Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M (2003) Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 9(3):294–299PubMedCrossRefGoogle Scholar
  54. Hipkiss AR (2005) Glycation, ageing and carnosine: Are carnivorous diets beneficial? Mech Ageing Dev 126(10):1034–1039PubMedCrossRefGoogle Scholar
  55. Hirsch MS, Lunsford LE, Trinkaus-Randall V, Svoboda KK (1997) Chondrocyte survival and differentiation in situ are integrin mediated. Dev Dyn 210(3):249–263PubMedCrossRefGoogle Scholar
  56. Hsu RL, Lee KT, Wang JH, Lee LY, Chen RP (2009) Amyloid-degrading ability of nattokinase from Bacillus subtilis natto. J Agric Food Chem 57(2):503–508PubMedCrossRefGoogle Scholar
  57. Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, Fishman MC (1995) Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377(6546):239–242PubMedCrossRefGoogle Scholar
  58. Januszewski AS, Alderson NL, Metz TO, Thorpe SR, Baynes JW (2003) Role of lipids in chemical modification of proteins and development of complications in diabetes. Biochem Soc Trans 31(Pt 6):1413–1416PubMedCrossRefGoogle Scholar
  59. Januszewski AS, Alderson NL, Jenkins AJ, Thorpe SR, Baynes JW (2005) Chemical modification of proteins during peroxidation of phospholipids. J Lipid Res 46:1440–1449PubMedCrossRefGoogle Scholar
  60. Jerums G, Panagiotopoulos S, Forbes J, Osicka T, Cooper M (2003) Evolving concepts in advanced glycation, diabetic nephropathy, and diabetic vascular disease. Arch Biochem Biophys 419(1):55–62PubMedCrossRefGoogle Scholar
  61. Kass DA, Shapiro EP, Kawaguchi M, Capriotti AR, Scuteri A, deGroof RC, Lakatta EG (2001) Improved arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation 104(13):1464–1470PubMedCrossRefGoogle Scholar
  62. Kass DA (2003) Getting better without AGE: new insights into the diabetic heart. Circ Res 92(7):704–706PubMedCrossRefGoogle Scholar
  63. Kikuchi S, Shinpo K, Takeuchi M, Yamagishi S, Makita Z, Sasaki N, Tashiro K (2003) Glycation – a sweet tempter for neuronal death. Brain Res Brain Res Rev 41(2–3):306–323PubMedCrossRefGoogle Scholar
  64. Kislinger T, Fu C., Huber B, Qu W, Taguchi A, Du Yan S, Hoffmann M, Yan SF, Pischetsrieder M, Stern D, Schmidt AM (1999) N-ɛ-(carboxymethyl)lysine adducts of proteins are ligands for receptors for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J Biol Chem 274:31740 - 31749PubMedCrossRefGoogle Scholar
  65. Kjær M, Magnusson P, Krogsgaard M, Møller JB, Olesen J, Heinemeier K, Hansen M, Haraldsson B, Koskinen S, Esmarck B, Langberg H (2006) Extracellular matrix adaptation of tendon and skeletal muscle to exercise. J Anat 208:445–450PubMedCrossRefGoogle Scholar
  66. Kohn RR (1978) Principles of Mammalian Aging, 2nd edn. Prentice-Hall, Englewood Cliffs, NJGoogle Scholar
  67. Kume S, Kato S, Yamagishi S, Inagaki Y, Ueda S, Arima N, Okawa T, Kojiro M, Nagata K (2005) Advanced glycation end-products attenuate human mesenchymal stem cells and prevent cognate differentiation into adipose tissue, cartilage, and bone. J Bone Miner Res 20(9):1647–1658PubMedCrossRefGoogle Scholar
  68. Labat-Robert J (2004) Cell-matrix interactions in aging: role of receptors and matricryptins. Ageing Res Rev 3(2):233–247PubMedCrossRefGoogle Scholar
