Abstract
SummaryIdentifying 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
Highlights
Ras proteins are members of a superfamily of small GTPases that transmit signals from cell-surface receptor tyrosine kinases (RTKs) to activate multiple downstream cell signaling pathways (Schlessinger, 2000)
We examine the role of Ras and its downstream signaling effectors, extracellular signal-regulated kinase (Erk), and the E-twenty six (ETS) transcription factors (TFs) during aging in Drosophila
By binding to Grb2/Drk protein—which in turn acts as an adaptor for the Ras guanine nucleotide exchange factors (GEFs), SOS—insulin receptor substrates (IRS) proteins recruit activated Ras to the activated insulin receptor
Summary
Ras proteins are members of a superfamily of small GTPases that transmit signals from cell-surface receptor tyrosine kinases (RTKs) to activate multiple downstream cell signaling pathways (Schlessinger, 2000). Ras proteins are molecular switches that cycle between an inactive GDP-bound state and an active GTP-bound state, the balance of which is determined by the competing activities of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) (Goitre et al, 2014; Stephen et al., 2014). GTP-bound conformation, Ras has high affinity for numerous downstream effectors of RTK signal transduction pathways, including Raf, thereby activating the extracellular signal-regulated kinase (Erk)/mitogen-activated protein kinase (Mapk)-signaling cascade and the p110 catalytic subunit of the class 1 phosphatidylinositol 3-kinase (PI3K), leading to activation of the PI3K-Akt-signaling cascade (Goitre et al, 2014; Stephen et al, 2014). Involvement of Ras in determining metazoan lifespan awaits direct confirmation, as RasGrf has affinity for several other ligands, including Rac, Rho, microtubules, PI[4,5]P2, and fasfatidic acid (Mirisola and Longo, 2011)
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