FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2000945958> ?p ?o ?g. }

• W2000945958 endingPage "811" @default.
• W2000945958 startingPage "809" @default.
• W2000945958 abstract "The mechanisms underlying the biological activity of metformin, a widely prescribed drug to treat type 2 diabetes, remain elusive. In a recent issue of Cell, Cabreiro et al. report that in C. elegans, metformin indirectly impacts lifespan by altering the methionine metabolism of its microbial partner E. coli (Cabreiro et al., 2013Cabreiro F. Au C. Leung K.Y. Vergara-Irigaray N. Cochemé H.M. Noori T. Weinkove D. Schuster E. Greene N.D. Gems D. Cell. 2013; 153: 228-239Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar). The mechanisms underlying the biological activity of metformin, a widely prescribed drug to treat type 2 diabetes, remain elusive. In a recent issue of Cell, Cabreiro et al. report that in C. elegans, metformin indirectly impacts lifespan by altering the methionine metabolism of its microbial partner E. coli (Cabreiro et al., 2013Cabreiro F. Au C. Leung K.Y. Vergara-Irigaray N. Cochemé H.M. Noori T. Weinkove D. Schuster E. Greene N.D. Gems D. Cell. 2013; 153: 228-239Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar). Metformin is a widely prescribed oral antihyperglycemic agent of the biguanide family recommended as first-line therapy for type 2 diabetes. One generally accepted mechanism for metformin action is a mild and transient inhibition of hepatocyte mitochondrial respiratory-chain complex-1, which restricts the hepatic gluconeogenic program (Viollet and Foretz, 2013Viollet B. Foretz M. Ann. Endocrinol. (Paris). 2013; 74: 123-129Crossref PubMed Scopus (52) Google Scholar). Despite its prominence on the antidiabetic drug market, the exact mechanism of metformin action has not been fully elucidated. Its impact on hepatic gluconeogenesis has been linked to the decrease of cellular energy status, which activates the cellular metabolic sensor AMP-activated protein kinase (AMPK). Recent studies have, however, challenged this view, revealing the importance of other AMPK-independent mechanisms (Miller et al., 2013Miller R.A. Chu Q. Xie J. Foretz M. Viollet B. Birnbaum M.J. Nature. 2013; 494: 256-260Crossref PubMed Scopus (606) Google Scholar). Metformin biological activity goes beyond its current therapeutic usage as it has been also shown to reduce the risk of cancer (Dowling et al., 2011Dowling R.J. Goodwin P.J. Stambolic V. BMC Med. 2011; 9: 33Crossref PubMed Scopus (314) Google Scholar) and delay aging in animal models such as rodents (Anisimov et al., 2011Anisimov V.N. Berstein L.M. Popovich I.G. Zabezhinski M.A. Egormin P.A. Piskunova T.S. Semenchenko A.V. Tyndyk M.L. Yurova M.N. Kovalenko I.G. Poroshina T.E. Aging (Albany NY). 2011; 3: 148-157Crossref PubMed Scopus (220) Google Scholar) and the nematode Caenorhabditis elegans (Onken and Driscoll, 2010Onken B. Driscoll M. PLoS ONE. 2010; 5: e8758Crossref PubMed Scopus (468) Google Scholar). Again, the underlying mechanisms are unclear, but studies suggest that metformin recapitulates the effects of dietary restriction, known to improve lifespan and/or healthspan of a variety of animals. In C. elegans, metformin treatment extends lifespan and increases healthspan via AMPK, suggesting that metformin engages an AMPK-dependent metabolic loop conserved across phyla (Onken and Driscoll, 2010Onken B. Driscoll M. PLoS ONE. 2010; 5: e8758Crossref PubMed Scopus (468) Google Scholar). In a follow-up study recently published in Cell, Cabreiro et al. reveal that metformin indirectly extends C. elegans lifespan by altering the metabolism of E. coli, its microbial trophic partner (Cabreiro et al., 2013Cabreiro F. Au C. Leung K.Y. Vergara-Irigaray N. Cochemé H.M. Noori T. Weinkove D. Schuster E. Greene N.D. Gems D. Cell. 2013; 153: 228-239Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar) (see Figure 1). Central to the study by Cabreiro et al. is the observation that, in worms, metformin is rather toxic and does not extend lifespan in the absence of their live trophic partner, the E. coliOP50 strain (Cabreiro et al., 2013Cabreiro F. Au C. Leung K.Y. Vergara-Irigaray N. Cochemé H.M. Noori T. Weinkove D. Schuster E. Greene N.D. Gems D. Cell. 2013; 153: 228-239Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar). This detrimental effect is observed either in axenic condition (i.e., strict germ-free setting) or upon feeding of the worms on dead E. coli, therefore establishing that active E. coliOP50 metabolism mediates lifespan extension upon metformin treatment. The authors then identified the bacterial folate metabolic pathway as a key player in the lifespan effect of metformin, making three observations: First, a genetic variant of the OP50 strain mutated for a folate cycle enzyme lacks the ability to promote lifespan extension upon metformin treatment; then metformin treatment markedly changed the folate’s