  69. Lachmann HJ, Hawkins PN (2006) Systemic amyloidosis. Curr Opin Pharmacol (2):214–20Google Scholar
  70. Lanthier J, Desrosiers RR (2004) Protein L-isoaspartyl methyltransferase repairs abnormal aspartyl residues accumulated in vivo in type-I collagen and restores cell migration. Exp Cell Res 293(1):96–105PubMedCrossRefGoogle Scholar
  71. Li Z, Froehlich J, Galis ZS, Lakatta EG (1999) Increased expression of matrix metalloproteinase-2 in the thickened intima of aged rats. Hypertension 33(1):116–23PubMedCrossRefGoogle Scholar
  72. Lingelbach LB, Mitchell AE, Rucker RB, McDonald RB (2000) Accumulation of advanced glycation endproducts in aging male Fischer 344 rats during long-term feeding of various dietary carbohydrates. J Nutr 130(5):1247–1255PubMedGoogle Scholar
  73. Little WC, Zile MR, Kitzman DW, Hundley WG, O’Brien TX, Degroof RC (2005) The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail 11(3):191–195PubMedCrossRefGoogle Scholar
  74. Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J (2000) Molecular Cell Biology. W.H. Freeman, New YorkGoogle Scholar
  75. Mathews CK, van Holde KE (1990) Biochemistry. Benjamin/Cummings, Redwood CityGoogle Scholar
  76. Metz TO, Alderson NL, Thorpe SR, Baynes JW (2003) Pyridoxamine, an inhibitor of advanced glycation and lipoxidation reactions: a novel therapy for treatment of diabetic complications. Arch Biochem Biophys 419(1):41–49PubMedCrossRefGoogle Scholar
  77. Miyata T, van Ypersele de Strihou C, Kurokawa K, Baynes JW (1999) Alterations in nonenzymatic biochemistry in uremia: origin and significance of “carbonyl stress” in long-term uremic complications. Kidney Int 55(2):389–399PubMedCrossRefGoogle Scholar
  78. Monnier VM, Sell DR, Saxena A, Saxena P, Subramaniam R, Tessier F, Weiss MF (2003) Glycoxidative and carbonyl stress in aging and age-related diseases. In: Cutler RG, Rodriguez H (eds) Critical Reviews of Oxidative Stress and Aging: Advances in Basic Science, Diagnostics and Intervention, vol 1. World Scientific, Singapore, pp. 413–433Google Scholar
  79. Morimitsu Y, Yoshida K, Esaki S, Hirota A (1995) Protein glycation inhibitors from thyme (Thymus Vulgaris). Biosci Biotechnol Biochem 59(11):2018–2021PubMedCrossRefGoogle Scholar
  80. Muneoka K, Han M, Gardiner DM (2008) Regrowing human limbs. Sci Am 298(4):56–63PubMedCrossRefGoogle Scholar
  81. Murphy G, Reynolds JJ (2002) Extracellular matrix degradation. In: Royce PM, Steinmann B (eds) Connective Tissue and its Heritable Disorders. Wiley-Liss, Wilmington, pp. 343–384CrossRefGoogle Scholar
  82. Nicholson IP, Gault EA, Foote CG, Nasir L, Bennett D (2007) Human telomerase reverse transcriptase (hTERT) extends the lifespan of canine chondrocytes in vitro without inducing neoplastic transformation. Vet J 174(3):570–576PubMedCrossRefGoogle Scholar
  83. Ohgami N, Nagai R, Ikemoto M, Arai H, Kuniyasu A, Horiuchi S, Nakayama H (2001) Cd36, a member of the class b scavenger receptor family, as a receptor for advanced glycation end products. J Biol Chem 276(5):3195–3202PubMedCrossRefGoogle Scholar
  84. Parrinello S, Coppe JP, Krtolica A, Campisi J (2005) Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J Cell Sci 118(Pt 3):485–496PubMedCrossRefGoogle Scholar
