@Krister_Kauppi another potential compound , a PAM mTOR inhibitor:
- In December 2023, Celcuity presented data from nonclinical studies evaluating gedatolisib and other PI3K/AKT/mTOR (PAM) inhibitors in breast cancer cell lines during a poster session at the 2023 San Antonio Breast Cancer Symposium (SABCS). In a panel of breast cancer cell lines, gedatolisib was found to be more cytotoxic and at least 300-fold more potent, on average, compared to the single node PAM inhibitors.
https://www.globenewswire.com/en/news-release/2024/03/27/2853589/0/en/Celcuity-Inc-Reports-Fourth-Quarter-and-Full-Year-2023-Financial-Results-and-Provides-Corporate-Update.html
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Berberine is another HDAC inhibitor.
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It was a surprise, but in my opinion with a million molecules, someone must sponsor the ones that are completely a mystery. The fact that not all CCBs have an impact on the lifespan of worms is that there are unknown targets of some CCBs.
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@Krister_Kauppi will you submit GSK2126458 to the ITP?
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One plan is to screen 200 mTOR inhibitors this year to find better ones than Rapamycin. So based on that results we can write some interesting ITP proposals on the best mTOR inhibitors. My guess we will find some interesting ones.
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@Krister_Kauppi Have you thought about submitting a proposal to Hevolution?
They plan 115 mln $ for longevity research - maybe it would be possible to get some money for grant:
https://hevolution.com/
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I had some contacts with them but the focus on supporting human clinical research so we will not get help from them in the initial stages of the research but we could get maybe grants from Impetus Grants (https://impetusgrants.org) and Hevolution grants money to them. We will need all the help we can get to finance the early stage of the research. The really nice thing is that it’s not so much money that is needed. For the screening of mTOR inhibitors in worms we need 60k and that is nothing for the big magnitude of valuable data which we will deliver to the field. I think that will be the first project to do. But first before we start scaling things we need to understand why Rapamycin lead to decrease in median lifespan. After that we can start scaling things 
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It seems like the combination of Rapamycin and Taurine had no significant effect on lifespan. Very curious.
Why isn’t Rapamycin prolonging the lives of these nematodes?
Well, at least it’s not harmful.
Order-8622_Rapamycin-15uM-and-Taurine-50uM_report_final.pdf (428.3 KB)
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It could be that they dont have that good a process of autophagy so increasing it has less of an effect.
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I’ve talked to other nematode / longevity researchers at conferences and they were telling me that its actually quite hard to get rapamycin taken up in nematodes. I forget the reasons why - but its hard. He was asking me if I knew of any ways to increase the bioavailability / uptake in these worms. (You know they’re scraping the bottom of the barrel when they are asking me about worm biology & rapamycin pharmacokinetics.). This is likely why you always see them use Metformin as the default comparison point in many of the Ora Biomedical comparison graphs, and not rapamycin. Its just too finicky.
I wonder if the issue that the nematode researchers have with rapamycin may be more generalizable to other mTOR inhibitors?
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Rapamycin extends lifespan of worms in dose 100uM - 6.67 times higher dose than tested here
When it comes to taurine, I don’t know specific dose, but it requires much higher dose than Rapamycin - so probably 300 uM dose would be more accurate
Also combinations are not predictable - 2 things may extend lifespan separately but not work in combination - taurine is anti oxidant and may cancel autophagy benefits from Rapamycin
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The worms eat bacteria. How to get anything into the bacteria to be eaten is an interesting thought.
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The researcher Jan Gruber who has studied worms said to me in a mail conversation I had with him last week that they also give rapamycin to the bacteria which they then give to the worms. The result is like some kind of double dosing. You have rapamycin on the plate and also on the bacteria that the worms eat.
I’ve started investigating recently how the methodology may differ between different labs when they test rapamycin. This is the current status of that investigation. I’m not an expert in worm research but step by step I’m learning more. If there are any columns that I have missed or some data that is wrong just let me know. All help with this investigation is appreciated
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Josh
#105
The video said their skin is thick and they have to use high doses to penetrate. Ingestion should work at lower doses I’d think.
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One conclusion I’ve come to is that taking rapamycin pills probably requires a lower dose than what is used in animal trials, be it in mice or worms.
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Josh
#107
Why lower dose than mice that get it from their feed? I agree dosing from nematode to human is basically impossible, the video said as much have to use a mammal.
Krister, here is another nematode researcher that you may want to talk to. He has a company that is also doing nematode longevity research (perhaps a little competitive with Ora Biomedical)…
https://twitter.com/dweinkove
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There are updates in the Ora Million Molecule Challenge Data Hub!, mixtures and some more compounds have been included.
https://orabiomedical.com/mmcleaderboard/
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GIven all the stress about Omega 6 it is interesting to see Linoleic Acid in the leaderboard.
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