Neurochemical Research

, Volume 34, Issue 4, pp 679–687 | Cite as

The Senescence-accelerated Mouse (SAM): A Higher Oxidative Stress and Age-dependent Degenerative Diseases Model

  • Yoichi Chiba
  • Atsuyoshi Shimada
  • Naoko Kumagai
  • Keisuke Yoshikawa
  • Sanae Ishii
  • Ayako Furukawa
  • Shiro Takei
  • Masaaki Sakura
  • Noriko Kawamura
  • Masanori Hosokawa


The SAM strain of mice is actually a group of related inbred strains consisting of a series of SAMP (accelerated senescence-prone) and SAMR (accelerated senescence-resistant) strains. Compared with the SAMR strains, the SAMP strains show a more accelerated senescence process, a shorter lifespan, and an earlier onset and more rapid progress of age-associated pathological phenotypes similar to human geriatric disorders. The higher oxidative stress status observed in SAMP mice is partly caused by mitochondrial dysfunction, and may be a cause of this senescence acceleration and age-dependent alterations in cell structure and function. Based on our recent observations, we discuss a possible mechanism for mitochondrial dysfunction resulting in the excessive production of reactive oxygen species, and a role for the hyperoxidative stress status in neurodegeneration in SAMP mice. These SAM strains can serve as a useful tool to understand the cellular mechanisms of age-dependent degeneration, and to develop clinical interventions.


Senescence-accelerated mouse Higher oxidative stress status Mitochondrial dysfunction Neurodegeneration Neuroinflammation 


  1. 1.
    Hosokawa M, Abe T, Higuchi K et al (1997) Management and design of the maintenance of SAM mouse strains: an animal model for accelerated senescence and age-associated disorders. Exp Gerontol 32:111–116. doi:10.1016/S0531-5565(96)00078-2 PubMedCrossRefGoogle Scholar
  2. 2.
    Hosokawa M, Kasai R, Higuchi K et al (1984) Grading score system: a method for evaluation of the degree of senescence in senescence accelerated mouse (SAM). Mech Ageing Dev 26:91–102. doi:10.1016/0047-6374(84)90168-4 PubMedCrossRefGoogle Scholar
  3. 3.
    Takeda T (1999) Senescence-accelerated mouse (SAM): a biogerontological resource in aging research. Neurobiol Aging 20:105–110. doi:10.1016/S0197-4580(99)00008-1 PubMedCrossRefGoogle Scholar
  4. 4.
    Strehler BL (1977) Time, cells, and aging, 2nd edn. Academic Press, New YorkGoogle Scholar
  5. 5.
    Takeda T, Hosokawa M, Higuchi K (1994) Senescence-accelerated mouse (SAM). A novel murine model of aging. In: Takeda T (ed) The SAM model of senescence. Excerpta Medica, Amsterdam, pp 15–22Google Scholar
  6. 6.
    Hosokawa M, Umezawa M, Higuchi K et al (1998) Interventions of senescence in SAM mice. J Anti Aging Med 1:27–37Google Scholar
  7. 7.
    Hosokawa M (2002) A higher oxidative status accelerates senescence and aggravates age-dependent disorders in SAMP strains of mice. Mech Ageing Dev 123:1553–1561. doi:10.1016/S0047-6374(02)00091-X PubMedCrossRefGoogle Scholar
  8. 8.
    Nomura Y, Takeda T, Okuma Y (eds) (2004) The Senescence-accelerated mouse (SAM): an animal model of senescence. International Congress Series 1260, Elsevier B·V, AmsterdamGoogle Scholar
  9. 9.
    Cotran RS (1989) Diseases of aging. In: Cotran RS, Kumar V, Robbins SL (eds) Robbins pathologic basis of disease, 4th edn. W·B. Saunders Company, Philadelphia, pp 543–551Google Scholar
  10. 10.
    Komura S, Yoshino K, Kondo K et al (1988) Lipid peroxide levels in the skin of the senescence-accelerated mouse. J Clin Biochem Nutr 5:255–260Google Scholar
  11. 11.
    Chiba Y, Yamashita Y, Ueno M et al (2005) Cultured murine dermal fibroblast-like cells from senescence-accelerated mice as in vitro models for higher oxidative stress due to mitochondrial alterations. J Gerontol A Biol Sci Med Sci 60A:1087–1098Google Scholar
  12. 12.
