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.

Agency
National Institute of Health (NIH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
3R37AG016667-15S1
Application #
8841109
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Guo, Max
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brown University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Providence
State
RI
Country
United States
Zip Code
02912
Wood, Jason G; Jones, Brian C; Jiang, Nan et al. (2016) Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila. Proc Natl Acad Sci U S A 113:11277-11282
Pu, Mintie; Ni, Zhuoyu; Wang, Minghui et al. (2015) Trimethylation of Lys36 on H3 restricts gene expression change during aging and impacts life span. Genes Dev 29:718-31
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
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
Ding, Feifei; Gil, M Pilar; Franklin, Michael et al. (2014) Transcriptional response to dietary restriction in Drosophila melanogaster. J Insect Physiol 69:101-6
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
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
Jiang, Nan; Du, Guyu; Tobias, Ethan et al. (2013) Dietary and genetic effects on age-related loss of gene silencing reveal epigenetic plasticity of chromatin repression during aging. Aging (Albany NY) 5:813-24

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