Figure 2. Gut-specific inhibition of Pol III extends lifespan, reduces protein synthesis and increases tolerance to proteostatic stress.

a, Activating RNAi against rpc-1 specifically in the worm gut, using the VP303 strain, extends worm lifespan at 20°C in presence of FUDR (p=0.02, log-rank test, n= 90 control, 67 rpc-1 RNAi animals; representative of two trials). b, Feeding RU486 to TIGS>dC160^RNAi female fruit flies to induce dC160^RNAi in the gut alone extends their lifespan (p=6x10^-16, log-rank test, n= 150 -RU486, 157 +RU486 animals; representative of three trials). c, Feeding RU486 to GS5961>dC160^RNAi female fruit flies to induce dC160^RNAi in the ISCs alone extends their lifespan (p=2x10^-4, log-rank test, n= 139 -RU486, 142 +RU486 animals; representative of three trials). Inducing dC160^RNAi in the gut with RU486 feeding of TIGS>dC160^RNAi females leads to: d, reduction in pre-tRNAs (mean ± SEM, p=0.04, Multivariate Analysis of Variance [MANOVA], n= 10 biologically independent samples per -/+RU486 condition, CI= 0.91-1.1, 0.76-1.0, 0.90-1.1, 0.75-0.92, 0.88-1.1, 0.68-1.0 left to right); e, reduction in gut protein synthesis, as quantified by ex-vivo puromycin incorporation and western blotting (representative of three biologically independent repeats; see Extended Data Fig. 6c); f, improved survival in response to tunicomycin challenge (p=3x10^-15, log-rank test, n=185 animals per condition; representative of two trials). For more detailed demography and summary of lifespan trials see Extended Data Fig. 2c and 4a. For gel source data, see Sup. Fig. 1.