Genetic Model of Caloric Restriction

University Of Connecticut Sch Of Med/Dnt, Farmington CT

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Abstract

DESCRIPTION (provided by applicant) Caloric restriction (CR) has emerged as the most successful way to extend the lifespan in several different experimental organisms. CR slows down irreversible physiological decline and occurrence of the age-related pathology of the animals. Although it is not yet known how CR leads to lifespan extension, a plausible hypothesis is that it acts by reducing oxidative damage. The investigators have identified mutations in the Indy gene that dramatically extend lifespan in fruit flies. The gene, a fly homologue of a human sodium decarboxylate co-transporter, is involved in transporting Krebs cycle intermediates. This suggests a possible role for Andy in energy production. Indy is expressed in fat body, oenocytes and digestive tract, all places of intermediary metabolism in flies. Based on the predicted role of the gene in energy balance, the investigators postulate that mutations in the Indy gene disrupt normal energy production and result in a condition in flies similar to CR. Therefore, they suggest that the mechanism of life extension in Indy mutants is similar to the mechanism in calorically-restricted animals. This allows the investigators to use the Indy mutant flies as a genetic model to study life extension by CR, as well the relationship between CR, stress resistance and defense mechanisms. The purpose of this study is to validate that the mechanism of life extension is similar to CR, and to determine if it is associated with an increase in stress resistance and/or higher defense against reactive oxidative species (ROS). The investigators will determine the span of lady mutant flies on normal-, low- and high-caloric diet and compare them to control flies. Second, to identify crucial changes in the metabolism of ROS, they will determine the resistance of Indy flies to temperature, starvation, paraquat and hyperoxia. Finally, they will examine the defense against ROS in Indy flies by determining if the Indy mutation can rescue the shortened lifespan of SOD and catalase mutant flies. The goal of these studies is to understand the molecular and genetic mechanisms underlying CR in lifespan extension. These studies aim to set the stage for future investigations to define the mechanisms by which CR may decrease ROS production leading to multiple beneficial effects for the organism.