title: Growth signaling promotes chronological aging in budding yeast by inducing superoxide anions that inhibit quiescence.
abstract: Inhibition of growth signaling pathways protects against aging and age-related diseases in parallel with reduced oxidative stress. The relationships between growth signaling, oxidative stress and aging remain unclear. Here we report that in Saccharomyces cerevisiae, alterations in growth signaling pathways impact levels of superoxide anions that promote chronological aging and inhibit growth arrest of stationary phase cells in G0/G1. Factors that decrease intracellular superoxide anions in parallel with enhanced longevity and more efficient G0/G1 arrest include genetic inactivation of growth signaling pathways that inhibit Rim15p, which activates oxidative stress responses, and downregulation of these pathways by caloric restriction. Caloric restriction also reduces superoxide anions independently of Rim15p by elevating levels of H₂O₂, which activates superoxide dismutases. In contrast, high glucose or mutations that activate growth signaling accelerate chronological aging in parallel with increased superoxide anions and reduced efficiency of stationary phase G0/G1 arrest. High glucose also activates DNA damage responses and preferentially kills stationary phase cells that fail to arrest growth in G0/G1. These findings suggest that growth signaling promotes chronological aging in budding yeast by elevating superoxide anions that inhibit quiescence and induce DNA replication stress. A similar mechanism likely contributes to aging and age-related diseases in complex eukaryotes.
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Weinberger
authors.forename: Ana
authors.initials: A
authors.lastname: Mesquita
authors.forename: Timothy
authors.initials: T
authors.lastname: Caroll
authors.forename: Laura
authors.initials: L
authors.lastname: Marks
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Zhaojie
authors.initials: Z
authors.lastname: Zhang
authors.forename: Paula
authors.initials: P
authors.lastname: Ludovico
authors.forename: William C
authors.initials: WC
authors.lastname: Burhans
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D031204:Caloric Restriction; D002374:Catalase / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D003470:Culture Media / Q000378:metabolism / Q000494:pharmacology; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology*; D017353:Gene Deletion; D005947:Glucose / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008136:Longevity / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000502:physiology*; D016196:S Phase / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D013482:Superoxide Dismutase / Q000235:genetics; D013481:Superoxides / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D002374:Catalase; D003470:Culture Media; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D005947:Glucose; D006861:Hydrogen Peroxide; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D029701:Saccharomyces cerevisiae Proteins; D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2; C086926:SIC1 protein, S cerevisiae; C410736:Rim15 protein, S cerevisiae; C071570:SNF1-related protein kinases; C530964:SCH9 protein, S cerevisiae