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RNA polymerase III limits longevity downstream of TORC1.

Nature. 2017 Dec 14;552(7684):263-267. Epub 2017 Nov 29
Danny Filer 1 , Maximillian A Thompson 2 , Vakil Takhaveev 3 , Adam J Dobson 1 , Ilektra Kotronaki 1 , James W M Green 2 , Matthias Heinemann 3 , Jennifer M A Tullet 2 , Nazif Alic 1
Danny Filer 1 , Maximillian A Thompson 2 , Vakil Takhaveev 3 , Adam J Dobson 1 , Ilektra Kotronaki 1 , James W M Green 2 , Matthias Heinemann 3 , Jennifer M A Tullet 2 , Nazif Alic 1
+ et al

[No authors listed]

Author information
  • 1 Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, Gower Street, London WC1E 6BT, UK.
  • 2 School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK.
  • 3 Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9747 AG Groningen, Netherlands.

摘要


Three distinct RNA polymerases transcribe different classes of genes in the eukaryotic nucleus. RNA polymerase (Pol) III is the essential, evolutionarily conserved enzyme that generates short, non-coding RNAs, including tRNAs and 5S rRNA. 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 longevity. 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.