#41

@Joseph Did you ever figure out cost and process to do that?

#42

If you review the original posting, and paper the test procedure and methods are in the paper.

All items are off the shelf.

You have to locate a PET scanning facility and a medical doctor will to write a prescription.

This is non-standard testing, such as you would pay, not billable to insurance.

#43

Thanks Joseph. Given that PET is invoiced I’ll skip, but thanks.

#44

I laid out my rationale in the post above.
In the Flu titer response study above a they had similar results with 0.5 mg daily dosing and weekly dosing.

So what makes you think that weekly is superior over daily ?

Read the full study and get back to me. Maybe I missed something.

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#45

FWIW he was on a daily low dose, 2 weeks on and 2 weeks off per this tweet:

Screenshot 2024-03-10 at 9.23.32 PM
Screenshot 2024-03-10 at 9.23.32 PM1498×374 72.1 KB

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#46

Well the researchers reached their endpoints by using rapa 0.5 mg daily at 3.5 mg/week, results on par with weekly dosing. So what makes you question the effectiveness of the “low” dose.

https://www.science.org/doi/10.1126/scitranslmed.3009892

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#47

@Dr.Bart I think it boils down to this (from your references paper):

(1) inhibit cell growth vs. (2) improve cell function while maintaining proliferative potential and preventing senescence

I cannot say that weekly (or biweekly) is better than daily (or EOD). That is beyond my understanding, so I cling to the devil I know, until convinced to shift

Reasons to do weekly / biweekly (higher doses with an effort to clear rapa to zero as quickly as possible)

  • it’s what most scientists do
  • it’s what I have done and know the observable effects
  • it’s like periodic fasting vs chronic CR
  • perhaps it allows a higher dose to penetrate the BBB without suppression of mTORC2
  • can use this approach without a rapa holiday (but many still take holidays)

Reason to do daily / EOD (low dose with long cycles of on/off rapa)

  • a few scientists do this
  • a focus on preventing senescent cells from proliferating and/or creating high inflammation (via SASP)
  • perhaps eliminate the acute side effects related to fatigue or other higher rapa doses
  • perhaps avoid mTORC2 suppression by staying very low in mTOC1 suppression even if for longer time periods
  • perhaps avoid the theoretical “rebound” effect on mTORC1

Due to a lack of education on these many topics I am left to (1) watch the behavior of people smarter than me whose incentives / motivations are not contrary to my own and (2) develop mental models which simplify the variables into systems of thought that I can understand (with a danger of being overly reductionist).

For me, I think the choice is similar to choosing between the periodic calorie and/or protein fasting approach or the continual calorie / protein minimization approach.

I think that using rapa to help me create cycles of high vs low mTOR will give me what I want. What I want is to remain youthful in my physical and mental abilities while improving my ability to recover from daily stress and periodic hard physical work.

My situation is important in this decision: I am already a very healthy person with low hsCRP, high muscle mass, and good body composition. My issues are managing stress and keeping blood sugar and apoB down.

A person with a high burden of senescent cells (high inflammation) might have a different priority.

What do you think?

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#48

That’s a lot hypotheses and assumptions. Ask any one of these scientists and they will agree.

I am glad is working for you, I am simply pointing out the dosing and frequency is still far from being set.

Hopefully the RAPID trail will address that. I asked them for a methodology and this the email I got back.

Hi Bart,

Thank you for your interest. We are evaluating multiple doses and frequencies of rapamycin and its impact on periodontal disease. We’re currently under an IND and will be unable to share anything specific until publication.

We intend to provide the general community updates as we proceed along the trial.

Thanks,

UW RAPID Trial Team

Seattle, WA

www.rapamycintrial.com

Dr. Stanfield unfortunately is too limited on funds to run a third arm of dosing. His is weekly dosing - rapa vs placebo.

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#49

I think a person’s pathology is a big determinant. If you are super healthy, then perhaps a weekly dose as it is with Peter Attia. If you have a low-grade chronic condition, then perhaps a daily low dose won’t hurt, perhaps even help, as the mice study from Germany (2024) concluded. The weekly dose is better vs the daily low dose (both with break) was never repeated after Joan B. Mannick, isn’t it?

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#50

…Joan B. Mannick ?

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#51

Yes sorry. In my mind, I call her Joannick :grinning:

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#52

Joseph,

I think your logic is very sensible.

The problem is a low evidence zone here. The article on the 3.5 mg/week has to do with improved immune function as I recall. That is certainly important, but does that come at a different dose and much lower mTOR inhibition than slowing aging?

I don’t know the answer to this.

However, for myself, and the patients whom I advise, I presently am heading toward periods of mTOR inhibition and recovery, and repeat. What ratio of time in inhibition vs. recovery and even how one defines that, and on what basis is a challenge.

I have my approach to this based on logic, but no proof of outcomes. We know it is safe, and my sense is longer term regular daily or every other day dosing is more likely to hit mTORC2 which we really don’t want.

I’m pretty content with my present approach, and in a low evidence zone, it’s in the middle area of those willing to enter.

Myself, I take 8 mg every 8 days. If I’m alive and mentally sharp 50 years from now, I’ll consider it a good call. If I get septic 2 days after a dose and that is my demise … then maybe not the best call.

