CoChat
Sign Up
Cited by 46Genetics, Aging, and Longevity in Model OrganismsPharmacogenetics and Drug MetabolismMetabolism, Diabetes, and Cancer

FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism in C. elegans

Open access
Choi, Hyo Sub, Bhat, Ajay, Howington, Marshall B., Schaller, Megan L., Cox, Rebecca L., Huang, Shijiao, Beydoun, Safa, Miller, Hillary A. +7 more·2023·Nature Communications
DOI 10.1038/s41467-023-36181-0PMC PMC9894935
Open this paper in CoChat — free accountOpen PDF

Abstract

Flavin containing monooxygenases (FMOs) are promiscuous enzymes known for metabolizing a wide range of exogenous compounds. In C. elegans, fmo-2 expression increases lifespan and healthspan downstream of multiple longevity-promoting pathways through an unknown mechanism. Here, we report that, beyond its classification as a xenobiotic enzyme, fmo-2 expression leads to rewiring of endogenous metabolism principally through changes in one carbon metabolism (OCM). These changes are likely relevant, as we find that genetically modifying OCM enzyme expression leads to alterations in longevity that interact with fmo-2 expression. Using computer modeling, we identify decreased methylation as the major OCM flux modified by FMO-2 that is sufficient to recapitulate its longevity benefits. We further find that tryptophan is decreased in multiple mammalian FMO overexpression models and is a validated substrate for FMO-2. Our resulting model connects a single enzyme to two previously unconnected key metabolic pathways and provides a framework for the metabolic interconnectivity of longevity-promoting pathways such as dietary restriction. FMOs are well-conserved enzymes that are also induced by lifespan-extending interventions in mice, supporting a conserved and important role in promoting health and longevity through metabolic remodeling.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-023-36181-0

