The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for Longevity

Cell. 2015 Jul 2;162(1):72-83. doi: 10.1016/j.cell.2015.06.023. Epub 2015 Jun 25.

Abstract

Identifying the molecular mechanisms that underlie aging and their pharmacological manipulation are key aims for improving lifelong human health. Here, we identify a critical role for Ras-Erk-ETS signaling in aging in Drosophila. We show that inhibition of Ras is sufficient for lifespan extension downstream of reduced insulin/IGF-1 (IIS) signaling. Moreover, direct reduction of Ras or Erk activity leads to increased lifespan. We identify the E-twenty six (ETS) transcriptional repressor, Anterior open (Aop), as central to lifespan extension caused by reduced IIS or Ras attenuation. Importantly, we demonstrate that adult-onset administration of the drug trametinib, a highly specific inhibitor of Ras-Erk-ETS signaling, can extend lifespan. This discovery of the Ras-Erk-ETS pathway as a pharmacological target for animal aging, together with the high degree of evolutionary conservation of the pathway, suggests that inhibition of Ras-Erk-ETS signaling may provide an effective target for anti-aging interventions in mammals.

Publication types

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

MeSH terms

  • Aging
  • Animals
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / metabolism*
  • Eye Proteins / metabolism
  • Insulin Receptor Substrate Proteins / metabolism
  • Longevity*
  • MAP Kinase Signaling System* / drug effects
  • Models, Animal
  • Protein Kinase Inhibitors / pharmacology
  • Pyridones / pharmacology
  • Pyrimidinones / pharmacology
  • Repressor Proteins / metabolism

Substances

  • AOP protein, Drosophila
  • Drosophila Proteins
  • Eye Proteins
  • Insulin Receptor Substrate Proteins
  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidinones
  • Repressor Proteins
  • chico protein, Drosophila
  • trametinib