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Another Longevity Target

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.

9 comments on “Another Longevity Target”

  1. Slicer says:

    Don’t mean to rain on everyone’s parade, but as Reason from Fight Aging! points out, this sort of basic “messing with metabolism” that has profound results in fruit flies and (occasionally) mice generally does exceptionally little for human beings and other long-lived species. Anyone remember sirtuins? Resveratrol?

  2. gippgig says:

    We still have too few of the pieces to assemble the jigsaw puzzle of aging, but that could soon change – and when it does, all @#$% will break loose.

  3. steve says:

    Even if it works there are major hurdles with ever getting an “anti-aging” drug to get FDA approval. You’re talking about a drug that would be taken over the course of decades by a healthy population. Even if FDA would consider allowing such a drug to go through clinical trials the safety data that would be required would be enormous and way beyond the reach of any pharmaceutical company. Moreover, getting the efficacy data would mean a clinical trial that lasts over multiple lifetimes. This is just an academic exercise that will never get translated into an actual drug.

  4. Jeff says:

    There’s a separate problem as well and that’s the sociological impact of such a drug. Can you imagine if such a thing was viable today? The profound impact it would have would FORCE a serious reconsideration of the entire regimen. Frankly, it’s hard not to see more socialist countries flat out counterfeiting the drug and giving it away as a right to their citizenry…
    I’m skeptical that, as these drugs get more and more realistic, that the drug companies will ultimately follow through…

  5. Slicer says:

    Jeff, have you forgotten that the executives and shareholders of drug companies, no matter how penny-pinching they may be, are also human beings with the same ultimate fate as the rest of us unless they do something about it?

  6. cancer_man says:

    So how far off will Kurzweil be that we will see a mouse that doesn’t age past the first year by 2019?

  7. steve says:

    Probably a bit off but we can also cure cancer in mice.

  8. Paul says:

    Sounds to me they simply found the mechanism by which caloric restriction diets work to extend lifespans in mice. So… we can now affect the same life extending results without the dietary restrictions? These diets haven’t been shown to work in humans, but it could just be that the experimental setup for human testing was not optimal to show effects.
    ¯\_(ツ)_/¯ not too excited about this one

  9. annonie says:

    In working on oncology, even Phase 1 is often not done in normal volunteers…so with the MEK inhibitors, data with patient without disease is unlikely to be available.
    Further, with one major company that followed up on the caloric observations, there were safety issues in animal studies.

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