We need a different mtor 1 inhibitor

[RapAdmin]

You may be entirely right… perhaps all mTORC1 inhibitors eventually inhibit mTORC2. It remains to be seen.

But it is interesting that Joan Mannick suggests that even with ongoing and very high dosing of their new mTOR1 inhibitor they don’t seem to see the lipid and glucose disregulation that is typically attributed to mTORC2 inhibition… I can’t wait to see more data on these compounds from Tornado therapeutics.

[Olafurpall]

That’s very interesting! If true, I wonder what causes that. Maybe the new inhibitor has different absorption in differnt tissues relative to rapamycin. One area that could be improved is tissue specifity. Maybe some new inhibitor is able to more easily cross the blood-brain-barrier or tends to accumulate less in whatever bodily compartments that result in the lipid and glucose dysregulation

[ORRAPA]

The wormbot data seems to suggest glucose issues are specific to Rapa. Berberine boosts the effectiveness of Rapa, but not any of the more effective mtor inhibitors (and seems to be a major negative with them).

[59vw]

Since mtor is present in both mtorc1 and mtorc2 complexes I think one would have to inhibit a downstream effector of the mtorc1 pathway to create an inhibitor that didn’t affect mtorc2.

[Olafurpall]

@ORRAPA

Berberine boosts the effectiveness of Rapa, but not any of the more effective mtor inhibitors (and seems to be a major negative with them).

I’m not aware of that data. Can you post a link to it?

@59vw

Since mtor is present in both mtorc1 and mtorc2 complexes I think one would have to inhibit a downstream effector of the mtorc1 pathway to create an inhibitor that didn’t affect mtorc2.

I agree with that.

[ORRAPA]

Sure. You are going to want to check both multiple and single interventions. https://orabiomedical.com/mmcleaderboard/

[RapamycinCurious]

@Olafurpall

Note that rapamycin given to old mice every 5 days (at a dose of 2 mg/kg intraperitoneally) also appears to increase lifespan, although more studies are needed testing such lower frequency. Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice - PubMed

That result has never been replicated, and there are important caveats to it, as noted here.

@Olafurpall

Importantly, that is a regimen that result in a low through level between doses. Their level is just under 5 ng/mL on day 3 after rapamycin dosing as seen by Figure 1 in PMID: 26463117. That should be enough to reach a low through on day 4-5.

This is a glass mostly full, not a glass partly empty. Three days after dosing, they still have plasma levels similar to transplant patients, and higher than humans 24 hours after taking a once-weekly 5 mg dose.

[Olafurpall]

@RapamycinCurious

That result has never been replicated, and there are important caveats to it, as noted here.

Yes and that’s a shame. I think it’s very important to do more studies on this kind of intermittent regimens that minimize side effects and translate into more realistic regimens for humans to follow. I think the ITP should do studies on rapamycin given every 3 or 5 days or so in mice.

@RapamycinCurious

This is a glass mostly full, not a glass partly empty. Three days after dosing, they still have plasma levels similar to transplant patients, and higher than humans 24 hours after taking a once-weekly 5 mg dose.

Yes, but despite that, the dose was still low enough to not result in significant impairment in glucose tolerance. That is a strong sign that it inhibited mTORC1 a lot while not resulting in a major inhibition of mTORC2. A somewhat equivalent regimen for humans in this respect would be to take a high dose of rapamycin at a very low frequency that does not influence glucose levels significantly, and then reduce the frequency of rapamycin dosing gradually just up to the point at which glucose tolerance starts getting worse. That point would be similar in that it would cause the most mTORC1 inhibition you can get without significant mTORC2 inhibition, which I think is a reasonable goal IMO.

[Samranas]

Does anybody know under which amount of sirolimus in blood (ng/ml) it no longer affects/inhibits mtorc1 much? Is it best to aim for a <0.5ng/ml

I saw a study where people taking 7mg once a week got a trough of about 1.2ng/ml, is that low enough