Dietary restriction (DR) extends animal lifespan, but imposes fitness costs. This phenomenon depends on dietary essential amino acids (EAAs) and TOR signalling, which exert systemic effects. However, the roles of specific tissues and cell-autonomous transcriptional regulators in diverse aspects of the DR phenotype are unknown. Manipulating relevant transcription factors (TFs) specifically in lifespan-limiting tissues may separate the lifespan benefits of DR from the early-life fitness costs. Here, we systematically analyse transcription across organs of Drosophila subjected to DR or low TOR and predict regulatory TFs. We predict and validate roles for the evolutionarily conserved GATA family of TFs, and identify conservation of this signal in mice. Importantly, restricting knockdown of the GATA TF srp to specific fly tissues recapitulated the benefits but not the costs of DR. Together, our data indicate that the GATA TFs mediate effects of dietary amino acids on lifespan, and that by manipulating them in specific tissues it is possible to reap the fitness benefits of EAAs, decoupled from a cost to longevity.

Highlights d Partial inhibition of RNA polymerase I (Pol I) can extend lifespan in the fruit fly d Reducing Pol I activity after development and only in the gut is sufficient d Pol I activity affects aging from both post-mitotic and mitotically active cells d Pol I activity affects the age-related decline in performance of multiple organs

Animal lifespan can be extended by dietary restriction (DR), but at a cost to fitness. 3This phenomenon depends on essential amino acids (EAAs) and TOR signalling, but 4 roles of specific tissues and downstream transcriptional regulators are poorly charac-5 terised. Manipulating relevant transcription factors (TFs) specifically in lifespan-6 limiting tissues may ameliorate ageing without costs of DR. Here we identify TFs 7 which regulate the DR phenotype in Drosophila, analysing organs as an interacting 8 system and reducing its transcriptional complexity by two orders of magnitude. Evolu-9 tionarily conserved GATA TFs are predicted to regulate the overlapping effects of DR 10 and TOR on organs, and genetic analyses confirmed that these TFs interact with diet 11 to determine lifespan. Importantly, Srp knockdown insulated fly lifespan from the per-12 nicious effects of EAAs, but tissue-specific knockdown reduced the corrolary costs. 13These results provide the first indication that benefits of EAAs for early-life fitness 14 can be decoupled from longevity by tissue-specific transcriptional reprogramming.

Web-based data analysis and visualization tools are mostly designed for specific purposes, such as the analysis of data from whole transcriptome RNA sequencing or single-cell RNA sequencing. However, generic tools designed for the analysis of common laboratory data for noncomputational scientists are also needed. The importance of such web-based tools is emphasized by the continuing increases in the sample capacity of conventional laboratory tools such as quantitative PCR, flow cytometry or ELISA instruments. We present a web-based application FaDA, developed with the R Shiny package that provides users with the ability to perform statistical group comparisons, including parametric and nonparametric tests, with multiple testing corrections suitable for most standard wet-laboratory analyses. FaDA provides data visualizations such as heatmaps, principal component analysis (PCA) plots, correlograms and receiver operating curves (ROCs). Calculations are performed through the R language. The FaDA application provides a free and intuitive interface that allows biologists without bioinformatic skill to easily and quickly perform common laboratory data analyses. The application is freely accessible at https://shiny-bird.univ-nantes.fr/app/Fada.