Aging is a complex process that influences many aspects of our lives yet little is known about the molecular pathways that regulate this process. Calorie Restriction (CR) extends life span in a wide sprectrum of organisms. Understanding the mechanism by which CR extends life span will help to elucidate the molecular pathways of longevity regulations. The main goal of this proposal is to utilize the genetically tractable yeast Saccharomyces cerevisiae as a model system to identify and unravel the longevity regulating pathways. The major hypothesis of this research is that longevity factors are subject to metabolic regulation under Calorie Restriction (CR) and the intracellular NAD/NADH homeostasis factors play an important role in mediating this regulation.
Aim 1) : To understand the role of metabolic enzymes in longevity regulation. Using Affinity-purification, molecular and genetic studies, we will elucidate how metabolic enzymes regulate longevity and to identify other longevity regulating metabolic factors.
Aim 2) : To study the role of NAD/NADH homeostasis in the metabolic regulation of longevity. In vivo levels of NAD and NADH will be determined using Nano-HPLC/AMS analysis. The mechanisms by which the NADINADH homeostasis factors regulate life span will be studied.
Aim 3) : To identify new components in the longevity signaling pathway. In this Specific Aim, we propose three different approaches that combine genetic, genomic and biochemical methods to detail the pathways of CR and to identify new longevity pathways. Many cellular pathways are conserved in yeast and mammals. Therefore, insight into these molecular processes in yeast will also provide clues to the molecular basis of human aging and age-associated diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG024351-04
Application #
7253947
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M3))
Program Officer
Finkelstein, David B
Project Start
2004-09-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$243,856
Indirect Cost
Name
University of California Davis
Department
Genetics
Type
Schools of Arts and Sciences
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Lu, Shu-Ping; Lin, Su-Ju (2011) Phosphate-responsive signaling pathway is a novel component of NAD+ metabolism in Saccharomyces cerevisiae. J Biol Chem 286:14271-81
Skinner, Craig; Lin, Su-Ju (2010) Effects of calorie restriction on life span of microorganisms. Appl Microbiol Biotechnol 88:817-28
Lu, Shu-Ping; Lin, Su-Ju (2009) Regulation of Yeast Sirtuins by NAD(+) Metabolism and Calorie Restriction. Biochim Biophys Acta :
Easlon, Erin; Tsang, Felicia; Skinner, Craig et al. (2008) The malate-aspartate NADH shuttle components are novel metabolic longevity regulators required for calorie restriction-mediated life span extension in yeast. Genes Dev 22:931-44
Easlon, Erin; Tsang, Felicia; Dilova, Ivanka et al. (2007) The dihydrolipoamide acetyltransferase is a novel metabolic longevity factor and is required for calorie restriction-mediated life span extension. J Biol Chem 282:6161-71
Dilova, I; Easlon, E; Lin, S-J (2007) Calorie restriction and the nutrient sensing signaling pathways. Cell Mol Life Sci 64:752-67