Credit: V. Summersby/Macmillan Publishers Limited

Understanding how lifespan might be prolonged has been a challenge for scientists and clinicians for decades. The nutrient sensor TOR complex 1 (TORC1) has emerged as an important regulator of lifespan, as shown by TORC1 inhibition increasing longevity. However, as TORC1 integrates various metabolic pathways in eukaryotes, exactly how TORC1 contributes to ageing remains elusive. Filer et al. now show that inhibition of RNA polymerase III (Pol III) promotes longevity in yeast, worms and flies, and that gut-specific deficiency of Pol III in flies is sufficient to extend animal lifespan, recapitulating the longevity-promoting effects of TORC1 inhibition.

Lifespan extension following TORC1 inhibition is associated with the downregulation of translation. One of the mechanisms through which TORC1 regulates translation is by promoting Pol III-mediated transcription, which generates tRNAs and 5S ribosomal RNA. Pol III depletion in Saccharomyces cerevisiae by depletion of one of the Pol III subunits increased cell survival over time (chronological lifespan). Similarly, depletion of Pol III subunits in adult Caenorhabditis elegans and Drosophila melanogaster had lifespan-promoting effects. Overall, systemic Pol III deficiency can extend organismal lifespan.

Pol III activity is the primary target through which TORC1 impacts on lifespan

Loss of gut homeostasis is one of the hallmarks of ageing, and reduced activity of nutrient sensing pathways in the gut, such as TORC1, has been linked to lifespan extension in model organisms. Importantly, gut-specific depletion of Pol III in both adult C. elegans and D. melanogaster ameliorated age-related defects in gut architecture and/or barrier function. Importantly, targeting Pol III subunits solely in the gut proved to be as efficient in extending lifespan as systemic Pol III depletion or TORC1 inhibition. Furthermore, Pol III was confirmed to be regulated by TORC1 in adult flies, and the effects of Pol III and TORC1 inhibition on lifespan extension were not additive, suggesting that Pol III and TORC1 function in a single pathway to regulate lifespan. These results suggest that Pol III activity is the primary target through which TORC1 impacts on lifespan and that TORC1–Pol III inhibition extends lifespan, at least in part, by maintaining intestinal homeostasis.

Gut-specific depletion of Pol III in D. melanogaster resulted in reduced protein synthesis in the gut and improved survival when animals were systemically challenged with high loads of unfolded proteins by treatment with tunicamycin — a potent inducer of the unfolded protein response. This suggests that low Pol III activity in the gut reduces animal sensitivity to proteotoxic stress, probably by reducing protein synthesis and therefore reducing the burden on protein folding machineries.

In summary, the longevity-promoting effects of TORC1 inhibition, at least in D. melanogaster, are largely mediated through Pol III inhibition and the resulting reduction in translation. As the tissue that governs the anti-ageing effects of Pol III inhibition in animals is the gut, gut-specific Pol III inhibition could be used as an alternative to systemic TORC1 inhibition in lifespan extension interventions. It remains to be established whether similar mechanisms operate in mammals.