Last week Ora Biomedical released their Million-Molecule Challenge database open to the public. So now it’s possible to see the results of different interventions that have been tested in roundworms (C. elegans). Thanks to Ora Biomedical’s wormbot technology I’m very happy to announce that the Rapamycin Longevity Lab has made its first important discovery in the longevity field! We have discovered a new interesting and potent PI3K/mTOR inhibitor called GSK2126458. Also known as Omipalisib and GSK458. Currently this compound is the best intervention that has been tested in the wormbot but more research is of course needed before we know what potential it has in other species.
The next project that the Rapamycin Longevity Lab will soon start is to test around 200 mTOR inhibitors in the wormbot. The purpose of this is to try to find even better compounds that have a good longevity potential. Thanks to this project we will in a high-efficient and very cost-effective way generate a big magnitude of unique data around mTOR inhibitors which no one else has done before. This will be the first step to take mTOR inhibitors to the next level. If you are interested in supporting this important project you can just join mailing list on the the lab page here.
From what I can see in the research unlike rapa Omipalisib/GSK2126458 target is the entire mtorc, both mtorc1 and mtorc2. This has been the focus of big pharma cancer pharmacology development in the mtorc ATP/autophagic target. My concern is in the targeted mtorc2 inhibition even if it may have the intial step of increasing the longjevity of some unique worms species.
Good feedback but it’s also important to keep in mind that the mTORC2 inhibition to be detrimental and mTORC1 is beneficial is still a hypothesis. It has some support but it is not validated yet. I will interview the researcher Dudley Lamming probably later this year and we will then discuss this more in detail. If I don’t remember it totally wrong it was he who founded this hypothesis and is a proponent of it. Another proponent of it is the researcher Joan Mannick. One potential bias in this area may be because they have conflicts of interests in the area. So that is also good to keep in mind. I like both but I think it’s important to not get blind and be humble in the field
I think for other mTor inhibitors, that failed here, dosage could be higher - I think the best approach would be to compare dosage for Rapamycin / GSK2126458 / other mTor inhibitors (from studies in humans or from mice / worms) and then use that dose to worms
Rapamycin was tested here at 15 uM - usually the best dose for worms for lifespan is 100 uM (6.67x higher)
Everolimus: hard to say dose in worms - but in humans it usually needs 2x higher dose than Rapa - so probably 200 uM for worms
Other mTor inhibitors: I would aim for dose about 100 uM (the same as Rapamycin, ideally with dose response - like NIA ITP - if it will work, then 3x higher or 3x lower dose) if there is no data about dosage
Also it would be interesting to do GSK458 with combination with other drug - for example with Rifampicin or Allantoin
In this clip Mitchell Lee, the CEO of Ora Biomedical, talks about why Rapamycin and other rapalogs are not working as expected. The problem is due to problems with crystallization on higher doses.
This is something I’m really trying to understand more around and compare how different methodologies differ between labs. Here is an overview I started working on this week. Let me know if there are some columns missing or anything else. All feedback is welcome!
