Abstract

Our long-term goal is to understand the genetic and molecular elements that determine the process of aging and life span.
The aim of this proposal is to test how specific genes and proteins affect the life span extension seen with caloric restriction. Studies of caloric restriction show changes in a large number of genes and physiological systems. One of these, the Rpd3/Sir2 pathway, has been implicated in life span extension in yeast, nematodes, and flies. A prerequisite to developing molecular genetic and pharmacological interventions that extend life span through the manipulation of the caloric restriction/Rpd3/Sir2 pathway is a better understanding of the pathway and the genes and proteins that are regulated by it. In this proposal we will confirm the importance of Sir2 in the caloric restriction pathway in flies, define the position of Sir2 within the pathway relative to Rpd3, determine the timing and site of tissues important for its action on longevity, and examine the effect of small exogenous molecules known to increase Sir2 activity on longevity. Using our fly model system we will then examine the role in life span extension of p53, a transcription factor and tumor suppressor in mammals whose activity is controlled by Sir2. Finally, we will use a comparative microarray analysis to identify genes and proteins important in effecting longevity in the Rpd3/Sir2/caloric restriction pathway in flies and initiate a genetic analysis of the potential effector molecules.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG024353-04
Application #
7271307
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M3))
Program Officer
Mccormick, Anna M
Project Start
2004-09-30
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
4
Fiscal Year
2007
Total Cost
$346,417
Indirect Cost

  Institution

Name
Brown University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912

  Publications

Wood, Jason G; Schwer, Bjoern; Wickremesinghe, Priyan C et al. (2018) Sirt4 is a mitochondrial regulator of metabolism and lifespan in Drosophila melanogaster. Proc Natl Acad Sci U S A 115:1564-1569
von Loeffelholz, Christian; Lieske, Stefanie; Neuschäfer-Rube, Frank et al. (2017) The human longevity gene homolog INDY and interleukin-6 interact in hepatic lipid metabolism. Hepatology 66:616-630
Jones, Brian C; Wood, Jason G; Chang, Chengyi et al. (2016) A somatic piRNA pathway in the Drosophila fat body ensures metabolic homeostasis and normal lifespan. Nat Commun 7:13856
Willmes, Diana M; Helfand, Stephen L; Birkenfeld, Andreas L (2016) The longevity transporter mIndy (Slc13a5) as a target for treating hepatic steatosis and insulin resistance. Aging (Albany NY) 8:208-9
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
Ding, Feifei; Gil, M Pilar; Franklin, Michael et al. (2014) Transcriptional response to dietary restriction in Drosophila melanogaster. J Insect Physiol 69:101-6
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

Showing the most recent 10 out of 35 publications