RNA polymerase III limits longevity downstream of TORC1

RNA polymerase III is a key evolutionarily conserved regulator of longevity that may have potential as a therapeutic target for age-related conditions. Inhibition of target of mTOR(definition)-inhibiting drug studied for extending healthspan and lifespan." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">rapamycin(definition) kinase complex 1 (TORC1) by rapamycin promotes longevity across the animal kingdom. TORC1 tightly regulates the activity of RNA polymerase III (Pol III). Nazif Alic and colleagues show that Pol III acts downstream of TORC1 to limit longevity in yeast, worms and flies. Increased degradation of Pol III extended the chronological lifespan of a yeast strain in culture and partial inhibition of Pol III expression extended the organismal lifespan of nematode worms and flies. Inhibiting Pol III activity exclusively in the gut of adult worms or flies was sufficient to achieve lifespan extension. In flies, longevity was achieved by Pol III inhibition specifically in intestinal stem cells. The longevity phenotype was associated with amelioration of age-related gut pathology and functional decline, reduced protein synthesis and increased resistance to proteostatic stress. 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.