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Project 2. Lipid Peroxidation & Aging in Invertebrate Models

Background

The oxidative theory of aging postulates that the cumulative energy metabolism of an individual, i.e., its metabolic rate integrated over time, codetermines life span. The underlying mechanism is thought to be an accumulation of mostly oxidative damage that eventually leads to loss of function and death. Considerable experimental evidence in support of this theory has been accumulated, especially for model invertebrate organisms including Drosophila melanogaster and Caenorhabditis elegans. Experimental interventions that facilitate the removal of reactive oxygen species (ROS) can confer on these organisms 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 hydroxyl radical.

Hypotheses and Aims

Project 2 tests the hypothesis that such damage is in part mediated by lipid peroxidation products formed when the hydroxyl radical attacks polyunsaturated fatty acids. The resulting lipid hydroperoxides (LOOH) and downstream 4-hydroxy- alkenals (e.g., 4-hydroxynonenal [4-HNE]) are formed in a chain reaction that can significantly amplify the original insult. In addition, 4-HNE is electrophilic, longer-lived than hydroxyl radical, 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 and C. elegans by transgenic overexpression of a set of mammalian glutathione S-transferases (GSTs) that metabolize LOOH, or LOOH and 4-HNE, with different ratios of catalytic efficiency for the two substrates. Furthermore, we will generate Drosophila stocks that express the mammalian GST transgenes in specific tissues, including neurons. Positional effects, as well as potential developmental consequences, of transgene expression will be minimized in Drosophila by the use of an inducible expression system and by examination of multiple transformed lines. Extrachromosomal maintenance of the transgene in C. elegans eliminates genetic positional effects. Effects of transgene expression on life span, total metabolic potential, and stress resistance will be examined.

Significance

These experiments offer 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. The use of two distinct organisms will help determine whether the uncovered mechanisms are universal.

Slide Presentation of Recent Data

Data Slides

Team

Piotr Zimniak, Ph.D., Core Leader

Helen Benes, Ph.D., Co-Leader

Ashis K. Mondal, Ph.D., Postdoc

Chhandra G. Mondal, M.S., Research Technician