Mechanisms of Longevity Regulation in Yeast

Summary

Principal Investigator: Valter Longo
Affiliation: University of Southern California
Country: USA
Abstract: Mutations in the Sch9 and Ras/cAMP signal transduction pathways, which promote reproduction in response to glucose/nutrients, activate multiple stress resistance systems and extend the life span of non-dividing yeast by up to three-fold. Sch9 is homologous to the C. elegans, Drosophila, and mammalian serine/threonine kinases Akt/PKB, which are also activated in response to glucose/nutrients and function in pathways that regulate reproduction and longevity. I propose that the modulation of analogous signal transduction pathways can increase resistance to damage and extend longevity in organisms ranging from yeast to mammals by shifting the investment of energy from growth and reproduction to multiple stress resistance systems. These mechanisms may have arisen early during evolution in order to minimize aging during periods of starvation. To test this hypothesis I propose to: 1) elucidate the molecular mechanisms responsible for the regulation of longevity by the yeast Ras/cAMP and Sch9 pathways, focusing on known stress resistance genes and on yeast homologs of genes that function in the IGF-1/insulin signaling pathway in higher eukaryotes, 2) perform unbiased screens and study uncharacterized stress resistant mutants isolated in previous screens to identify novel genes that mediate longevity-regulation downstream of Ras/cAMP/Msn2/4 and Sch9, 3) characterize further the post-diauxic life span in wild type and long-lived mutants to understand the relationship between aging in yeast and in higher eukaryotes, 4) identify the distinct mechanisms that regulate the "chronological life span" (survival of non-dividing yeast) and "replicative life span" (budding potential). The combination of the short, high-metabolism post-diauxic life span with transposon mutagenesis provides a rapid method to identify the mediators of stress resistance and longevity extension. The identification and characterization of these mutations should contribute to the identification and understanding of putative dormant starvation-response pathways in mammals, which may be activated to protect cells against aging and age-related diseases without affecting normal functions.
Funding Period: 2003-01-01 - 2008-02-29
more information: NIH RePORT

Top Publications

  1. ncbi Tor1/Sch9-regulated carbon source substitution is as effective as calorie restriction in life span extension
    Min Wei
    Andrus Gerontology Center, University of Southern California, Los Angeles, CA, USA
    PLoS Genet 5:e1000467. 2009
  2. ncbi Sir2 blocks extreme life-span extension
    Paola Fabrizio
    Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA
    Cell 123:655-67. 2005
  3. ncbi Oncogene homologue Sch9 promotes age-dependent mutations by a superoxide and Rev1/Polzeta-dependent mechanism
    Federica Madia
    Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
    J Cell Biol 186:509-23. 2009
  4. ncbi Turning anti-ageing genes against cancer
    Valter D Longo
    Andrus Gerontology Center, Molecular and Computational Biology Department, University of Southern California, 3715 McClintock Avenue, Los Angeles, California 90089 0191, USA
    Nat Rev Mol Cell Biol 9:903-10. 2008
  5. ncbi SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons
    Ying Li
    Neuroscience Program, University of Southern California, Los Angeles, CA 90089 2520, USA
    Cell Metab 8:38-48. 2008
  6. ncbi Chronological aging-induced apoptosis in yeast
    Paola Fabrizio
    Andrus Gerontology Center, Division of Biogerontology, University of Southern California, Los Angeles, CA 90089 0191, USA
    Biochim Biophys Acta 1783:1280-5. 2008
  7. ncbi Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy
    Lizzia Raffaghello
    Andrus Gerontology Center, Department of Biological Sciences and Norris Cancer Center, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089 0191, USA
    Proc Natl Acad Sci U S A 105:8215-20. 2008
  8. ncbi Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9
    Min Wei
    Andrus Gerontology Center, University of Southern California, Los Angeles, California, United States of America
    PLoS Genet 4:e13. 2008
  9. ncbi Longevity mutation in SCH9 prevents recombination errors and premature genomic instability in a Werner/Bloom model system
    Federica Madia
    Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
    J Cell Biol 180:67-81. 2008
  10. ncbi A simple model system for age-dependent DNA damage and cancer
    F Madia
    Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089 0191, United States
    Mech Ageing Dev 128:45-9. 2007

