"....the upper limits of rapamycin?...The more important question?

The more important question?

At what level in the blood stream of humans is best to effect mTOR1?

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@ Joseph

Even more importantly (and the only importance I would argue) is…CELLULAR.

There are many agents where blood markers that have very POOR correlation with cellular.

Example, magnesium (perhaps a poor one). My doc has been trying to get me to increase my “blood” level of Magnesium for a while. The more I take, the less my blood marker moves.

I did a deep dive, and there is almost no correlation between blood and tissue.

Without going back into the literature on mice (likely lots of data) and humans (likely much less), I believe there is some strong connection between the two, but I don’t know the CURVE between blood and cellular. Of course they measure proxies for Rapamycin, namely, phosphorylation of p70 S6 kinase.

The mTOR activity measurements may be used to show in vivo inhibition in renal allograft patients during everolimus treatment and to study mTOR activity in various (tumor) cell types.

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I post this in another thread on this forum

In my opinion the best way to measure would be;

Non-invasive measurement of mTORC1 signaling with 89Zr-transferrin

The real issue would be cost, all is off the shelf equipment, Not covered by insurance

A PET scan as in the published would cost around $3,000. per scan

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FWIW…Just a comment of the above, if you are taking Mg orally try magnesium orotate{should be fully reacted magnesium orotate, not just mg mixed with orotic acid]

The only brand I know that is fully reacted magnesium orotate is Cardio Mag 2.0 by AOC{Advanced Orthomolecular Research] have used this magnesium orotate for several years.

Another way to increase mg, IV with magnesium chloride{not magnesium sulfate] the magnesium chloride works much faster. Have done this dozens of times in my life.

Thanks for the suggestions. I take liquid magnesium chloride. I put it into empty veggie caps, as it tastes like battery acid. I know it’s crossing the blood brain barrier, it knocks me out at night.

But even studies where they controlled for magnesium dose, the correlation with blood was very poor, almost meaningless. < 1% magnesium is stored in blood, rest is sequestered in cells and bone marrow.

FWIW…Mg is used in over 300 enzyme reactions in humans

I know it’s critical importance, why it’s a top supplement for a long time. I am quite sure I am loaded with magnesium…it just doesn’t show up on blood tests.

Which is your original post query…what do we really know about mTOR/blood/cellular impact of any blood Sirolimus level? That’s why other tests from other tissues (liver, kidney) are also very important proxy markers for us laypersons, outside clinical access.

Sadly, this is one area where it doesn’t seem we know much. In the mouse studies they dose every day at high levels with rapamycin, so obviously mTORC1 and mTORC2 are highly inhibited over time… and we lack the human data since the studies have not really been done on healthy populations.

It seems we are trying to understand a couple of questions related to mTOR and rapamycin in an anti-aging application:

  1. What is the optimal level (or inhibition level and schedule) for mTORC1 inhibition for maximum lifespan extension.
  2. What is the rapamycin dosing level and schedule (at a personalized level) that achieves this type of mTORC1 inhibition profile?
  3. What exactly is the timeline/dosing/schedule for Rapamycin’s impact on mTORC2 inhibition and how does that increase map to the individual’s optimal dosing with regard to mTORC1… , so in other words what is the rapamycin dose and schedule that is optimal for life extension while balancing the immune suppression risk due to mTORC2 inhibition.

We may be getting close to point 1 for mice in lab environs, but the rest are all areas where we need more research, it seems.