The oxidative theory of aging postulates that the cumulative energy metabolism of an individual, i.e., its metabolic rate integrated over time, co-determines life span. The underlying mechanism is thought to be a stochastic accumulation of mostly oxidative damage to cellular macromolecules, eventually leading to loss of function and/or cell death. Considerable experimental evidence in support of this theory has been accumulated for mammals as well as for model organisms including Drosophila melanogaster. Blocking the oxidative stress cascade at its initial stage, i.e., the formation of ROS (reactive oxygen species), can confer to Drosophila a statistically significant extension of life span. The mechanism by which excessive levels of ROS shorten life span is not fully understood. It is often assumed that cellular damage relevant to aging is caused directly by ROS such as OH. We propose to test the hypothesis that such damage is in part mediated by lipid peroxidation products which are formed when the OH radical attacks polyunsaturated fatty acids. The resulting lipid hydroperoxides (LOOH) and downstream 4-hydroxyalkenals (e.g., 4-hydroxynonenal or 4HNE) are formed in a chain reaction which can amplify the original insult hundred or thousand fold. In addition, 4HNE is electrophilic, longer-lived than OH, and diffusible, extending the types and sites of possible damage. To test this hypothesis, we will modulate the levels of lipid peroxidation products in D. melanogaster by: (1) transgenic overexpression of a set of mammalian glutathione S-transferases (GSTs) which metabolize LOOH, or LOOH and 4HNE with different ratios of catalytic efficiency for the two substrates, and (2) generation of Drosophila stocks that express the mammalian GST transgenes in specific tissues, including neurons. A system of inducible transgene expression will be used to eliminate both insertion position effects and possible impact of transgene expression on development. Effects of these interventions on life span and stress resistance will be examined. This model system offers a unique opportunity to determine whether lipid peroxidation products are significantly involved in oxidative damage that leads to aging, and if so, whether lipid hydroperoxides or electrophilic aldehydes are responsible.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG018845-05
Application #
7022212
Study Section
Geriatrics and Rehabilitation Medicine (GRM)
Program Officer
Velazquez, Jose M
Project Start
2002-03-01
Project End
2009-02-28
Budget Start
2006-03-15
Budget End
2009-02-28
Support Year
5
Fiscal Year
2006
Total Cost
$272,443
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
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Sawicki, Rafal; Singh, Sharda P; Mondal, Ashis K et al. (2003) Cloning, expression and biochemical characterization of one Epsilon-class (GST-3) and ten Delta-class (GST-1) glutathione S-transferases from Drosophila melanogaster, and identification of additional nine members of the Epsilon class. Biochem J 370:661-9