  85. Pathak P, Gupta R, Chaudhari A, Shiwalkar A, Dubey A, Mandhare AB, Gupta RC, Joshi D, Chauthaiwale V (2008) TRC4149 a novel advanced glycation end product breaker improves hemodynamic status in diabetic spontaneously hypertensive rats. Eur J Med Res 13(8):388–398PubMedGoogle Scholar
  86. Peng X, Cheng KW, Ma J, Chen B, Ho CT, Lo C, Chen F, Wang M (2008) Cinnamon bark proanthocyanidins as reactive carbonyl scavengers to prevent the formation of advanced glycation endproducts. J Agric Food Chem 56(6):1907–1911PubMedCrossRefGoogle Scholar
  87. Pepys MB (2006) Amyloidosis. Annu Rev Med 57:223–241PubMedCrossRefGoogle Scholar
  88. Perry G, Smith MA (2001) Active glycation in neurofibrillary pathology of Alzheimer’s disease: N-(Carboxymethyl) lysine and hexitol-lysine. Free Radic Biol Med 31(2):175–180PubMedCrossRefGoogle Scholar
  89. Piez KA (2002) Research on collagen in the author’s laboratory, 1952–1982. In: Royce PM, Steinmann B (eds) Connective tissue and its heritable disorders. Wiley-Liss, Wilmington, pp. 1–11CrossRefGoogle Scholar
  90. Rahbar S, Natarajan R, Yerneni K, Scott S, Gonzales N, Nadler JL (2000) Evidence that pioglitazone, metformin and pentoxifylline are inhibitors of glycation. Clin Chim Acta 301(1–2):65–77PubMedCrossRefGoogle Scholar
  91. Rahbar S, Figarola JL (2003) Novel inhibitors of advanced glycation endproducts. Arch Biochem Biophys 419:63–79PubMedCrossRefGoogle Scholar
  92. Rahbar S (2007) Novel inhibitors of glycation and AGE formation. Cell Biochem Biophys 48(2–3):147–157PubMedCrossRefGoogle Scholar
  93. Requena JR, Stadtman ER (1999) Conversion of lysine to N(epsilon)-(carboxymethyl)lysine increases susceptibility of proteins to metal-catalyzed oxidation. Biochem Biophys Res Commun 264(1):207–211PubMedCrossRefGoogle Scholar
  94. Scheid A, Wenger RH, Schäffer L, Camenisch I, Distler O, Ferenc A, Cristina H, Ryan HE, Johnson RS, Wagner KF, Stauffer UG, Bauer C, Gassmann M, Meuli M (2002) Physiologically low oxygen concentrations in fetal skin regulate hypoxia-inducible factor 1 and transforming growth factor-beta3. FASEB J 16(3):411–413PubMedGoogle Scholar
  95. Rinn JL, Bondre C, Gladstone HB, Brown PO, Chang HY (2006) Anatomic demarcation by positional variation in fibroblast gene expression programs. PLoS Genet 2(7):e119PubMedCrossRefGoogle Scholar
  96. Ritz-Timme S, Collins MJ (2002) Racemization of aspartic acid in human proteins. Ageing Res Rev 1(1):43–59PubMedCrossRefGoogle Scholar
  97. Robert L, Robert AM, Fülöp T (2008) Rapid increase in human life expectancy: will it soon be limited by the aging of elastin? Biogerontology 9(2):119–133PubMedCrossRefGoogle Scholar
  98. Sajithlal GB, Chithra P, Chandrakasan G (1999) An in vitro study on the role of metal catalyzed oxidation in glycation and crosslinking of collagen. Mol Cell Biochem 194(1–2):257–263PubMedCrossRefGoogle Scholar
  99. Saxena AK, Saxena P, Wu X, Obrenovich M, Weiss MF, Monnier VM (1999) Protein aging by carboxymethylation of lysines generates sites for divalent metal and redox active copper binding: relevance to diseases of glycoxidative stress. Biochem Biophys Res Commun 260(2):332–338PubMedCrossRefGoogle Scholar
  100. Schrementi ME, Ferreira AM, Zender C, DiPietro LA (2008) Site-specific production of TGF-β in oral mucosal and cutaneous wounds. Wound Repair Regen 16(1):80–86PubMedCrossRefGoogle Scholar
