臨床泌尿器科67巻13号

2013年12月発行

特集 アンチエイジング医学と泌尿器科

酸化ストレスと健康長寿

著者： 清水孝彦¹

所属機関： ¹千葉大学大学院医学研究院先進加齢医学

ページ範囲：P.1023 - P.1034

文献概要

要旨　酸化-抗酸化バランス破綻による酸化ストレス蓄積が健康障害の要因になることが示唆されている。生理的な酸素代謝で生じた活性酸素の基点物質スーパーオキサイド（O₂^・－）は，superoxide dismutase（SOD）の触媒作用ですみやかに処理される。細胞内には，細胞質にSOD1が，ミトコンドリアマトリクス内にSOD2がそれぞれ局在化している。本稿では，それぞれの抗酸化酵素SODの遺伝子欠損マウスの解析から，in vivoでの酸化-抗酸化バランス破綻の病態への影響と，抗酸化剤による健康障害抑制の実例を紹介する。

参考文献

1）Shimizu T, Nojiri H, Kawakami S, et al：Model mice for tissue-specific deletion of the manganese superoxide dismutase（Mn-SOD）gene. Geriatr Gerontol Int 10：S70-S79, 2010

2）McCay CM, Crowell MF and Maynard LA：The effect of retarded growth upon the length of life span and upon the ultimate body size. J Nutrition 10：63-79, 1935

3）Weindruch R：Caloric restriction and aging. Sci Am 274：46-52, 1996

4）Baba T, Shimizu T, Suzuki Y, et al：Estrogen, insulin, and dietary signals cooperatively regulate longevity signals to enhance resistance to oxidative stress in mice. J Biol Chem 280：16417-16426, 2005

5）Rosen DR, Siddique T, Patterson D, et al：Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362：59-62, 1993

6）Deng HX, Hentati A, Tainer JA, et al：Amyotrophic lateral sclerosis and structural defects in Cu, Zn superoxide dismutase. Science 261：1047-1051, 1993

7）Reaume AG, Elliott JL, Hoffman EK, et al：Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet 13：43-47, 1996

8）Ho YS, Gargano M, Cao J, et al：Reduced fertility in female mice lacking copper-zinc superoxide dismutase. J Biol Chem 273：7765-7769, 1998

9）Matzuk MM, Dionne L, Guo Q, et al：Ovarian function in superoxide dismutase 1 and 2 knockout mice. Endocrinology 139：4008-4011, 1998

10）Gurney ME, Pu H, Chiu AY, et al：Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264：1772-1775, 1994

11）Imamura Y, Noda S, Hashizume K, et al：Drusen, choroidal neovascularization, and retinal pigment epithelium dysfunction in SOD1-deficient mice：a model of age-related macular degeneration. Proc Natl Acad Sci U S A 103：11282-11287, 2006

12）Hashizume K, Hirasawa M, Imamura Y, et al：Retinal dysfunction and progressive retinal cell death in SOD1-deficient mice. Am J Pathol 172：1325-1331, 2008

13）Ohlemiller KK, Mofadden SL, Ding DL, et al：Targeted deletion of the cytosolic Cu/Zn-superoxide dismutase gene（Sod1）increases susceptibility to noise-induced hearing loss. Audiol Neurootol 4：237-246, 1999

14）Muller FL, Song W, Liu Y, et al：Absence of CuZn superoxide dismutase leads to elevated oxidative stress and acceleration of age-dependent skeletal muscle atrophy. Free Radic Biol Med 40：1993-2004, 2006

15）Jang YC, Lustgarten MS, Liu Y, et al：Increased superoxide in vivo accelerates age-associated muscle atrophy through mitochondrial dysfunction and neuromuscular junction degeneration. FASEB J 24：1376-1390, 2010

16）Iuchi Y, Lustgarten MS, Liu Y, et al：Elevated oxidative stress in erythrocytes due to a SOD1 deficiency causes anaemia and triggers autoantibody production. Biochem J 402：219-227, 2007

17）Iuchi Y, Okada F, Takamiya R, et al：Rescue of anaemia and autoimmune responses in SOD1-deficient mice by transgenic expression of human SOD1 in erythrocytes. Biochem J 422：313-320, 2009

