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Nat Commun. 2015 Dec 1;6:10043. doi: 10.1038/ncomms10043.

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

Author information

1
Energy Metabolism Laboratory, Swiss Federal Institute of Technology (ETH) Zurich, CH-8603 Zurich, Switzerland.
2
DFG Graduate School of Adaptive Stress Response #1715, D-07745 Jena, Germany.
3
Department of Human Nutrition, Institute of Nutrition, Friedrich-Schiller-University Jena, D-07743 Jena, Germany.
4
GerontoSysJenAge Consortium, BMBF 0315581, D-07745 Jena, Germany.
5
Biocomputing Group, Leibniz Institute on Aging-Fritz Lipmann Institute, D-07745 Jena, Germany.
6
Systems Biology and Bioinformatics Group, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, D-07745 Jena, Germany.
7
Genome Analysis, Leibniz Institute on Aging-Fritz Lipmann Institute, D-07745 Jena, Germany.
8
Hans Berger Department of Neurology, Jena University Hospital, D-07747 Jena, Germany.
9
Molecular Genetics, Leibniz Institute on Aging-Fritz Lipmann Institute, D-07745 Jena, Germany.
10
Research Group Theoretical Systems Biology, Friedrich-Schiller-University Jena, D-07743 Jena, Germany.
11
German Institute of Human Nutrition Potsdam-Rehbrücke, D-14558 Nuthetal, Germany.
12
Imaging Facility, Leibniz Institute on Aging-Fritz Lipmann Institute, D-07745 Jena, Germany.
13
Institute of Clinical Chemistry and Laboratory Medicine, University of Jena, D-07743 Jena, Germany.
14
Institute of Molecular Systems Biology, Swiss Federal Institute of Technology (ETH) Zurich, CH-8093 Zürich, Switzerland.
15
Faculty of Biology and Pharmacy, Friedrich-Schiller-University Jena, 07743 Jena, Germany.

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.

PMID:
26620638
PMCID:
PMC4686672
DOI:
10.1038/ncomms10043
[Indexed for MEDLINE]
Free PMC Article

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