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 73

  1. [1]Rossner R Kaeberlein M Leiser SF Flavin-containing monooxygenases in aging and disease: emerging roles for ancient enzymes J. Biol. Chem. 2017 292 11138 11146 28515321 PMC5500783
  2. [2]Ziegler D. M. An overview of the mechanism, substrate specificities, and structure of FMOs. Drug Metab. Rev.10.1081/DMR-120005650 (2002). 12214662 · DOI
  3. [3]Krueger SK Williams DE Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism Pharm. Ther. 2005 106 357 387 PMC1828602 15922018
  4. [4]Leiser SF Cell nonautonomous activation of flavin-containing monooxygenase promotes longevity and health span Science 2015 350 1375 1378 26586189 PMC4801033
  5. [5]Steinbaugh, M. J., Sun, L. Y., Bartke, A. & Miller, R. A. Activation of genes involved in xenobiotic metabolism is a shared signature of mouse models with extended lifespan. Am. J. Physiol. Metab. 10.1152/ajpendo.00110.2012 (2012). PMC3423099 22693205 · DOI
  6. [6]Swindell WR Genes and gene expression modules associated with caloric restriction and aging in the laboratory mouse BMC Genom. 2009 10 585 PMC2795771 19968875
  7. [7]Bennett CF Transaldolase inhibition impairs mitochondrial respiration and induces a starvation-like longevity response in Caenorhabditis elegans PLoS Genet. 2017 13 e1006695 28355222 PMC5389855
  8. [8]Veeravalli S The phenotype of a flavin-containing monooyxgenase knockout mouse implicates the drug-metabolizing enzyme FMO1 as a novel regulator of energy balance Biochem Pharmacol. 2014 90 88 95 24792439
  9. [9]Scott F Identification of flavin-containing monooxygenase 5 (FMO5) as a regulator of glucose homeostasis and a potential sensor of gut bacteria Drug Metab. Dispos. 2017 45 982 989 28646079 PMC5539585
  10. [10]Huang S Howington MB Dobry CJ Evans CR Leiser SF Flavin-containing monooxygenases are conserved regulators of stress resistance and metabolism Front. Cell Dev. Biol. 2021 9 9 PMC7907451 33644069
  11. [11]Gao AW Identification of key pathways and metabolic fingerprints of longevity in C. elegans Exp. Gerontol. 2018 113 128 140 30300667 PMC6224709
  12. [12]Menendez JA Joven J One-carbon metabolism: an aging-cancer crossroad for the gerosuppressant metformin Aging (Albany NY). 2012 4 894 898 23525940 PMC3708048
  13. [13]Cabreiro F Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism Cell 2013 153 228 239 23540700 PMC3898468
  14. [14]Annibal A Regulation of the one carbon folate cycle as a shared metabolic signature of longevity Nat. Commun. 2021 12 3486 34108489 PMC8190293
  15. [15]Locasale JW Serine, glycine and one-carbon units: cancer metabolism in full circle Nat. Rev. Cancer 2013 13 572 583 23822983 PMC3806315
  16. [16]Kabil H Kabil O Banerjee R Harshman LG Pletcher SD Increased transsulfuration mediates longevity and dietary restriction in Drosophila Proc. Natl Acad. Sci. USA 2011 108 16831 16836 21930912 PMC3189063
  17. [17]Hansen M Hsu A-L Dillin A Kenyon C New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen PLoS Genet. 2005 1 e17 e28 16103914 PMC1183531
  18. [18]Oxenkrug GF The extended life span of Drosophila melanogaster eye-color (white and vermilion) mutants with impaired formation of kynurenine J. Neural Transm. 2010 117 23 26 19941150 PMC3013506
  19. [19]Van Der Goot AT Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation Proc. Natl Acad. Sci. USA 2012 109 14912 14917 22927396 PMC3443121
  20. [20]Sutphin GL Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity Aging Cell. 2017 16 672 682 28401650 PMC5506438
  21. [22]Liu YJ Glycine promotes longevity in Caenorhabditis elegans in a methionine cycle-dependent fashion PLoS Genet. 2019 15 e1007633 30845140 PMC6424468
  22. [23]Depuydt G LC-MS proteomics analysis of the insulin/IGF-1-deficient Caenorhabditis elegans daf-2(e1370) mutant reveals extensive restructuring of intermediary metabolism J. Proteome Res. 2014 13 1938 1956 24555535 PMC3993954
  23. [24]Johnson TE Gerontogenes mediate health and longevity in nematodes through increasing resistance to environmental toxins and stressors Exp. Gerontol. 2000 35 687 694 11053658
  24. [25]Finkel T Holbrook NJ Oxidants, oxidative stress and the biology of ageing Nature 2000 408 239 247 11089981
  25. [26]Johnson TE Longevity genes in the nematode Caenorhabditis elegans also mediate increased resistance to stress and prevent disease J. Inherit. Metab. Dis. 2002 25 197 206 12137228
  26. [27]Miller, R. A. Cell stress and aging: New emphasis on multiplex resistance mechanisms. J. Gerontol. - Ser. A Biol. Sci. Med. Sci.10.1093/gerona/gln072 (2009) PMC2655020 19225033 · DOI
  27. [28]Wani KA NHR-49/PPAR-α and HLH-30/TFEB cooperate for C. elegans host defense via a flavin-containing monooxygenase Elife 2021 10 10 PMC8139828 33978570