    Hosokawa M, Ashida Y, Nishikawa T et al (1994) Accelerated aging of dermal fibroblast-like cells from senescence-accelerated mouse (SAM). 1. Acceleration of population aging in vitro. Mech Ageing Dev 74:65–77PubMedCrossRefGoogle Scholar
  13. 13.
    Fujisawa H, Nishikawa T, Zhu BH et al (1999) Aminoguanidine supplementation delays the onset of senescence in vitro in dermal fibroblast-like cells from senescence-accelerated mice. J Gerontol A Biol Sci Med Sci 54A:B276–B282Google Scholar
  14. 14.
    Shigenaga MK, Hagen TM, Ames BN (1994) Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA 91:10771–10778. doi:10.1073/pnas.91.23.10771 PubMedCrossRefGoogle Scholar
  15. 15.
    Lenaz G, Bovina C, D’Aurelio M et al (2002) Role of mitochondria in oxidative stress and aging. Ann N Y Acad Sci 959:199–213PubMedCrossRefGoogle Scholar
  16. 16.
    The Council for SAM Research (1998) SAM microsatellite marker. Retrieved April 30, 2008, from
  17. 17.
    Barja G (2004) Free radicals and aging. Trends Neurosci 27:595–600. doi:10.1016/j.tins.2004.07.005 PubMedCrossRefGoogle Scholar
  18. 18.
    Flood JF, Morley JE (1998) Learning and memory in the SAMP8 mouse. Neurosci Biobehav Rev 22:1–20. doi:10.1016/S0149-7634(96)00063-2 PubMedCrossRefGoogle Scholar
  19. 19.
    Takemura M, Nakamura S, Akiguchi I et al (1993) β/A4 proteinlike immunoreactive granular structures in the brain of senescence-accelerated mouse. Am J Pathol 142:1887–1897PubMedGoogle Scholar
  20. 20.
    Nomura Y, Okuma Y (1999) Age-related defects in lifespan and learning ability in SAMP8 mice. Neurobiol Aging 20:111–115. doi:10.1016/S0197-4580(99)00006-8 PubMedCrossRefGoogle Scholar
  21. 21.
    Kumar VB, Farr SA, Flood JF et al (2000) Site-directed antisense oligonucleotide decreases the expression of amyloid precursor protein and reverses deficits in learning and memory in aged SAMP8 mice. Peptides 21:1769–1775. doi:10.1016/S0196-9781(00)00339-9 PubMedCrossRefGoogle Scholar
  22. 22.
    Poon HF, Joshi G, Sultana R et al (2004) Antisense directed at the Aβ region of APP decreases brain oxidative markers in aged senescence accelerated mice. Brain Res 1018:86–96. doi:10.1016/j.brainres.2004.05.048 PubMedCrossRefGoogle Scholar
  23. 23.
    Poon HF, Farr SA, Banks WA et al (2005) Proteomic identification of less oxidized brain proteins in aged senescence-accelerated mice following administration of antisense oligonucleotide directed at the Aβ region of amyloid precursor protein. Brain Res Mol Brain Res 138:8–16. doi:10.1016/j.molbrainres.2005.02.020 PubMedCrossRefGoogle Scholar
  24. 24.
    Banks WA, Farr SA, Morley JE et al (2007) Anti-amyloid beta protein antibody passage across the blood-brain barrier in the SAMP8 mouse model of Alzheimer’s disease: an age-related selective uptake with reversal of learning impairment. Exp Neurol 206:248–256. doi:10.1016/j.expneurol.2007.05.005 PubMedCrossRefGoogle Scholar
  25. 25.
    Nomura Y, Wang BX, Qi SB et al (1989) Biochemical changes related to aging in the senescence-accelerated mouse. Exp Gerontol 24:49–55. doi:10.1016/0531-5565(89)90034-X PubMedCrossRefGoogle Scholar
  26. 26.
    Liu J, Mori A (1993) Age-associated changes in superoxide dismutase activity, thiobarbituric acid reactivity and reduced glutathione level in the brain and liver in senescence accelerated mice (SAM): a comparison with ddY mice. Mech Ageing Dev 71:23–30. doi:10.1016/0047-6374(93)90032-M PubMedCrossRefGoogle Scholar
  27. 27.
