#21

Randomized, clinical trial, good team, good journal:

mTOR inhibition improves immune function in the elderly

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

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#22

On the one hand it is an immunosuppressant, on the other hand it might improve immunosenesence. I think it would be wrong to say it is either or in general. It is in my opinion most likely suppressing the immune system short-term but could improve it long-term.

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#23

Yes, that is my point and thought you were ending more in suppressant only direction.

We agree, all good.

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#24

No, no I have read the Mannick 2014 paper.
They also take a break from rapamycin I guess to enjoy the benefits?

But it is still true that rapamycin is an immunosupressant.

#25

When taken daily at higher or at least moderate (by most measures) dosesā€¦ which is a different dosing protocol that is typically used for longevity purposes.

#26

Matt got a bacterial infection on Rapamycin that required use of an antibiotic. An infection that could lead to sepsis if untreated. And he has only taken antibiotics twice in his life. It canā€™t be a coincidence this happens just as he starts this protocol this time, with the other evidence suggesting it is an immunosuppressant in general.

Do we even know that 5 mg a week doesnā€™t suppress the immune system? What does the distribution of responses look like?

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#27

I suspect that while under high levels of MTORC1 inhibition, one does have some decreased ability to protect oneself against bacterial infection.
It is a risk:benefit. The risks, I think are well known, and are minor for most people. The benefits are the struggle, and donā€™t have definitive proof in humans, yet.
The biggest issue with any bacterial infection is to identify that you have one, and treat it early.
Even if a 50% increase in incidence, it is still a rare event, and we donā€™t really know if he had a cut or abrasion leading to this soft tissue infection or some other skin integrity issue there. It may well be related to the rapamycin, or bad luck.
I do give my patients warning regarding bacterial infections when I Rx rapamycin, and Rx a supply of an antibiotic that does a good job with soft tissue infection and pneumonia. Iā€™ve not had anyone need to use the Rx yet.
There is no pharmacological agent I know of that comes with no risks.

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#28

That title is soooo misleading.

They really should say, improved Flu antibody titers in elderly treated with rapa for ONLY 6 weeks with 2 week wash out - thatā€™s improvement in an extremely tiny sliver of the overall function of the immune system in very specific circumstances.

I know that Kaberlein, Attia and others used this study to based their rapamycin dosing. However from everything that I read, it appears that using weekly pulse dosing makes one vulnerable for few days - lowered HRV, fatigue, stomatitis, etc.
I am not sure why they chose weekly, since I didnā€™t see a clear advantage in efficacy or side effects between daily and weekly, but daily was a overall lower dose which for prolonged use could have a impact on side effects.

Interestingly in topical rapamycin studies on skin, the researchers picked daily very low dosing for these reasons:

We chose to use (DAILY) rapamycin at a ten-fold lower dose because the concentrations used in TSC patients are intended to inhibit cell growth, while our aim was to improve cell function while maintaining proliferative potential and preventing senescence similar to our in vitro studies
Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial - PMC

Personally when I decide to use it, I would base my frequency on the very well established regimen of alternate day OCS dosing. The Effects of Alternate-Day Corticosteroids in Autoimmune Disease Patients - PMC
and start with 1 mg PO QOD equivalent dose of 3.5 mg / week just like in the Flu study.

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#29

@Dr.Bart Im not following what frequency you would follow for Rapaā€¦ Longer than weekly? Several people here do 10 or 14 days. I do 14 days with an extra week off after two cycles (essentially 2 doses per month).

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#30

Would a course of Doxycycline or Trimethoprim fit the bill for soft tissue infections or would you recommend something stronger?

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#31

The main issue with this study is that it relies on self-reported data, which can be influenced by the nocebo effect and the perception of rapamycinā€™s immunosuppressant function as the most critical aspect. Side effects are often reported in RCTs involving transplant patients who are typically on multiple medications.

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#32

I usually use doxycycline as it does a reasonable job covering streptococcus and staphylococcus, including most of the resistant ones (MRSA) and probably hits gut bacteria a bit less than some of the other antibiotics. It also does a good job for pneumonia, the other infection that would be most common.
Trimethoprim fails to treat strep, and Sulphamethoxazole with TMP does very well against Staph, but we cannot rely on it for soft tissue infection due to little strep cover - same issue with pneumonia and is going to hit gut flora harder.

