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

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

Graphical Abstract

Highlights

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  Reduced insulin/IGF-1 (IIS) signaling involves Ras inhibition for longevity

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  Attenuation of Ras-Erk signaling extends lifespan via the Aop transcription factor

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  Treatment with trametinib, an inhibitor of Ras-Erk signaling, extends lifespan

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  Ras-Erk-ETS signaling may provide targets for anti-aging interventions in mammals

Abstract

Ras inhibition is implicated in the longevity that arises from reduced insulin/IGF-1 signaling. In adult flies, pharmacological inhibition of Ras signaling using the Mek kinase inhibitor, trametinib, extends lifespan, revealing a new potential target for midlife anti-aging interventions.