Folate Acts in E. coli to Accelerate C. elegans Aging Independently of Bacterial Biosynthesis
Identifieur interne : 000410 ( Ncbi/Merge ); précédent : 000409; suivant : 000411Folate Acts in E. coli to Accelerate C. elegans Aging Independently of Bacterial Biosynthesis
Auteurs : Bhupinder Virk [Royaume-Uni] ; Jie Jia [Royaume-Uni, République populaire de Chine] ; Claire A. Maynard [Royaume-Uni] ; Adelaide Raimundo [Royaume-Uni] ; Jolien Lefebvre [Royaume-Uni, Belgique] ; Shane A. Richards [Royaume-Uni] ; Natalia Chetina [Royaume-Uni] ; Yen Liang [Royaume-Uni] ; Noel Helliwell [Royaume-Uni] ; Marta Cipinska [Royaume-Uni] ; David Weinkove [Royaume-Uni]Source :
- Cell Reports [ 2211-1247 ] ; 2016.
Abstract
Folates are cofactors for biosynthetic enzymes in all eukaryotic and prokaryotic cells. Animals cannot synthesize folate and must acquire it from their diet or microbiota. Previously, we showed that inhibiting
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DOI: 10.1016/j.celrep.2016.01.051
PubMed: 26876180
PubMed Central: 4767678
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Richards</name><affiliation wicri:level="1"><nlm:aff id="aff1">School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation></author><author><name sortKey="Chetina, Natalia" sort="Chetina, Natalia" uniqKey="Chetina N" first="Natalia" last="Chetina">Natalia Chetina</name><affiliation wicri:level="1"><nlm:aff id="aff1">School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation></author><author><name sortKey="Liang, Yen" sort="Liang, Yen" uniqKey="Liang Y" first="Yen" last="Liang">Yen Liang</name><affiliation wicri:level="1"><nlm:aff id="aff1">School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation></author><author><name sortKey="Helliwell, Noel" sort="Helliwell, Noel" uniqKey="Helliwell N" first="Noel" last="Helliwell">Noel Helliwell</name><affiliation wicri:level="1"><nlm:aff id="aff1">School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation></author><author><name sortKey="Cipinska, Marta" sort="Cipinska, Marta" uniqKey="Cipinska M" first="Marta" last="Cipinska">Marta Cipinska</name><affiliation wicri:level="1"><nlm:aff id="aff1">School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6">Biophysical Sciences Institute, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biophysical Sciences Institute, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation></author><author><name sortKey="Weinkove, David" sort="Weinkove, David" uniqKey="Weinkove D" first="David" last="Weinkove">David 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3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation></author><author><name sortKey="Jia, Jie" sort="Jia, Jie" uniqKey="Jia J" first="Jie" last="Jia">Jie Jia</name><affiliation wicri:level="1"><nlm:aff id="aff1">School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2">Department of Nutrition, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Nutrition, Shanghai Jiao Tong University School of Medicine, Shanghai 200025</wicri:regionArea><wicri:noRegion>Shanghai 200025</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3">Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai 200092, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai 200092</wicri:regionArea><wicri:noRegion>Shanghai 200092</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4">Department of Clinical Nutrition, Xin Hua Hospital affiliated to SJTU School of Medicine, Shanghai 200092, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Clinical Nutrition, Xin Hua Hospital affiliated to SJTU School of Medicine, Shanghai 200092</wicri:regionArea><wicri:noRegion>Shanghai 200092</wicri:noRegion></affiliation></author><author><name sortKey="Maynard, Claire A" sort="Maynard, Claire A" uniqKey="Maynard C" first="Claire A." last="Maynard">Claire A. Maynard</name><affiliation wicri:level="1"><nlm:aff id="aff1">School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation></author><author><name sortKey="Raimundo, Adelaide" sort="Raimundo, Adelaide" uniqKey="Raimundo A" first="Adelaide" last="Raimundo">Adelaide Raimundo</name><affiliation wicri:level="1"><nlm:aff id="aff1">School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation></author><author><name sortKey="Lefebvre, Jolien" sort="Lefebvre, Jolien" uniqKey="Lefebvre J" first="Jolien" last="Lefebvre">Jolien Lefebvre</name><affiliation wicri:level="1"><nlm:aff