Mechanisms of Longevity Regulation in Yeast

Summary

Principal Investigator: Valter Longo
Affiliation: University of Southern California
Country: USA
Abstract: [unreadable] DESCRIPTION (provided by applicant): 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. pmc 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. pmc Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression
    Chia Wei Cheng
    Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089, USA
    Cell Stem Cell 14:810-23. 2014
  3. pmc Fasting and differential chemotherapy protection in patients
    Lizzia Raffaghello
    Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
    Cell Cycle 9:4474-6. 2010
  4. ncbi Insulin/IGF-I and related signaling pathways regulate aging in nondividing cells: from yeast to the mammalian brain
    Edoardo Parrella
    Division of Neurogerontology Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
    ScientificWorldJournal 10:161-77. 2010
  5. pmc Comparative analyses of time-course gene expression profiles of the long-lived sch9Delta mutant
    Huanying Ge
    Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
    Nucleic Acids Res 38:143-58. 2010
  6. pmc Replicative and chronological aging in Saccharomyces cerevisiae
    Valter D Longo
    Longevity Institute, School of Gerontology, Department of Biological Sciences, and Norris Cancer Center, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089 0191, USA
    Cell Metab 16:18-31. 2012
  7. pmc Fasting enhances the response of glioma to chemo- and radiotherapy
    Fernando Safdie
    Longevity Institute and Department of Biological Sciences, School of Gerontology, University of Southern California, Los Angeles, California, United States of America
    PLoS ONE 7:e44603. 2012
  8. pmc Short-term calorie and protein restriction provide partial protection from chemotoxicity but do not delay glioma progression
    Sebastian Brandhorst
    Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089 0191, USA
    Exp Gerontol 48:1120-8. 2013
  9. pmc Somatotropic signaling: trade-offs between growth, reproductive development, and longevity
    Andrzej Bartke
    Southern Illinois University School of Medicine, Department of Internal Medicine, Geriatric Research, Springfield, Illinois 62703, USA
    Physiol Rev 93:571-98. 2013
  10. pmc Fasting: molecular mechanisms and clinical applications
    Valter D Longo
    Longevity Institute, Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089 2520, USA Electronic address
    Cell Metab 19:181-92. 2014

Scientific Experts

  • Valter Longo
  • Caleb Finch
  • Luigi Fontana
  • Paola Fabrizio
  • Min Wei
  • Federica Madia
  • Changhan Lee
  • Jia Hu
  • Lizzia Raffaghello
  • Sebastian Brandhorst
  • Giovanna Bianchi
  • Stavros Gonidakis
  • Huanying Ge
  • Chia Wei Cheng
  • Mario G Mirisola
  • Hamed Mirzaei
  • Saewon Hwang
  • Fernando Safdie
  • Edoardo Parrella
  • Fernando M Safdie
  • Mario Mirisola
  • Morgan E Levine
  • Andrzej Bartke
  • Pinchas Cohen
  • Steven E Finkel
  • Lei M Li
  • Chao Cheng
  • Cristina Gattazzo
  • Ying Li
  • F Madia
  • Camille Amparo
  • Xiaoying Zhou
  • Giusi Taormina
  • John J Kopchick
  • Stefano DA Sacco
  • Giuseppe Passarino
  • Ben S Lam
  • Gregor B Adams
  • Junxiang Wan
  • Shawna Chagoury
  • Brian K Kennedy
  • Laura Perin
  • Priya Balasubramanian
  • Jorge A Suarez
  • Jaime Guevara-Aguirre
  • Eileen M Crimmins
  • Tanya B Dorff
  • David I Quinn
  • Brian Kennedy
  • Todd E Morgan
  • Liou Y Sun
  • Alejandro Martín-Montalvo
  • Vito Pistoia
  • Weijun Wang
  • Thomas C Chen
  • Rafael De Cabo
  • Peter S Conti
  • Annalisa Merlino
  • Laura Emionite
  • Tanya Dorff
  • David Hwang
  • Valerie Yuan
  • Myron F Goodman
  • Phuong Pham
  • Christopher Nguyen
  • Martin Weinberger
  • Lucio Comai
  • Jesse R Smith
  • Michael W McBurney
  • Selina Huey
  • Lei Li
  • Wei Xu
  • William C Burhans
  • Abdoulaye Galbani
  • C Gattazzo

