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

Abstract

SummaryIdentifying 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

Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans

“…Such an approach has previously been employed for the Hnrnpa1 and Hnrnpa2b1 genes where upregulation of the Hnrnpa1 gene or the Hnrnpa2 isoform of the Hnrnpa2b1 gene in mouse hepatocarcinoma cells was shown to cause activation of the RAS‐MAPK‐ERK pathway (Shilo et al ., 2014). This is potentially important since a recent study has shown that activation of the RAS‐ERK‐ETS pathway is a key determinant of lifespan in Drosophila species (Slack et al ., 2015). …”

COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors

“…Cancers with constitutively activated MAPK signaling exhibit elevated ERK-dependent transcriptional output, and inhibition of this output is correlated with a therapeutic response to targeted therapies (10,11). While one characterized mode of transcriptional regulation is direct ERKmediated phosphorylation of transcription factors (12)(13)(14), other mechanisms that dynamically couple ERK activity and modulate the nuclear transcriptional output response in ERK-dependent cancers have not been elucidated.…”

Could cancer drugs provide ammunition against aging?

“…5 We found that selective inhibition of signaling through either of these pathways increased longevity. Moreover, direct genetic inhibition of Ras or Erk extended lifespan through activation of the E-twenty six (ETS) transcription factor, Anterior Open (AOP).…”

“…5 Hyperactivation of the Ras oncogene is believed to be responsible for around 30% of all human tumors. The Ras proteins function as small GTPases, cycling between inactive GDP-bound and active GTP-bound states to transmit signals from receptor tyrosine kinases (RTKs).…”