id="aff1">School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff5">Department HIVB, VIVES, Wilgenstraat 32, 8800 Roeselare, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Department HIVB, VIVES, Wilgenstraat 32, 8800 Roeselare</wicri:regionArea><wicri:noRegion>8800 Roeselare</wicri:noRegion></affiliation></author><author><name sortKey="Richards, Shane A" sort="Richards, Shane A" uniqKey="Richards S" first="Shane A." last="Richards">Shane A. Richards</name><affiliation wicri:level="1"><nlm:aff id="aff1">School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation></author><author><name sortKey="Chetina, Natalia" sort="Chetina, Natalia" uniqKey="Chetina N" first="Natalia" last="Chetina">Natalia Chetina</name><affiliation wicri:level="1"><nlm:aff id="aff1">School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation></author><author><name sortKey="Liang, Yen" sort="Liang, Yen" uniqKey="Liang Y" first="Yen" last="Liang">Yen Liang</name><affiliation wicri:level="1"><nlm:aff id="aff1">School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation></author><author><name sortKey="Helliwell, Noel" sort="Helliwell, Noel" uniqKey="Helliwell N" first="Noel" last="Helliwell">Noel Helliwell</name><affiliation wicri:level="1"><nlm:aff id="aff1">School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation></author><author><name sortKey="Cipinska, Marta" sort="Cipinska, Marta" uniqKey="Cipinska M" first="Marta" last="Cipinska">Marta Cipinska</name><affiliation wicri:level="1"><nlm:aff id="aff1">School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6">Biophysical Sciences Institute, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biophysical Sciences Institute, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation></author><author><name sortKey="Weinkove, David" sort="Weinkove, David" uniqKey="Weinkove D" first="David" last="Weinkove">David Weinkove</name><affiliation wicri:level="1"><nlm:aff id="aff1">School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6">Biophysical Sciences Institute, Durham University, South Road, Durham DH1 3LE, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biophysical Sciences Institute, Durham University, South Road, Durham DH1 3LE</wicri:regionArea><wicri:noRegion>Durham DH1 3LE</wicri:noRegion></affiliation></author></analytic><series><title level="j">Cell Reports</title><idno type="eISSN">2211-1247</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Summary</title><p>Folates are cofactors for biosynthetic enzymes in all eukaryotic and prokaryotic cells. Animals cannot synthesize folate and must acquire it from their diet or microbiota. Previously, we showed that inhibiting <italic>E. coli</italic> folate synthesis increases <italic>C. elegans</italic> lifespan. Here, we show that restriction or supplementation of <italic>C. elegans</italic> folate does not influence lifespan. Thus, folate is required in <italic>E. coli</italic> to shorten worm lifespan. Bacterial proliferation in the intestine has been proposed as a mechanism for the life-shortening influence of <italic>E. coli</italic>. However, we found no correlation between <italic>C. elegans</italic> survival and bacterial growth in a screen of 1,000+ <italic>E. coli</italic> deletion mutants. Nine mutants increased worm lifespan robustly, suggesting specific gene regulation is required for the life-shortening activity of <italic>E. coli</italic>. Disrupting the biosynthetic folate cycle did not increase lifespan. Thus, folate acts through a growth-independent route in <italic>E. coli</italic> to accelerate animal aging.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Asrar, F M" uniqKey="Asrar F">F.M. Asrar</name></author><author><name sortKey="O Onnor, D L" uniqKey="O Onnor D">D.L. O’Connor</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Baba, T" uniqKey="Baba T">T. Baba</name></author><author><name sortKey="Ara, T" uniqKey="Ara T">T. Ara</name></author><author><name sortKey="Hasegawa, M" uniqKey="Hasegawa M">M. Hasegawa</name></author><author><name sortKey="Takai, Y" uniqKey="Takai Y">Y. Takai</name></author><author><name sortKey="Okumura, Y" uniqKey="Okumura Y">Y. Okumura</name></author><author><name sortKey="Baba, M" uniqKey="Baba M">M. Baba</name></author><author><name sortKey="Datsenko, K A" uniqKey="Datsenko K">K.A. Datsenko</name></author><author><name sortKey="Tomita, M" uniqKey="Tomita M">M. