Letter

RNA polymerase III limits longevity downstream of TORC1

Received:
Accepted:
Published online:

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.

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Acknowledgements

The authors thank S. Grewal, B. Ohlstein, L. Partridge and S. Pletcher for fly lines; C. Bouchoux and F. Uhlmann for yeast reagents; G. Juhasz and A. Teleman for antibodies; E. Bolukbasi and L. Partridge for the Flag-tagged dTor construct and S2 cells; M. Hill and D. Ivanov for help with RNA-seq analysis; L. Conder, A. Garaeva, D. Mostapha, G. Phillips and P. van der Poel for technical assistance, and M. Piper, J. Bähler and the IHA members for support, comments and critical reading of the manuscript. 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.

Author information

Affiliations

  1. Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, Gower Street, London WC1E 6BT, UK

    • Danny Filer
    • , Adam J. Dobson
    • , Ilektra Kotronaki
    •  & Nazif Alic
  2. School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK

    • Maximillian A. Thompson
    • , James W. M. Green
    •  & Jennifer M. A. Tullet
  3. Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9747 AG Groningen, Netherlands

    • Vakil Takhaveev
    •  & Matthias Heinemann

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Contributions

N.A. conceived the study; D.F. and N.A. made the yeast strains and performed chronological lifespan experiments; V.T. performed and analysed yeast replicative lifespan experiments under the supervision of M.H.; M.A.T. and J.W.M.G. performed and analysed worm experiments under the supervision of J.M.A.T.; D.F., A.J.D., I.K. and N.A. performed and analysed fly experiments under the supervision of N.A.; D.F., M.A.T., J.M.A.T. and N.A. wrote the manuscript with contributions from A.J.D.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jennifer M. A. Tullet or Nazif Alic.

Reviewer Information Nature thanks N. Blewett, R. Maraia and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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    Life Sciences Reporting Summary

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    Supplementary Fig. 1

    This file contains source data for gels.

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