Life Span Extension by Calorie Restriction Depends on Rim15 and Transcription Factors Downstream of Ras/PKA, Tor, and Sch9
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{"title"=>"Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9", "type"=>"journal", "authors"=>[{"first_name"=>"Min", "last_name"=>"Wei", "scopus_author_id"=>"35363140800"}, {"first_name"=>"Paola", "last_name"=>"Fabrizio", "scopus_author_id"=>"35615904900"}, {"first_name"=>"Jia", "last_name"=>"Hu", "scopus_author_id"=>"55499379500"}, {"first_name"=>"Huanying", "last_name"=>"Ge", "scopus_author_id"=>"19638286100"}, {"first_name"=>"Chao", "last_name"=>"Cheng", "scopus_author_id"=>"57198496682"}, {"first_name"=>"Lei", "last_name"=>"Li", "scopus_author_id"=>"55584803709"}, {"first_name"=>"Valter D.", "last_name"=>"Longo", "scopus_author_id"=>"7005786660"}], "year"=>2008, "source"=>"PLoS Genetics", "identifiers"=>{"issn"=>"15537390", "scopus"=>"2-s2.0-38949137849", "pui"=>"351230881", "doi"=>"10.1371/journal.pgen.0040013", "isbn"=>"1553-7404 (Electronic)\\n1553-7390 (Linking)", "sgr"=>"38949137849", "pmid"=>"18225956"}, "id"=>"7043f4df-581e-3cae-92d3-c6a36ab99c3c", "abstract"=>"Calorie restriction (CR), the only non-genetic intervention known to slow aging and extend life span in organisms ranging from yeast to mice, has been linked to the down-regulation of Tor, Akt, and Ras signaling. In this study, we demonstrate that the serine/threonine kinase Rim15 is required for yeast chronological life span extension caused by deficiencies in Ras2, Tor1, and Sch9, and by calorie restriction. Deletion of stress resistance transcription factors Gis1 and Msn2/4, which are positively regulated by Rim15, also caused a major although not complete reversion of the effect of calorie restriction on life span. The deletion of both RAS2 and the Akt and S6 kinase homolog SCH9 in combination with calorie restriction caused a remarkable 10-fold life span extension, which, surprisingly, was only partially reversed by the lack of Rim15. These results indicate that the Ras/cAMP/PKA/Rim15/Msn2/4 and the Tor/Sch9/Rim15/Gis1 pathways are major mediators of the calorie restriction-dependent stress resistance and life span extension, although additional mediators are involved. Notably, the anti-aging effect caused by the inactivation of both pathways is much more potent than that caused by CR.", "link"=>"http://www.mendeley.com/research/life-span-extension-calorie-restriction-depends-rim15-transcription-factors-downstream-raspka-tor-sc", "reader_count"=>234, "reader_count_by_academic_status"=>{"Unspecified"=>4, "Professor > Associate Professor"=>16, "Researcher"=>47, "Student > Doctoral Student"=>8, "Student > Ph. D. Student"=>81, "Student > Postgraduate"=>12, "Student > Master"=>29, "Other"=>4, "Student > Bachelor"=>26, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>2, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>4, "Professor > Associate Professor"=>16, "Researcher"=>47, "Student > Doctoral Student"=>8, "Student > Ph. D. Student"=>81, "Student > Postgraduate"=>12, "Student > Master"=>29, "Other"=>4, "Student > Bachelor"=>26, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>2, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>5, "Agricultural and Biological Sciences"=>149, "Business, Management and Accounting"=>1, "Chemistry"=>6, "Computer Science"=>3, "Engineering"=>2, "Biochemistry, Genetics and Molecular Biology"=>48, "Nursing and Health Professions"=>2, "Medicine and Dentistry"=>10, "Neuroscience"=>1, "Sports and Recreations"=>1, "Physics and Astronomy"=>1, "Psychology"=>1, "Social Sciences"=>1, "Immunology and Microbiology"=>3}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>10}, "Social