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Cell Rep</journal-id><journal-id journal-id-type="iso-abbrev">Cell Rep</journal-id><journal-title-group><journal-title>Cell Reports</journal-title></journal-title-group><issn pub-type="epub">2211-1247</issn><publisher><publisher-name>Cell Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26876180</article-id><article-id pub-id-type="pmc">4767678</article-id><article-id pub-id-type="publisher-id">S2211-1247(16)30029-8</article-id><article-id pub-id-type="doi">10.1016/j.celrep.2016.01.051</article-id><article-categories><subj-group subj-group-type="heading"><subject>Report</subject></subj-group></article-categories><title-group><article-title>Folate Acts in <italic>E. coli</italic> to Accelerate <italic>C. elegans</italic> Aging Independently of Bacterial Biosynthesis</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Virk</surname><given-names>Bhupinder</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn1" ref-type="fn">7</xref><xref rid="fn2" ref-type="fn">8</xref></contrib><contrib contrib-type="author"><name><surname>Jia</surname><given-names>Jie</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff4" ref-type="aff">4</xref><xref rid="fn1" ref-type="fn">7</xref></contrib><contrib contrib-type="author"><name><surname>Maynard</surname><given-names>Claire A.</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn1" ref-type="fn">7</xref></contrib><contrib contrib-type="author"><name><surname>Raimundo</surname><given-names>Adelaide</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Lefebvre</surname><given-names>Jolien</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Richards</surname><given-names>Shane A.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Chetina</surname><given-names>Natalia</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Liang</surname><given-names>Yen</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Helliwell</surname><given-names>Noel</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Cipinska</surname><given-names>Marta</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Weinkove</surname><given-names>David</given-names></name><email>david.weinkove@durham.ac.uk</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff6" ref-type="aff">6</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1"><label>1</label>School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK</aff><aff id="aff2"><label>2</label>Department of Nutrition, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China</aff><aff id="aff3"><label>3</label>Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai 200092, China</aff><aff id="aff4"><label>4</label>Department of Clinical Nutrition, Xin Hua Hospital affiliated to SJTU School of Medicine, Shanghai 200092, China</aff><aff id="aff5"><label>5</label>Department HIVB, VIVES, Wilgenstraat 32, 8800 Roeselare, Belgium</aff><aff id="aff6"><label>6</label>Biophysical Sciences Institute, Durham University, South Road, Durham DH1 3LE, UK</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>david.weinkove@durham.ac.uk</email></corresp><fn id="fn1"><label>7</label><p id="ntpara0010">Co-first author</p></fn><fn id="fn2"><label>8</label><p id="ntpara0015">Present address: Bioinformatics Department, The Babraham Institute, Cambridge CB22 3AT, UK</p></fn></author-notes><pub-date pub-type="pmc-release"><day>11</day><month>2</month><year>2016</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="collection"><day>23</day><month>2</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>11</day><month>2</month><year>2016</year></pub-date><volume>14</volume><issue>7</issue><fpage>1611</fpage><lpage>1620</lpage><history><date date-type="received"><day>3</day><month>8</month><year>2015</year></date><date date-type="rev-recd"><day>18</day><month>11</month><year>2015</year></date><date date-type="accepted"><day>14</day><month>1</month><year>2016</year></date></history><permissions><copyright-statement>© 2016 The Authors</copyright-statement><copyright-year>2016</copyright-year><license license-type="CC BY" xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).