Skip to main content
SpringerLink
Log in

Glykotoxine und Zellaktivierung

Neuere Erklärungsmodelle zum Mechanismus präventiv wirksamer Lebensstilmodifikationen

Glycotoxins and cellular dysfunction. A new mechanism for understanding the preventive effects of lifestyle modifications

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz volume 49, pages 773–779 (2006)Cite this article

Zusammenfassung

Die AGE-RAGE-Interaktion ist ein kürzlich beschriebener möglicher pathogenetischer Mechanismus chronischer und inflam matorischer Erkrankungen wie Arterio sklerose, Diabetes mellitus oder Niereninsuffizienz. AGEs (advanced glycation end products) werden in einer Glykierungsreaktion von Zuckern mit Eiweißen und/oder Fetten aus der Nahrung in Abhängigkeit von der Zubereitungszeit, Zubereitungstemperatur und Sauerstoffverfügbarkeit gebildet. Im Körper akkumulieren sie in Geweben und Gefäßen. Die Bindung von AGEs an den AGE-Rezeptor (RAGE) auf der Oberfläche von Zellen induziert eine ausgeprägte inflammatorische Reaktion. Entsprechende Reaktionen werden auch durch andere Faktoren wie Rauchen und psychosozialen Stress hervor gerufen. Vor dem Hintergrund des AGE-RAGE-Modells finden präventiv wirksame Ernährungsformen wie Mittelmeerkost/vegetarische Frischkost, aber auch die günstigen Wirkungen von Kalorienrestriktion und therapeutischem Fasten eine Erklärung. Das gesundheitsfördernde Potenzial dieser Maßnahmen sollte in klinischen Studien weiter evaluiert werden.

Abstract

Recently the AGE-RAGE interaction was identified as a potential mechanism underlying chronic and inflammatory diseases like atherosclerosis, diabetes mellitus and kidney disease. Advanced glycation end products (AGEs) are the derivatives of glucose-protein or glucose-lipid reactions and are mainly generated from the diet (depending on intensity of heating, cooking time and oxygenation). Binding of AGEs or other ligands to the AGE receptor (RAGE) results in cellular activation, i.e. increased expression of inflammatory mediators and oxidative stress. Diet-derived AGEs thus induce deleterious effects on tissues and the cardiovascular system. Recent research also found that other lifestyle factors are associated with pronounced inflammatory activation, e.g. psychosocial stress and smoking. In addition, each intake of meals is associated with proinflammatory cellular changes. The AGE-RAGE model and investigations of the underlying cellular mechanisms thus may lead to a better understanding of the health benefits of diets (Mediterranean diet, uncooked vegetarian diets), caloric restriction and intermittent fasting. The clinical impact of low-AGE diets and fasting and the interaction between stress and food intake should be further investigated in controlled trials.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Literatur

  1. de Lorgeril M, Salen P, Martin JL et al. (1999) Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation 99: 779–785

    PubMed  CAS  Google Scholar 

  2. Libby P (2002) Inflammation in atherosclerosis. Nature 420: 868–874

    Article  PubMed  CAS  Google Scholar 

  3. Bierhaus A, Humpert PM, Morcos M et al. (2005) Understanding RAGE, the receptor for advanced glycation end products. J Mol Med 83: 876–886

    Article  PubMed  CAS  Google Scholar 

  4. Bierhaus A, Humpert PM, Stern DM et al. (2005) Advanced glycation end product receptormediated cellular dysfunction. Ann N Y Acad Sci 1043: 676–680

    Article  PubMed  CAS  Google Scholar 

  5. Vlassara H (2005) Advanced glycation in health and disease: role of the modern environment. Ann N Y Acad Sci 1043: 452–460

    Article  PubMed  CAS  Google Scholar 

  6. Uribarri J, Peppa M, Cai W et al. (2003) Restriction of dietary glycotoxins reduces excessive advanced glycation end products in renal failure patients. J Am Soc Nephrol 14: 728–731

    Article  PubMed  CAS  Google Scholar 

  7. Vlassara H, Palace MR (2002) Diabetes and advanced glycation endproducts. J Intern Med 251: 87–101

    Article  PubMed  CAS  Google Scholar 

  8. Wendt TM, Tanji N, Guo J et al. (2003) RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol 162: 1123–1137

    PubMed  CAS  Google Scholar 

  9. Lin RY, Choudhury RP, Cai W et al. (2003) Dietary glycotoxins promote diabetic atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis 168: 213–220

    Article  PubMed  CAS  Google Scholar 

  10. Isermann B, Bierhaus A, Humpert PM et al. (2004) AGE-RAGE: A hypothesis or a mechanism? Herz 29: 504–509

    Article  PubMed  Google Scholar 

  11. Bierhaus A, Hofmann MA, Ziegler R, Nawroth PP (1998) AGEs and their interaction with AGEreceptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovasc Res 37: 586–600