  28. [29]Amrit FRG The longevity-promoting factor, TCER-1, widely represses stress resistance and innate immunity Nat. Commun. 2019 10 3042 31316054 PMC6637209
  29. [30]Ding W s-Adenosylmethionine levels govern innate immunity through distinct methylation-dependent pathways Cell Metab. 2015 22 633 645 26321661 PMC4598287
  30. [31]Lee HJ Prostaglandin signals from adult germline stem cells delay somatic ageing of Caenorhabditis elegans Nat. Metab. 2019 1 790 810 31485561 PMC6726479
  31. [32]Hine C Endogenous hydrogen sulfide production is essential for dietary restriction benefits Cell 2015 160 132 144 25542313 PMC4297538
  32. [33]Wei Y Kenyon C Roles for ROS and hydrogen sulfide in the longevity response to germline loss in Caenorhabditis elegans Proc. Natl Acad. Sci. USA 2016 113 E2832 E2841 27140632 PMC4878494
  33. [34]Wall M Shim JH Benkovic SJ Human AICAR transformylase: role of the 4-carboxamide of AICAR in binding and catalysis Biochemistry 2000 39 11303 11311 10985775
  34. [35]Sun Y Connors KE Yang DQ AICAR induces phosphorylation of AMPK in an ATM-dependent, LKB1-independent manner Mol. Cell Biochem. 2007 306 239 245 17786544
  35. [36]Apfeld J O’Connor G McDonagh T DiStefano PS Curtis R The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans Genes Dev. 2004 18 3004 3009 15574588 PMC535911
  36. [37]Obata F Miura M Enhancing S-adenosyl-methionine catabolism extends Drosophila lifespan Nat. Commun. 2015 6 1 9 PMC4595730 26383889
  37. [39]Singh, S. et al. Flux-based classification of reactions reveals a functional bow-tie organization of complex metabolic networks. Phys. Rev. E - Stat. Nonlinear, Soft Matter. Phys. 10.1103/PhysRevE.87.052708 (2013). 23767567 · DOI
  38. [40]Walker AK A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans Cell 2011 147 840 852 22035958 PMC3384509
  39. [41]Choi H DDS promotes longevity through a microbiome-mediated starvation signal Transl. Med. Aging 2019 3 64 69 32190786 PMC7080190
  40. [42]Yi P Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation J. Biol. Chem. 2000 275 29318 29323 10884384
  41. [43]Yuasa HJ Ball HJ Efficient tryptophan-catabolizing activity is consistently conserved through evolution of TDO enzymes, but not IDO enzymes J. Exp. Zool. B Mol. Dev. Evol. 2015 324 128 140 25702628
  42. [44]Brosnan, M. E. & Brosnan, J. T. Formate: the neglected member of one-carbon metabolism. Annu. Rev. Nutr.36, 369–388 (2016). 27431368
  43. [45]Lemieux GA Kynurenic acid is a nutritional cue that enables behavioral plasticity Cell 2015 160 119 131 25594177 PMC4334586
  44. [46]Moroni F Russi P Carlá V Lombardi G Kynurenic acid is present in the rat brain and its content increases during development and aging processes Neurosci. Lett. 1988 94 145 150 2468114
  45. [47]Santi, D. V. & Mchenry, C. S. 5-Fluoro-2’-Deoxyuridylate: Covalent Complex with Thymidylate Synthetase (Affinity Labeling/Enzyme Mechanism/Inhibition/Fluorinated Pyrimidines) Vol. 69. https://www.pnas.org (1972). PMC426818 4505665
  46. [48]Lim C-Y SAMS-1 coordinates HLH-30/TFEB and PHA-4/FOXA activities through histone methylation to mediate dietary restriction-induced autophagy and longevity Autophagy 2022 19 1 17 35503435 PMC9809948
  47. [49]Veeravalli S Flavin-containing monooxygenase 1 catalyzes the production of taurine from hypotaurine Drug Metab. Dispos. Drug Metab. Dispos. 2020 48 378 385 32156684
  48. [50]Sun, L., Sadighi Akha, A. A., Miller, R. A. & Harper, J. M. Life-span extension in mice by preweaning food restriction and by methionine restriction in middle age. J. Gerontol. - Ser. A Biol. Sci. Med. Sci. 10.1093/gerona/glp051 (2009). PMC2691799 19414512 · DOI
  49. [51]Lee BC Methionine restriction extends lifespan of Drosophila melanogaster under conditions of low amino-acid status Nat. Commun. 2014 5 3592 24710037 PMC4350766
  50. [52]Parkhitko AA Tissue-specific down-regulation of S-adenosyl-homocysteine via suppression of dAhcyL1/dAhcyL2 extends health span and life span in Drosophila Genes Dev. 2016 30 1409 1422 27313316 PMC4926864
  51. [53]Maddocks ODK Labuschagne CF Adams PD Vousden KH Serine metabolism supports the methionine cycle and DNA/RNA methylation through de novo ATP synthesis in cancer cells Mol. Cell. 2016 61 210 221 26774282 PMC4728077
  52. [54]Dues DJ Andrews EK Senchuk MM Van Raamsdonk JM Resistance to stress can be experimentally dissociated from longevity J. Gerontol. Ser. A. 2019 74 1206 1214 PMC6625593 30247515
  53. [55]Reddy RR Ralph EC Motika MS Zhang J Cashman JR Characterization of human flavin-containing monooxygenase (FMO) 3 and FMO5 expressed as maltose-binding protein fusions Drug Metab. Dispos. 2010 38 2239 2245 20810540 PMC2993457