    Butterfield DA, Howard BJ, Yatin S et al (1997) Free radical oxidation of brain proteins in accelerated senescence and its modulation by N-tert-butyl-α-phenylnitrone. Proc Natl Acad Sci USA 94:674–678. doi:10.1073/pnas.94.2.674 PubMedCrossRefGoogle Scholar
  28. 28.
    Poon HF, Castegna A, Farr SA et al (2004) Quantitative proteomics analysis of specific protein expression and oxidative modification in aged senescence-accelerated-prone 8 mice brain. Neuroscience 126:915–926. doi:10.1016/j.neuroscience.2004.04.046 PubMedCrossRefGoogle Scholar
  29. 29.
    Nabeshi H, Oikawa S, Inoue S et al (2006) Proteomic analysis for protein carbonyl as an indicator of oxidative damage in senescence-accelerated mice. Free Radic Res 40:1173–1181. doi:10.1080/10715760600847580 PubMedCrossRefGoogle Scholar
  30. 30.
    Sato E, Oda N, Ozaki N et al (1996) Early and transient increase in oxidative stress in the cerebral cortex of senescence-accelerated mouse. Mech Ageing Dev 86:105–114. doi:10.1016/0047-6374(95)01681-3 PubMedCrossRefGoogle Scholar
  31. 31.
    Matsugo S, Kitagawa T, Minami S et al (2000) Age-dependent changes in lipid peroxide levels in peripheral organs, but not in brain, in senescence-accelerated mice. Neurosci Lett 278:105–108. doi:10.1016/S0304-3940(99)00907-6 PubMedCrossRefGoogle Scholar
  32. 32.
    Yasui F, Ishibashi M, Matsugo S et al (2003) Brain lipid hydroperoxide level increases in senescence-accelerated mice at an early age. Neurosci Lett 350:66–68. doi:10.1016/S0304-3940(03)00827-9 PubMedCrossRefGoogle Scholar
  33. 33.
    Álvarez-García Ó, Vega-Naredo I, Sierra V et al (2006) Elevated oxidative stress in the brain of senescence-accelerated mice at 5 months of age. Biogerontology 7:43–52. doi:10.1007/s10522-005-6041-2 PubMedCrossRefGoogle Scholar
  34. 34.
    Nishikawa T, Takahashi JA, Fujibayashi Y et al (1998) An early stage mechanism of the age-associated mitochondrial dysfunction in the brain of SAMP8 mice; an age-associated neurodegeneration animal model. Neurosci Lett 254:69–72. doi:10.1016/S0304-3940(98)00646-6 PubMedCrossRefGoogle Scholar
  35. 35.
    Fujibayashi Y, Yamamoto S, Waki A et al (1998) Increased mitochondrial DNA deletion in the brain of SAMP8, a mouse model for spontaneous oxidative stress brain. Neurosci Lett 254:109–112. doi:10.1016/S0304-3940(98)00667-3 PubMedCrossRefGoogle Scholar
  36. 36.
    Xu J, Shi C, Li Q et al (2007) Mitochondrial dysfunction in platelets and hippocampi of senescence-accelerated mice. J Bioenerg Biomembr 39:195–202. doi:10.1007/s10863-007-9077-y PubMedCrossRefGoogle Scholar
  37. 37.
    Nakahara H, Kanno T, Inai Y et al (1998) Mitochondrial dysfunction in the senescence accelerated mouse (SAM). Free Radic Biol Med 24:85–92. doi:10.1016/S0891-5849(97)00164-0 PubMedCrossRefGoogle Scholar
  38. 38.
    Gutierrez-Cuesta J, Sureda FX, Romeu M et al (2007) Chronic administration of melatonin reduces cerebral injury biomarkers in SAMP8. J Pineal Res 42:394–402. doi:10.1111/j.1600-079X.2007.00433.x PubMedCrossRefGoogle Scholar
  39. 39.
    Farr SA, Poon HF, Dogrukol-Ak D et al (2003) The antioxidants α-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. J Neurochem 84:1173–1183. doi:10.1046/j.1471-4159.2003.01580.x PubMedCrossRefGoogle Scholar
  40. 40.
    Poon HF, Farr SA, Thongboonkerd V et al (2005) Proteomic analysis of specific brain proteins in aged SAMP8 mice treated with alpha-lipoic acid: implications for aging and age-related neurodegenerative disorders. Neurochem Int 46:159–168. doi:10.1016/j.neuint.2004.07.008 PubMedCrossRefGoogle Scholar
  41. 41.
