Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice.

Oxidative damage has been implicated in the aging process and in a number of degenerative diseases. To investigate the role of oxygen radicals in the aging process in mammals, the life spans of transgenic mice on a CD-1 background expressing increased levels of CuZn superoxide dismutase (CuZnSOD), the enzyme that metabolizes superoxide radicals, were determined. Homozygous transgenic mice with a two- to five-fold elevation of CuZnSOD in various tissues showed a slight reduction of life span, whereas hemizygous mice with a 15- to 3-fold increase of CuZnSOD showed no difference in life span from that of the nontransgenic littermate controls. The results suggest that constitutive and ubiquitous overexpression of CuZnSOD alone is not sufficient to extend the life spans of transgenic mice.

[1]  J. Lotem,et al.  Thymic abnormalities and enhanced apoptosis of thymocytes and bone marrow cells in transgenic mice overexpressing Cu/Zn‐superoxide dismutase: implications for Down syndrome. , 1995, The EMBO journal.

[2]  J. Beckman,et al.  The importance of superoxide in nitric oxide-dependent toxicity: evidence for peroxynitrite-mediated injury. , 1996, Advances in experimental medicine and biology.

[3]  C. Epstein,et al.  Overexpression of copper/zinc superoxide dismutase: A novel cause of murine muscular dystrophy , 1998, Annals of neurology.

[4]  C. Epstein,et al.  3‐Nitropropionic Acid Neurotoxicity Is Attenuated in Copper/Zinc Superoxide Dismutase Transgenic Mice , 1995, Journal of neurochemistry.

[5]  K. Avraham,et al.  Down's syndrome: morphological remodelling and increased complexity in the neuromuscular junction of transgenic CuZn-superoxide dismutase mice , 1991, Journal of neurocytology.

[6]  Charles J. Epstein,et al.  Overexpressing Cu/Zn superoxide dismutase enhances survival of transplanted neurons in a rat model of Parkinson's disease , 1995, Nature Medicine.

[7]  J S Beckman,et al.  Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. , 1996, The American journal of physiology.

[8]  C. Epstein,et al.  Copper/zinc superoxide dismutase transgenic brain accumulates hydrogen peroxide after perinatal hypoxia ischemia , 1998, Annals of neurology.

[9]  B. Ames,et al.  The free radical theory of aging matures. , 1998, Physiological reviews.

[10]  C. Epstein,et al.  Relationship of resistance to oxygen free radicals to CuZn‐superoxide dismutase activity in transgenic, transfected, and trisomic cells , 1992, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[11]  A. Niedzwiecki,et al.  Expression of bovine superoxide dismutase in Drosophila melanogaster augments resistance of oxidative stress , 1991, Molecular and cellular biology.

[12]  D. Murphy,et al.  Transgenic mice with high levels of superoxide dismutase activity are protected from the neurotoxic effects of 2'-NH2-MPTP on serotonergic and noradrenergic nerve terminals. , 1996, Molecular pharmacology.

[13]  R. S. Sohal,et al.  Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. , 1994, Science.

[14]  R. S. Sohal,et al.  Effects of Cu-Zn superoxide dismutase overexpression of life span and resistance to oxidative stress in transgenic Drosophila melanogaster. , 1993, Archives of biochemistry and biophysics.

[15]  R. S. Sohal,et al.  Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[16]  J. Thompson,et al.  Decreased Zinc Affinity of Amyotrophic Lateral Sclerosis‐Associated Superoxide Dismutase Mutants Leads to Enhanced Catalysis of Tyrosine Nitration by Peroxynitrite , 1997, Journal of neurochemistry.

[17]  C. Masters,et al.  Reactive oxygen species and Alzheimer's disease. , 1997, Biochemical pharmacology.

[18]  R. Arking,et al.  Immunological Confirmation of Elevated Levels of CuZn Superoxide Dismutase Protein in an Artificially Selected Long-Lived Strain of Drosophila melanogaster , 1998, Experimental Gerontology.

[19]  M. Lovett,et al.  Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down syndrome. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[20]  L. Weiner,et al.  Oxidative stress mediates impairment of muscle function in transgenic mice with elevated level of wild-type Cu/Zn superoxide dismutase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[21]  P. Sinet,et al.  Age-related changes in antioxidant enzymes and lipid peroxidation in brains of control and transgenic mice overexpressing copper-zinc superoxide dismutase. , 1992, Mutation research.

[22]  P. L. Larsen.  Aging and resistance to oxidative damage in Caenorhabditis elegans. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[23]  C. G. Liddle,et al.  Alteration of life span of mice chronically exposed to 2.45 GHz CW microwaves. , 1994, Bioelectromagnetics.

[24]  C. Epstein,et al.  Attenuation of acute and chronic damage following traumatic brain injury in copper, zinc-superoxide dismutase transgenic mice. , 1996, Journal of neurosurgery.

[25]  K. Avraham,et al.  Expression of manganese superoxide dismutase is not altered in transgenic mice with elevated level of copper-zinc superoxide dismutase. , 1993, Free radical biology & medicine.

[26]  S. Dudas,et al.  A coordinate upregulation of antioxidant gene activities is associated with the delayed onset of senescence in a long-lived strain of Drosophila. , 1995, The journals of gerontology. Series A, Biological sciences and medical sciences.

[27]  D. Sapoznikov,et al.  Premature aging changes in neuromuscular junctions of transgenic mice with an extra human CuZnSOD gene: A model for tongue pathology in Down's syndrome , 1988, Journal of the Neurological Sciences.

[28]  G. M. Tener,et al.  Overexpression of Cu-Zn superoxide dismutase in Drosophila does not affect life-span. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[29]  A. Hilliker,et al.  Phenotypic consequences of copper-zinc superoxide dismutase overexpression in Drosophila melanogaster. , 1990, Genome.

[30]  J. Tower,et al.  FLP Recombinase-Mediated Induction of Cu/Zn-Superoxide Dismutase Transgene Expression Can Extend the Life Span of Adult Drosophila melanogaster Flies , 1999, Molecular and Cellular Biology.

[31]  D. Harman.  Extending Functional Life Span , 1998, Experimental Gerontology.

[32]  C. Epstein,et al.  Superoxide Dismutase, Catalase, and Glutathione Peroxidase Activities in Copper/Zinc‐Superoxide Dismutase Transgenic Mice , 1992, Journal of neurochemistry.

[33]  S. Barnes,et al.  Superoxide Dismutase Catalyzes Nitration of Tyrosines by Peroxynitrite in the Rod and Head Domains of Neurofilament‐L , 1997, Journal of neurochemistry.