Sciences"=>{"Social Sciences"=>1}, "Sports and Recreations"=>{"Sports and Recreations"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Psychology"=>{"Psychology"=>1}, "Unspecified"=>{"Unspecified"=>5}, "Engineering"=>{"Engineering"=>2}, "Chemistry"=>{"Chemistry"=>6}, "Neuroscience"=>{"Neuroscience"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>149}, "Computer Science"=>{"Computer Science"=>3}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>48}}, "reader_count_by_country"=>{"United States"=>5, "Japan"=>1, "United Kingdom"=>1, "Portugal"=>1, "Switzerland"=>1, "Spain"=>2, "Canada"=>1, "Austria"=>1, "Sweden"=>1, "South Korea"=>1, "Luxembourg"=>1, "Mexico"=>4, "Italy"=>1}, "group_count"=>9}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/938982"], "description"=>"<div><p>(A) Effects of extreme CR/starvation and glucose reduction on cellular protection against thermal and oxidative stress. For extreme CR/starvation, cells from day 3 SDC cultures were switched to water. For glucose reduction, cells were grown in SC + 0.5% glucose medium. Stress resistance assay was performed at day 5 (48 h after switching to water). Cells were subject to heat shock (55 °C) or H<sub>2</sub>O<sub>2</sub> (176 mM, 60 min) stress.</p><p>(B) CLS under extreme CR/starvation. Strains shown are wild-type (DBY746), <i>msn2</i>Δ <i>msn4</i>Δ, <i>gis1</i>Δ, <i>msn2</i>Δ <i>msn4</i>Δ <i>gis1</i>Δ, and <i>rim15</i>Δ.</p><p>(C) CLS under CR modeled by glucose reduction (SC + 0.5% glucose). Strains shown are wild-type, <i>msn2</i>Δ <i>msn4</i>Δ, <i>gis1</i>Δ, <i>msn2</i>Δ <i>msn4</i>Δ <i>gis1</i>Δ, and <i>rim15</i>Δ.</p><p>(D,E) Day 1 SDC wild-type cells were switched to water. The STRE-lacZ (D) and PDS-lacZ (E) activities were measured 2 h, 4 h, and 8 h after the initiation of CR and shown as the percentage of time 0. Data shown are mean ± standard error of the mean of four independent samples assayed. *, <i>p</i> < 0.01; **, <i>p</i> < 0.05, two-tailed t-test, CR versus SDC.</p></div>", "links"=>[], "tags"=>["cellular", "span", "rim15", "transcription"], "article_id"=>609425, "categories"=>["Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Min Wei", "Paola Fabrizio", "Jia Hu", "Huanying Ge", "Chao Cheng", "Lei Li", "Valter D Longo"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.0040013.g004", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CR_Induced_Cellular_Protection_and_Life_Span_Extension_Require_Rim15_and_Stress_Response_Transcription_Factors_/609425", "title"=>"CR-Induced Cellular Protection and Life Span Extension Require Rim15 and Stress Response Transcription Factors", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-01-25 02:37:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/938540"], "description"=>"<div><p>(A) CLS of wild-type (DBY746) and mutants lacking Rim15 or downstream stress response transcription factors: Msn2/4 and/or Gis1.</p><p>(B–D) Deletion of <i>RIM15</i> reverses life span extension associated with deficiencies in Sch9 (B), Tor1 (C), or Ras2 (D). Deletion of <i>GIS1</i> partially reverses CLS extension of <i>sch9</i>Δ (B) and <i>ras2</i>Δ (D) mutants.</p><p>(E) Day 3 cells were subject to thermal (55 °C, 45 min) and oxidative stress (hydrogen peroxide, 100 mM, 60 min). Strains shown are wild-type, <i>rim15</i>Δ, <i>tor1</i>Δ, and <i>tor1</i>Δ <i>rim15</i>Δ.</p><p>(F) Day 3 cells were subject to thermal (55 °C, 100 min) and oxidative stress (hydrogen peroxide, 150 mM, 60 min). Strains shown are wild-type, <i>sch9</i>Δ, <i>sch9</i>Δ <i>gis1</i>Δ, <i>sch9</i>Δ <i>rim15</i>Δ, <i>ras2</i>Δ, <i>ras2</i>Δ <i>gis1</i>Δ, and <i>ras2</i>Δ <i>rim15</i>Δ.