Add another potential target to the longevity list: this paper in Cell (open access, actually) provides evidence that the well-known Ras-ERK-ETS pathway is also involved in lifespan. This is work in Drosophila, which is one of the usual places to look for this sort of thing.
Figure 6 in the paper proposes a way to tie several longevity targets together – insulin signaling, PI3K/AKT, these current Ras/ERK results, and Aop-Foxo. Do any of these apply to mammals? The authors think they may well:
. . .This role of cAMP/PKA in aging may be conserved in mammals, as disruption of adenylyl cyclase 50 and PKA function extend murine lifespan (Enns et al., 2009; Yan et al., 2007). However, cAMP/PKA are not generally considered mediators of Ras function in metazoa. Instead, our data suggest that signaling through Erk and the ETS TFs mediates the longevity response to Ras. Interestingly, fibroblasts isolated from long-lived mutant strains of mice and long-lived species of mammals and birds show altered dynamics of Erk phosphorylation in response to stress (Elbourkadi et al., 2014; Sun et al., 2009), further suggesting a link between Erk activity and longevity. Importantly, the ETS TFs are conserved mediators of Ras-Erk signaling in mammals (Sharrocks, 2001). Investigation of the effects of Ras inhibition on mammalian lifespan and the role of the mammalian Aop ortholog Etv6 are now warranted.
This work in fruit flies relied on trametinib, an MEK inhibitor used in oncology, and you would have to wonder what its effects would be in humans who don’t have metastatic melanoma. It would seem certain that no one in that position has ever taken it since its Phase I trials (and those must not have been for very long). The authors strongly suggest taking a look at this, and it’s going to be interesting to see if someone takes them up on it.