Abstract
Healthy lifespan can be extended in eukaryotes by dietary restriction (DR). In Drosophila, DR of essential amino acids (EAAs) extends lifespan, which is thought to be dependent on the Target of Rapamycin (TOR) pathway, but the transcriptional bases of these effects are poorly understood. Identifying these transcriptional changes and their regulators offers the prospect of correctly coordinating physiology to mimic the benefits of DR. We have analysed how DR and TOR alter transcriptional networks in adult female Drosophila, by specifically diluting EAAs or adding the TOR-suppressive drug rapamycin and analysing the transcriptomes of dissected organs. This network analysis simplified the description of the organ system by two orders of magnitude whilst retaining ∼80% of information. The broad transcriptional effects of DR were recapitulated by rapamycin, indicating that DR exerts its transcriptional effects via TOR. At a finer resolution, one particular transcriptional module was associated with transcriptional changes induced by both DR and rapamycin, suggesting a general anti-ageing role for this module. However there were also treatment-specific effects of both DR and rapamycin, with the important implication that not all transcriptional effects of TOR suppression are obligately coupled, which may offer the possibility of separating lifespan benefits from costs of intervention. These changes across organs were mirrored by changes within organs. Lifespan-associated transcriptional changes were strongly associated with binding sites for GATA transcription factors, providing a candidate mechanism to regulate the observed transcriptional effects of diet. Collectively these results show that diet and TOR signaling have extensive effects on transcription across organs, isolate transcriptional changes that may be generally associated with longevity from other effects of DR and of drugs, and show that the genes associated with lifespan extension are enriched in GATA motifs.