Detail Information

Publications35

  1. pmc 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. pmc Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression
    Chia Wei Cheng
    Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089, USA
    Cell Stem Cell 14:810-23. 2014
    ..These findings link the reduced levels of IGF-1 caused by fasting to PKA signaling and establish their crucial role in regulating hematopoietic stem cell protection, self-renewal, and regeneration. ..
  3. pmc Fasting and differential chemotherapy protection in patients
    Lizzia Raffaghello
    Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
    Cell Cycle 9:4474-6. 2010
    ..Here we briefly discuss the basic, pre-clinical, and clinical studies on fasting and cancer therapy...
  4. ncbi Insulin/IGF-I and related signaling pathways regulate aging in nondividing cells: from yeast to the mammalian brain
    Edoardo Parrella
    Division of Neurogerontology Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
    ScientificWorldJournal 10:161-77. 2010
    ..Taken together, these studies indicate that simple model systems will contribute to our comprehension of aging of the mammalian nervous system and will stimulate novel neurotherapeutic strategies in humans...
  5. pmc Comparative analyses of time-course gene expression profiles of the long-lived sch9Delta mutant
    Huanying Ge
    Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
    Nucleic Acids Res 38:143-58. 2010
    ....
  6. pmc Replicative and chronological aging in Saccharomyces cerevisiae
    Valter D Longo
    Longevity Institute, School of Gerontology, Department of Biological Sciences, and Norris Cancer Center, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089 0191, USA
    Cell Metab 16:18-31. 2012
    ..cerevisiae will continue to serve as a leading model organism for studying pathways relevant to human aging and disease...
  7. pmc Fasting enhances the response of glioma to chemo- and radiotherapy
    Fernando Safdie
    Longevity Institute and Department of Biological Sciences, School of Gerontology, University of Southern California, Los Angeles, California, United States of America
    PLoS ONE 7:e44603. 2012
    ..We have previously reported that short-term starvation (STS) enhances the therapeutic index of chemo-treatments by differentially protecting normal cells against and/or sensitizing tumor cells to chemotoxicity...
  8. pmc Short-term calorie and protein restriction provide partial protection from chemotoxicity but do not delay glioma progression
    Sebastian Brandhorst
    Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089 0191, USA
    Exp Gerontol 48:1120-8. 2013
    ..These results indicate that the protection from chemotoxicity and retardation of the progression of certain tumors achieved with fasting is not obtained with short-term calorie and/or macronutrient restriction. ..
  9. pmc Somatotropic signaling: trade-offs between growth, reproductive development, and longevity
    Andrzej Bartke
    Southern Illinois University School of Medicine, Department of Internal Medicine, Geriatric Research, Springfield, Illinois 62703, USA
    Physiol Rev 93:571-98. 2013
    ....
  10. pmc Fasting: molecular mechanisms and clinical applications
    Valter D Longo
    Longevity Institute, Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089 2520, USA Electronic address
    Cell Metab 19:181-92. 2014
    ..Thus, fasting has the potential to delay aging and help prevent and treat diseases while minimizing the side effects caused by chronic dietary interventions. ..
  11. pmc Serine- and threonine/valine-dependent activation of PDK and Tor orthologs converge on Sch9 to promote aging
    Mario G Mirisola
    Dipartimento di Biotecnologie Mediche e Forensi DiBiMeF Università di Palermo, Palermo, Italy
    PLoS Genet 10:e1004113. 2014
    ..Because of the conserved pro-aging role of nutrient and growth signaling pathways in higher eukaryotes, these results raise the possibility that similar mechanisms contribute to aging in mammals. ..
  12. pmc Acetyl-CoA synthetase is a conserved regulator of autophagy and life span
    Hamed Mirzaei
    Longevity Institute, School of Gerontology and Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089, USA
    Cell Metab 19:555-7. 2014
    ..Eisenberg and colleagues (Eisenberg et al., 2014) now describe the central and conserved role for acetyl-CoA synthetase in regulating life span in yeast and flies by a mechanism involving autophagy. ..
  13. pmc Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population
    Morgan E Levine
    Davis School of Gerontology, University of Southern California, Los Angeles, CA 90033, USA
    Cell Metab 19:407-17. 2014
    ..These results suggest that low protein intake during middle age followed by moderate to high protein consumption in old adults may optimize healthspan and longevity...
