Charles Brenner, Rapamycin and Muscle Synthesis

#1

https://www.twitter.com/CharlesMBrenner/status/1801074509069648233

my hot take is that rapamycin, by inhibiting skeletal muscle mass, will degrade human quality of life >while NR, by lowering inflammation–shown in 7 human clinical studies–will improve human quality of >life

note that old mice don’t die from falls but frail people do

Charles Brenner has a financial itnerest in NR (Nicotinamide Riboside). However, it is worth looking at his criticism of Rapamycin and I found this.

Our results indicate that although neither rapamycin-sensitive mTOR/mTORC1 nor mTORC2 is necessary for contraction-induced muscle protein synthesis, combined inhibition of rapamycin-sensitive mTOR/mTORC1 and mTORC2 synergistically inhibits contraction-induced muscle protein synthesis.

I don’t think any of this surprises anyone. I think it justifies the more infrequent dosing of Rapamycin, but weekly may be OK.

Whichever way it indicates strongly against inhibiting mTORC2.

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#2

I think the one takeaway from this is that Brenner pans everything he does not have a financial interest in.

I tend to ignore everything from him as he is the eternal pessimist. Except for his cash cow NR.

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#3

@John_Hemming I’m sick of Brenner’s constant pushing of NR which is a scam that does nothing that Nicatinamide can’t do for 90% less money. And after listening to Matt Karberlein’s latest optispan podcast I am no longer interested in NAD+. I just blocked Brenner on X so I don’t have to see his BS anymore.

The research study you posted is interesting. Thanks. Your long rapa cycles will prove to be correct I do believe.

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#4

I find Charles Brenner useful as his critiques of David Sinclair’s work have in my view turned out to be correct. I do note his financial interest in NR which to me seems much the same as the other versions of B3.

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#6

I agree but that ship has sailed. Now he just bothers me.

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#7

What is Brenner’s financial interest? Tru niagen?

#8

Moreso Chromadex, but much the same really

I find often I learn more from people I disagree with than from people I agree with.

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#9

Charles Brenner is a doomsday guy who thinks everything doesn’t work and that we should basically have no hope for anything being good for lifespan. I appreciate that he’s helped expose Sinclair but he doesn’t seem to have much else to offer.

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#10

That’s wise. I agree. Still I have to curate my feed of trusted experts to avoid overwhelm. It starts with people who don’t know what they are broadcasting. The second cut is for annoying people who don’t add enough value to be worth the annoyance.

@John_Hemming you are still in my list of people I listen to even if I don’t agree with / understand everything.

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#11

For a quality of life I think nothing really matters for strength except actually doing exercise.

Not protein, not rapamycin, etc.

Exercise and you’ll be strong enough for quality of life. Don’t exercise and you won’t.

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#12

Reading John’s remarks constantly reminds me that the only thing I’m an expert at is knowing how ignorant I am.

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#13

Eating enough protein, especially as you get older is Vital to quality of life.

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#14

I think more relevant than this mouse study is the following human study: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2678224/, “Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis”. This appears to be carefully done, with 15 young (28-29yr) human subjects, 7 taking Rapamycin and 8 as controls, doing the same exercises and getting the same tests. But note that the exercises and tests were done 2 hours after taking a 12mg dose of Rapamycin. For those of us on once-weekly Rapamycin doses, it strongly suggests that exercise just hours after dosing is not a great idea, but as noted in John_Hemming’s original post, I don’t think it says much about the rest of the week. Intermittent dosing is a very important part of the protocol.

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#15

I squint my eyes and try really hard, yet he is so many levels above me in knowledge I don’t understand most of his explanations. :slight_smile:

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#16

The inhibition from rapamycin lasts a while because of the half life being 60 hours.

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#17

But I don’t think you can simply draw a conclusion from the half-life of 60 hours or so. Its really much more non-linear in the first 8 hours after dosing as this graph suggests (below). If the mTORC1 inhibition is proportional to the blood level of sirolimus, then it goes down very quickly the first 24 hours after dosing. I’m going to upload soon an interview with Adam Salmon (of the Marmoset studies with rapamycin at UT southwestern) and we discuss this a bit. (I’m just waiting for Adam’s review and OK of the recording).

I agree with @tahoedenizen and I suspect that the mTORC inhibition after that first day of dosing probably minimally impacts muscle growth / regeneration and protein synthesis after workouts.

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#18

The level of inhibition will depend pretty well on the serum level, which will drive the cytosolic level in cells. That will vary depending upon how close cells are to the blood stream.

This says Rapamycin (Sirolimus) is a specific mTOR inhibitor with IC50 of ~0.1 nM HEK293 cells.
https://www.selleckchem.com/products/Rapamycin.html

The molar mass of Rapamyc is is 914 grams. Hence 0.1nM is 0.0914 ng/ml. (1nM=914ng/L =0.914ng/ml)

IC50 means when half of the kinases are inhibited. (in those particular cells). However, it would imply a good threshold for activity is 1ng/ml (actually it is going to be active below that level).

The serum level will be higher than that in the cell as well.

I think the surface area of human skin is something like 1.6-1.8 metres.

Hence the doses above are roughly 50% higher than the values.

Say 0.45, 1.5, 4.5, 7.5, 12.

That, however, is not with accelerators.

That gives a rough number of hours for which 50% of the kinases are inhibited as being

3?, 24, 72, 144, 192.
In days
1/8, 1, 3, 6, 8

On the chart above it clearly has a long half life. Rapamcyin is, however, effective at just under nanomolar levels of concentration.

The body has got lots of ways of getting around different parts not working which means inhibition of 50% of the mTOR complexes will not bring things to a total halt. However, it does seem pretty clear that Rapamycin’s immediate negative effects of inhibition last for quite a while for higher doses.

The interesting questions are what the minimum measurement threshold and what the minimum activity level area.

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#19

@John_Hemming This is a good issue to run to ground. Many of us here are using resistance training as a part of a longevity/ Healthspan protocol. I have in the past wrestled with multiple thoughts about doing resistance exercise close to a rapa dose, such as

  • don’t want to break a good habit
  • don’t want to miss out on an enjoyable experience
  • might turn mTOR back up in muscles while leaving the rest of the body with lower mTOR / higher autophagy

The one thing that I still worry about is the possibility that I am injuring myself by doing hard resistance training while unable to respond normally to that stimulus. I wonder if I could be accelerating the breakdown of muscle tissue without a muscle build up reaction from the stimulus.

What do you think, John?

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#20

I don’t think there is any harm from doing training around a Rapa dose. I would just not expect that much of a response, nor would I do any particular endurance orientated exercise.

The issue for me is Rapa preventing new cell growth (be that immune cells or stem cells in other parts of the body).

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#21

I always felt it was important to exercise at some levels while fasting - say 5 days. My general impression is that it preserves muscle - if that stimulus isn’t there then I think one is more vulnerable to muscle being the source of protein for the body. Evidence of that is in the research literature. Certainly the dose of exercise is important. I think rapamycin dosing is similar to fasting but that might be a leap. I have had some calve strains while running recently so I have dropped rapamycin during the recovery out of caution.

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