  101. Sell DR, Carlson EC, Monnier VM (1993) Differential effects of type 2 (non-insulin-dependent) diabetes mellitus on pentosidine formation in skin and glomerular basement membrane. Diabetologia 36(10):936–941PubMedCrossRefGoogle Scholar
  102. Sell DR, Monnier VM (2004) Conversion of arginine into ornithine by advanced glycation in senescent human collagen and lens crystallins. J Biol Chem 279(52):54173–54184PubMedCrossRefGoogle Scholar
  103. Sell DR, Biemel KM, Reihl O, Lederer MO, Strauch CM, Monnier VM (2005) Glucosepane is a major protein cross-link of the senescent human extracellular matrix: relationship with diabetes. J Biol Chem 280(13):12310–12315PubMedCrossRefGoogle Scholar
  104. Shifren A, Mecham RP (2006) The stumbling block in lung repair of emphysema: elastic fiber assembly. Proc Am Thorac Soc 3(5):428–433PubMedCrossRefGoogle Scholar
  105. Shimizu T, Matsuoka Y, Shirasawa T (2005) Biological significance of isoaspartate and its repair system. Biol Pharm Bull 28(9):1590–1596PubMedCrossRefGoogle Scholar
  106. Sivan SS, Wachtel E, Tsitron E, Sakkee N, van der Ham F, Degroot J, Roberts S, Maroudas A (2008) Collagen turnover in normal and degenerate human intervertebral discs as determined by the racemization of aspartic acid. J Biol Chem 283(14):8796–801PubMedCrossRefGoogle Scholar
  107. Spencer VA, Xu R, Bissell MJ (2007) Extracellular matrix, nuclear and chromatin structure, and gene expression in normal tissues and malignant tumors: a work in progress. Adv Cancer Res 97:275–294PubMedCrossRefGoogle Scholar
  108. Steenvoorden MM, Toes RE, Ronday HK, Huizinga TW, Degroot J (2007) RAGE activation induces invasiveness of RA fibroblast-like synoviocytes in vitro. Clin Exp Rheumatol. 25(5):740–742Google Scholar
  109. Stern DM, Yan SD, Yan SF, Schmidt AM (2002) Receptor for advanced glycation endproducts (RAGE) and the complications of diabetes. Ageing Res Rev 1(1):1–15.PubMedCrossRefGoogle Scholar
  110. Stracke H, Hammes HP, Werkmann D, Mavrakis K, Bitsch I, Netzel M, Geyer J, Kopcke W, Sauerland C, Bretzel RG, Federlin KF (2001) Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats. Exp Clin Endocrinol Diabetes 109(6):330–336PubMedCrossRefGoogle Scholar
  111. Sturchler E, Galichet A, Weibel M, Leclerc E, Heizmann CW (2008) Site-specific blockade of RAGE-Vd prevents amyloid-β oligomer neurotoxicity. J Neurosci 28(20):5149–5158PubMedCrossRefGoogle Scholar
  112. Szwergold BS, Howell SK, Beisswenger PJ (2001) Human fructosamine-3-kinase (FN3K): purification, sequencing, substrate specificity and evidence of activity in vivo. Diabetes 50:2139–2147PubMedCrossRefGoogle Scholar
  113. Szwergold BS, Howell SK, Beisswenger PJ (2005) Transglycation - a potential new mechanism for deglycation of Schiff’s bases. Ann NY Acad Sci 1043:845–864PubMedCrossRefGoogle Scholar
  114. Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, Tanji N, Lu Y, Lalla E, Fu C, Hofmann MA, Kislinger T, Ingram M, Lu A, Tanaka H, Hori O, Ogawa S, Stern DM, Schmidt AM (2000) Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405:354–360PubMedCrossRefGoogle Scholar