    Article  PubMed  CAS  Google Scholar 

  12. Bierhaus A, Illmer T, Kasper M et al. (1997) Advanced glycation end product (AGE)-mediated induction of tissue factor in cultured endothelial cells is dependent on RAGE. Circulation 96: 2262–2271

    PubMed  CAS  Google Scholar 

  13. Hofmann MA, Drury S, Fu C et al. (1999) RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97: 889–901

    Article  PubMed  CAS  Google Scholar 

  14. Vlassara H, Uribarri J (2004) Glycoxidation and diabetic complications: modern lessons and a warning? Rev Endocr Metab Disord 5: 181–188

    Article  PubMed  CAS  Google Scholar 

  15. Munch G et al. (2002) Glyoxidative stress creates a vicious circle of neurodegeneration in Alzheimer‘s disease – a target for neuroprotective treatment strategies? J Neural Transm 62:303–307

    CAS  Google Scholar 

  16. Sell DR, Lane MA, Johnson WA et al. (1996) Longevity and the genetic determination of collagen glycoxidation kinetics in mammalian senescence. Proc Natl Acad Sci USA 93: 485–490

    Article  PubMed  CAS  Google Scholar 

  17. Nawroth P, Bierhaus A, Marrero M et al. (2005) Atherosclerosis and restenosis: Is there a role for RAGE? Curr Diab Rep 5: 1–16

    Google Scholar 

  18. Koschinsky T, He CJ, Mitsuhashi T et al. (1997) Orally absorbed reactive glycation products (glycotoxins): an environmental risk factor in diabetic nephropathy. Proc Natl Acad Sci USA 94: 647–649

    Article  Google Scholar 

  19. Goldberg T, Cai W, Peppa M et al. (2004) Advanced glycoxidation end products in commonly consumed foods. J Am Diet Assoc 104: 1287–1291

    Article  PubMed  CAS  Google Scholar 

  20. McCarty MF (2005) The low-AGE content of lowfat vegan diets could benefit diabetics – though concurrent taurine supplementation may be needed to minimize endogenous AGE production. Med Hypotheses 64: 394–398

    Article  PubMed  CAS  Google Scholar 

  21. Peppa M, Goldberg T, Cai W et al. (2002) Glycotoxins: a missing link in the „relationship of dietary fat and meat intake in relation to risk of type 2 diabetes in men“. Diabetes Care 25: 1898–1899

    PubMed  Google Scholar 

  22. Lin RY, Reis ED, Dore AT et al. (2002) Lowering of dietary advanced glycation endproducts (AGE) reduces neointimal formation after arterial injury in genetically hypercholesterolemic mice. Atherosclerosis 163: 303–311

    Article  PubMed  CAS  Google Scholar 

  23. Wendt T, Tanji N, Guo J et al. (2003) Glucose, glycation, and RAGE: implications for amplification of cellular dysfunction in diabetic nephropathy. J Am Soc Nephrol 14: 1383–1395

    Article  PubMed  CAS  Google Scholar 

  24. Bierhaus A, Schiekofer S, Schwaninger M et al. (2001) Diabetes-associated sustained activation of the transcription factor nuclear factor-kB. Diabetes 50: 2792–2808

    PubMed  CAS  Google Scholar 

  25. Krajcovicova-Kudlackova M, Sebekova K, Schinzel R, Klvanova J (2002) Advanced glycation end products and nutrition. Physiol Res 51: 313–316

    PubMed  CAS  Google Scholar 

  26. Esposito K, Marfella R, Ciotola M et al. (2004) Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. Jama 292: 1440–1446

    Article  PubMed  CAS  Google Scholar 

  27. Skoldstam L, Hagfors L, Johansson G (2003) An experimental study of a Mediterranean diet intervention for patients with rheumatoid arthritis. Ann Rheum Dis 62: 208–214

    Article  PubMed  CAS  Google Scholar 

  28. Ornish D, Scherwitz LW, Billings JH et al. (1998) Intensive lifestyle changes for reversal of coronary heart disease. JAMA 280: 2001–2027

    Article  PubMed  CAS  Google Scholar 

  29. Peltonen R, Nenonen M, Helve T et al. (1997) Faecal microbial flora and disease activity in rheumatoid arthritis during a vegan diet. Br J Rheumatol 36: 64–68

    Article  PubMed  CAS  Google Scholar 

  30. Wendt L, Wendt T (1973) Die Eiweißspeicherkrankheiten. Haug, Heidelberg

  31. Cai W, He JC, Zhu L et al. (2004) High levels of dietary advanced glycation end products transform low-density lipoprotein into a potent redox-sensitive mitogen-activated protein kinase stimulant in diabetic patients. Circulation 110: 285–291

    Article  PubMed  CAS  Google Scholar 

  32. Holloszy JO (1997) Mortality rate and longevity of food-restricted exercising male rats: a reevaluation. J Appl Physiol 82: 399–403

