Identification and Application of Gene Expression Signatures Associated with Lifespan Extension

Several pharmacological, dietary, and genetic interventions that increase mammalian lifespan are known, but general principles of lifespan extension remain unclear. Here, we performed RNA sequencing (RNA-seq) analyses of mice subjected to 8 longevity interventions. We discovered a feminizing effect associated with growth hormone regulation and diminution of sex-related differences. Expanding this analysis to 17 interventions with public data, we 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 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, this study describes general and specific transcriptomic programs of lifespan extension in mice and provides tools to discover new interventions. [Display omitted] •Sex-specific differences are decreased in response to longevity interventions•Many interventions, but not rapamycin, exhibit similar transcriptomic responses•Certain gene expression changes are associated with longevity across interventions•Longevity signatures may be used to discover new lifespan-extending interventions Tyshkovskiy et al. performed a comprehensive analysis of 17 known lifespan-extending interventions in mice at the level of gene expression to better understand general principles of lifespan control and generate gene expression signatures associated with longevity. They applied these signatures to predict new candidate compounds for lifespan extension.