Scientific Experts

  • Valter Longo
  • Paola Fabrizio
  • Min Wei
  • Federica Madia
  • Changhan Lee
  • Lizzia Raffaghello
  • Jia Hu
  • Fernando M Safdie
  • Giovanna Bianchi
  • Cristina Gattazzo
  • Huanying Ge
  • Ying Li
  • F Madia
  • Edoardo Parrella
  • Pinchas Cohen
  • David Hwang
  • Valerie Yuan
  • Myron F Goodman
  • Phuong Pham
  • Lei M Li
  • Martin Weinberger
  • Lucio Comai
  • Jesse R Smith
  • Michael W McBurney
  • Wei Xu
  • William C Burhans
  • Abdoulaye Galbani
  • Christopher Nguyen
  • Chao Cheng
  • Selina Huey
  • Lei Li
  • C Gattazzo

Detail Information

Publications12

  1. ncbi Tor1/Sch9-regulated carbon source substitution is as effective as calorie restriction in life span extension
    Min Wei
    Andrus Gerontology Center, University of Southern California, Los Angeles, CA, USA
    PLoS Genet 5:e1000467. 2009
    ....
  2. ncbi Sir2 blocks extreme life-span extension
    Paola Fabrizio
    Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA
    Cell 123:655-67. 2005
    ..Our results demonstrate that effects of SIR2 on chronological life span are opposite to replicatve life span and suggest that the relevant activities of Sir2-like deacetylases may also be complex in higher eukaryotes...
  3. ncbi Oncogene homologue Sch9 promotes age-dependent mutations by a superoxide and Rev1/Polzeta-dependent mechanism
    Federica Madia
    Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
    J Cell Biol 186:509-23. 2009
    ....
  4. ncbi Turning anti-ageing genes against cancer
    Valter D Longo
    Andrus Gerontology Center, Molecular and Computational Biology Department, University of Southern California, 3715 McClintock Avenue, Los Angeles, California 90089 0191, USA
    Nat Rev Mol Cell Biol 9:903-10. 2008
    ..This raises the possibility that cancer can be reduced by chronic downregulation of pro-ageing pathways...
  5. ncbi SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons
    Ying Li
    Neuroscience Program, University of Southern California, Los Angeles, CA 90089 2520, USA
    Cell Metab 8:38-48. 2008
    ..These results are consistent with findings in S. cerevisiae and other model systems, suggesting that mammalian sirtuins can play both protective and proaging roles...
  6. ncbi Chronological aging-induced apoptosis in yeast
    Paola Fabrizio
    Andrus Gerontology Center, Division of Biogerontology, University of Southern California, Los Angeles, CA 90089 0191, USA
    Biochim Biophys Acta 1783:1280-5. 2008
    ..cerevisiae. We also describe the use of a genome-wide screening technique to gain further insights into the mechanisms of programmed death in populations of chronologically aging S. cerevisiae...
  7. ncbi Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy
    Lizzia Raffaghello
    Andrus Gerontology Center, Department of Biological Sciences and Norris Cancer Center, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089 0191, USA
    Proc Natl Acad Sci U S A 105:8215-20. 2008
    ....
  8. ncbi Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9
    Min Wei
    Andrus Gerontology Center, University of Southern California, Los Angeles, California, United States of America
    PLoS Genet 4:e13. 2008
    ..Notably, the anti-aging effect caused by the inactivation of both pathways is much more potent than that caused by CR...
  9. ncbi Longevity mutation in SCH9 prevents recombination errors and premature genomic instability in a Werner/Bloom model system
    Federica Madia
    Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
    J Cell Biol 180:67-81. 2008
    ..The conserved function of Akt/S6k homologues in lifespan regulation raises the possibility that modulation of the IGF-I-Akt-56K pathway can protect against premature aging syndromes in mammals...
  10. ncbi A simple model system for age-dependent DNA damage and cancer
    F Madia
    Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089 0191, United States
    Mech Ageing Dev 128:45-9. 2007
    ..Here, we describe the use of this system to monitor the age-dependent accumulation of different types of DNA mutations including base substitutions, frame-shift mutations, and gross chromosomal rearrangements (GCRs)...
  11. ncbi Sirtuins in aging and age-related disease
    Valter D Longo
    Department of Molecular and Computational Biology, Andrus Gerontology Center, University of Southern California, Los Angeles, CA 90089, USA
    Cell 126:257-68. 2006
    ..Here we examine the roles of Sirtuins in diverse eukaryotic species, with special emphasis on their links to aging and age-related diseases including cancer, diabetes, and neurodegenerative disorders...
  12. ncbi Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index
    Changhan Lee
    Andrus Gerontology Center, Department of Biological Sciences and Norris Cancer Center, University of Southern California, Los Angeles, California 90089 0191, USA
    Cancer Res 70:1564-72. 2010
    ..We conclude that normal cells and mice can be protected against chemotherapy-dependent damage by reducing circulating IGF-I levels and by a mechanism that involves downregulation of proto-oncogene signals...