Identification and Application of Gene Expression Signatures Associated with Lifespan Extension

Cell Metab. 2019 Sep 3;30(3):573-593.e8. doi: 10.1016/j.cmet.2019.06.018. Epub 2019 Jul 25.


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.

Keywords: GENtervention; aging; caloric restriction; feminizing effect; gene expression; growth hormone; lifespan extension; lifespan-extending interventions; longevity; longevity signatures; rapamycin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / drug effects
  • Aging / genetics*
  • Animals
  • Ascorbic Acid / analogs & derivatives
  • Ascorbic Acid / pharmacology
  • Caloric Restriction
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Knockout Techniques
  • Hypoxia / genetics
  • Kelch-Like ECH-Associated Protein 1 / genetics
  • Life Expectancy
  • Liver / metabolism
  • Longevity / drug effects
  • Longevity / genetics*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Morpholines / pharmacology
  • Pyrimidines / pharmacology
  • Sirolimus / pharmacology
  • Transcriptome*


  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • Morpholines
  • Pyrimidines
  • Ku 0063794
  • Ascorbic Acid
  • 6-O-palmitoylascorbic acid
  • Sirolimus