18）Uchiyama S, Shimizu T and Shirasawa T：CuZn-SOD deficiency causes apoB degradation and induces hepatic lipid accumulation by impaired lipoprotein secretion in mice. J Biol Chem 281：31713-31719, 2006

19）Busuttil RA, Garcia AM, Cabrera C, et al：Organ-specific increase in mutation accumulation and apoptosis rate in CuZn-superoxide dismutase-deficient mice. Cancer Res 65：11271-11275, 2005

20）Elchuri S, Oberley TD, Qi W, et al：CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene 24：367-380, 2005

21）Kojima T, Wakamatsu TH, Dogru M, et al：Age-related dysfunction of the lacrimal gland and oxidative stress：evidence from the cu, zn-superoxide dismutase-1（sod1）knockout mice. Am J Pathol 180：1879-1896, 2012

22）Murakami K, Inagaki J, Saito M, et al：Skin atrophy in cytoplasmic SOD-deficient mice and its complete recovery using a vitamin C derivative. Biochem Biophys Res Commun 382：457-461, 2009

23）Shibuya S, Kinoshita K, Shimizu T, et al：Protective effects of vitamin C derivatives on skin atrophy caused by Sod1 deficiency. In：Handbook of Diet, Nutrition and the Skin. edited by Preedy VR. Wageningen Academic Publishers, Wageningen, pp350-364, 2012

24）Nojiri H, Saita Y, Morikawa D, et al：Cytoplasmic superoxide causes bone fragility owing to low-turnover osteoporosis and impaired collagen cross-linking. J Bone Miner Res 26：2682-2694, 2011

25）Morikawa D, Nojiri H, Saita Y, et al：Cytoplasmic reactive oxygen species and SOD1 regulate bone mass during mechanical unloading. J Bone Miner Res. 2013 May 14. doi：10.1002/jbmr. 1981.［Epub ahead of print］

26）Noda Y, Ota K, Shirasawa T, et al：Copper/Zinc superoxide dismutase insufficiency impairs progesterone secretion and fertility in female mice. Biol Reprod 86：1-8 2012

27）Mount C and Downton C：Alzheimer disease：progress or profit? Nat Med 12：780-784, 2006

28）Braak H and Braak E：Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 18：351-357, 1997

29）Hardy J and Selkoe DJ：The amyloid hypothesis of Alzheimer's disease：progress and problems on the road to therapeutics. Science 297：353-356, 2002

30）Murakami K, Murata N, Noda Y, et al：SOD1（Copper/Zinc superoxide dismutase）deficiency drives amyloid beta protein oligomerization and memory loss in mouse model of Alzheimer disease. J Biol Chem 286：44557-44568, 2011

31）Murakami K, Murata N, Noda Y, et al：Stimulation of the amyloidogenic pathway by cytoplasmic superoxide radicals in an Alzheimer's disease mouse model. Biosci Biotechnol Biochem 76：1098-1103, 2012

32）Murakami K and Shimizu T, et al：Cytoplasmic superoxide radical：a possible contributing factor to intracellular Aβ oligomerization in Alzheimer's disease. Commun Integr Biol 5：255-258, 2012

33）Murakami K, Murata N, Ozawa Y, et al：Vitamin C restores behavioral deficits and Amyloid-beta oligomerization without affecting plaque formation in a mouse model of Alzheimer's disease. J Alzheimers Dis 26：7-18, 2011

34）Ruiz-Romero C, Calamia V, Mateos J, et al：Mitochondrial dysregulation of osteoarthritic human articular chondrocytes analyzed by proteomics：a decrease in mitochondrial superoxide dismutase points to a redox imbalance. Mol Cell Proteomics 8：172-189, 2009

35）Scott JL, Gabrielides C, Davidson RK, et al：Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease. Ann Rheum Dis 69：1502-1510, 2010

36）Maggio D, Barabani M, Pierandrei M, et al：Marked decrease in plasma antioxidants in aged osteoporotic women：results of a cross-sectional study. J Clin Endocrinol Metab 88：1523-1527, 2003