composition in OP50; and finally, pharmacological inhibition of the bacterial folate cycle mimics metformin treatment. Despite showing the importance of the microbial folate metabolic pathway in the metformin response, the authors did not observe significantly modified folate levels in the worms. Subsequently, they obtained several key results that mapped the metabolic effect of metformin at the level of the methionine cycle, a folate-associated pathway. They first identified strong perturbations in the bacterial methionine cycle upon metformin treatment, consistent with reduced microbial methionine production. Using a C. elegans methionine synthetase mutant incapable of producing methionine in the worm, they further showed that metformin lifespan extension was strongly enhanced. Finally, they identified altered levels of methionine-related metabolites (S-adenosylmethionine and S-adenosylhomocystein) in C. elegans, suggesting a disrupted methionine cycle linked to reduced microbial methionine availability. S-adenosylmethionine synthase (SAMS-1) inhibition had already been linked to lifespan extension in C. elegans via an unknown mechanism shared with eating-impaired dietary restriction mutants (Hansen et al., 2005Hansen M. Hsu A.L. Dillin A. Kenyon C. PLoS Genet. 2005; 1: 119-128Crossref PubMed Scopus (378) Google Scholar). A previous study showed that metformin effect on lifespan extension is abrogated in these mutants (Onken and Driscoll, 2010Onken B. Driscoll M. PLoS ONE. 2010; 5: e8758Crossref PubMed Scopus (468) Google Scholar). Similarly, Cabreiro et al. showed that in sams-1 mutants metformin-induced lifespan extension is lost, suggesting that both metformin and dietary restriction mutation act by disrupting methionine-associated functions. Onken and Driscoll, 2010Onken B. Driscoll M. PLoS ONE. 2010; 5: e8758Crossref PubMed Scopus (468) Google Scholar had previously found that metformin-induced lifespan extension requires AMPK. Cabreiro et al. further demonstrated that the longevity effect of metformin is also dependent on the stress resistance activator SKN-1, which induces the expression of glutathione-S-transferase-4, a detoxification gene, in an AMPK-dependent manner. Through a worm growth inhibition assay, the authors demonstrated that AMPK and SKN-1 protect worms against metformin toxicity. SKN-1-dependent gst-4 expression was also observed in worms fed on another E. coli strain (HB101), which does not sustain metformin lifespan extension, suggesting an uncoupling of E. coli-mediated lifespan extension and SKN-1 drug detoxification activity. The authors directly addressed this hypothesis by selectively probing AMPK and SKN-1 importance in E. coli-mediated lifespan extension by metformin, independently of their function in drug detoxification. In an elegant assay using worms fed with metformin-pretreated E. coli, the authors revealed that only AMPK deficiency altered the lifespan extension phenotype in this setting. This result demonstrated that AMPK-dependence of lifespan extension by metformin is partly due to resistance against drug toxicity via SKN-1 activation and partly to AMPK involvement in the bacteria-mediated effects on the worm. Collectively, this study reports how metformin slows aging in C. elegans by metabolic alteration of its trophic microbial partner, E. coli. The deep mechanistic resolution of the study in both the worm and its bacterial partner reveals that metformin disrupts the bacterial folate cycle, which in turn reduces the levels of S-adenosylmethionine in the worm, slowing its aging by both metabolic “dietary” restriction-like phenomenon and AMPK activation (see Figure 1). Obvious mechanistic questions remain to be elucidated, such as how metformin impacts folate cycle in the bacteria and, on the worm side, how AMPK activation and metabolic “dietary” restriction mediate lifespan extension. Nevertheless, the important message is that the effects of metformin on worm lifespan are strongly dependent upon its accompanying microbe. Indeed, metformin impact on worm is the sum of both direct and indirect effects, i.e., drug toxicity versus microbe-mediated lifespan extension, with the actual influence of metformin on lifespan depending on whether the direct or indirect effect predominates (see Figure 1). The C. elegans/E. coli trophic association, although not a host/microbiota association per se in the absence of an obvious colonization pattern of the host by E. coli, is an excellent model providing a mechanistic framework of how a drug impacts the influence of microbial metabolism on the physiology of its eukaryote partner. This theme is of particular relevance to the host/microbiota field. This raises the question of whether metformin alters human microbiota metabolism as well, in particular folate and methionine cycles, and if this contributes to the efficacy of metformin therapy and/or its side effects in humans." @default.
