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

Johannes Mansfeld, Nadine Urban, Steffen Priebe, Marco Groth, Christiane Frahm, Nils Hartmann, Juliane Gebauer, Meenakshi Ravichandran, Anne Dommaschk, Sebastian Schmeisser, Doreen Kuhlow, Shamci Monajembashi, Sibylle Bremer-Streck, Peter Hemmerich, Michael Kiehntopf, Nicola Zamboni, Christoph Englert, Reinhard Guthke, Christoph Kaleta, Matthias Platzer, Jürgen Sühnel, Otto W. Witte, Kim Zarse and Michael Ristow ()
Additional contact information
Johannes Mansfeld: Energy Metabolism Laboratory, Swiss Federal Institute of Technology (ETH) Zurich
Nadine Urban: Institute of Nutrition, Friedrich-Schiller-University Jena
Steffen Priebe: GerontoSysJenAge Consortium, BMBF 0315581
Marco Groth: GerontoSysJenAge Consortium, BMBF 0315581
Christiane Frahm: GerontoSysJenAge Consortium, BMBF 0315581
Nils Hartmann: GerontoSysJenAge Consortium, BMBF 0315581
Juliane Gebauer: GerontoSysJenAge Consortium, BMBF 0315581
Meenakshi Ravichandran: Energy Metabolism Laboratory, Swiss Federal Institute of Technology (ETH) Zurich
Anne Dommaschk: Institute of Nutrition, Friedrich-Schiller-University Jena
Sebastian Schmeisser: Institute of Nutrition, Friedrich-Schiller-University Jena
Doreen Kuhlow: Institute of Nutrition, Friedrich-Schiller-University Jena
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
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
Reinhard Guthke: GerontoSysJenAge Consortium, BMBF 0315581
Christoph Kaleta: GerontoSysJenAge Consortium, BMBF 0315581
Matthias Platzer: GerontoSysJenAge Consortium, BMBF 0315581
Jürgen Sühnel: GerontoSysJenAge Consortium, BMBF 0315581
Otto W. Witte: GerontoSysJenAge Consortium, BMBF 0315581
Kim Zarse: Energy Metabolism Laboratory, Swiss Federal Institute of Technology (ETH) Zurich
Michael Ristow: Energy Metabolism Laboratory, Swiss Federal Institute of Technology (ETH) Zurich

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms10043

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DOI: 10.1038/ncomms10043

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