TY - JOUR
T1 - The Ras-Erk-ETS-signaling pathway is a drug target for longevity
AU - Slack, Cathy
AU - Alic, Nazif
AU - Foley, Andrea
AU - Cabecinha, Melissa
AU - Hoddinott, Matthew P.
AU - Partridge, Linda
N1 - This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
PY - 2015/7/2
Y1 - 2015/7/2
N2 - 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
AB - 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
UR - http://www.scopus.com/inward/record.url?scp=84934434966&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2015.06.023
DO - 10.1016/j.cell.2015.06.023
M3 - Article
C2 - 26119340
AN - SCOPUS:84934434966
SN - 0092-8674
VL - 162
SP - 72
EP - 83
JO - Cell
JF - Cell
IS - 1
ER -