RNA polymerase III limits longevity downstream of TORC1

Filer, D., Thompson, M. A., Takhaveev, V., Dobson, A. J. , Kotronaki, I., Green, J. W.M., Heinemann, M., Tullet, J. M.A. and Alic, N. (2017) RNA polymerase III limits longevity downstream of TORC1. Nature, 552(7684), pp. 263-267. (doi: 10.1038/nature25007) (PMID:29186112) (PMCID:PMC5732570)

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Abstract

Three distinct RNA polymerases transcribe different classes of genes in the eukaryotic nucleus1. RNA polymerase (Pol) III is the essential, evolutionarily conserved enzyme that generates short, non-coding RNAs, including tRNAs and 5S rRNA2. The historical focus on transcription of protein-coding genes has left the roles of Pol III in organismal physiology relatively unexplored. Target of rapamycin kinase complex 1 (TORC1) regulates Pol III activity, and is also an important determinant of longevity3. This raises the possibility that Pol III is involved in ageing. Here we show that Pol III limits lifespan downstream of TORC1. We find that a reduction in Pol III extends chronological lifespan in yeast and organismal lifespan in worms and flies. Inhibiting the activity of Pol III in the gut of adult worms or flies is sufficient to extend lifespan; in flies, longevity can be achieved by Pol III inhibition specifically in intestinal stem cells. The longevity phenotype is associated with amelioration of age-related gut pathology and functional decline, dampened protein synthesis and increased tolerance of proteostatic stress. Pol III acts on lifespan downstream of TORC1, and limiting Pol III activity in the adult gut achieves the full longevity benefit of systemic TORC1 inhibition. Hence, Pol III is a pivotal mediator of this key nutrient-signalling network for longevity; the growth-promoting anabolic activity of Pol III mediates the acceleration of ageing by TORC1. The evolutionary conservation of Pol III affirms its potential as a therapeutic target.

Item Type:Articles
Additional Information:Reagents were obtained from Developmental Studies Hybridoma Bank, Vienna Drosophila Resource Centre, Bloomington Stock Center and the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). This work was funded in part by Biotechnology and Biological Sciences Research Council grant BB/M029093/1, Royal Society grant RG140694 and Medical Research Council grant MR/L018802/1 to N.A., and Royal Society grant RG140122 to J.M.A.T. M.H. and V.T. received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement 642738. D.F. is a recipient of the UCL Impact PhD studentship.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Dobson, Dr Adam
Authors: Filer, D., Thompson, M. A., Takhaveev, V., Dobson, A. J., Kotronaki, I., Green, J. W.M., Heinemann, M., Tullet, J. M.A., and Alic, N.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Nature
Publisher:Nature Publishing Group
ISSN:0028-0836
ISSN (Online):1476-4687
Published Online:29 November 2017
Copyright Holders:Copyright © 2017 Macmillan Publishers Limited, part of Springer Nature
First Published:First published in Nature 552(7684): 263-267
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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