Rescuing SOD Knockout Mice

Simon Melov[1], Susan R. Doctrow[2], Julie A. Schneider[3], Joanna Haberson[1], Manisha Patel[4], Pinar E. Coskun[5], Karl Huffman[2], Douglas C. Wallace[5], and Bernard Malfroy[2], "Lifespan Extension and Rescue of Spongiform Encephalopathy in Superoxide Dismutase-2 Nullizygous Mice Treated with Superoxide Dismutase-Catalase Mimetics," Journal of Neuroscince. Vol. 21, pp. 8348-53.(November 1, 2001).

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1. Buck Institute for Age Research, Novato, California 94945,
2. Eukarion Inc., Bedford, Massachusetts 01730,
3. Rush Alzheimer's Disease Center, Rush Institute for Healthy Aging, Rush-Presbyterian St. Luke's Hospital, Chicago, Illinois 60612,
4. National Jewish Medical Research Institute, Denver, Colorado 80206,
5. Center for Molecular Medicine, Emory University, Atlanta, Georgia 30322

ABSTRACT:

Superoxide is produced as a result of normal energy metabolism within the mitochondria and is scavenged by the mitochondrial form of Superoxide Dismutase (SOD-2). Mice with inactivated SOD-2 (SOD-2 nullizygous mice) die prematurely, exhibiting several metabolic and mitochondrial defects and severe tissue pathologies, including a lethal Spongiform Neurodegenerative Disorder (Li, et al., 1995; Melov, et al., 1998, 1999). We show that treatment of SOD-2 nullizygous mice with synthetic Superoxide Dismutase (SOD)-Catalase mimetics extends their lifespan by threefold, rescues the Spongiform Encephalopathy, and attenuates mitochondrial defects. This class of antioxidant compounds has been shown previously to extend lifespan in the nematode Caenorhabditis elegans (Melov, et al., 2000). These new findings in mice suggest novel therapeutic approaches to neurodegenerative diseases associated with oxidative stress such as Friedreich Ataxia, Spongiform Encephalopathies, and Alzheimer's and Parkinson's Diseases, in which chronic oxidative damage to the brain has been implicated.

Study: Drugs Quadruple Life Span of Mice

November 2, 2001; San Francisco, CA ( Reuters) -- Anti-oxidant drugs have quadrupled the life span of mice genetically engineered to live only a week, according to a new study that researchers say may represent a step toward unlocking the secrets of aging. Dr. Simon Melov, a molecular gerontologist at the private, nonprofit Buck Institute for Age Research in Novato, California, said on Thursday that the study builds on his previous research that used anti-oxidants to lengthen the life span of nematode worms. But he cautioned that it was one thing to extend the life of a worm or a genetically engineered mouse and another to make humans live longer.

Melov said the study, published in the Journal of Neuroscience, showed for the first time that these drugs work in making mammals live longer. We are starting to have a very good understanding of the types of damage that can arise in the aging process," he said. Oxidation is the chemical reaction that causes metals to rust, but in cells, it can damage DNA, leading sometimes to cancer, other diseases and, many scientists believe, to the changes associated with aging.

Anti-Oxidants Include Vitamins C and E

The mice in Melov's study were genetically engineered to undergo a form of oxidative damage and without drugs only live about a week, allowing researchers to quickly see the results. Melov explained that the drugs work by zeroing in on so-called free radicals -- toxic molecules produced in every cell in the body that are necessary pollutants in burning energy.

The anti-oxidant compounds move into cells and even into the mitochondria -- the centers of metabolism -- to counter the aging effects wrought by the free radicals. The research showed the genetically-engineered mice lived about four weeks using the drugs -- four times longer than normal, Melov said.

"What this paper shows is these drugs are very effective against preventing oxidative damage in the brain," Melov said. "That may have utility in diseases like Alzheimer's disease and Parkinson's disease. He said the next step in the research will be to use the anti-oxidants in normal mice. "If the evidence continues to accumulate in relation to the effectiveness of these drugs against free radical damage related to aging, then I don't think its an improbable prediction that they will be effective in prolonging life span in mammals," Melov said.