Branched-chain amino acid catabolism is a conserved regulator of physiological ageing
| Autor: | Johannes Mansfeld, Juliane Gebauer, Otto W. Witte, Christoph Kaleta, Marco Groth, Doreen Kuhlow, Kim Zarse, Nils Hartmann, Jürgen Sühnel, Michael Kiehntopf, Peter Hemmerich, Matthias Platzer, Nadine Urban, Steffen Priebe, Sibylle Bremer-Streck, Nicola Zamboni, Christoph Englert, Sebastian Schmeisser, Shamci Monajembashi, Michael Ristow, Reinhard Guthke, Christiane Frahm, Anne Dommaschk, Meenakshi Ravichandran |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Cell signalling Medical research Ageing Metabolism Aging Branched-chain amino acid Longevity General Physics and Astronomy General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Animals Caenorhabditis elegans Caenorhabditis elegans Proteins Transcription factor Zebrafish Gene Transaminases 030304 developmental biology chemistry.chemical_classification 0303 health sciences Multidisciplinary biology Catabolism fungi General Chemistry biology.organism_classification Amino acid Mice Inbred C57BL chemistry Biochemistry Female 030217 neurology & neurosurgery Amino Acids Branched-Chain |
| Zdroj: | Nature Communications ResearcherID Nature Communications, 6 Nature Communications, 6:10043 |
| ISSN: | 2041-1723 |
| DOI: | 10.3929/ethz-b-000108449 |
| Popis: | 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. Nature Communications, 6 ISSN:2041-1723 |
| Databáze: | OpenAIRE |
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