, Volume 35, Issue 4, pp 1205–1217 | Cite as

Biomarkers of oxidative stress, antioxidant defence and inflammation are altered in the senescence-accelerated mouse prone 8

  • Banu Bayram
  • Sibylle Nikolai
  • Patricia Huebbe
  • Beraat Ozcelik
  • Stefanie Grimm
  • Tilman Grune
  • Jan Frank
  • Gerald RimbachEmail author


In this study we compared biomarkers of oxidative stress, stress response, antioxidant defence and inflammation between mice (n = 10 per group, female, 7 months old) with an accelerated (SAMP8) and a normal ageing phenotype (SAMR1). As compared to SAMR1 mice, SAMP8 mice exhibited higher levels of lipid peroxides and protein carbonyls as well as a lower activity of the proteasomal subunit β-5. Furthermore, heme oxygenase-1 and paraoxonase-1 (PON-1) status was lower in SAMP8 mice indicating impaired stress response. Biomarkers of inflammation such as C-reactive protein and serum amyloid P were elevated in SAMP8 mice. Interestingly, impaired stress response and increased inflammation in SAMP8 mice were associated with elevated concentrations of ascorbic acid and α-tocopherol in the liver. An age-dependent increase in hepatic vitamin E and a decline in PON-1 gene expression were also observed in aged compared to young C57BL/6 mice.


SAMP8 Accelerated ageing Stress response Proteasomal activity Ascorbic acid Tocopherol 



BB is supported by TUBITAK (The Scientific and Technological Research Council of Turkey). JF is supported by grant no. FR 2478/4-1 from the German Research Foundation (DFG) and grant no. 0315679A from the German Federal Ministry of Education and Research (BMBF). GR is supported by the BMBF and the DFG Cluster of Excellence “Inflammation at Interfaces”.


