Caloric restriction, stress resistance and longevity in Drosophila melanogaster

The goal of this study is to understand the mechanisms underlying the aging process. It has been widely demonstrated that limiting caloric intake without deprivation of nutrients extends mean and maximal lifespan in animals ranging from yeast to mammals. The mechanism by which caloric restriction extends lifespan is not clear but there is a wealth of correlative data in support of the oxidative stress hypothesis of aging, which suggests caloric restriction extends lifespan by reducing the rate at which oxidative damage accumulates. ^ Dysfunction of the Drosophila melanogaster gene Indy nearly doubles the fly\u27s average lifespan. The Indy gene product functions as a novel sodium independent transporter of important Krebs Cycle intermediates. Indy may play a central role in the energy balance of the fly as it is expressed in areas involved in intermediary metabolism. Thus, a reduction of the Indy gene product, i.e. Indy heterozygotes, may induce a state analogous to caloric restriction while further attenuation of Indy activity, i.e. Indy homozygotes, may result in malnutrition. ^ Extension of the oxidative stress hypothesis of aging suggests normal flies will become increasingly susceptible to oxidative stress with age, whereas flies with experimental increased lifespans, i.e. calorie restricted flies or Indy flies, will be resistant to oxidative stress. To that end, this study seeks to test the validity of the oxidative stress hypothesis, which mechanistically links caloric restriction, oxidative stress resistance and longevity by altering the cellular redox state and metabolic status of Indy and wild type animals. Thus, Indy may serve as an invaluable model to dissect the complex relationships involved in aging, namely caloric restriction, environmental stress resistance and longevity.