The long-term goal of this study is to understand the role of oxidative stress in the aging process. Mitochondria have been widely hypothesized to play a key role in the causation of oxidative stress and aging in animals. This hypothesis has been based on the findings that mitochondria are the main intracellular producers of superoxide anion radical (O2-) and H2O2, which are the progenitors of a variety of other reactive oxygen species (ROS). Furthermore, the rates of mitochondrial O2- and H2O2 generation as well as amounts of mitochondrial oxidative damage increase with age, whereas oxidative phosphorylation capacity declines during aging. It has been shown that oxidative damage to mitochondria can cause both the age-related increase in O2- and H2O2 generation and the loss in respiratory capacity. The hypothesis that attenuation of mitochondrial oxidative damage will retard the progression of age-related deleterious alterations and extend the life span of the organism, will be tested in Drosophila melanogaster using transgenic approaches. Three different experimental strategies will be used to decrease the level of mitochondrial oxidative damage. The first will be to simultaneously overexpress Mn-SOD and ectopic catalase in the mitochondrial matrix; some lines of flies will additionally overexpress CuZn-SOD and catalase in the cytosol. Such overexpression of antioxidant enzymes should decrease the rates of mitochondrial O2- and H2O2 generation and lower the overall level of oxidative stress in cells. The second strategy will be to use regulatable gene promoters to overexpress SOD and catalase in order to control the timing and tissue-specificity of antioxidant gene overexpression. This approach may uncover beneficial effects of reduced oxidant production, which are masked by counterbalancing harmful effects of antioxidant elevation during sensitive stages of development. The third strategy will be to overexpress DNA glycosylase within the mitochondrial matrix to enhance DNA oxidative damage repair capacity. This latter approach is expected to result in an actual reversal of damage, whereas all previous strategies have concentrated on slowing the rate at which it accumulates. The effects of the different gene overexpression on age-related changes in mitochondria, and on the biochemical and physiological patterns of aging of the flies, including life spans, will be determined. The significance of this study is that it will provide a direct test of a basic tenet of the oxidative stress hypothesis of aging, namely that mitochondrial oxidative damage plays a key role in the aging process.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-OBM-2 (03))
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Finkelstein, David B
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University of Southern California
Schools of Pharmacy
Los Angeles
United States
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Sohal, Rajindar S; Forster, Michael J (2014) Caloric restriction and the aging process: a critique. Free Radic Biol Med 73:366-82
Klichko, Vladimir; Sohal, Barbara H; Radyuk, Svetlana N et al. (2014) Decrease in cytochrome c oxidase reserve capacity diminishes robustness of Drosophila melanogaster and shortens lifespan. Biochem J 459:127-35
Orr, William C; Radyuk, Svetlana N; Sohal, Rajindar S (2013) Involvement of redox state in the aging of Drosophila melanogaster. Antioxid Redox Signal 19:788-803
Sohal, Rajindar S; Orr, William C (2012) The redox stress hypothesis of aging. Free Radic Biol Med 52:539-555
Ren, Jian-Ching; Rebrin, Igor; Klichko, Vladimir et al. (2010) Cytochrome c oxidase loses catalytic activity and structural integrity during the aging process in Drosophila melanogaster. Biochem Biophys Res Commun 401:64-8
Mockett, Robin J; Sohal, Barbara H; Sohal, Rajindar S (2010) Expression of multiple copies of mitochondrially targeted catalase or genomic Mn superoxide dismutase transgenes does not extend the life span of Drosophila melanogaster. Free Radic Biol Med 49:2028-31
Radyuk, Svetlana N; Michalak, Katarzyna; Klichko, Vladimir I et al. (2009) Peroxiredoxin 5 confers protection against oxidative stress and apoptosis and also promotes longevity in Drosophila. Biochem J 419:437-45
Sohal, Rajindar S; Toroser, Dikran; Bregere, Catherine et al. (2008) Age-related decrease in expression of mitochondrial DNA encoded subunits of cytochrome c oxidase in Drosophila melanogaster. Mech Ageing Dev 129:558-61
Rebrin, Igor; Sohal, Rajindar S (2008) Pro-oxidant shift in glutathione redox state during aging. Adv Drug Deliv Rev 60:1545-52
Toroser, Dikran; Orr, William C; Sohal, Rajindar S (2007) Carbonylation of mitochondrial proteins in Drosophila melanogaster during aging. Biochem Biophys Res Commun 363:418-24

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