  1. Álvarez-García O, Vega-Naredo I, Sierra V, Caballero B, Tomás-Zapico C, Camins A, Garciá JJ, Palls M, Coto-Montes A (2006) Elevated oxidative stress in the brain of senescence-accelerated mice at 5 months of age. Biogerontology 7:43–52PubMedCrossRefGoogle Scholar
  2. Amano A, Aigaki T, Maruyama N, Ishigami A (2010) Ascorbic acid depletion enhances expression of the sodium-dependent vitamin C transporters, SVCT1 and SVCT2, and uptake of ascorbic acid in livers of SMP30/GNL knockout mice. Arch Biochem Biophys 496:38–44PubMedCrossRefGoogle Scholar
  3. Azzi A, Gysin R, Kempná P, Ricciarelli R, Villacorta L, Visarius T, Zingg JM (2003) The role of α-tocopherol in preventing disease: from epidemiology to molecular events. Mol Aspects Med 24:325–336PubMedCrossRefGoogle Scholar
  4. Breusing N, Arndt J, Voss P, Bresgen N, Wiswedel I, Gardemann A, Siems W, Grune T (2009) Inverse correlation of protein oxidation and proteasome activity in liver and lung. Mech Ageing Dev 130:748–753PubMedCrossRefGoogle Scholar
  5. Brigelius-Flohé R, Traber MG (1999) Vitamin E: function and metabolism. FASEB J 13:1145–1155PubMedGoogle Scholar
  6. Brigelius-Flohé R, Roob JM, Tiran B, Wuga S, Ribalta J, Rock E, Winklhofer-Roob BM (2004) The effect of age on vitamin E status, metabolism, and function metabolism as assessed by labeled tocopherols. Ann NY Acad Sci 1031:40–43PubMedCrossRefGoogle Scholar
  7. Burton G, Joyce A, Ingold KU (1982) First proof that vitamin E is a major lipid soluble, chain-breaking antioxidant in human blood plasma. Lancet 320:327CrossRefGoogle Scholar
  8. Buss H, Chan TP, Sluis KB, Domigan NM, Winterbourn CC (1997) Protein carbonyl measurement by a sensitive ELISA method. Free Radic Biol Med 23:361–366PubMedCrossRefGoogle Scholar
  9. Caliebe A, Kleindorp R, Blanché H, Christiansen L, Puca AA, Rea IM, Slagboom E, Flachsbart F, Christensen K, Rimbach G, Schreiber S, Nebel A (2010) No or only population-specific effect of PON1 on human longevity: a comprehensive meta-analysis. Ageing Res Rev 9:238–244PubMedCrossRefGoogle Scholar
  10. Carretero M, Escames G, López LC, Venegas C, Dayoub JC, García L, Acuňa-Castroviejo D (2009) Long-term melatonin administration protects brain mitochondria from ageing. J Pineal Res 47:192–200PubMedCrossRefGoogle Scholar
  11. Chatterjee IB, Kar NC, Ghosh NC, Guha BC (1961) Biosynthesis of L-ascorbic acid: missing steps in animals incapable of synthesizing the vitamin. Nature 192:163–164PubMedCrossRefGoogle Scholar
  12. Chondrogianni N, Tzavelas C, Pemberton AJ, Nezis IP, Rivett AJ, Gonos ES (2005) Overexpression of proteasome β-5 subunit increases the amount of assembled proteasome and confers ameliorated response to oxidative stress and higher survival rates. J Biol Chem 280:11840–11850PubMedCrossRefGoogle Scholar
  13. Chung HY, Cesari M, Anton S, Marzetti E, Giovannini S, Seo AY, Carter C, Yu BP, Leeuwenburgh C (2009) Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res Rev 8:18–30PubMedCrossRefGoogle Scholar
  14. Constantinescu A, Han D, Packer L (1993) Vitamin E recycling in human erythrocyte membranes. J Biol Chem 268:10906–10913PubMedGoogle Scholar
  15. Cuesta S, Kireev R, Forman K, García C, Escames G, Ariznavarreta C, Vara E, Tresguerres JAF (2010) Melatonin improves inflammation processes in liver of senescence-accelerated prone male mice (SAMP8). Exp Gerontol 45:950–956PubMedCrossRefGoogle Scholar
  16. Cuesta S, Kireev R, García C, Rancan L, Vara E, Tresguerres JA (2012) Melatonin can improve insulin resistance and aging-induced pancreas alterations in senescence-accelerated prone male mice (SAMP8). Age. doi: 10.1007/s11357-012-9397-7
  17. Dullaart RPF, de Vries R, Sluiter WJ, Voorbij HAM (2009) High plasma C-reactive protein (CRP) is related to low paraoxonase-I (PON-I) activity independently of high leptin and low adiponectin in type 2 diabetes mellitus. Clin Endocrinol 70:221–226CrossRefGoogle Scholar
  18. Fan X, Leneker LW, Obrenovich ME, Strauch C, Cheng R, Jarvis SM, Ortwerth BJ, Monnier VM (2006) Vitamin C mediates chemical aging of lens crystallins by the Millard reaction in a humanized mouse model. PNAS 103:16912–16917PubMedCrossRefGoogle Scholar
  19. Farr SA, Poon HF, Dogrukol-Ak D, Drake J, Banks WA, Eyerman E, Butterfield A, Morley JE (2003) The antioxidants α-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. J Neurochem 84:1173–1183PubMedCrossRefGoogle Scholar
  20. Fenton M, Huang HL, Hong Y, Hawe E, Kurz DJ, Erusalimsky JD (2004) Early atherogenesis in senescence-accelerated mice. Exp Gerontol 39:115–122PubMedCrossRefGoogle Scholar
