It has been demonstrated that limiting caloric intake without deprivation of nutrients extends mean lifespan in mammals. The mechanism by which caloric restriction (CR) extends lifespan is not clear, but there is a plethora of correlative data suggesting that CR decreases the rate at which oxidative damage accrues. Mutations in the D. melanogaster gene Indy (I'm Not Dead Yet) double the fly's average lifespan. The Indy gene product functions as a transporter of important Krebs cycle intermediates. Indy's localization in areas involved in the uptake, utilization, and storage of nutrients suggests that it plays a central role in the energy balance of the fly. It is hypothesized that a reducation in the Indy gene product creates genetic caloric restriction, resulting in the observed increase of lifespan in Drosophila. This hypothesis may be mechanistically linked to the oxidative stress hypothesis. The proposed study will determine if reduction of Indy's putative mouse homologue confers longevity and genetic caloric restriction, as shown in Drosophila studies by generating a knockout mouse. If Indy knockout mice are long lived and display genetic caloric restriction, the validity of the oxidative stress hypothesis will be investigated. Thus, this mouse model will serve as an invaluable tool to investigate the mechanism by which caloric restriction extends lifespan and provide insight into the genetic influence of aging in mammals.