  54. [56]Lončar N Characterization of a thermostable flavin-containing monooxygenase from Nitrincola lacisaponensis (NiFMO) Appl. Microbiol. Biotechnol. 2019 103 1755 1764 30607493
  55. [57]Chen Y Patel NA Crombie A Scrivens JH Murrell JC Bacterial flavin-containing monooxygenase is trimethylamine monooxygenase Proc. Natl Acad. Sci. USA 2011 108 17791 17796 22006322 PMC3203794
  56. [58]Fiorentini F Biocatalytic characterization of human FMO5: unearthing Baeyer-Villiger reactions in humans ACS Chem. Biol. 2016 11 1039 1048 26771671
  57. [60]Ogata H KEGG: Kyoto encyclopedia of genes and genomes Nucleic Acids Res. 1999 27 29 34 9847135 PMC148090
  58. [61]Kanehisa M Sato Y Furumichi M Morishima K Tanabe M New approach for understanding genome variations in KEGG Nucleic Acids Res. 2019 47 D590 D595 30321428 PMC6324070
  59. [62]Treichel JL Henry MM Skumatz CMB Eells JT Burke JM Formate, the toxic metabolite of methanol, in cultured ocular cells Neurotoxicology 2003 24 825 834 14637377
  60. [63]Kapahi P Kaeberlein M Hansen M Dietary restriction and lifespan: lessons from invertebrate models Ageing Res. Rev. 2017 39 3 14 28007498 PMC5476520
  61. [64]Gu X SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway Science 2017 358 813 818 29123071 PMC5747364
  62. [65]Metz R IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: a novel IDO effector pathway targeted by D-1-methyl-tryptophan Oncoimmunology 2012 1 1460 1468 23264892 PMC3525601
  63. [66]Wang H L-Tryptophan activates mammalian target of rapamycin and enhances expression of tight junction proteins in intestinal porcine epithelial cells J. Nutr. 2015 145 1156 1162 25878205
  64. [67]Newman AC Maddocks ODK One-carbon metabolism in cancer Br. J. Cancer 2017 116 1499 1504 28472819 PMC5518849
  65. [68]Beydoun S An alternative food source for metabolism and longevity studies in Caenorhabditis elegans Commun. Biol. 2021 4 258 33637830 PMC7910432
  66. [69]Overmyer KA Thonusin C Qi NR Burant CF Evans CR Impact of anesthesia and euthanasia on metabolomics of mammalian tissues: studies in a C57BL/6J mouse model PLoS ONE 2015 10 e0117232 25658945 PMC4319778
  67. [70]Overmyer KA Maximal oxidative capacity during exercise is associated with skeletal muscle fuel selection and dynamic changes in mitochondrial protein acetylation PLoS ONE 2015 21 468 478 PMC4350023 25738461
  68. [71]Smith CA Want EJ O’Maille G Abagyan R Siuzdak G XCMS: processing mass spectrometry data for metabolite profiling using nonlinear peak alignment, matching, and identification Anal. Chem. 2006 78 779 787 16448051
  69. [72]Zhang Y Chen D Smith MA Zhang B Pan X Selection of reliable reference genes in Caenorhabditis elegans for analysis of nanotoxicity PLoS ONE 2012 7 31849 PMC3305280 22438870
  70. [73]Taki FA Zhang B Determination of reliable reference genes for multi-generational gene expression analysis on C. elegans exposed to abused drug nicotine Psychoparmacology 2013 230 77 88 PMC3795882 23681163
  71. [74]Motika MS Zhang J Zheng X Riedler K Cashman JR Novel variants of the human flavin-containing monooxygenase 3 (FMO3) gene associated with trimethylaminuria Mol. Genet. Metab. 2009 97 128 135 19321370 PMC2739593
  72. [75]Blaženović I Structure annotation of all mass spectra in untargeted metabolomics Anal. Chem. 2019 91 2155 2162 30608141 PMC11426395
  73. [76]Han SK OASIS 2: Online application for survival analysis 2 with features for the analysis of maximal lifespan and healthspan in aging research Oncotarget 2016 7 56147 56152 27528229 PMC5302902

Cited by

Sorted by citations

Authors
Choi, H. S., Bhat, A., Howington, M. B., Schaller, M. L., Cox, R. L., Huang, S., Beydoun, S., Miller, H. A., Tuckowski, A. M., Mecano, J., Dean, E. S., Jensen, L., Beard, D. A., Evans, C. R., & Leiser, S. F.
Affiliations
University of Michigan (US)
Corresponding author
Leiser, Scott F.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-02-02
Volume
14
Issue
1
Pages
562-562
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-36181-0
PMC
PMC9894935
OpenAlex
W4318983128
Cited by
46
References
3
Citations by year
2026: 12 · 2025: 20 · 2024: 9 · 2023: 5
FWCI
3.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (R01AG075061, R21AG059117)
  • Glenn Foundation for Medical Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
flavin-containing monooxygenase, longevity, healthspan, one-carbon metabolism, tryptophan metabolism, methylation, metabolic reprogramming, dietary restriction, Caenorhabditis elegans, metabolic modeling, xenobiotic metabolism
MeSH terms
Animals, Carbon, Longevity, Mammals, Oxygenases, Tryptophan, Caenorhabditis elegans, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review