  14. pmc Tor-Sch9 deficiency activates catabolism of the ketone body-like acetic acid to promote trehalose accumulation and longevity
    Jia Hu
    Longevity Institute, Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA Department of Biological Sciences, School of Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA
    Aging Cell 13:457-67. 2014
    ..These effects are reminiscent of those described for ketone bodies in fasting mammals and raise the possibility that the lifespan extension caused by Tor-S6K inhibition may also involve analogous metabolic changes in higher eukaryotes...
  15. pmc Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy
    Changhan Lee
    Andrus Gerontology Center, Department of Biological Sciences, Norris Cancer Center, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089 0191, USA
    Sci Transl Med 4:124ra27. 2012
    ....
  16. pmc Starvation, detoxification, and multidrug resistance in cancer therapy
    Changhan Lee
    Andrus Gerontology Center, Dept of Biological Sciences and Norris Cancer Center, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089 0191, United States
    Drug Resist Updat 15:114-22. 2012
    ....
  17. pmc Growth factors, nutrient signaling, and cardiovascular aging
    Luigi Fontana
    Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
    Circ Res 110:1139-50. 2012
    ..Here, we review the link between growth factors, cardiac function, and heart disease with focus on the cardioprotective and sensitizing effect of growth factors in both model organisms and humans...
  18. pmc Genome-wide screen identifies Escherichia coli TCA-cycle-related mutants with extended chronological lifespan dependent on acetate metabolism and the hypoxia-inducible transcription factor ArcA
    Stavros Gonidakis
    Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
    Aging Cell 9:868-81. 2010
    ....
  19. doi E. coli hypoxia-inducible factor ArcA mediates lifespan extension in a lipoic acid synthase mutant by suppressing acetyl-CoA synthetase
    Stavros Gonidakis
    Integrative and Evolutionary Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
    Biol Chem 391:1139-47. 2010
    ..These results provide evidence for the role of Acs in regulating lifespan and/or stress resistance by both carbon source uptake-dependent and -independent mechanisms...
  20. pmc Genome-wide screen in Saccharomyces cerevisiae identifies vacuolar protein sorting, autophagy, biosynthetic, and tRNA methylation genes involved in life span regulation
    Paola Fabrizio
    Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America
    PLoS Genet 6:e1001024. 2010
    ..The high degree of conservation of these novel yeast longevity determinants in other species raises the possibility that their role in senescence might be conserved...
  21. pmc Cell resilience in species life spans: a link to inflammation?
    Caleb E Finch
    University of Southern California, Los Angeles, CA 90089 0191, USA
    Aging Cell 9:519-26. 2010
    ..We suggest expanding the battery of stressors and markers used for comparative studies to additional cell types and additional parameters relevant to host defense and to their ecological specificities...
  22. pmc Extending healthy life span--from yeast to humans
    Luigi Fontana
    Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St Louis, MO 63110, USA
    Science 328:321-6. 2010
    ..We discuss these findings and their potential application to prevention of age-related disease and promotion of healthy aging in humans, and the challenge of possible negative side effects...
  23. pmc Calorie restriction and cancer prevention: metabolic and molecular mechanisms
    Valter D Longo
    The Andrus Gerontology Center, University of Southern California, Los Angeles, CA, USA
    Trends Pharmacol Sci 31:89-98. 2010
    ..Here, we discuss the link between nutritional interventions and cancer prevention with focus on the mechanisms that might be responsible for these effects in simple systems and mammals with a view to developing chemoprevention agents...
  24. 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...
  25. pmc 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)...
  26. pmc 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...
  27. pmc 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...
  28. pmc 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
    ....
  29. pmc 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...
  30. pmc 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...
  31. 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...
  32. pmc 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
    ....
  33. pmc 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...
  34. 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...