  115. Taniguchi N, Caramés B, Ronfani L, Ulmer U, Komiya S, Bianchi ME, Lotz M (2009) Aging-related loss of the chromatin protein HMGB2 in articular cartilage is linked to reduced cellularity and osteoarthritis. Proc Natl Acad Sci USA 106(4):1181–1186PubMedCrossRefGoogle Scholar
  116. Tanskanen M, Peuralinna T, Polvikoski T, Notkola IL, Sulkava R, Hardy J, Singleton A, Kiuru-Enari S, Paetau A, Tienari PJ, Myllykangas L (2008) Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med 40(3):232–239PubMedCrossRefGoogle Scholar
  117. Thornalley PJ, Minhas HS (1999) Rapid hydrolysis and slow alpha,β-dicarbonyl cleavage of an agent proposed to cleave glucose-derived protein cross-links. Biochem Pharmacol 57:303–307PubMedCrossRefGoogle Scholar
  118. Thornalley PJ (2003) Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation endproducts. Arch Biochem Biophys 419(1):31–40PubMedCrossRefGoogle Scholar
  119. Tikellis C, Thomas MC, Harcourt BE, Coughlan MT, Pete J, Bialkowski K, Tan A, Bierhaus A, Cooper ME, Forbes JM (2008) Cardiac inflammation associated with a Western diet is mediated via activation of RAGE by AGEs. Am J Physiol Endocrinol Metab 295(2):E323–E330PubMedCrossRefGoogle Scholar
  120. Tredget EE, Ding J (2009) Wound healing: from embryos to adults and back again. Lancet 373(9671):1226–1228PubMedCrossRefGoogle Scholar
  121. Ulrich P, Zhang X (1997) Pharmacological reversal of advanced glycation end-product-mediated protein crosslinking. Diabetologia 40:S157–S159PubMedCrossRefGoogle Scholar
  122. Ulrich P, Cerami A (2001) Protein glycation, diabetes, and aging. Recent Prog Horm Res 56:1–21PubMedCrossRefGoogle Scholar
  123. Usta MF, Kendirci M, Bivalacqua TJ, Gur S, Hellstrom WJG, Foxwell NA, Cellek S (2004) Delayed administration of ALT-711, but not of aminoguanidine, improves erectile function in streptozotocin diabetic rats: curative versus preventive medicine. Paper presented at the 11th World Congress of the International Society for Sexual and Impotence Research, Buenos Aires, October 2004Google Scholar
  124. Usta MF, Kendirci M, Gur S, Foxwell NA, Bivalacqua TJ, Cellek S, Hellstrom WJ (2006) The breakdown of preformed advanced glycation end products reverses erectile dysfunction in streptozotocin-induced diabetic rats: preventive versus curative treatment. J Sex Med 3(2):242–250PubMedCrossRefGoogle Scholar
  125. Vaitkevicius PV, Lane M, Spurgeon H, Ingram DK, Roth GS, Egan JJ, Vasan S, Wagle DR, Ulrich P, Brines M, Wuerth JP, Cerami A, Lakatta EG (2001) A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys. Proc Natl Acad Sci USA 98(3):1171–1175PubMedCrossRefGoogle Scholar
  126. Vasan S, Zhang X, Zhang X, Kapurniotu A, Bernhagen J, Teichberg S, Basgen J, Wagle D, Shih D, Terlecky I, Bucala R, Cerami A, Egan J, Ulrich P (1996) An agent cleaving glucose- derived protein crosslinks in vitro and in vivo. Nature 382(6588):275–278PubMedCrossRefGoogle Scholar
  127. Vasan S, Foiles PG, Founds HW (2001) Therapeutic potential of AGE inhibitors and breakers of AGE protein cross-links. Expert Opin Investig Drugs 10(11):1977–1987PubMedCrossRefGoogle Scholar
  128. Vasan S, Foiles P, Founds H (2003) Therapeutic potential of breakers of advanced glycation end product-protein crosslinks. Arch Biochem Biophys 419(1):89–96PubMedCrossRefGoogle Scholar
