Ageing, TOR and amino acid restriction: a cross-tissue transcriptional network connects GATA factors to Drosophila longevity

Abstract

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