    PubMed  CAS  Google Scholar 

  33. Weindruch R (2003) Caloric restriction, gene expression, and aging. Alzheimer Dis Assoc Disord 17 [Suppl 2]: 58–59

    Article  Google Scholar 

  34. Mattson MP (2005) Energy intake, meal frequency, and health: a neurobiological perspective. Annu Rev Nutr 25: 237–260

    Article  PubMed  CAS  Google Scholar 

  35. Mattson MP (2005) The need for controlled studies of the effects of meal frequency on health. Lancet 365: 1978–1980

    Article  PubMed  Google Scholar 

  36. Michalsen A, Hoffmann B, Moebus S et al. (2005) Incorporation of fasting therapy in an integrative medicine ward: evaluation of outcome, safety, and effects on lifestyle adherence in a large prospective cohort study. J Altern Complement Med 11: 601–607

    Article  PubMed  Google Scholar 

  37. Schubmann R, Graban I, Hölz G, Zwingmann C (1997) Ergebnisqualität stationärer Rehabilitation bei Patienten mit Adipositas. Dtsch Rentenversicherung 9–10: 1–22

    Google Scholar 

  38. Kjeldsen-Kragh J, Haugen M, Borchgrevink CF et al. (1991) Controlled trial of fasting and one-year vegetarian diet in rheumatoid arthritis. Lancet 338: 899–902

    Article  PubMed  CAS  Google Scholar 

  39. Müller H, Wilhelmi de Toledo F, Resch KL (2000) A systematic review of clinical studies on fasting and vegetarian diets in the treatment of rheumatoid arthritis. Scand J Rheumatol 30: 1–10

    Google Scholar 

  40. Aljada A, Mohanty P, Ghanim H et al. (2004) Increase in intranuclear nuclear factor kappaB and decrease in inhibitor kappaB in mononuclear cells after a mixed meal: evidence for a proinflammatory effect. Am J Clin Nutr 79: 682–690

    PubMed  CAS  Google Scholar 

  41. Schiekofer S, Franke S, Andrassy M et al. (2006) Postprandial mononuclear NF-kB activation is independent of the AGE-content of a single meal. Experimental Clin Endocrinol Diabetes 114: 160–167

    Article  CAS  Google Scholar 

  42. Huether G, Schmidt S, Rüther E (1998) Essen, Serotonin und Psyche: Die unbewusste nutritive Manipulation von Stimmungen und Gefühlen. Dtsch Ärztebl 95: A-477–479

    Google Scholar 

  43. Michalsen A, Schneider S, Rodenbeck A et al. (2003) The short-term effects of fasting on the neuroendocrine system in patients with chronic pain syndromes. Nutr Neurosci 6: 11–18

    PubMed  CAS  Google Scholar 

  44. Michalsen A, Schlegel F, Rodenbeck A et al. (2003) Effects of short-term modified fasting on sleep patterns and daytime vigilance in non-obese subjects: results of a pilot study. Ann Nutr Metab 47:194–200

    Article  PubMed  CAS  Google Scholar 

  45. Owen OE, Smalley KJ, D‘Alessio DA et al. (1998) Protein, fat, and carbohydrate requirements during starvation: anaplerosis and cataplerosis. Am J Clin Nutr 68: 12–34

    PubMed  CAS  Google Scholar 

  46. Wechsler J et al. (1983) Fastentherapie der Adipositas. Thieme Verlag, Stuttgart 11: 71–79

  47. Esch T, Stefano GB, Fricchione GL, Benson H (2002) Stress-related diseases – a potential role for nitric oxide. Med Sci Monit 8: RA103–118

    PubMed  CAS  Google Scholar 

  48. Bierhaus A, Wolf J, Andrassy M et al. (2003) A mechanism converting psychosocial stress into mononuclear cell activation. Proc Natl Acad Sci USA 100: 1920–1925

    Article  PubMed  CAS  Google Scholar 

  49. David M (2004) Eating from the tree: nutrition lessons for the scientific soul. Altern Ther Health Med 10: 10–13, 78–81

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Abteilung Innere Medizin, Naturheilkunde und Integrative Medizin, Kliniken Essen Mitte, Am Deimelsberg 34a, 45276, Essen, BRD

    A. Michalsen

  2. Universitätsklinik Heidelberg, Heidelberg, BRD

    A. Bierhaus, P. P. Nawroth & G. J. Dobos

Authors
  1. A. Michalsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Bierhaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. P. Nawroth
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. J. Dobos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Michalsen.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Michalsen, A., Bierhaus, A., Nawroth, P.P. et al. Glykotoxine und Zellaktivierung. Bundesgesundheitsbl. 49, 773–779 (2006). https://doi.org/10.1007/s00103-006-0007-7

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00103-006-0007-7

Schlüsselwörter

Keywords

search

Navigation