The more I learn (and I have 4 board certifications) the more I realize how much more there is to learn and how little certainty there is. I used to be much more certain of things 25 years ago.

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#53

Joseph,
I love the reference and wish I had that ability. It would be brilliant to be able to track degree of inhibition in patients, as knowing this, regardless of how someone got there (drugs, fasting, supplements) and tracking mTORC1 and C2 activity and looking at that versus disease/longevity would be amazing.

One day this will have to be done - some pharma company will make a fortune, as they’ll find some proprietary agent better or different than rapamycin to accomplish the outcome.

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#54

What evidence are you basing this strategy on?
Rapamycin selectively inhibits mTORC1 and doesn’t directly affect mTORC2 (as I’ve shared some papers on this topic before). It’s important to note that rapamycin doesn’t act as a simple on/off switch for mTOR. Animal models have consistently shown that chronic rapamycin treatment leads to improved median and maximum lifespan, with higher doses proving more effective than lower ones. Additionally, there’s a possibility of mTOR rebound effect with large intermittent doses, where mTOR activity can temporarily rise above baseline levels after rapamycin clearance. Both animal and human studies have demonstrated enhanced immune function with rapamycin treatment. Considering the hyperfunction theory of aging (which provides a compelling explanation for the aging process), it’s challenging to argue that weekly intermittent dosing is superior. While intermittent dosing may effectively induce autophagy due to the larger doses administered, rapamycin is rapidly metabolized within hours, and its concentration typically decreases below therapeutic levels after 24 hours, despite its long half-life. Thus, it’s questionable whether a few hours of stronger inhibition would significantly impact outcomes. Fasting studies have shown that sustained mTOR inhibition is necessary to stimulate autophagy. Is your perspective on this matter different?

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#55

@DrFraser Thanks for sharing your thinking in this important and complicated question. This is why I am on this forum.

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#56

The “retail cost” in the US is around $4,000 + or - $500 to have a scan.

You do not know a colleague who has access to a PET scanner?

A pro-bono/professional courtesy scan.

Do an N=1/N of 1 “trial/experiment”.

FWIW

“COMPARE PET SCAN (POSITRON EMISSION TOMOGRAPHY) PRICES AROUND THE WORLD”

Country Cost
United States 3460€
Turkey 718€

Above from;

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#57

Thanks for the response. I am basing this on a whole lot of factors. Would I have it rise to the level of “evidence?” I’m not sure it would, as in every other area I practice evidence based medicine and have high levels of evidence for my choices and recommendations.

First factor is that I must make sure that the risk of harm is mitigated. I’m not at all convinced that daily regular dosing of rapamycin is without much more risk. I do know that cyclic rapamycin has a reasonable risk profile, and the long list of potential side effects listed for sirolimus, really don’t occur when dosed cyclically.

I know that Dr. Green’s approach has been cyclic, and he has not had complications, to his reporting, and furthermore has several hundred individuals over many years who are at moderate to high risk of progressing to have dementia (due to ApoE4’s) and have not done so.

Many of my patients have a real worry, often for good reason of neurocognitive decline.

I don’t think it is correct to say rapamycin is rapidly metabolized within hours and its concentration typically decreases below therapeutic levels within 24 hours … it depends upon the dose. This is why I measure this and make sure we are getting a reasonable period of time in what is considered the “therapeutic” area — e.g. >3. Getting a level at 20-24 hrs then repeat in another 48 hours once we are getting levels in the range of 5-6 is a reasonable way to plot an individual’s pharmacodynamics. The single doses tend to have shorter half lives … e.g. 30-36 hrs, but bigger doses, in many individuals tend to head more toward the reported T1/2 on daily dosing which is >60 hrs.

The bottom line is we can go back and forth on theories, which is well worth the time to do. But I need to decide my approach with patients; and safety is first, then proposed efficacy second.

It is a tough area to navigate, as I don’t think we’ll have clear evidence. I will start tracking a number of things in my patients, and hope to get an evidence base - or better yet, have someone else accomplish this in a research setting.

The nice thing on this board is everyone can do as they wish as most are self managing. If you mess things up - you suffer - if you do it right you benefit. At the point I’m consulted as a professional, then I have responsibility - and take on shared decision making, but I do not foresee the situation in which I’d be prescribing daily Rapamycin without a significant amount of new data supporting safety.

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#58

Have some friends … just not the right one for this task!

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#59

Here is Kaeberlein’s pilot study on dogs published in 2017. According to Kaeberlein, dogs are the best proxy for humans because the live in the same environment…

Recently, we carried out a randomized double-blind veterinary clinical trial to assess dosing, safety, and effects of rapamycin treatment for 10 weeks in healthy middle-aged companion dogs. Here, we report the results of this study, finding that 10 weeks of rapamycin treatment at either 0.05 or 0.1 mg/kg delivered orally three times per week did not cause significant clinical side effects or abnormal hematological changes, but did result in favorable changes in cardiac left ventricular function during both diastole and systole.

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#60

There is a great dosing discussion between Kaeberlein and Attia about rapa dosing on this drive episode on dosing chapter.

I listened to this section few times. They don’t provide any compelling evidence of either frequency. It seems that once weekly was popularized by Green. Kaeberlein will be using weekly dosing for his big dog trial to increase compliance.

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