caa a22 4500 528785206 20190713030951.0 cr unu---uuuuu 180924s2015 xx s 000 0 eng 10.3929/ethz-b-000108449 doi 10.1038/ncomms10043 doi (ETHRESEARCH)oai:www.research-collection.ethz.ch:20.500.11850/108449 Branched-chain amino acid catabolism is a conserved regulator of physiological ageing [Elektronische Daten] [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; id_orcid 0000-0003-1271-1021 Zamboni, Christoph Englert, Reinhard Guthke, Christoph Kaleta, Matthias Platzer, Jürgen Sühnel, Otto W. Witte, Kim Zarse, Michael; id_orcid 0000-0003-2109-2453 Ristow] Nat Commun Open access ethresearch 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. Creative Commons Attribution 4.0 International http://creativecommons.org/licenses/by/4.0 ethresearch Mansfeld Johannes joint author Urban Nadine joint author Priebe Steffen joint author Groth Marco joint author Frahm Christiane joint author Hartmann Nils joint author Gebauer Juliane joint author Ravichandran Meenakshi joint author Dommaschk Anne joint author Schmeisser Sebastian joint author Kuhlow Doreen joint author Monajembashi Shamci joint author Bremer-Streck Sibylle joint author Hemmerich Peter joint author Kiehntopf Michael joint author Zamboni Nicola; id_orcid 0000-0003-1271-1021 joint author Englert Christoph joint author Guthke Reinhard joint author Kaleta Christoph joint author Platzer Matthias joint author Sühnel Jürgen joint author Witte Otto W. joint author Zarse Kim joint author Ristow Michael; id_orcid 0000-0003-2109-2453 joint author Nature Communications London : Nature Publishing Group 6, p. 10043 2041-1723 http://hdl.handle.net/20.500.11850/108449 text/html WWW-Backlink auf das Repository (Open access) 1 Journal Article ethresearch ETHRESEARCH 856 40 http://hdl.handle.net/20.500.11850/108449 text/html WWW-Backlink auf das Repository (Open access) ETHRESEARCH 700 1- Mansfeld Johannes joint author ETHRESEARCH 700 1- Urban Nadine joint author ETHRESEARCH 700 1- Priebe Steffen joint author ETHRESEARCH 700 1- Groth Marco joint author ETHRESEARCH 700 1- Frahm Christiane joint author ETHRESEARCH 700 1- Hartmann Nils joint author ETHRESEARCH 700 1- Gebauer Juliane joint author ETHRESEARCH 700 1- Ravichandran Meenakshi joint author ETHRESEARCH 700 1- Dommaschk Anne joint author ETHRESEARCH 700 1- Schmeisser Sebastian joint author ETHRESEARCH 700 1- Kuhlow Doreen joint author ETHRESEARCH 700 1- Monajembashi Shamci joint author ETHRESEARCH 700 1- Bremer-Streck Sibylle joint author ETHRESEARCH 700 1- Hemmerich Peter joint author ETHRESEARCH 700 1- Kiehntopf Michael joint author ETHRESEARCH 700 1- Zamboni Nicola; id_orcid 0000-0003-1271-1021 joint author ETHRESEARCH 700 1- Englert Christoph joint author ETHRESEARCH 700 1- Guthke Reinhard joint author ETHRESEARCH 700 1- Kaleta Christoph joint author ETHRESEARCH 700 1- Platzer Matthias joint author ETHRESEARCH 700 1- Sühnel Jürgen joint author ETHRESEARCH 700 1- Witte Otto W. joint author ETHRESEARCH 700 1- Zarse Kim joint author ETHRESEARCH 700 1- Ristow Michael; id_orcid 0000-0003-2109-2453 joint author ETHRESEARCH 773 0- Nature Communications London : Nature Publishing Group 6, p. 10043 2041-1723 BK010053 XK010053 XK010000 ETHRESEARCH ETHRESEARCH ETHRESEARCH Journal Article Open access