title: Excessive folate synthesis limits lifespan in the C. elegans: E. coli aging model.
abstract: BACKGROUND
  Gut microbes influence animal health and thus, are potential targets for interventions that slow aging. Live E. coli provides the nematode worm Caenorhabditis elegans with vital micronutrients, such as folates that cannot be synthesized by animals. However, the microbe also limits C. elegans lifespan. Understanding these interactions may shed light on how intestinal microbes influence mammalian aging.
  
  
  RESULTS
  Serendipitously, we isolated an E. coli mutant that slows C. elegans aging. We identified the disrupted gene to be aroD, which is required to synthesize aromatic compounds in the microbe. Adding back aromatic compounds to the media revealed that the increased C. elegans lifespan was caused by decreased availability of para-aminobenzoic acid, a precursor to folate. Consistent with this result, inhibition of folate synthesis by sulfamethoxazole, a sulfonamide, led to a dose-dependent increase in C. elegans lifespan. As expected, these treatments caused a decrease in bacterial and worm folate levels, as measured by mass spectrometry of intact folates. The folate cycle is essential for cellular biosynthesis. However, bacterial proliferation and C. elegans growth and reproduction were unaffected under the conditions that increased lifespan.
  
  
  CONCLUSIONS
  In this animal:microbe system, folates are in excess of that required for biosynthesis. This study suggests that microbial folate synthesis is a pharmacologically accessible target to slow animal aging without detrimental effects.
authors: School of Biological and Biomedical Sciences, Durham University, UK.
authors: Bhupinder
authors: B
authors: Virk
authors: Gonçalo
authors: G
authors: Correia
authors: David P
authors: DP
authors: Dixon
authors: Inna
authors: I
authors: Feyst
authors: Jie
authors: J
authors: Jia
authors: Nikolin
authors: N
authors: Oberleitner
authors: Zoe
authors: Z
authors: Briggs
authors: Emily
authors: E
authors: Hodge
authors: Robert
authors: R
authors: Edwards
authors: John
authors: J
authors: Ward
authors: David
authors: D
authors: Gems
authors: David
authors: D
authors: Weinkove
mesh_terms: D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000254:growth & development* / Q000382:microbiology*; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000254:growth & development*; D005492:Folic Acid / Q000096:biosynthesis*; D005798:Genes, Bacterial / Q000235:genetics; D008136:Longevity / Q000187:drug effects / Q000502:physiology*; D055442:Metabolome / Q000187:drug effects; D050296:Microbial Viability / Q000187:drug effects; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D010957:Plasmids / Q000378:metabolism; D034622:RNA Interference / Q000187:drug effects; D013420:Sulfamethoxazole / Q000494:pharmacology
chemical_list: D005492:Folic Acid; D013420:Sulfamethoxazole; D010129:4-Aminobenzoic Acid