Targeting the Ras-Erk-ETS pathway for longevity
Ageing and the associated functional decline are of growing medical, social and economic importance. Identifying the molecular mechanisms that underlie aging, and their pharmacological manipulation, are key aims for improving lifelong human health. We have recently identified a critical role for Ras-Erk-ETS signaling in aging in Drosophila. Inhibition of Ras is both necessary and sufficient for lifespan-extension downstream of reduced insulin/IGF-1 (IIS) signaling, a nutrient signaling pathway whose effects on lifespan are highly evolutionarily conserved. Moreover, direct reduction of Ras or Erk activity increases longevity. We identified the E-twenty six (ETS) transcriptional repressor Anterior open (Aop) as central to lifespan extension caused by reduced IIS or Ras attenuation. Indeed, Aop and the canonical transcriptional regulator downstream of IIS, dFoxo, overlap significantly at the level of DNA occupancy in vivo, indicating concerted transcriptional output. 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, suggest that inhibition of Ras-Erk-ETS signaling may provide an effective target for anti-aging interventions in mammals.
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Dr Olivia Casanueva
The Brian Heap Seminar Room