Calorie restriction (CR) improves health and extends life span in a variety of species. Despite many downstream molecules and physiological systems having been identified as being regulated by CR, the mechanism by which CR extends life span remains unclear. The Drosophila gene Indy (for I'm not dead yet), involved in the transport and storage of Krebs cycle intermediates in tissues important in fly metabolism, was proposed to regulate life span via an effect on metabolism that could overlap with CR. In this study, we report that CR down regulates Indy mRNA expression, and that CR and the level of Indy expression interact to affect longevity. Optimal life span extension is seen when Indy expression is decreased between 25 and 75% of normal. Indy long-lived flies show several phenotypes that are shared by long-lived CR flies, including decreased insulin-like signaling, lipid storage, weight gain, and resistance to starvation as well as an increase in spontaneous physical activity. We conclude that Indy and CR interact to affect longevity and that a decrease in Indy may induce a CR-like status that confers life span extension.