</p></div>", "links"=>[], "tags"=>["chronological", "span", "cellular"], "article_id"=>608981, "categories"=>["Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Min Wei", "Paola Fabrizio", "Jia Hu", "Huanying Ge", "Chao Cheng", "Lei Li", "Valter D Longo"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.0040013.g001", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rim15_Is_Required_for_Chronological_Life_Span_Extension_and_Cellular_Protection_/608981", "title"=>"Rim15 Is Required for Chronological Life Span Extension and Cellular Protection", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-01-25 02:29:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/462524", "https://ndownloader.figshare.com/files/462554", "https://ndownloader.figshare.com/files/462595"], "description"=>"<div><p>Calorie restriction (CR), the only non-genetic intervention known to slow aging and extend life span in organisms ranging from yeast to mice, has been linked to the down-regulation of Tor, Akt, and Ras signaling. In this study, we demonstrate that the serine/threonine kinase Rim15 is required for yeast chronological life span extension caused by deficiencies in Ras2, Tor1, and Sch9, and by calorie restriction. Deletion of stress resistance transcription factors Gis1 and Msn2/4, which are positively regulated by Rim15, also caused a major although not complete reversion of the effect of calorie restriction on life span. The deletion of both <em>RAS2</em> and the <em>Akt</em> and S6 kinase homolog <em>SCH9</em> in combination with calorie restriction caused a remarkable 10-fold life span extension, which, surprisingly, was only partially reversed by the lack of Rim15<em>.</em> These results indicate that the Ras/cAMP/PKA/Rim15/Msn2/4 and the Tor/Sch9/Rim15/Gis1 pathways are major mediators of the calorie restriction-dependent stress resistance and life span extension, although additional mediators are involved. Notably, the anti-aging effect caused by the inactivation of both pathways is much more potent than that caused by CR.</p></div>", "links"=>[], "tags"=>["span", "calorie", "depends", "rim15", "transcription", "factors", "downstream", "sch9"], "article_id"=>151159, "categories"=>["Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Min Wei", "Paola Fabrizio", "Jia Hu", "Huanying Ge", "Chao Cheng", "Lei Li", "Valter D Longo"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.0040013.sg001", "https://dx.doi.org/10.1371/journal.pgen.0040013.st001", "https://dx.doi.org/10.1371/journal.pgen.0040013.st002"], "stats"=>{"downloads"=>17, "page_views"=>36, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Life_Span_Extension_by_Calorie_Restriction_Depends_on_Rim15_and_Transcription_Factors_Downstream_of_Ras_PKA_Tor_and_Sch9/151159", "title"=>"Life Span Extension by Calorie Restriction Depends on Rim15 and Transcription Factors Downstream of Ras/PKA, Tor, and Sch9", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2008-01-25 00:19:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/938660"], "description"=>"<div><p>(A) Day 1 and day 3 cells were exposed to heat stress (55 °C). Strains shown are wild-type (DBY746), <i>msn2</i>Δ <i>msn4</i>Δ, <i>msn2</i>Δ <i>msn4</i>Δ <i>gis1</i>Δ, and <i>msn2</i>Δ <i>msn4</i>Δ <i>rim15</i>Δ.</p><p>(B) Day 3 cells were subject of heat stress (55 °C). Strains shown are wild-type, <i>msn2</i>Δ <i>msn4</i>Δ, and <i>msn2</i>Δ <i>msn4</i>Δ mutants overexpressing <i>ras2<sup>val19</sup></i> or <i>SCH9</i>.</p></div>", "links"=>[], "tags"=>["oxidative", "cells", "deficient", "transcription"], "article_id"=>609098, "categories"=>["Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Min Wei", "Paola Fabrizio", "Jia Hu", "Huanying Ge", "Chao Cheng", "Lei Li", "Valter D Longo"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.0040013.