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#33

From a mechanistic perspective of anti-aging, daily or EOD as proposed by you makes more sense. Iā€™m also uncertain whether the decision to try pulsed dosing was based on a correct mechanistic understanding of mTORC2 inhibition and the effects of rapamycin. Iā€™ve decided to try a daily dose of 1 mg for three weeks out of every four. Iā€™ve observed that all effects on HRV and fatigue have disappeared. Iā€™m experiencing fewer symptoms related to autoimmune activity, such as dermatitis, rhinitis, and joint pain. Additionally, my inflammatory biomarkers derived from CBC appear unchanged or improved. Over the past year of rapamycin usage, Iā€™ve noticed a decrease in the number of viral infections Iā€™ve experienced - zero, despite exposure to viral infections. I did experience one bacterial infection in this year, which was likely salmonella food poisoning, during a recent trip with my colleagues. However, my symptoms appeared more rapidly, prompting me to start antibiotic treatment early. In contrast, my colleagues experienced prolonged, milder symptoms and eventually required antibiotics as well.

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#34

But still (I shared this a while ago, but seems appropriate ro do it again):

Our results show that immunomodulation caused by rapamycin treatment is beneficial to the survival from acute infection.

Several mechanisms could explain why rapamycin increases resilience against pathogen infection. Immunosuppressive properties of rapamycin could prevent the activation of an overzealous immune response [29, 41]. A more effective immune response could stem from elevated numbers of T regulatory (Treg) cells seen after rapamycin treatment [29, 42]. Treg cells cause immune suppression to maintain homeostasis, for example reducing cytokine production which in turn ameliorates tissue damage [43]. Rapamycin may also improve immune memory [44,45,46], possibly fitting with the trend that secondary infections showed a stronger response to treatment. Rapamycinā€™s ability to reduce the debilitating effects of ageing on a systemic level could directly or indirectly benefit the immune system [47]. It remains to be determined to what degree the life-extending effects of rapamycin are due to its modulation of the immune system.

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#35

It looks like a mice or mechanistic study. I am a human outcomes boi. Youā€™d need a human outcomes study in a clinical trial to prove that rapamycin is beneficial for infection to me.

#36

QOD - every other day,

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#37

Thatā€™s a new one. I suppose youā€™d take a very low dose like 1-2mg every other day. Of course Rapa would be >0 for as long as you took it. No doubt your AUC would be much higher than mine given my ~12mg once every 14 days but my peak rapa would be much higher than yours. Why do you think a continual low suppression of mTOR is preferable to a larger, brief mTOR suppression? I wonder what I am missing?

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#38

That is my rationale aswell. High rapa doses better suppress mTOR which leads to higher autophagy rates.

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#39

With a very low dose QOD do we even get to a therapeutic level? If we do, which I doubt, is there continual MTORC1 (and also C2) inhibition, and if so, is there more risk of sarcopenia and true immunosuppression?
I donā€™t know the answer to that.
I know in one of my patients who is up to 8 mg at a time, the level at 24 hours was just barely therapeutic (just over 3, where therapeutic is 3-18) - so even with that dosing, youā€™d only be in the therapeutic range for max 30 hours, at least per current thoughts on therapeutic ranges.
Iā€™d be pretty confident in that patient, if I did 1 mg QOD theyā€™d never get anywhere into the therapeutic range.
Anyway, itā€™s a gamble as to oneā€™s perspective and theories - but we are in a no-definitive evidence zone here.
I personally think a goal of ~30% of the time under some MTORC1 inhibition then 70% of the time in recovery would be one approach - which in the aforementioned example, I suspect will end up with a dose of something like 11-12 mg q7 days to achieve that.
There are also folks who want a high level and theorize to get maximal BBB penetrance that going for a higher peak level, and then longer intervals might be preferential. I suspect this might look like 20 mg in this individual, but then dosing q10-14 days, based on individual pharmacokinetics.
All this is based upon oneā€™s approach and what they think might be the secret sauce in the dosing and activity and how one should address inhibition of MTORC1 and C2.

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#40

You can measure mTORC1