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Branched-chain amino acid catabolism is a conserved regulator of physiological ageing

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  • Johannes Mansfeld

    (Energy Metabolism Laboratory, Swiss Federal Institute of Technology (ETH) Zurich
    DFG Graduate School of Adaptive Stress Response #1715
    Institute of Nutrition, Friedrich-Schiller-University Jena
    GerontoSysJenAge Consortium, BMBF 0315581)

  • Nadine Urban

    (Institute of Nutrition, Friedrich-Schiller-University Jena
    Present address: Department of Nutrigenomics, Institute of Nutrition, Friedrich-Schiller-University Jena, D-07743 Jena, Germany)

  • Steffen Priebe

    (GerontoSysJenAge Consortium, BMBF 0315581
    Biocomputing Group, Leibniz Institute on Aging—Fritz Lipmann Institute
    Systems Biology and Bioinformatics Group, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute)

  • Marco Groth

    (GerontoSysJenAge Consortium, BMBF 0315581
    Genome Analysis, Leibniz Institute on Aging—Fritz Lipmann Institute)

  • Christiane Frahm

    (GerontoSysJenAge Consortium, BMBF 0315581
    Jena University Hospital)

  • Nils Hartmann

    (GerontoSysJenAge Consortium, BMBF 0315581
    Molecular Genetics, Leibniz Institute on Aging—Fritz Lipmann Institute)

  • Juliane Gebauer

    (GerontoSysJenAge Consortium, BMBF 0315581
    Research Group Theoretical Systems Biology, Friedrich-Schiller-University Jena)

  • Meenakshi Ravichandran

    (Energy Metabolism Laboratory, Swiss Federal Institute of Technology (ETH) Zurich)

  • Anne Dommaschk

    (Institute of Nutrition, Friedrich-Schiller-University Jena
    Present address: Department of Respiratory Medicine, Hannover Medical School, D-30625 Hannover, Germany)

  • Sebastian Schmeisser

    (Institute of Nutrition, Friedrich-Schiller-University Jena
    Present address: Department of Biology, McGill University, Montréal, Quebec, Canada H3A 0G4)

  • Doreen Kuhlow

    (Institute of Nutrition, Friedrich-Schiller-University Jena
    GerontoSysJenAge Consortium, BMBF 0315581
    German Institute of Human Nutrition Potsdam-Rehbrücke)

  • Shamci Monajembashi

    (Imaging Facility, Leibniz Institute on Aging—Fritz Lipmann Institute)

  • Sibylle Bremer-Streck

    (Institute of Clinical Chemistry and Laboratory Medicine, University of Jena)

  • Peter Hemmerich

    (GerontoSysJenAge Consortium, BMBF 0315581
    Imaging Facility, Leibniz Institute on Aging—Fritz Lipmann Institute)

  • Michael Kiehntopf

    (Institute of Clinical Chemistry and Laboratory Medicine, University of Jena)

  • Nicola Zamboni

    (Institute of Molecular Systems Biology, Swiss Federal Institute of Technology (ETH) Zurich)

  • Christoph Englert

    (GerontoSysJenAge Consortium, BMBF 0315581
    Molecular Genetics, Leibniz Institute on Aging—Fritz Lipmann Institute
    Faculty of Biology and Pharmacy, Friedrich-Schiller-University Jena)

  • Reinhard Guthke

    (GerontoSysJenAge Consortium, BMBF 0315581
    Systems Biology and Bioinformatics Group, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute)

  • Christoph Kaleta

    (GerontoSysJenAge Consortium, BMBF 0315581
    Research Group Theoretical Systems Biology, Friedrich-Schiller-University Jena
    Faculty of Biology and Pharmacy, Friedrich-Schiller-University Jena
    Present address: Research Group Medical Systems Biology, Institute of Experimental Medicine, Christian-Albrechts-University Kiel, D-24105 Kiel, Germany)

  • Matthias Platzer

    (GerontoSysJenAge Consortium, BMBF 0315581
    Genome Analysis, Leibniz Institute on Aging—Fritz Lipmann Institute)

  • Jürgen Sühnel

    (GerontoSysJenAge Consortium, BMBF 0315581
    Biocomputing Group, Leibniz Institute on Aging—Fritz Lipmann Institute)

  • Otto W. Witte

    (GerontoSysJenAge Consortium, BMBF 0315581
    Jena University Hospital)

  • Kim Zarse

    (Energy Metabolism Laboratory, Swiss Federal Institute of Technology (ETH) Zurich
    Institute of Nutrition, Friedrich-Schiller-University Jena
    GerontoSysJenAge Consortium, BMBF 0315581)

  • Michael Ristow

    (Energy Metabolism Laboratory, Swiss Federal Institute of Technology (ETH) Zurich
    DFG Graduate School of Adaptive Stress Response #1715
    Institute of Nutrition, Friedrich-Schiller-University Jena
    GerontoSysJenAge Consortium, BMBF 0315581)

Abstract

Ageing has been defined as a global decline in physiological function depending on both environmental and genetic factors. Here we identify gene transcripts that are similarly regulated during physiological ageing in nematodes, zebrafish and mice. We observe the strongest extension of lifespan when impairing expression of the branched-chain amino acid transferase-1 (bcat-1) gene in C. elegans, which leads to excessive levels of branched-chain amino acids (BCAAs). We further show that BCAAs reduce a LET-363/mTOR-dependent neuro-endocrine signal, which we identify as DAF-7/TGFβ, and that impacts lifespan depending on its related receptors, DAF-1 and DAF-4, as well as ultimately on DAF-16/FoxO and HSF-1 in a cell-non-autonomous manner. The transcription factor HLH-15 controls and epistatically synergizes with BCAT-1 to modulate physiological ageing. Lastly and consistent with previous findings in rodents, nutritional supplementation of BCAAs extends nematodal lifespan. Taken together, BCAAs act as periphery-derived metabokines that induce a central neuro-endocrine response, culminating in extended healthspan.

Suggested Citation

  • Johannes Mansfeld & Nadine Urban & Steffen Priebe & Marco Groth & Christiane Frahm & Nils Hartmann & Juliane Gebauer & Meenakshi Ravichandran & Anne Dommaschk & Sebastian Schmeisser & Doreen Kuhlow & , 2015. "Branched-chain amino acid catabolism is a conserved regulator of physiological ageing," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms10043
    DOI: 10.1038/ncomms10043
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    Cited by:

    1. Tomás Clive Barker-Tejeda & Elisa Zubeldia-Varela & Andrea Macías-Camero & Lola Alonso & Isabel Adoración Martín-Antoniano & María Fernanda Rey-Stolle & Leticia Mera-Berriatua & Raphaëlle Bazire & Pau, 2024. "Comparative characterization of the infant gut microbiome and their maternal lineage by a multi-omics approach," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    2. Juewon Kim & Yunju Jo & Donghyun Cho & Dongryeol Ryu, 2022. "L-threonine promotes healthspan by expediting ferritin-dependent ferroptosis inhibition in C. elegans," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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