The long-term goal of our studies is to understand the molecular and genetic elements that underlie the process of aging and determine longevity.
The aim of this proposal is to understand how mutations in a single gene, Indy, result in a dramatic increase in life span in Drosophila melanogaster without a concomitant loss of reproduction, physical activity or metabolic rate. In particular we will seek to determine where and when Indy mutations act to extend life span. The function of the INDY protein as a tranporter of Krebs cycle intermediates and its preliminary localization to regions of the fly important in uptake, utilization and storage of nutrients, indicate that reductions in the level of INDY protein alters the metabolic state of the fly in a way that favors life span extension. INDY's similarity in sequence, function, and tissue expression to mammalian and human dicarboxylate transporters suggests that knowledge of how Indy mutations extend life span in flies may be useful for the development of therapeutic interventions for extending healthy life in humans. We will first examine the tissues and times during life INDY expression is altered in the long-lived Indy mutant animals. Using molecular genetic approaches we will restore Indy function to directly determine where and when Indy mutations act to extend life span. Finally we will determine which of the several possible human Indy-like genes can functionally rescue the Indy mutation. A more complete understanding of how mutations in Indy lead to life span extension should yield valuable insights into general mechanisms of life span extension relevant to a variety of organisms including humans.

National Institute of Health (NIH)
Method to Extend Research in Time (MERIT) Award (R37)
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No Study Section (in-house review) (NSS)
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Guo, Max
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Brown University
Schools of Medicine
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Zhu, Chen-Tseh; Chang, Chengyi; Reenan, Robert A et al. (2014) Indy gene variation in natural populations confers fitness advantage and life span extension through transposon insertion. Aging (Albany NY) 6:58-69
Gorbunova, Vera; Boeke, Jef D; Helfand, Stephen L et al. (2014) Human Genomics. Sleeping dogs of the genome. Science 346:1187-8
Whitaker, Rachel; Gil, M Pilar; Ding, Feifei et al. (2014) Dietary switch reveals fast coordinated gene expression changes in Drosophila melanogaster. Aging (Albany NY) 6:355-68
Savva, Yiannis A; Jepson, James E C; Chang, Yao-Jen et al. (2013) RNA editing regulates transposon-mediated heterochromatic gene silencing. Nat Commun 4:2745
Rogina, Blanka; Helfand, Stephen L (2013) Indy mutations and Drosophila longevity. Front Genet 4:47
Whitaker, Rachel; Faulkner, Shakeela; Miyokawa, Reika et al. (2013) Increased expression of Drosophila Sir2 extends life span in a dose-dependent manner. Aging (Albany NY) 5:682-91
Antosh, Michael; Fox, David; Helfand, Stephen L et al. (2011) New comparative genomics approach reveals a conserved health span signature across species. Aging (Albany NY) 3:576-83
Birkenfeld, Andreas L; Lee, Hui-Young; Guebre-Egziabher, Fitsum et al. (2011) Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell Metab 14:184-95
Antosh, Michael; Whitaker, Rachel; Kroll, Adam et al. (2011) Comparative transcriptional pathway bioinformatic analysis of dietary restriction, Sir2, p53 and resveratrol life span extension in Drosophila. Cell Cycle 10:904-11
Shulman, Gerald I; Helfand, Stephen L (2011) Indy knockdown in mice mimics elements of dietary restriction. Aging (Albany NY) 3:701

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