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

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

Author information

1
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.
2
Institute of Healthy Ageing, Department of Genetics, Evolution, and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
3
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.

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.

PMID:
26119340
PMCID:
PMC4518474
DOI:
10.1016/j.cell.2015.06.023
[Indexed for MEDLINE]
Free PMC Article

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