Abstract
Indy (I’m not dead yet) encodes the fly homolog of a mammalian mIndy (SLC13A5) plasma membrane citrate transporter. Reduction of Indy gene activity in flies, or its homolog in worm extends longevity. Decreased expression of INDY in flies, worms, rats, and mice has beneficial effects on energy balance because the levels of cytoplasmic citrate play a central role in metabolism. INDY is predominantly expressed in the midgut, fat body and oenocytes, all tissues with a key role in metabolism. Our first goal was to determine which tissue is the most important for INDY-mediated benefits. We used Indy RNAi-mediated silencing and tissue-specific Gene-switch drivers. We found that reduction of Indy mRNA levels in female fly gut and fat body increases stress resistance and longevity but not to extend found in original Indy flies suggesting synergistic contribution of each of the tissues. Down-regulation of the Indy gene in flies preserves intestinal stem cell homeostasis (ISC) and midgut integrity. ISC homeostasis is crucial for midgut homeostasis and contributes to health and longevity in a variety of species. The Insulin/Insulin-like signaling (IIS) is a key nutrient sensing pathway, which regulates growth, metabolism and longevity. Indy reduction is associated with decreased IIS activity as illustrated by decreased dilps levels in heads and thoraces of Indy flies. Our second goal was to examine the role of IIS in Indy mediated changes in ISC homeostasis and health. We found that at least some of INDY’s beneficial effects on fly health are mediated by the IIS.