  21. Forman K, Vara E, García C, Kireev R, Cuesta S, Acuña-Castroviejo D, Tresguerres JA (2010) Beneficial effects of melatonin on cardiological alterations in a murine model of accelerated aging. J Pineal Res 49:312–320PubMedCrossRefGoogle Scholar
  22. Frank J, Budek A, Lundh T, Parker RS, Swanson JE, Lourenco B, Gago J, Laranjinha J, Vessby B, Kamal-Eldin A (2006) Dietary flavonoids with a catechol structure increase α-tocopherol in rats and protect the vitamin from oxidation in vitro. J Lipid Res 47:2718–2725PubMedCrossRefGoogle Scholar
  23. Fuhrman B, Volkova N, Aviram A (2006) Postprandial serum triacylglycerols and oxidative stress in mice after consumption of fish oil, soy oil or olive oil: possible role for paraoxonase-1 triacylglycerol lipase-like activity. Nutrition 22:922–930PubMedCrossRefGoogle Scholar
  24. Gaedicke S, Zhang X, Schmelzer C, Lou Y, Doering F, Frank J, Rimbach G (2008) Vitamin E dependent microRNA regulation in rat liver. FEBS Lett 582:3542–3546PubMedCrossRefGoogle Scholar
  25. Gong Y, Liu L, Xie B, Liao Y, Yang E, Sun Z (2008) Ameliorative effects of lotus seedpod proanthocyanidins on cognitive deficits and oxidative damage in senescence-accelerated mice. Behav Brain Res 194:100–107PubMedCrossRefGoogle Scholar
  26. Han SN, Adolfsson O, Lee CK, Prolla TA, Ordovas J, Meydani SN (2004) Vitamin E and gene expression in immune cells. Ann NY Acad Sci 1031:96–101PubMedCrossRefGoogle Scholar
  27. Hoare M, Das T, Alexander G (2010) Ageing, telomeres, senescence, and liver injury. J Hepatol 53:950–961PubMedCrossRefGoogle Scholar
  28. Idriss NK, Blann AD, Lip GYH (2008) Hemoxygenase-1 in cardiovascular disease. J Am Coll Cardiol 52:971–978PubMedCrossRefGoogle Scholar
  29. Jula A, Marniemi J, Huupponen R, Virtanen A, Rastas M, Rönnemaa T (2002) Effects of diet and simvastatin on serum lipids, insulin, and antioxidants in hypercholesterolemic men: a randomized controlled trial. JAMA 287:598–605PubMedCrossRefGoogle Scholar
  30. Kourtis N, Tavernarakis N (2011) Cellular stress response pathways and ageing: intricate molecular relationships. EMBO J 30:2520–2531PubMedCrossRefGoogle Scholar
  31. Kunes JP, Cordero-Koning KS, Lee LH, Lynch SM (2009) Vitamin C attenuates hypochlorite-mediated loss of paraoxonase-1 activity from human plasma. Nutr Res 29:114–122PubMedCrossRefGoogle Scholar
  32. Liu Y, He J, Ji S, Wang S, Pu H, Jiang T, Meng L, Yang X, Ji J (2008) Comparative studies of early liver dysfunction in senescence-accelerated mouse using mitochondrial proteomics approaches. Mol Cell Proteomics 7:1737–1747PubMedCrossRefGoogle Scholar
  33. Mármol F, Sánchez J, López D, Martínez N, Xaus C, Peralta C, Roselló-Catafau J, Mitjavila MT, Puig-Parellada P (2010) Role of oxidative stress and adenosine nucleotides in the liver of aging rats. Physiol Res 59:553–560PubMedGoogle Scholar
  34. Matsugo S, Kitagawa T, Minami S, Esashi Y, Oomura Y, Tokumaru S, Kojo S, Matsushima K, Sasaki K (2000) Age-dependent changes in lipid peroxide levels in peripheral organs, but not in brain, in senescence-accelerated mice. Neurosci Lett 278:105–108PubMedCrossRefGoogle Scholar
  35. Morel DW, Hessler JR, Chisolm GM (1983) Low density lipoprotein cytotoxicity induced by free radical peroxidation of lipid. J Lipid Res 24:1070–1076PubMedGoogle Scholar
  36. Mueller PY, Netscher T, Frank J, Stöcklin E, Rimbach G, Barella L (2005) Comparative quantification of pharmacodynamic parameters of chiral compounds by global gene expression profiling. J Plant Physiol 162:811–817CrossRefGoogle Scholar
  37. Packer L, Weber SU, Rimbach G (2001) Molecular aspects of α-tocotrienol antioxidant action and cell signalling. J Nutr 131:369–373Google Scholar
  38. Petursdottir AL, Farr SA, Morley JE, Banks WA, Skuladottir GV (2007) Lipid peroxidation in brain during aging in the senescence-accelerated mouse (SAM). Neurobiol Aging 28:1170–1178PubMedCrossRefGoogle Scholar
  39. Radák Z, Chung HY, Naito H, Takahashi R, Jung KJ, Kim HJ, Goto S (2004) Age-associated increase in oxidative stress and nuclear factor kappaB activation are attenuated in rat liver by regular exercise. FASEB J 18:749–750PubMedGoogle Scholar
  40. Rebrin I, Zicker S, Wedekind KJ, Paetau-Robinson I, Packer L, Sohal RS (2005) Effect of antioxidant-enriched diets on glutathione redox status in tissue homogenates and mitochondria of the senescence-accelerated mouse. Free Radic Biol Med 39:549–557PubMedCrossRefGoogle Scholar
  41. Rimbach G, Minihane AM, Macewicz J, Fischer A, Pallauf J, Virgili F, Weinberg PD (2002) Regulation of cell signalling by vitamin E. Proc Nutr Soc 61:415–425PubMedCrossRefGoogle Scholar