• W2000945958 created "2016-06-24" @default.
• W2000945958 creator A5006853157 @default.
• W2000945958 creator A5018045023 @default.
• W2000945958 creator A5020742210 @default.
• W2000945958 date "2013-06-01" @default.
• W2000945958 modified "2023-10-18" @default.
• W2000945958 title "Metformin, Microbes, and Aging" @default.
• W2000945958 cites W1500247249 @default.
• W2000945958 cites W2026413615 @default.
• W2000945958 cites W2032462953 @default.
• W2000945958 cites W2042008937 @default.
• W2000945958 cites W2082603625 @default.
• W2000945958 cites W2084784711 @default.
• W2000945958 cites W2152839556 @default.
• W2000945958 doi "https://doi.org/10.1016/j.cmet.2013.05.014" @default.
• W2000945958 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23747239" @default.
• W2000945958 hasPublicationYear "2013" @default.
• W2000945958 type Work @default.
• W2000945958 sameAs 2000945958 @default.
• W2000945958 citedByCount "10" @default.
• W2000945958 countsByYear W20009459582013 @default.
• W2000945958 countsByYear W20009459582016 @default.
• W2000945958 countsByYear W20009459582018 @default.
• W2000945958 countsByYear W20009459582019 @default.
• W2000945958 countsByYear W20009459582021 @default.
• W2000945958 countsByYear W20009459582023 @default.
• W2000945958 crossrefType "journal-article" @default.
• W2000945958 hasAuthorship W2000945958A5006853157 @default.
• W2000945958 hasAuthorship W2000945958A5018045023 @default.
• W2000945958 hasAuthorship W2000945958A5020742210 @default.
• W2000945958 hasBestOaLocation W20009459581 @default.
• W2000945958 hasConcept C134018914 @default.
• W2000945958 hasConcept C2780323712 @default.
• W2000945958 hasConcept C555293320 @default.
• W2000945958 hasConcept C70721500 @default.
• W2000945958 hasConcept C71924100 @default.
• W2000945958 hasConcept C86803240 @default.
• W2000945958 hasConceptScore W2000945958C134018914 @default.
• W2000945958 hasConceptScore W2000945958C2780323712 @default.
• W2000945958 hasConceptScore W2000945958C555293320 @default.
• W2000945958 hasConceptScore W2000945958C70721500 @default.
• W2000945958 hasConceptScore W2000945958C71924100 @default.
• W2000945958 hasConceptScore W2000945958C86803240 @default.
• W2000945958 hasIssue "6" @default.
• W2000945958 hasLocation W20009459581 @default.
• W2000945958 hasLocation W20009459582 @default.
• W2000945958 hasOpenAccess W2000945958 @default.
• W2000945958 hasPrimaryLocation W20009459581 @default.
• W2000945958 hasRelatedWork W2059172185 @default.
• W2000945958 hasRelatedWork W2171172226 @default.
• W2000945958 hasRelatedWork W2464808367 @default.
• W2000945958 hasRelatedWork W2597257596 @default.
• W2000945958 hasRelatedWork W2748952813 @default.
• W2000945958 hasRelatedWork W2899084033 @default.
• W2000945958 hasRelatedWork W2996523451 @default.
• W2000945958 hasRelatedWork W3032375762 @default.
• W2000945958 hasRelatedWork W3130901238 @default.
• W2000945958 hasRelatedWork W4318829708 @default.
• W2000945958 hasVolume "17" @default.
• W2000945958 isParatext "false" @default.
• W2000945958 isRetracted "false" @default.
• W2000945958 magId "2000945958" @default.
• W2000945958 workType "article" @default.