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

[RapamycinCurious]

@Olafurpall

@RapamycinCurious

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.

Two things. First, whatever you think is going on with the mTORC complexes, the bottom line remains that these mice retained much higher rapa concentrations for many days, which is unlike what happens with once-weekly human dosing.

Second, the study on which you’re basing this can’t be used to draw that conclusion: they only “performed a fasting glucose tolerance test 7 days after the most recent rapamycin treatment of the weekly (1×/7 days) group”. That doesn’t tell you that their glucose tolerance was normal for the 3 or more days at which their plasma levels are still high, or that their glucose tolerance won’t degrade over a longer timeframe.

[Olafurpall]

@RapamycinCurious

the bottom line remains that these mice retained much higher rapa concentrations for many days, which is unlike what happens with once-weekly human dosing.

Yes and I’m not saying this every 5 days for the mice is like once a week for humans, it’s more similar to taking a massive dose every 3-5 weeks for a human. That to me indicates that a lower frequency than once weekly may be a way to get benefits with less side effects.

@RapamycinCurious

Second, the study on which you’re basing this can’t be used to draw that conclusion: they only “performed a fasting glucose tolerance test 7 days after the most recent rapamycin treatment of the weekly (1×/7 days) group”.

Where do you see that they measured it 7 days after the most recent rapamycin dose? It looks to me it was tested after 5 days. The full text states this:

“We assessed the effect of intermittent rapamycin administration on glucose homeostasis by performing fasting glucose (Figure 2A) and insulin (Figure 2B) tolerance tests after 8 weeks of treatment; each test was performed 5 days after the previous administration of rapamycin.”

@RapamycinCurious

That doesn’t tell you that their glucose tolerance was normal for the 3 or more days at which their plasma levels are still high, or that their glucose tolerance won’t degrade over a longer timeframe.

They tested it after 8 weeks of dosing. That’s a very long time for a mouse. While it’s possible that glucose tolerance gets worse after an even longer time, no effects after 8 weeks is very positive.

[RapamycinCurious]

@Olafurpall

Yes and I’m not saying this every 5 days for the mice is like once a week for humans, it’s more similar to taking a massive dose every 3-5 weeks for a human. That to me indicates that a lower frequency than once weekly may be a way to get benefits with less side effects.

That’s one half of the glass: the other half is that since it stays in their blood at transplant dose equivalents for days, it’s like taking large doses every day for weeks. IAC, neither is equivalent to a human taking 6 mg once a week.

@Olafurpall

Where do you see that they measured it 7 days after the most recent rapamycin dose? It looks to me it was tested after 5 days. The full text states this:

“We assessed the effect of intermittent rapamycin administration on glucose homeostasis by performing fasting glucose (Figure 2A) and insulin (Figure 2B) tolerance tests after 8 weeks of treatment; each test was performed 5 days after the previous administration of rapamycin.”

I quoted directly from their dedicated paper on glucose metabolism (which I linked). Five days is closer than seven, but still leaves a void about what was going on while their drug levels were higher on days 1-3.

@Olafurpall

They tested it after 8 weeks of dosing. That’s a very long time for a mouse. While it’s possible that glucose tolerance gets worse after an even longer time, no effects after 8 weeks is very positive.

It’s not very positive — it’s just not obviously bad. And we have the “blackout” interim.

[Olafurpall]

@RapamycinCurious

That’s one half of the glass: the other half is that since it stays in their blood at transplant dose equivalents for days, it’s like taking large doses every day for weeks. IAC, neither is equivalent to a human taking 6 mg once a week.

I never said it’s equivalent to 6 mg once a week. It’s close to equivalent to a massive dose every 3-5 weeks. Alternatively it would also be kind of close to taking rapamycin daily for 1-2 weeks and then take a few week break.

@RapamycinCurious

I quoted directly from their dedicated paper on glucose metabolism (which I linked). Five days is closer than seven, but still leaves a void about what was going on while their drug levels were higher on days 1-3.

I see. I was quoting the lifespan study. That one did not show impaired glucose tolerance 5 days after dosing. That’s good news. Of course that doesn’t mean glucose tolerance is just as good in the first days after dosing, it might be worse, but at least it means it’s not chronically worse. The important takeaway is that it suggests that side effects can likely be minimized while still getting a good chunk of the benefits.

@RapamycinCurious

It’s not very positive — it’s just not obviously bad. And we have the “blackout” interim.

It is positive relative to the alternative, which is taking high dose rapamycin too frequently and suffering from chronic glucose intolerance. I don’t think any of use are expecting to get the same doses as the mice and similarly strong benefits for aging. That would be too extreme. We’re figuring out how to get as close to that as is reasonable while minimizing side effects. Intermittent exposure appears to be the best way to do that.