title: The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for Longevity.
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.
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution, and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany.
authors.forename: Cathy
authors.initials: C
authors.lastname: Slack
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution, and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Nazif
authors.initials: N
authors.lastname: Alic
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution, and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Foley
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution, and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany.
authors.forename: Melissa
authors.initials: M
authors.lastname: Cabecinha
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution, and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Hoddinott
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution, and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany. Electronic address: l.partridge@ucl.ac.uk.
authors.forename: Linda
authors.initials: L
authors.lastname: Partridge
mesh_terms: D000375:Aging; D000818:Animals; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism*; D005136:Eye Proteins / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008136:Longevity; D020935:MAP Kinase Signaling System / Q000187:drug effects; D023421:Models, Animal; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: C076188:AOP protein, Drosophila; D029721:Drosophila Proteins; D005136:Eye Proteins; D055504:Insulin Receptor Substrate Proteins; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D012097:Repressor Proteins; C120233:chico protein, Drosophila; C560077:trametinib