  42. Rimbach G, Moehring J, Huebbe P, Lodge JK (2010) Gene-regulatory activity of alpha-tocopherol. Molecules 15:1746–1761PubMedCrossRefGoogle Scholar
  43. Ristow M, Zarse K, Oberbach A, Klöting N, Birringer M, Kiehntopf M, Stumvoll M, Kahn CR, Blüher M (2009) Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci 106:8665–8670PubMedCrossRefGoogle Scholar
  44. Sato E, Oda N, Ozaki N, Hashimoto S, Kurokawa T, Ishibashi S (1996) Early and transient increase in oxidative stress in the cerebral cortex of senescence-accelerated mouse. Mech Ageing Dev 86:105–114PubMedCrossRefGoogle Scholar
  45. Satoh T, Okamoto SI, Cui J, Watanabe Y, Furuta K, Suzuki M, Tohyama K, Lipton SA (2006) Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophilic phase II inducers. Proc Natl Acad Sci USA 103:768–773PubMedCrossRefGoogle Scholar
  46. Savini I, Rossi A, Pierro C, Avigliano L, Catani MV (2008) SVCT1 and SVCT2: key proteins for vitamin C uptake. Amino Acids 34:347–355PubMedCrossRefGoogle Scholar
  47. Scarpa M, Rigo A, Maiorino M, Ursini F, Gregolin C (1984) Formation of α-tocopherol radical and recycling of α-tocopherol by ascorbate during peroxidation of phosphatidylcholine liposomes. An electron paramagnetic resonance study. Biochim Biophys Acta 801:215–219PubMedCrossRefGoogle Scholar
  48. Schiborr C, Eckert GP, Weissenberger J, Müller WE, Schwamm D, Grune T, Rimbach G, Frank J (2010) Cardiac oxidative stress and inflammation are similar in SAMP8 and SAMR1 mice and unaltered by curcumin and Ginkgo biloba extract intake. Curr Pharm Biotechnol 11:861–867PubMedCrossRefGoogle Scholar
  49. Schrader C, Rimbach G (2011) Determinants of paraoxonase 1 status: genes, drugs and nutrition. Curr Med Chem 18:5624–5643PubMedCrossRefGoogle Scholar
  50. Sun LY, Bokov AF, Richardson A, Miller RA (2011) Hepatic response to oxidative injury in long-lived Ames dwarf mice. FASEB J 25:398–408PubMedCrossRefGoogle Scholar
  51. Takeda T (1999) Senescence-accelerated mouse (SAM): a biogerontological resource in aging research. Neurobiol Aging 20:105–110PubMedCrossRefGoogle Scholar
  52. Tan Q, Christiansen L, Bathum L, Li S, Kruse TA, Christensen K (2006) Genetic association analysis of human longevity in cohort studies of elderly subjects: an example of the PON1 gene in the Danish 1905 birth cohort. Genetics 172:1821–1828PubMedCrossRefGoogle Scholar
  53. Tha KK, Okuma Y, Miyazaki H, Murayama T, Uehara T, Hatakeyama R, Hayashi Y, Nomura Y (2000) Changes in expressions of proinflammatory cytokines IL-1β, TNF-α and IL-6 in the brain of senescence accelerated mouse (SAM) P8. Brain Res 885:25–31PubMedCrossRefGoogle Scholar
  54. Traber MG, Stevens JF (2011) Vitamins C and E: beneficial effects from a mechanistic perspective. Free Radic Biol Med 51:1000–1013PubMedCrossRefGoogle Scholar
  55. Tsakiris S, Karikas GA, Parthimos T, Tsakiris T, Bakogiannis C, Schulpis KH (2009) Alpha-tocopherol supplementation prevents the exercise-induced reduction of serum paraoxonase 1/arylesterase activities in healthy individuals alpha-T vs PON 1/aryl activities. Eur J Clin Nutr 63:215–221PubMedCrossRefGoogle Scholar
  56. Wagner AE, Boesch-Saadatmandi C, Breckwoldt D, Schrader C, Schmelzer C, Döring F, Hashida K, Hori O, Matsugo S, Rimbach G (2011) Ascorbic acid partly antagonizes resveratrol mediated heme oxygenase-1 but not paraoxonase-1 induction in cultured hepatocytes—role of the redox-regulated transcription factor Nrf2. BMC Complement Altern Med 11:1–8PubMedCrossRefGoogle Scholar
  57. Yu HP, Hwang TL, Hsieh PW, Lau YT (2011) Role of estrogen receptordependent upregulation of p38MAPK/hemeoxygenase-1 in resveratrol-mediated attenuation of intestinal injury after trauma-hemorrhage. Shock 35:517–523PubMedCrossRefGoogle Scholar
  58. Yuan M, Wen-Xi Z, Jun-Ping C, Yong-Xiang Z (2005) Age-related changes in the oestrous cycle and reproductive hormones in senescence-accelerated mouse. Reprod Fertil Dev 17:507–512PubMedCrossRefGoogle Scholar

Copyright information

© American Aging Association 2012

Authors and Affiliations

  • Banu Bayram
    • 1
    • 2
  • Sibylle Nikolai
    • 1
  • Patricia Huebbe
    • 1
  • Beraat Ozcelik
    • 2
  • Stefanie Grimm
    • 3
  • Tilman Grune
    • 3
  • Jan Frank
    • 4
  • Gerald Rimbach
    • 1
    Email author
  1. 1.Institute of Human Nutrition and Food ScienceChristian-Albrechts-UniversityKielGermany
  2. 2.Department of Food EngineeringIstanbul Technical UniversityIstanbulTurkey
  3. 3.Institute of Nutrition, Department of Nutritional ToxicologyFriedrich Schiller UniversityJenaGermany
  4. 4.Institute of Biological Chemistry and NutritionUniversity of HohenheimStuttgartGermany

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