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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZAG1-ZIJ-5 (M3))
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Finkelstein, David B
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University of California Davis
Schools of Arts and Sciences
United States
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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
Li, Bin; Skinner, Craig; Castello, Pablo R et al. (2011) Identification of potential calorie restriction-mimicking yeast mutants with increased mitochondrial respiratory chain and nitric oxide levels. J Aging Res 2011:673185
Lin, Su-Ju (2011) Large at birth lifespan dearth? Cell Cycle 10:577-8
Lu, Shu-Ping; Lin, Su-Ju (2010) Regulation of yeast sirtuins by NAD(+) metabolism and calorie restriction. Biochim Biophys Acta 1804:1567-75
Skinner, Craig; Lin, Su-Ju (2010) Effects of calorie restriction on life span of microorganisms. Appl Microbiol Biotechnol 88:817-28
Wang, Chen; Skinner, Craig; Easlon, Erin et al. (2009) Deleting the 14-3-3 protein Bmh1 extends life span in Saccharomyces cerevisiae by increasing stress response. Genetics 183:1373-84
Lu, Shu-Ping; Kato, Michiko; Lin, Su-Ju (2009) Assimilation of endogenous nicotinamide riboside is essential for calorie restriction-mediated life span extension in Saccharomyces cerevisiae. J Biol Chem 284:17110-9
Sporty, Jennifer; Lin, Su-Ju; Kato, Michiko et al. (2009) Quantitation of NAD+ biosynthesis from the salvage pathway in Saccharomyces cerevisiae. Yeast 26:363-9
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

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