Chronological Age-Dependent Genomic Instability in Yeast

Summary

Principal Investigator: Valter Longo
Abstract: Aging is the major risk factor for many human cancers. However, the mechanisms responsible for the effect of aging on tumor incidence are poorly understood, in part because few model systems are available to study age-dependent genomic instability . Furthermore, the role of DNA mutations in "normal aging" and "life span extension" is unclear. We will test the hypothesis that the histone deacetylase Sir2, and the signal transduction proteins Ras and Sch9 synergistically regulate aging and genomic instability in S. cerevisiae. We propose that the effect of Sir2, Sch9, and Ras2 on chronological life span and genomic instability is mediated in part by the down-regulation of enzymes that repair DNA. Finally, we will test the role of different DNA repair systems in chronological aging and life span extension. My laboratory has developed a novel method to study aging in yeast based on the survival of non-dividing populations (chronological life span). This system allowed us to identify two pathways that regulate longevity in yeast: the Ras and Sch9 pathways. Notably yeast Ras2 and Sch9 are functional homologs of mammalian Ras and Akt, two of the major human oncogenes. Akt also functions in insulin-like pathways that regulates longevity in C. elegans, Drosophila, and mice. Thus, chronologically aging S. cerevisiae can serve as a model to identify genes that regulate genomic instability and understand the mechanisms responsible for age-dependent DNA mutations and cancer in mammals.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. 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
  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 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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

Scientific Experts

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

Detail Information

Publications25

  1. 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)...
  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 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...
  4. 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...
  5. 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. ..
  6. 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
    ....
  7. 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. ..
  8. 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. ..
  9. 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...
  10. 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. ..
  11. 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...
  12. 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...
  13. 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...
  14. 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
    ....
  15. 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...
  16. 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...
  17. 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
    ....
  18. 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
    ....
  19. 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...
  20. 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...
  21. 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...
  22. 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
    ....
  23. 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
    ....
  24. 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...