The long term objective of the proposed study is to test the validity of the oxidative stress hypothesis of aging, which postulates that deleterious changes caused by reactive oxygen species (ROS) are the primary cause of senescence. The historical approach to establish causality between oxidative stress and aging have been the manipulation of the latter by overexpression of antioxidant enzyme defenses, however, results of such studies have been quite equivocal. In the prospective study, an alternative approach that alters the rate of mitochondrial production of ROS will be used to manipulate oxidative stress. Mitochondrial superoxide generation is known to be controlled by the activity of cytochrome c oxidase (COX), the terminal component of the mitochondrial electron transport chain. In Drosophila melanogaster, COX activity and the abundance of some COX subunits, encoded in both nuclear and mitochondrial DNA, decline while mitochondrial ROS generation increases during aging. Experimental decrease in COX activity causes an increase in mitochondrial ROS production. Accordingly, the specific hypothesis to be tested is that enhancement of COX activity will decrease the rate of mitochondrial superoxide and hydrogen peroxide generation, lower the level of oxidative stress, and extend the life span of D. melanogaster. The three specific aims are: (I) Determine the effect of over- and underexpression of nuclear DNA-encoded COX subunits, exhibiting age-associated decline in abundance on COX activity, mitochondrial production of superoxide/hydrogen, life span, markers of oxidative stress and aging in transgenic D. melanogaster. (II) Determine the effects of overexpression of mitochondrial DNA- encoded COX subunits, showing decline with age, on COX activity, life span and indicators of oxidative stress and aging. (Ill) Determine the effects of co-overexpression of selected COX subunits on COX activity and various indicators of aging. A novel feature of this study is that results should indicate whether attenuation of the rate of production of ROS rather than their elimination after they have been generated would lower the level of oxidative stress, slow the age-associated changes and extend the life span of flies. More broadly, results should provide a direct test of the validity of oxidative stress hypothesis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG007657-23
Application #
8046334
Study Section
Special Emphasis Panel (ZRG1-BDA-A (02))
Program Officer
Finkelstein, David B
Project Start
1988-08-01
Project End
2014-03-31
Budget Start
2011-04-01
Budget End
2014-03-31
Support Year
23
Fiscal Year
2011
Total Cost
$300,907
Indirect Cost
Name
University of Southern California
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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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