  129. Vater CA, Harris ED Jr, Siegel RC (1979) Native cross-links in collagen fibrils induce resistance to human synovial collagenase. Biochem J 181(3):639–645PubMedGoogle Scholar
  130. Verzijl N, DeGroot J, Thorpe SR, Bank RA, Shaw JN, Lyons TJ, Bijlsma JW, Lafeber FP, Baynes JW, TeKoppele JM (2000) Effect of collagen turnover on the accumulation of advanced glycation end products. J Biol Chem 275(50):39027–39031PubMedCrossRefGoogle Scholar
  131. Verzijl N, DeGroot J, Bank RA, Bayliss MT, Bijlsma JW, Lafeber FP, Maroudas A, TeKoppele JM (2001) Age-related accumulation of the advanced glycation endproduct pentosidine in human articular cartilage aggrecan: the use of pentosidine levels as a quantitative measure of protein turnover. Matrix Biol 20(7):409–417PubMedCrossRefGoogle Scholar
  132. Verzijl N, Bank RA, TeKoppele JM, DeGroot J (2003) AGEing and osteoarthritis: a different perspective. Curr Opin Rheumatol (5):616–622Google Scholar
  133. Vlassara H, Cai W, Crandall J, Goldberg T, Oberstein R, Dardaine V, Peppa M, Rayfield EJ (2002) Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. Proc Natl Acad Sci USA 99(24):15596–15601PubMedCrossRefGoogle Scholar
  134. Vlassara H, Palace MR (2003) Glycoxidation: the menace of diabetes and aging. Mt Sinai J Med 70(4):232–241PubMedGoogle Scholar
  135. Wagenseil JE, Mecham RP (2007) New insights into elastic fiber assembly. Birth Defects Res C Embryo Today 81(4):229–240PubMedCrossRefGoogle Scholar
  136. Wang M, Lakatta EG (2002) Altered regulation of matrix metalloproteinase-2 in aortic remodeling during aging. Hypertension 39(4):865–873PubMedCrossRefGoogle Scholar
  137. Wang M, Takagi G, Asai K, Resuello RG, Natividad FF, Vatner DE, Vatner SF, Lakatta EG (2003) Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates. Hypertension 41(6):1308–1316PubMedCrossRefGoogle Scholar
  138. Weber DJ, McFadden PN (1997) Injury-induced enzymatic methylation of aging collagen in the extracellular matrix of blood vessels. J Protein Chem 16(4):269–281PubMedCrossRefGoogle Scholar
  139. Wolffenbuttel BH, Boulanger CM, Crijns FR, Huijberts MS, Poitevin P, Swennen GN, Vasan S, Egan JJ, Ulrich P, Cerami A, Lévy BI (1998) Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proc Natl Acad Sci USA 95(8):4630–4634PubMedCrossRefGoogle Scholar
  140. Wu CH, Yen GC (2005) Inhibitory effect of naturally occurring flavonoids on the formation of advanced glycation endproducts. J Agric Food Chem 53(8):3167–3173PubMedCrossRefGoogle Scholar
  141. Xiao H, Cai G, Liu M (2007) Fe2+-catalyzed non-enzymatic glycosylation alters collagen conformation during AGE-collagen formation in vitro. Arch Biochem Biophys 468(2):183–192PubMedCrossRefGoogle Scholar
  142. Yang S, Litchfield JE, Baynes JW (2003) AGE-breakers cleave model compounds, but do not break Maillard crosslinks in skin and tail collagen from diabetic rats. Arch Biochem Biophys 412(1):42–46PubMedCrossRefGoogle Scholar
  143. Zieman SJ, Melenovsky V, Clattenburg L, Corretti MC, Capriotti A, Gerstenblith G, Kass DA (2007) Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension. J Hypertens 25(3):577–583PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.Legendary PharmaceuticalsGainesvilleUSA

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