Caloric restriction (CR) has emerged as the most successful way to extend the life span of a number of experimental organisms. CR slows down physiological decline and occurrence of some of the age-related pathology of animals. Suggested mechanisms include reduced oxidative damage caused by reactive oxidative species, slower metabolic rate, reduction in body temperature, alterations in gene expression and reduction in DNA damage. The main changes include a shift in metabolism, particularly glucose, protein and lipids. Paradoxically, the molecular mechanisms underlying life span extension have not been revealed. We have identified mutations in the Indy (I'm not dead yet) gene that extends life span of adult fruit flies. The gene, a fly homologue of a human, a mice and a rat sodium dicarboxylate cotransporter is involved in uptake, utilization and storage of Krebs cycle intermediates. This suggests a possible role of Indy in energy production. Indy is expressed in fat body, oenocytes and digestive tract, places of intermediary metabolism in flies. Based on the predicted role of the gene in energy production and its tissue expression we suggest that mutations in Indy disrupt normal energy production and result in a condition in flies similar to CR. The mechanism of life extension in Indy mutants may be the same as or similar to caloric restriction. We will determine the critical changes in the level of glucose, glycogen, trehalose, tryglyceride and proteins in aging populations of normal flies on low and high caloric food and compare them to metabolic changes in Indy aging flies. The changes observed in Indy flies should be similar to the metabolic changes observed for control flies on low caloric food supporting our hypothesis that Indy is a genetic model for CR. The data described in our proposal will provide new information on the critical metabolic changes associated with aging and CR in fruit flies. Second, we will obtain metabolic profile of Indy mutant flies during their extended life span. This study will provide a direct link between the role of Indy gene in intermediary metabolism and metabolic changes associated with life span extension. The goal of our studies is to examine and understand the molecular and genetic mechanisms of caloric restriction and its effect on life span extension.
