Our long-term goal is to understand the genetic and molecular elements that determine the process of aging and life span. The focus of this proposal is to identify molecular genetic effectors that mediate calorie/dietary restriction (CR/DR) life span extension as a prerequisite to developing molecular genetic and pharmacological interventions that can extend healthy life span. Examination of CR/DR in a variety of species shows changes in a large number of genes and physiological systems. A central question in translating this information to therapeutic interventions is which of the many changes seen are involved in extending healthy life span? In flies molecular genetic studies have led to a model in which a portion of the life span extending effect of CR/DR is mediated by alterations in the activity of the histone deacetylases Rpd3 and Sir2, and the transcription factor p53. This model provides a framework for use in identifying genetic, biochemical, and pharmacological effectors of CR/DR mediated longevity. In this proposal we will (i) further examine the mechanisms by which an increase in dSir2 extends life span in the fly, (ii) confirm the life span extending effect of a gene identified through our genomic analysis of the CR/Sir2/p53 pathway and begin to determine it's relationship to CR/DR life span extension, (iii) utilize genome based tools to determine genes and gene sets important for CR/DR life span extension in flies and (iv) test the effect of these newly identified genes on life span using molecular genetic tools.

Public Health Relevance

Calorie/dietary restriction extends life span and delays the onset of age-related pathology in organisms from worms to mice. Understanding the molecular genetic interactions in the calorie/dietary restriction pathway of Drosophila will contribute to the development of interventions to prevent or delay age-dependent decline in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG024353-10
Application #
8474674
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Guo, Max
Project Start
2004-09-30
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2013
Total Cost
$298,642
Indirect Cost
$114,295
Name
Brown University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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
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
Bauer, Johannes; Antosh, Michael; Chang, Chengyi et al. (2010) Comparative transcriptional profiling identifies takeout as a gene that regulates life span. Aging (Albany NY) 2:298-310
Wood, Jason G; Hillenmeyer, Sara; Lawrence, Charles et al. (2010) Chromatin remodeling in the aging genome of Drosophila. Aging Cell 9:971-8

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