Longitudinal RNA-Seq Analysis of Vertebrate Aging Identifies Mitochondrial Complex I as a Small-Molecule-Sensitive Modifier of Lifespan

Cell Syst. 2016 Feb 24;2(2):122-32. doi: 10.1016/j.cels.2016.01.014. Epub 2016 Feb 24.


Mutations and genetic variability affect gene expression and lifespan, but the impact of variations in gene expression within individuals on their aging-related mortality is poorly understood. We performed a longitudinal study in the short-lived killifish, Nothobranchius furzeri, and correlated quantitative variations in gene expression during early adult life with lifespan. Shorter- and longer-lived individuals differ in their gene expression before the onset of aging-related mortality; differences in gene expression are more pronounced early in life. We identified mitochondrial respiratory chain complex I as a hub in a module of genes whose expression is negatively correlated with lifespan. Accordingly, partial pharmacological inhibition of complex I by the small molecule rotenone reversed aging-related regulation of gene expression and extended lifespan in N. furzeri by 15%. These results support the use of N. furzeri as a vertebrate model for identifying the protein targets, pharmacological modulators, and individual-to-individual variability associated with aging.

Keywords: GAGE; Nothobranchius furzeri; RNA transport; RNA-seq; aging; history trait; hormesis; hourglass; life ribosome; lifespan regulation; longevity; longitudinal study; mitohormesis; rejuvenation; weighted gene coexpression network analysis (WGCNA); zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyprinodontiformes
  • Longitudinal Studies
  • RNA
  • Sequence Analysis, RNA
  • Vertebrates*


  • RNA