title: Branched-chain amino acid catabolism is a conserved regulator of physiological ageing.
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.
authors.affiliation: Energy Metabolism Laboratory, Swiss Federal Institute of Technology (ETH) Zurich, CH-8603 Zurich, Switzerland.|DFG Graduate School of Adaptive Stress Response #1715, D-07745 Jena, Germany.|Department of Human Nutrition, Institute of Nutrition, Friedrich-Schiller-University Jena, D-07743 Jena, Germany.|GerontoSysJenAge Consortium, BMBF 0315581, D-07745 Jena, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Mansfeld
authors.affiliation: Department of Human Nutrition, Institute of Nutrition, Friedrich-Schiller-University Jena, D-07743 Jena, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Urban
authors.affiliation: GerontoSysJenAge Consortium, BMBF 0315581, D-07745 Jena, Germany.|Biocomputing Group, Leibniz Institute on Aging-Fritz Lipmann Institute, D-07745 Jena, Germany.|Systems Biology and Bioinformatics Group, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, D-07745 Jena, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Priebe
authors.affiliation: GerontoSysJenAge Consortium, BMBF 0315581, D-07745 Jena, Germany.|Genome Analysis, Leibniz Institute on Aging-Fritz Lipmann Institute, D-07745 Jena, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Groth
authors.affiliation: GerontoSysJenAge Consortium, BMBF 0315581, D-07745 Jena, Germany.|Hans Berger Department of Neurology, Jena University Hospital, D-07747 Jena, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Frahm
authors.affiliation: GerontoSysJenAge Consortium, BMBF 0315581, D-07745 Jena, Germany.|Molecular Genetics, Leibniz Institute on Aging-Fritz Lipmann Institute, D-07745 Jena, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Hartmann
authors.affiliation: GerontoSysJenAge Consortium, BMBF 0315581, D-07745 Jena, Germany.|Research Group Theoretical Systems Biology, Friedrich-Schiller-University Jena, D-07743 Jena, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Gebauer
authors.affiliation: Energy Metabolism Laboratory, Swiss Federal Institute of Technology (ETH) Zurich, CH-8603 Zurich, Switzerland.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Ravichandran
authors.affiliation: Department of Human Nutrition, Institute of Nutrition, Friedrich-Schiller-University Jena, D-07743 Jena, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Dommaschk
authors.affiliation: Department of Human Nutrition, Institute of Nutrition, Friedrich-Schiller-University Jena, D-07743 Jena, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schmeisser
authors.affiliation: Department of Human Nutrition, Institute of Nutrition, Friedrich-Schiller-University Jena, D-07743 Jena, Germany.|GerontoSysJenAge Consortium, BMBF 0315581, D-07745 Jena, Germany.|German Institute of Human Nutrition Potsdam-Rehbrücke, D-14558 Nuthetal, Germany.
authors.forename: Doreen
authors.initials: D
authors.lastname: Kuhlow
authors.affiliation: Imaging Facility, Leibniz Institute on Aging-Fritz Lipmann Institute, D-07745 Jena, Germany.
authors.forename: Shamci
authors.initials: S
authors.lastname: Monajembashi
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University of Jena, D-07743 Jena, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Bremer-Streck
authors.affiliation: GerontoSysJenAge Consortium, BMBF 0315581, D-07745 Jena, Germany.|Imaging Facility, Leibniz Institute on Aging-Fritz Lipmann Institute, D-07745 Jena, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hemmerich
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University of Jena, D-07743 Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kiehntopf
authors.affiliation: Institute of Molecular Systems Biology, Swiss Federal Institute of Technology (ETH) Zurich, CH-8093 Zürich, Switzerland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Zamboni
authors.affiliation: GerontoSysJenAge Consortium, BMBF 0315581, D-07745 Jena, Germany.|Molecular Genetics, Leibniz Institute on Aging-Fritz Lipmann Institute, D-07745 Jena, Germany.|Faculty of Biology and Pharmacy, Friedrich-Schiller-University Jena, 07743 Jena, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Englert
authors.affiliation: GerontoSysJenAge Consortium, BMBF 0315581, D-07745 Jena, Germany.|Systems Biology and Bioinformatics Group, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, D-07745 Jena, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Guthke
authors.affiliation: GerontoSysJenAge Consortium, BMBF 0315581, D-07745 Jena, Germany.|Research Group Theoretical Systems Biology, Friedrich-Schiller-University Jena, D-07743 Jena, Germany.|Faculty of Biology and Pharmacy, Friedrich-Schiller-University Jena, 07743 Jena, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kaleta
authors.affiliation: GerontoSysJenAge Consortium, BMBF 0315581, D-07745 Jena, Germany.|Genome Analysis, Leibniz Institute on Aging-Fritz Lipmann Institute, D-07745 Jena, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Platzer
authors.affiliation: GerontoSysJenAge Consortium, BMBF 0315581, D-07745 Jena, Germany.|Biocomputing Group, Leibniz Institute on Aging-Fritz Lipmann Institute, D-07745 Jena, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Sühnel
authors.affiliation: GerontoSysJenAge Consortium, BMBF 0315581, D-07745 Jena, Germany.|Hans Berger Department of Neurology, Jena University Hospital, D-07747 Jena, Germany.
authors.forename: Otto W
authors.initials: OW
authors.lastname: Witte
authors.affiliation: Energy Metabolism Laboratory, Swiss Federal Institute of Technology (ETH) Zurich, CH-8603 Zurich, Switzerland.|Department of Human Nutrition, Institute of Nutrition, Friedrich-Schiller-University Jena, D-07743 Jena, Germany.|GerontoSysJenAge Consortium, BMBF 0315581, D-07745 Jena, Germany.
authors.forename: Kim
authors.initials: K
authors.lastname: Zarse
authors.affiliation: Energy Metabolism Laboratory, Swiss Federal Institute of Technology (ETH) Zurich, CH-8603 Zurich, Switzerland.|DFG Graduate School of Adaptive Stress Response #1715, D-07745 Jena, Germany.|Department of Human Nutrition, Institute of Nutrition, Friedrich-Schiller-University Jena, D-07743 Jena, Germany.|GerontoSysJenAge Consortium, BMBF 0315581, D-07745 Jena, Germany.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0003-2109-2453
authors.initials: M
authors.lastname: Ristow
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D008136:Longevity; D008297:Male; D051379:Mice / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D008810:Mice, Inbred C57BL; D000637:Transaminases / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development / Q000378:metabolism
chemical_list: D000597:Amino Acids, Branched-Chain; D029742:Caenorhabditis elegans Proteins; D000637:Transaminases; C019798:branched-chain-amino-acid transaminase