    Edamatsu R, Mori A, Packer L (1995) The spin-trap N-tert-α -phenyl-butylnitrone prolongs the life span of the senescence accelerated mouse. Biochem Biophys Res Commun 211:847–849. doi:10.1006/bbrc.1995.1889 PubMedCrossRefGoogle Scholar
  42. 42.
    Yasui F, Matsugo S, Ishibashi M et al (2002) Effects of chronic acetyl-L-carnitine treatment on brain lipid hydroperoxide level and passive avoidance learning in senescence-accelerated mice. Neurosci Lett 334:177–180. doi:10.1016/S0304-3940(02)01127-8 PubMedCrossRefGoogle Scholar
  43. 43.
    Chan YC, Hosoda K, Tsai CJ et al (2006) Favorable effects of tea on reducing the cognitive deficits and brain morphological changes in senescence-accelerated mice. J Nutr Sci Vitaminol (Tokyo) 52:266–273. doi:10.3177/jnsv.52.266 CrossRefGoogle Scholar
  44. 44.
    Liao JW, Hsu CK, Wang MF et al (2006) Beneficial effect of Toona sinensis Roemor on improving cognitive performance and brain degeneration in senescence-accelerated mice. Br J Nutr 96:400–407. doi:10.1079/BJN20061823 PubMedCrossRefGoogle Scholar
  45. 45.
    Lü L, Li J, Yew DT et al (2008) Oxidative stress on the astrocytes in culture derived from a senescence accelerated mouse strain. Neurochem Int 52:282–289. doi:10.1016/j.neuint.2007.06.016 PubMedCrossRefGoogle Scholar
  46. 46.
    Shimada A (1999) Age-dependent cerebral atrophy and cognitive dysfunction in SAMP10 mice. Neurobiol Aging 20:125–136. doi:10.1016/S0197-4580(99)00044-5 PubMedCrossRefGoogle Scholar
  47. 47.
    Shimada A, Keino H, Satoh M et al (2002) Age-related progressive neuronal DNA damage associated with cerebral degeneration in a mouse model of accelerated senescence. J Gerontol A Biol Sci Med Sci 57:B415–B421PubMedGoogle Scholar
  48. 48.
    Shimada A, Keino H, Satoh M et al (2003) Age-related loss of synapses in the frontal cortex of SAMP10 mouse: a model of cerebral degeneration. Synapse 48:198–204. doi:10.1002/syn.10209 PubMedCrossRefGoogle Scholar
  49. 49.
    Shimada A, Tsuzuki M, Keino H et al (2006) Apical vulnerability to dendritic retraction in prefrontal neurones of ageing SAMP10 mouse: a model of cerebral degeneration. Neuropathol Appl Neurobiol 32:1–14. doi:10.1111/j.1365-2990.2006.00632.x PubMedCrossRefGoogle Scholar
  50. 50.
    Shimada A, Keino H, Kawamura N et al (2008) Limbic structures are prone to age-related impairments in proteasome activity and neuronal ubiquitinated inclusions in SAMP10 mouse: a model of cerebral degeneration. Neuropathol Appl Neurobiol 34:33–51PubMedGoogle Scholar
  51. 51.
    Carter TA, Greenhall JA, Yoshida S et al (2005) Mechanisms of aging in senescence-accelerated mice. Genome Biol 6:R48. doi:10.1186/gb-2005-6-6-r48 PubMedCrossRefGoogle Scholar
  52. 52.
    Saitoh Y, Matsui F, Chiba Y et al (2008) Reduced expression of MAb6B4 epitopes on chondroitin sulfate proteoglycan aggrecan in perineuronal nets from cerebral cortices of SAMP10 mice: a model for age-dependent neurodegeneration. J Neurosci Res 86:1316–1323. doi:10.1002/jnr.21582 PubMedCrossRefGoogle Scholar
  53. 53.
    Unno K, Takabayashi F, Yoshida H et al (2007) Daily consumption of green tea catechin delays memory regression in aged mice. Biogerontology 8:89–95. doi:10.1007/s10522-006-9036-8 PubMedCrossRefGoogle Scholar
  54. 54.
