Indy Encodes a Regulator of Intermediary Metabolism that Modulates Longevity in Drosophila melanogaster

The Drosophila I’m Not Dead Yet (Indy) gene encodes a plasma membrane transporter of Krebs cycle intermediates, with robust expression in tissues associated with metabolism. Reduced INDY alters metabolism and extends longevity in a manner similar to caloric restriction (CR) with few biological tradeoffs; however, little is known about the tissue specific physiological effects of INDY reduction or how such changes contribute to fly health and longevity. The experiments described in this dissertation are focused on the effects of INDY reduction in the Drosophila midgut due to the importance of intestinal tissue homeostasis in healthy aging and longevity. The expression of Indy mRNA in the midgut was found to change in response to aging and nutrition. Genetic reduction of Indy expression leads to increased midgut expression of the mitochondrial regulator spargel/dPGC-1, which is accompanied by increased mitochondrial biogenesis and reduced reactive oxygen species (ROS). These physiological changes in the Indy mutant midgut preserve intestinal stem cell (ISC) homeostasis and are associated with healthy aging. The data suggest INDY may be a physiological regulator that modulates intermediary metabolism in response to changes in nutrient availability and organismal needs. Genetic studies confirm that dPGC-1 mediates regulatory effects of INDY, as illustrated by lack of longevity extension and ISC homeostasis in flies with mutations in both Indy and dPGC1. Together, the data support a model of INDY as a physiological regulator that is responsive to aging and nutritional conditions, which acts by modulating dPGC-1