The medications you have sponsored are among those with the highest expectations in the forum. These results seem to contrast with rapamycin, which has always had favorable results.
Your contribution seems very valuable to me, you have invested a lot of money, thank you very much for sharing.
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Really interesting - thanks for posting. I find the shape of the curve of Depagliflozin interesting when compared to the other flozins.
All in all rather disappointing, but interesting to see. Given the results in mice, I guess this just drives home the point that c.elegans is not a perfect model organism for predictive outcomes in longevity?
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Neo
#64
I think it depends what mechanism one thinks the longevity pathway one is interested in works through
For instance, if it works through something very conserved like mTOR then worms and most organisms might be helpful
If one is looking at something like SGLT2i that has the bulk of its effect via the kidneys, then one probably would want to look at a species that actually has kidneys?
Said differently a negative effect of mTOR inhibitors in worms might mean something. A negative effect of a kidney focused drug tested in an animals without kidneys most likely is simply not a signal either way.
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AnUser
#65
Having kidneys would help in a model organism, but they are all not so very good either way. It says more of the model than SGLT2i.
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Neo
#66
On the other hand (while we, including I, expect it to be positive) we do not have human data on health span and longevity in healthy individuals from rapa.
There is nothing that says that the only way to increase human longevity is to limit the search for mechanisms that have stayed conserved through billions of years of evolution.
We are human after all. Complete longevity will have to solve things that humans / higher primates / mammals have, that worms and flies do not have.
For instance, we need to ensure that our neocortex stays young and healthy which is something that worms and flies do not have.
See also my most recent post above about worms not having kidneys. But human longevity will require optimized kidney health.
We cannot only look for our keys under the lamp light (non human model organisms), but should look anywhere they keys (human longevity interventions) could be. Including via human Mendelian Randomization studies, hypotheses obtained from human clinical trials from compounds used for other diseases in humans, etc, etc.
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adssx
#67
I want to sponsor the following:
- Semaglutide
- Selegiline
- Obicetrapib
- Urolithin A
Ora Biomedical don’t have them in stock. They told me to find the references among these “reputable chemical suppliers”:
I’m not sure how to choose between the various forms. Can anyone help?
For selegiline, there are the following options: are they all the same?!
Obicetrapib seems only available here: https://www.sigmaaldrich.com/GB/en/product/targetmolchemicalsinc/ta9h98772346?context=bbe
Semaglutide: which one is the oral formulation (and not the injection form) between these:
And can we assume that these Urolithin A products are equivalent to Mitopure?
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It may be dose, type of animal or both:
- Male mice live longer on Cana, where female mice live exactly the same - female mice and male mice have 1% different DNA from each other and 70% different DNA from worms
- Dose is hard to predict - in NIA ITP they measure drug blood levels in blood before giving a drug - and when they test different doses, they still don’t know what dose to choose (when Resveratol was asked what dose to test to humans to scientists working with Resveratol, they gave 1000x different dose)
- Changing even one, single gene of mice can change lifespan effect of drug in mice - even for Rapamycin (Rapamycin shortens lifespan of GH KO mice where it extends lifespan of mice in 90% of normal mice strains)
2 Likes
Related - on the top compound, GSK2126458 , well done @Krister_Kauppi
First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor Malignancies
These results highlight the need for more effective biomarkers to predict which subset of tumors are highly dependent on PI3K/mTOR signaling for proliferation and therefore more likely to respond to targeted PI3K inhibition. Without such biomarkers, the clinical development of targeted PI3K/mTOR pathway inhibitors will be hindered.
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adssx
#71
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So it seems like the best are:
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- mTor inhibitor (GSK2126458)
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- Berberine
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- Punicalagin
Other:
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- Other mTor inhibitors failed (probably too low doses, maybe 6-15x higher dose would work - from what I remember, dose for lifespan extension was 100uM - 6.67x times higher, for other Rapalogs it could look different)
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- Acarbose failed (maybe 100-200x higher dose would work, in NIA ITP dose for lifespan extension was 71x higher than dose for Rapamycin (1000 ppm vs 14 ppm) - but it may differently translate to worms)
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- Canagliflozin : probably 20x higher dose could work - but it works only in male mice - so lifespan effect may be not conserved
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- Also statistical error may be about 7% of lifespan (and biological error can be even larger - sometimes placebo lives shorter or longer without any reason, even in NIA ITP)
There are only 72 entries - Wormbot probably tested 100x more (database only shows community-sponsored drugs - without company-sponsored drugs)
4 Likes
AnUser
#73
It is not sodium salt or acetate version:
Additionally, FDA has received reports that in some cases, compounders may be using salt forms of semaglutide, including semaglutide sodium and semaglutide acetate. The salt forms are different active ingredients than is used the approved drugs, which contain the base form of semaglutide. The agency is not aware of any basis for compounding using the salt forms that would meet the FD&C requirements for types of active ingredients that can be compounded.
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It seems to work very similar to Rapamycin and other Rapalogs - even with the same side effects:
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GSK458:
The most common grade ≥3 treatment-related adverse events included diarrhea (8%) and skin rash (5%). Pharmacokinetic analyses demonstrated increased duration of drug exposure above target level with twice daily dosing. Fasting insulin and glucose levels increased with dose and exposure of GSK458
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Temsirolimus:
There is a significant risk of developing skin rash and stomatitis in cancer patients receiving temsirolimus
The overall incidence of high-grade rash was 3.3% (95% CI: 1.9–5.6%), with a RR of 13.70 (95% CI: 0.82–227.50, p = 0.07).
It seems like all mTor inhibitors can have the same side effects:
- Diarrhea
- Skin rash (also canker sores)
- Headache
- High glucose
Everolimus, Rapamycin, etc also have the same side effects (probably mTorC1 may be related to wound healing.
Diarrhea and headache are side effects that are often in all drugs)
3 Likes
Neo
#75
What do you think the mechanisms would be in worms, something with sirtuins or just a version of AmPK up/mTOR down?
As mentioned above worms do not have kidneys and they do not have SGLT2 to inhibit.
Neo
#76
Yes agree. 
And is the No 2 from our forum member @AmyK ?
3 Likes
I wonder what berberine does in a worm? C elegans eat bacteria. In Ora’s lab they are only fed 1 kind of bacteria so diversity isn’t an issue.
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Neo
#78
The controls in mine where also shorter lived controls than in most of @adssx experiments
No signal in this configuration for Dimethyl fumarate
Would be interesting if they could report maximum life span and not just median
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Neo
#79
From what is conserved across evolution one pathway could perhaps be a version of our common favorite AMPK up/mTOR down?
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I see on their website it states “Ora has already identified one that works better than rapamycin. How much better can we get? It’s speculation at this point, but our preliminary data lead us to believe that combinations of 2-5 different longevity interventions have the potential to be twice to ten times as effective as the current best-in-class.”
What compound are they referring to - the GSK compound mentioned above?
1 Like