    Kishido T, Unno K, Yoshida H et al (2007) Decline in glutathione peroxidase activity is a reason for brain senescence: consumption of green tea catechin prevents the decline in its activity and protein oxidative damage in ageing mouse brain. Biogerontology 8:423–430. doi:10.1007/s10522-007-9085-7 PubMedCrossRefGoogle Scholar
  55. 55.
    Unno K, Takabayashi F, Kishido T et al (2004) Suppressive effect of green tea catechins on morphologic and functional regression of the brain in aged mice with accelerated senescence (SAMP10). Exp Gerontol 39:1027–1034. doi:10.1016/j.exger.2004.03.033 PubMedCrossRefGoogle Scholar
  56. 56.
    Brunk UT, Jones CB, Sohal RS (1992) A novel hypothesis of lipofuscinogenesis and cellular aging based on interactions between oxidative stress and autophagocytosis. Mutat Res 275:395–403PubMedGoogle Scholar
  57. 57.
    Chondrogianni N, Gonos ES (2005) Proteasome dysfunction in mammalian aging: steps and factors involved. Exp Gerontol 40:931–938. doi:10.1016/j.exger.2005.09.004 PubMedCrossRefGoogle Scholar
  58. 58.
    Sasaki T, Unno K, Tahara S et al (2008) Age-related increase of superoxide generation in the brains of mammals and birds. Aging Cell. doi:10.1111/j.1474-9726.2008.00394.x
  59. 59.
    Lucius R, Mentlein R (1995) Development of a culture system for pure rat neurons: advantages of a sandwich technique. Ann Anat 177:447–454PubMedGoogle Scholar
  60. 60.
    Dringen R (2005) Oxidative and antioxidative potential of brain microglial cells. Antioxid Redox Signal 7:1223–1233. doi:10.1089/ars.2005.7.1223 PubMedCrossRefGoogle Scholar
  61. 61.
    Mander P, Brown GC (2005) Activation of microglial NADPH oxidase is synergistic with glial iNOS expression in inducing neuronal death: a dual-key mechanism of inflammatory neurodegeneration. J Neuroinflammation 2:20. doi:10.1186/1742-2094-2-20 PubMedCrossRefGoogle Scholar
  62. 62.
    Streit WJ, Mrak RE, Griffin WS (2004) Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 1:14. doi:10.1186/1742-2094-1-14 PubMedCrossRefGoogle Scholar
  63. 63.
    Kumagai N, Chiba Y, Hosono M et al (2007) Involvement of pro-inflammatory cytokines and microglia in an age-associated neurodegeneration model, the SAMP10 mouse. Brain Res 1185:75–85. doi:10.1016/j.brainres.2007.09.021 PubMedCrossRefGoogle Scholar
  64. 64.
    Qiu Z, Sweeney DD, Netzeband JG et al (1998) Chronic interleukin-6 alters NMDA receptor-mediated membrane responses and enhances neurotoxicity in developing CNS neurons. J Neurosci 18:10445–10456PubMedGoogle Scholar
  65. 65.
    Takeuchi H, Mizuno T, Zhang G et al (2005) Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport. J Biol Chem 280:10444–10454. doi:10.1074/jbc.M413863200 PubMedCrossRefGoogle Scholar
  66. 66.
    Butterfield DA, Poon HF (2005) The senescence-accelerated prone mouse (SAMP8): a model of age-related cognitive decline with relevance to alterations of the gene expression and protein abnormalities in Alzheimer’s disease. Exp Gerontol 40:774–783. doi:10.1016/j.exger.2005.05.007 PubMedCrossRefGoogle Scholar
  67. 67.
    Liu J (2008) The effects and mechanisms of mitochondrial nutrient α-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview. Neurochem Res 33:194–203. doi:10.1007/s11064-007-9403-0 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Yoichi Chiba
    • 1
  • Atsuyoshi Shimada
    • 1
  • Naoko Kumagai
    • 1
  • Keisuke Yoshikawa
    • 1
  • Sanae Ishii
    • 1
  • Ayako Furukawa
    • 1
  • Shiro Takei
    • 1
  • Masaaki Sakura
    • 1
  • Noriko Kawamura
    • 1
  • Masanori Hosokawa
    • 1
  1. 1.Department of Pathology, Institute for Developmental ResearchAichi Human Service CenterKasugai, AichiJapan

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