</license-p></license></permissions><abstract><title>Summary</title><p>Folates are cofactors for biosynthetic enzymes in all eukaryotic and prokaryotic cells. Animals cannot synthesize folate and must acquire it from their diet or microbiota. Previously, we showed that inhibiting <italic>E. coli</italic> folate synthesis increases <italic>C. elegans</italic> lifespan. Here, we show that restriction or supplementation of <italic>C. elegans</italic> folate does not influence lifespan. Thus, folate is required in <italic>E. coli</italic> to shorten worm lifespan. Bacterial proliferation in the intestine has been proposed as a mechanism for the life-shortening influence of <italic>E. coli</italic>. However, we found no correlation between <italic>C. elegans</italic> survival and bacterial growth in a screen of 1,000+ <italic>E. coli</italic> deletion mutants. Nine mutants increased worm lifespan robustly, suggesting specific gene regulation is required for the life-shortening activity of <italic>E. coli</italic>. Disrupting the biosynthetic folate cycle did not increase lifespan. Thus, folate acts through a growth-independent route in <italic>E. coli</italic> to accelerate animal aging.</p></abstract><abstract abstract-type="graphical"><title>Graphical Abstract</title><fig id="undfig1" position="anchor"><graphic xlink:href="fx1"></graphic></fig></abstract><abstract abstract-type="author-highlights"><title>Highlights</title><p><list list-type="simple"><list-item id="u0010"><label>•</label><p>Limiting folate in <italic>E. coli</italic>, not in <italic>C. elegans</italic>, increases worm lifespan</p></list-item><list-item id="u0015"><label>•</label><p>An <italic>E. coli</italic> screen for worm longevity identifies folate synthesis as a target</p></list-item><list-item id="u0020"><label>•</label><p>Folate synthesis influences <italic>E. coli</italic> physiology independently of growth</p></list-item><list-item id="u0025"><label>•</label><p>Bacterial folate synthesis may be a sustainable target for chronic disease</p></list-item></list></p></abstract><abstract abstract-type="teaser"><p>Virk et al. show that inhibiting <italic>E. coli</italic> folate synthesis does not increase <italic>C. elegans</italic> lifespan through changes to <italic>C. elegans</italic> folate, but by acting through an <italic>E. coli</italic> activity. They find nine <italic>E. coli</italic> mutants that extend lifespan. The gene identities suggest that mild bacterial toxicities accelerate host aging.</p></abstract></article-meta><notes><p id="misc0010">Published: February 11, 2016</p></notes></front><floats-group><fig id="fig1"><label>Figure 1</label><caption><p>The <italic>C. elegans gcp-2.1</italic> Folate Uptake Mutant Is Sensitive to SMX-Treated <italic>E. coli</italic> and Is Rescued by Folinic Acid</p><p>(A) <italic>gcp-2.1</italic> mutants develop as wild-type worms on untreated OP50 <italic>E. coli</italic>, but SMX treatment delays the growth of <italic>gcp-2.1</italic> mutants, and this defect can be rescued by 10 μM folinic acid. The images were taken after 48 hr of growth at 25°C.</p><p>(B) Quantification of the growth, as measured by body length. The error bars represent SD. The <italic>gcp-2.1</italic> mutant growth on SMX is restored at 5 μM and 10 μM folinic acid and partially with 1 μM folinic acid (<sup>∗</sup>p < 0.05, <sup>∗∗</sup>p < 0.01, and <sup>∗∗∗</sup>p < 0.005) (t test). Folic acid can fully rescue growth only at 250 μM.</p><p>(C) Model showing that <italic>E. coli</italic> folate synthesis generates THFs with up to eight glutamate residues and various one carbon groups, xTHFGlu<sub>1–8</sub> (x = methyl, formyl, methenyl, and methylene). The <italic>C. elegans</italic> GCPII GCP-2.1 cleaves glutamate residues from xTHFGlu<sub>2–8</sub> to generate xTHFGlu<sub>1</sub>, the preferred substrates of the <italic>C. elegans</italic> reduced folate transporter FOLT-1. Folinic acid, as an xTHFGlu<sub>1</sub> (5-formyl THF), can be taken up directly by FOLT-1, bypassing GCP-2.1.</p></caption><graphic xlink:href="gr1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>Lifespan Analyses of Perturbations to <italic>C. elegans</italic> Folate and Comparison of SMX and Kanamycin Treatment</p><p>(A) The <italic>gcp-2.1(ok1004)</italic> mutant does not increase lifespan.</p><p>(B) 10 μM folinic acid does not affect the lifespan extension caused by 128 μg/ml SMX.</p><p>(C) MTX has no effect on <italic>C. elegans</italic> lifespan.</p><p>(D) Kanamycin and SMX have a very similar effect on <italic>C. elegans</italic> lifespan. See <xref rid="mmc2" ref-type="supplementary-material">Table S1</xref> for lifespan conditions and statistics.