ИСТИНА

Dozens of pharmacological, genetic and dietary interventions leading to lifespan extension are known for a variety of organisms ranging from yeasts to mammals. Although some key molecular players behind lifespan extension have been uncovered, common mechanisms of different interventions remain unclear. Here we fill this gap by performing systemic analyses of gene expression across longevity interventions in mouse using our RNA-seq data and integrating publicly available data into a single study. By carrying hepatic RNA-seq across 8 longevity interventions in mice, we showed that interventions tend to regulate number of common pathways. We also discovered a feminizing effect associated with growth hormone regulation and diminution of sex-related differences in response to the longevity interventions. Using public data, we expanded this analysis to 17 interventions and observed that many interventions induced similar gene expression changes. We identified hepatic gene signatures associated with lifespan extension across interventions, including upregulation of oxidative phosphorylation and drug metabolism, and showed that perturbed pathways may be shared across tissues. We further found that genes related to oxidative phosphorylation and hepatic regulation of immune response could serve as both qualitative and quantitative predictors of lifespan extension. We applied the discovered longevity signatures to identify new lifespan-extending candidates, such as chronic hypoxia, KU-0063794 and ascorbyl-palmitate. Finally, we developed GENtervention, an app that visualizes associations between gene expression changes and longevity. Overall, our work investigates gene expression of longevity interventions, describes general and specific transcriptomic programs of lifespan extension in mice and provides tools to discover new interventions.