The Ras Erk ETS Signaling Pathway Is a Drug Target for Longevity
Summary 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. Video Abstract
Cell