</p></caption><graphic xlink:href="gr2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>Intestinal Accumulation of Bacteria Does Not Occur in All Animals and Is Not Prevented by SMX</p><p>(A) Accumulation in recently dead animals as assessed by visualizing <italic>E. coli</italic> GFP in the intestinal lumen. The data are pooled from two biological replicates.</p><p>(B) Numbers of alive worms at indicated time points with classification of accumulation.</p><p>(C) Motility analysis of <italic>glp-4(bn2)</italic> worms on OP50 treated with 0, 16 μg/ml, and 128 μg/ml SMX. Each worm was scored as belonging to motility class A (constantly moving), B (moves when prodded), or C (twitches only) as described (<xref rid="bib26" ref-type="bibr">Herndon et al., 2002</xref>).</p></caption><graphic xlink:href="gr3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>A Screen of <italic>E. coli</italic> Deletion Mutants for <italic>C. elegans</italic> Survival Identified Nine Mutants that Robustly Extend Lifespan</p><p>(A) No correlation between growth of mutant strains in LB (<xref rid="bib2" ref-type="bibr">Baba et al., 2006</xref>) and normalized <italic>C. elegans</italic> survival at day 11 or 12. The mutants that increase lifespan after the fourth round of the screen are indicated.</p><p>(B) <italic>pabA</italic> and <italic>pabB</italic> mutants increase <italic>C. elegans</italic> lifespan, and this increase is reversed by gene complementation. See <xref rid="mmc2" ref-type="supplementary-material">Table S1</xref> for details.</p><p>(C) Mean lifespan (with SD) at various concentrations of PABA on defined media plates, comparing worms on the <italic>E. coli pabA</italic> mutant with worms on WT <italic>E. coli</italic>. At 0.1 and 0.2 μM PABA, the lifespans on <italic>pabA</italic> and wild-type <italic>E. coli</italic> are significantly different (see <xref rid="sec2" ref-type="sec">Results</xref> and <xref rid="mmc2" ref-type="supplementary-material">Table S1</xref> for details). The error bars represent SD.</p></caption><graphic xlink:href="gr4"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Belgique</li><li>Royaume-Uni</li><li>République populaire de Chine</li></country></list><tree><country name="Royaume-Uni"><noRegion><name sortKey="Virk, Bhupinder" sort="Virk, Bhupinder" uniqKey="Virk B" first="Bhupinder" last="Virk">Bhupinder Virk</name></noRegion><name sortKey="Chetina, Natalia" sort="Chetina, Natalia" uniqKey="Chetina N" first="Natalia" last="Chetina">Natalia Chetina</name><name sortKey="Cipinska, Marta" sort="Cipinska, Marta" uniqKey="Cipinska M" first="Marta" last="Cipinska">Marta Cipinska</name><name sortKey="Cipinska, Marta" sort="Cipinska, Marta" uniqKey="Cipinska M" first="Marta" last="Cipinska">Marta Cipinska</name><name sortKey="Helliwell, Noel" sort="Helliwell, Noel" uniqKey="Helliwell N" first="Noel" last="Helliwell">Noel Helliwell</name><name sortKey="Jia, Jie" sort="Jia, Jie" uniqKey="Jia J" first="Jie" last="Jia">Jie Jia</name><name sortKey="Lefebvre, Jolien" sort="Lefebvre, Jolien" uniqKey="Lefebvre J" first="Jolien" last="Lefebvre">Jolien Lefebvre</name><name sortKey="Liang, Yen" sort="Liang, Yen" uniqKey="Liang Y" first="Yen" last="Liang">Yen Liang</name><name sortKey="Maynard, Claire A" sort="Maynard, Claire A" uniqKey="Maynard C" first="Claire A." last="Maynard">Claire A. Maynard</name><name sortKey="Raimundo, Adelaide" sort="Raimundo, Adelaide" uniqKey="Raimundo A" first="Adelaide" last="Raimundo">Adelaide Raimundo</name><name sortKey="Richards, Shane A" sort="Richards, Shane A" uniqKey="Richards S" first="Shane A." last="Richards">Shane A. Richards</name><name sortKey="Weinkove, David" sort="Weinkove, David" uniqKey="Weinkove D" first="David" last="Weinkove">David Weinkove</name><name sortKey="Weinkove, David" sort="Weinkove, David" uniqKey="Weinkove D" first="David" last="Weinkove">David Weinkove</name></country><country name="République populaire de Chine"><noRegion><name sortKey="Jia, Jie" sort="Jia, Jie" uniqKey="Jia J" first="Jie" last="Jia">Jie Jia</name></noRegion><name sortKey="Jia, Jie" sort="Jia, Jie" uniqKey="Jia J" first="Jie" last="Jia">Jie Jia</name><name sortKey="Jia, Jie" sort="Jia, Jie" uniqKey="Jia J" first="Jie" last="Jia">Jie Jia</name></country><country name="Belgique"><noRegion><name sortKey="Lefebvre, Jolien" sort="Lefebvre, Jolien" uniqKey="Lefebvre J" first="Jolien" last="Lefebvre">Jolien Lefebvre</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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