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Thermal_and_Oxidative_Stress_Resistance_of_Cells_Deficient_of_Stress_Response_Transcription_Factors_Msn2_4_and_or_Gis1_/609098", "title"=>"Thermal and Oxidative Stress Resistance of Cells Deficient of Stress Response Transcription Factors Msn2/4 and/or Gis1", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-01-25 02:31:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/938878"], "description"=>"<div><p>(A) Calcofluor staining of wild-type (DBY746), <i>tor1</i>Δ, <i>sch9</i>Δ, <i>ras2</i>Δ, and <i>ras2</i>Δ <i>sch9</i>Δ mutants. Bar, 10 μm. Scatter plot of cell diameters (the average of the long and short axes of the cell) with the bar indicating median. Fifty to 75 cells were measured per genotype.</p><p>(B,C) Extreme CR, where day 3 SDC cultures were switched to water, further extends the life span of already long-lived genetic mutants. Strains shown are wild-type, <i>tor1</i>Δ <i>ras2</i>Δ, <i>sch9</i>Δ, and <i>ras2</i>Δ <i>sch9</i>Δ.</p></div>", "links"=>[], "tags"=>["cls"], "article_id"=>609323, "categories"=>["Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Min Wei", "Paola Fabrizio", "Jia Hu", "Huanying Ge", "Chao Cheng", "Lei Li", "Valter D Longo"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.0040013.g003", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cell_Size_Analysis_and_CLS_under_Extreme_CR_/609323", "title"=>"Cell Size Analysis and CLS under Extreme CR", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-01-25 02:35:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/938747"], "description"=>"<div><p>(A) CLS under extreme CR. Strains shown are wild-type (DBY746), <i>ras2</i>Δ <i>sch9</i>Δ, and <i>ras2</i>Δ <i>sch9</i>Δ <i>rim15</i>Δ in standard SDC and under extreme CR.</p><p>(B) Longevity regulatory pathways. In yeast, nutrient-sensing pathways controlled by Sch9, Tor, and Ras converge on the protein kinase Rim15. In turn, the stress response transcription factors Msn2, Msn4, and Gis1 transactivate stress response genes and enhance cellular protection, which leads to life span extension. Although a major portion of the effect of CR on longevity appears to be mediated by the down-regulation of the Ras and Tor-Sch9 pathways and consequent activation of the Rim15-controlled Msn2/4 and Gis1 protection system, additional mediators are involved. In mice, the partially conserved insulin/IGF-I-like pathways negatively regulate the FoxO family transcription factors through the Sch9 homolog Akt. Ras and Tor also function downstream of IGF-I, although their role in the regulation of stress resistance and aging are poorly understood. Mice deficient in type 5 adenylyl cyclase are long-lived and stress resistant analogously to the adenylate cyclase deficient yeast. However, the mediators of life-span extension in GH-, IGF-I-, or AC-deficient as well as CR mice have yet to be identified.</p></div>", "links"=>[], "tags"=>["maximal", "span"], "article_id"=>609194, "categories"=>["Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Min Wei", "Paola Fabrizio", "Jia Hu", "Huanying Ge", "Chao Cheng", "Lei Li", "Valter D Longo"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.0040013.g005", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rim15_independent_Mechanism_s_Is_Required_for_Maximal_Life_Span_Extension_/609194", "title"=>"Rim15-independent Mechanism(s) Is Required for Maximal Life Span Extension", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-01-25 02:33:14"}

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Relative Metric

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