Ora Biomedical and the Rapamycin Longevity Lab have launched a project to screen more than 600 mTOR inhibitors in the hope of finding some that are superior to geroscience’s poster child, rapamycin.
One found, 600 to go
The newest Ora’s project is a collaboration with the Rapamycin Longevity Lab led by Krister Kauppi. It entails screening more than 600 mTOR inhibitors to find the ones that work best.
“Currently, rapamycin is considered the gold standard longevity intervention – it works across many animal and even non-animal fungal models,” said Ora CEO Mitchell Lee. “The mechanism of mTOR inhibition has seen extensive development in cancer therapeutics. There’s a broad toolkit of mTOR inhibitors with different patterns of inhibition between mTOR complex 1, mTOR complex 2, and impacts on other kinases. Nobody has comprehensively looked to see if any are better than rapamycin.”
The current project began as a smaller partnership within the Million Molecule Challenge when, in an experiment funded by Kauppi and the Rapamycin Longevity Lab, Ora discovered an mTOR inhibitor that was superior to rapamycin in worms at the same dose. This molecule, called omepalisib, has already been approved by the FDA for treating certain types of cancer, so its way to the clinic as a geroprotector (anti-aging drug) might be relatively short.
Be a part of new longevity discoveries by helping out in funding $100 to the largest lifespan analysis of 601 mTOR inhibitors. Thanks to this project we will deliver a big magnitude of unique data to the longevity field. We will also most likely discover mTOR inhibitors that are better than one of the most promising longevity compounds which is Rapamycin. We only need 250 funders who contribute with $100 each to be able to start the first sub project. So let’s together start moving this field forward! You find the link to the fundraising page below. If you can’t contribute financially then one other way is to help out in spreading the word about the project. Every bit of support counts!
Big thanks for highlighting this project! The latest update is that we currently need 167 people who donate 100$ each to get things started. So step by step closer but very frustrating that it goes so slow forward. I’m constantly trying to contact different companies and organizations to see if they can help out. If someone stumbles upon someone who may be interested please reach out. All help is appreciated. I also want to point out that I’m not taking part in any provision or commission for the money which is donated. I’m doing this fully on a philanthropic basis.
@KarlT Rapamycin Longevity Lab discovered a new dual PI3K/mTOR inhibitor, GSK2126458 (also known as Omipalisib, in January this year which may be better than rapamycin. The lifespan experiments that Ora Biomedical has done on worms showed good lifespan effects. These results were also reproduced by a lab in Europe. This or next week Rapamycin Longevity Lab will initiate studies in flies to see if the lifespan effects also translate to these species. If that is the case then the goal is to send in a proposal to the ITP next year and test if it also translates to mice
Regarding your question then I would guess that we will find better mTOR inhibitors if we start to look upstreams of mTOR. The below image is a rough image of different direct and indirect mTOR inhibitors.
Am I wrong when I say that I only see relative new substances?
For me this implies no big safety record in humans and unlikely to be affordable for persons with a small budget.
Big pharma will walk away with the big money…
@John_Hemming This is a great question, John! If we look at the ITP (=Intervention Testing Program) setup then they start with looking at lifespan and if they find promising interventions that results in lifespan extension then they start a new project where they do deeper analysis around healthspan improvements. This way they can keep their experiments very cost-effective but one risk is of course that they miss out compounds that increase healthspan but not lifespan. I think that is one risk now in the beginning we need to take because the goal is to find compounds that both increase lifespan and healthspan and not just healthspan.
If we also look at rapamycin then it results in good life extension in multiple species. So it would be great if a new promising mTOR inhibitor, which is better than rapamycin, would be able to do the same but with better results. If we look at for example the dual PI3K/mTOR inhibitor GSK2126458 then it looks good in worms.
But we need to get great results also in at least flies and mice. The flies experiment will start very soon and the mice experiments will hopefully be approved next year by the ITP. If the lifespan data is better than rapamycin then I think this increases the chances that we may have found something that we need to study more and push eventually to clinical trials.
Curious question, what’s your view on the topic when it comes to finding a better mTOR inhibitor than rapamycin?
@Karel1 You are fully right that these initial studies are not intended as data for people to start directly prescribing or self-experimenting with these compounds. The experiments in this project will be done in worms and let’s say we find 10-50 compounds that are very interesting then we test them in other species like flies, mice etc. After that we can start taking steps into clinical trials. The goal with this project is to start moving the longevity needle and not just settle with the known compounds we have in the field. If we want to live very long and well then we really need to start exploring things outside the known and push the field forward. That is one key reason why this project is so important. To push things even further then if we look at Rapamycin Longevity Lab then we will focus on engineering combination therapies in which we use the next generation of mTOR inhibitor as a base ingredient in these longevity cocktails. Below is a rough roadmap on what my lab’s mission is. If this is possible to achieve no one knows but together with other people I will do what it takes to see how far we can reach.
I wonder myself if a shorter half life would be better for humans. The difficulty really is that there are lots of questions
a) How effectively does it inhibit mTOR
b) What else does it do
Hence that leads to any questions of side effects. Much of what Rapamycin does both positively and negatively comes from inhibiting mTOR.
It may be that it doesnt have any other major mechanisms.
It is sad that we don’t have answers to these basic questions. My guess which I more and more lean towards is that individualized protocols is most likely the best approach. I have tried to lift this up in some of the talks and interviews I have been giving. Because what is best depends on many factors and by creating some kind of way to find the sweet spot here in an easier way I think is the thing that will give the best effect. In some situations we don’t want to inhibit mTOR like after a surgery. So here it would be really great if we could have some kind of overall metrics which could give guidance. If I have started sketching on one and I’m working on an updated version. Will try to publish it soon. My guess is that if we would also use a similar overall metric in for example mice lifespan studies, but of course adapted to that species, then we would be able to extend lifespan even more than we do today with rapamycin. Because I don’t think for example that it’s optimal to take high doses of rapamycin when the mice are close to dying. It’s like a weak human is lying in a sick bed and that person doesn’t have a long time to live but despite that we continue to give rapamycin to that person. I’m skeptical if that is the right approach. If we are in a weak state then activating powerful catabolic processes is most likely not the best way to go. But this is just my guess and it would be very interesting to test this hypothesis out.
I think the hard question is working out when you need to ensure mTOR is not inhibited. You are welcome to republish my results published on this forum from a single high dose.
I am a bit put off by the high costs charged by so many antiaging docs. It feels predatory.
But… I found 2 new sources to share.
Agelessrx.com is offering a simple and affordable monthly fee model for sirolimus among others.
And mobilecarehealth.com - a telemedicine company that I initially used for GLP1 meds, is preparing a sirolimus protocol. Their pricing seemed a bit high for the GLP.1s so I will be curious to see what they charge.
If they are doing a compounded version of rapamycin I would avoid it. There have been many problems with bioavailability of the compounded rapamycin efforts.
AgelessRx offers both the compounded and non-compounded (generic) forms.
Compounded form is more economical. We account for the reduced absorption by increasing the total dose.
I personally take compounded, 15 mg per week. My sirolimus levels are comparable to somebody taking 4 to 6mg of the generic.
I found that the generic 6MG per week was too strong for me caused side effects such as fatigue and canker sores. Probably because I’m taking other things like metformin, and I’m still in my 40s.
Clinically, I don’t have a strong preference on which one patients take. The generic form is more expensive, but is “tried and true”. But I’m confident enough in the compounding version that I take it myself
