#21

The risk of adding one supplement/drug to another, to another … each with independent sensible evidence, but in isolation is a serious problem. We saw the same thing AKG and NAD boosting medications simultaneously dosed with the wormbot.

It’ll be an unfortunate irony when many of us end up finding out that we are taking things that when taken together net us zero or harm, when had we simply been more limited in what we take, we’d have had benefit.

This is the worry with stacks like Bryan Johnson takes … each for a good reason … but might have a net of zero when had he just taken 5 items, carefully selected, he’d been way better off?

I’m continuing to decrease the number of things I take, or taking something for a short duration for a really specific reason, or cycling rather than having a stack of things all the time.

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#22

For targeting the brain the high peak dose approach may be a way to overcome the BBB yet another approach (for animals) is discussed in the topic Intranasal Rapamycin Lessens Alzheimer-like Cognitive Decline in a Mouse Model of Down Syndrome - #6 by MAC.

The effects that we look for require different plasma levels for different organs early research in marmosets has shows. Fat tissue getting lower concentrations then other at the same plasma levels. Most likely because intracellular processes negatively influence binding of rapamycin to mTor1 I suppose

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#23

This is why I like to start with a mechanistic thesis. It allows at least a thought as to what have synergistic and what have antagonistic effects.

Also I tend to run with a configuration to end at a point when I do another blood test. That allows me to compare weeks and retry configurations that seem to have better outcomes.

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#24

I can find no studies, but we deduce that it has an effect because
taurine is an amino acid derivative, and amino acids are known to influence mTORC1 activation.

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#25

I have been wondering about the efficacy of rapamycin dosing similar to the dasatinib + quercetin. Any thoughts on higher dose, monthly rapamycin protocol?

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#26

I don’t have enough information in your question to answer it. What is a higher dose? What is the “dasatinib + quercetin”?

#27

See:

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#28

Not all amino acids, specifically branched chain aa appear to have the predominant affect on mtorc1 activation. Not sure where the statement that taurine activates mtorc1 derives its basis, it’s not a branched chain amino acid. Does someone have a reference?

#29

Perhaps this one:

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#30

I prescribe Sirolimus for my patients in our Longevity Program. I have them check a blood level 90 minutes after ingestion. I am satisfied with a blood level in the upper quartile of the therapeutic range.
I think the conversation would be more meaningful if it was based on therapeutic blood levels after dosing rather than relying on ‘feelings’ and symptoms only.

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#31

Taking blood levels is always the best. However, not everyone in the world has access to this. It would be better to use blood results to determine the ideal dosage. However do we know the blood concentration of Rapamycin that will guarantee longevity?

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#32

Where did the “therapeutic range” come from?

I’d be interested in knowing if I was taking too little to do any good. However, I wouldn’t take more, I’d quit all together if I knew I needed to take more. The side effects would be too great. But I already am getting some short term health benefits (allergies gone, fewer illnesses, no joint pain)

I’d be interested in knowing that I’m taking too much to avoid damaging my health. I am tracking my blood markers frequently for such evidence but I’d rather use the therapeutic range to tell me that, if it can. I didn’t think anyone knew enough about rapamycin for such a test to help me.

What can you tell me?

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#33

This would seem to be the key question.

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#34

My understanding is you want a rapid high peak of Rap, then a rapid fall with minimal AUC… because of this I don’t use olive oil any longer when I take my Rap so as to minimize AUC which a fatty meal seems to enhance.

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#35

90 minutes post ingestion doesn’t even fully represent absorption, let along tissue redistribution into a pretty large Vd for this drug, then what about T1/2 which would be totally different based upon what it was taken with. Where are the upper quartiles of therapeutic range for 90 minutes available? I’ve never seen this, and would genuinely like to understand the pharmacology of how such a range would be established, given that the AUC or duration over a therapeutic range to generate mTORC1 inhibition would be the most relevant target from a pharmacology/pharmacokinetics standpoint.

@RufusDawes This isn’t a Rapa specific item - it is almost all orally taken drugs - the efficacy and toxicity of the drug however relates more to duration above a given threshold that is biologically active. The high peak is pretty much everything – e.g. Tylenol - peak at 45-60 minutes - huge levels … then not much by 4 hours … it is all tissue redistribution … usual and expected stuff. Depends on the Vd and T1/2.

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#36

Probably worth a comment on turnover of cells. Nerve cells (neurons) are not replaced. For example, the sciatic nerve is formed in the embryonic stage of our life and lasts (hopefully) our whole life. Glial cells try to keep the neurons healthy, but the actual neurons don’t reproduce. Also, for me (a new rapamycin user) despite a BMI of 22.8, my blood sugars run high. I started using a CGM when my A1c rose to 5.7. My excursions were way too high and my fasting baseline > 100. I started metformin (1000mg each evening) and it dropped my fasting about 8-10 points. Then after months, I started rapamycin and my fasting BS went back up by 8-10 points. Metformin was no panacea in controlling my blood sugar.

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#37

You may want to try an SGLT2I like empagliflozin.

#38

The rise in BS again is disappointing. I’ve noticed mine creeping up and was considering Metformin also. Any others on metformin find it has reduced effect while on rapamycin?

#39

For me, 500 mg of daily Metformin reduced my HBA1C from 5.7 to 5.4. It’s enough to keep me out of pre-diabetes.

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#40

I agree. It is a cost issue in US, but offshore isn’t. Especially in older individuals, the sarcopenia risk isn’t good w metformin, and an SGLT2 agent is looking much better to me.

I don’t see decreased efficacy w metformin, but expect many on Rapamycin will have worse insulin sensitivity. I anticipate this and usually don’t start Rapamycin without also having hypoglycemic and hypolipemic agents added.

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