Rapamune / Rapamycin/ mTOR

ScottTriGuy

Senior Member (Voting Rights)
Discovered on Easter Island, rapamycin has a unique history and impacts the mTOR pathways in our bodies.

mTOR is like a general contractor in sensing nutrients and regulating homeostasis in all cells.

The chat touches on ME-related things like how mTOR senses ATP, keto diets, methionine, diabetes, longevity.

Fwiw, I've been taking Rapamune, an mTOR inhibitor, since November. Its doubled my capacity: I can now walk up 2 flights of stair in a row.

After hearing the Sabatini interview, I have reduced my daily 1mg to every other day.

STEM Talk podcast: https://itunes.apple.com/ca/podcast/stem-talk/id1091402153?mt=2

From the podcast:

...describes David Sabatini’s discovery of mTOR ...gives us a first-hand account of how his research into rapamycin in 1994 as a graduate student led him to the discovery of mTOR, which we now know is a critical regulator of cellular growth.

Our interview with David delves into his continuing research into mTOR, which has led to promising opportunities for the development of new treatments for debilitating diseases such as cancer, diabetes and neurological disorders. He also discusses mTOR’s role in healthspan and lifespan.

David is a molecular cell biologist who, according to Reuters News Service, is on the short list for a Nobel Prize. David is on the faculty at MIT and heads up the Sabatini Lab at the Whitehead Institute.

In today’s episode, we discuss:
Rapamycin, a macrolide antibiotic discovered in the soil of Easter Island David’s discovery of mTOR while a grad student at Johns Hopkins mTOR’s role as one of the major growth pathways in the body mTOR’s role as a nutrient sensor How mTOR inhibiton has become one of the hottest topics in longevity research mTOR’s role in diseases, especially its connection to cancer The role of RAG GTPases as key mTOR mediators Protein intake and downstream mTOR activation Research into ketogenic diets effect on longevity and healthspan Whether David would take rapamycin as a means to enhance his longevity And much, much more
 
My experience with Rapamycin. I started a few weeks back and would just like to share progress.

Background: I've been housebound with ME/CFS for the past 13 years (diagnosed 2002). My main symptoms: fatigue, brain fog and sore lymph nodes (groin, under arms, and occassionally spleen).
I am aiming to maintain the dose used for antiaging (5-6 mg taken weekly).

Week 1 on Rapamycin: Possible lessening of lymph node pain? No significant change in ME.

Week 2 : More definite lessening of lymph node pain. Pain returned as I came toward the day for my next dose. Possibly a little better generally.

Week 3. Very little lymph node pain. My capacity beginning to improve.

Week 4 and 5. No lymph node pain. And capacity increased. Still housebound but able to function longer. Also, it is usual for me to do 'mental/physical activity' before my usual morning routine because by the time I have had breakfast, dressed etc., I am exhausted again. Now I can do my morning routine and then sit down to some task. Haven't been able to do that for over a decade!!

Week 6. Busy week at home and lymph node pain and fatigue returned. No words for disappointment! You'll know. I will increase the dose by 1mg and see what happens. Can't go any higher than that, though I would love to.

Side effects: second day after I've taken the weekly dose, I get agitated. It passes but is a noticeable pattern.
Possible concerns: Before starting treatment my lymphocyte count was below the normal range, so will need to keep an eye on that.
 
Latest update on rapamycin/rapamune/sirolimus:

I increased the dose but the lymph node pain and fatigue flared up badly afterwards.
So, I am back to cold baths and using ice packs to calm down my immune system.
Very sadly, I think my experiment with rapamycin is at an end.

Possible reasons it worked initially and then stopped: a) it does exacerbate some autoimmune conditions and has some proinflammatory effects so perhaps it was triggering something in this way b) even anti-inflammatory effects make me feel ill* so perhaps this was the cause c) who knows???

*Any med or supplement that is proinflammatory makes me feel terrible straightaway, but anti-inflammatories also make me ill, it just takes longer to manifest and the effect is less pronounced than with proinflammatories. I had hoped as rapamycin is immune suppressant that I could bypass all of this, but from my browsing of the literature it seems rapamycin's effect on the body is more complicated than I hoped
 
The comments mentioned another thread about someone who benefited from it, but also a comment from someone who almost died from taking it.

I remember coming across a list of treatments PWME have tried, and how they rated them. The results didn't seem all that useful, at least for trying to figure out which ones were really worth trying.
 
The comments mentioned another thread about someone who benefited from it, but also a comment from someone who almost died from taking it.

I remember coming across a list of treatments PWME have tried, and how they rated them. The results didn't seem all that useful, at least for trying to figure out which ones were really worth trying.
There is the ME Association survey from 2010
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https://www.meassociation.org.uk/wp-content/uploads/2010/09/2010-survey-report-lo-res10.pdf
 
Apparently a Rapamycin clinical trial will also start in the US come January.

PolyBio news about the planned Rapamycin trial.
https://polybio.org/polybio-supports-helps-conceptualize-long-covid-rapamycin-clinical-trial/
The trial will test a low dose of the drug rapamycin in participants across a 3-month period. Analysis of participant blood samples will determine if rapamycin improves components of the immune response that can control infection.
 
Trial registration for Simmaron Research study: Rapamycin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

They will be giving a max dose of 6 mg/week to people with ME/CFS (IOM criteria), comparing outcomes between those with "serological evidence of autophagy disruption" to those without.

Estimated enrollment: 100

Outcomes are SF-36 (primary, 1 year) and "change in mTOR activation panel and blood markers involved in autophagy function" (secondary, 1.5 years).

Estimated study completion: 2026-06-11

From SimmaronResearch.com:

We have recently identified elevated levels of inactive ATG-13 as a testable and targetable pathway for treating symptoms of post-exertional malaise.
Rapamycin therapy inhibits mTOR and reduces autophagy disruption. We believe that a subset of patients may have chronic mTOR activation that can lead to the symptoms of ME/CFS. By taking rapamycin, the mTOR inhibitor, we hope that these people may see a significant reduction in symptoms.

We will track symptoms and autophagy markers in this study.
Our publication on elevated ATG13 showed that a significant number of ME/CFS patients display serological evidence of autophagy disruption. We have shown that this deficit in autophagy is due to the chronic activation of mTOR. Without properly functioning autophagy, there is significant cellular stress, immune activation, and not enough energy for the cell to do well.

Rapamycin is an mTOR inhibitor. It is an FDA approved drug that was initially developed to protect patients during a kidney transplant. It has a well understood safety profile. This study will track autophagy markers and ME/CFS symptoms in patients who are treated with low-dose rapamycin by participating clinicians.

The mentioned study (thread):
Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE), 2022, Gottschalk et al
 
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I don't see the PolyBio study on long COVID on ClinicalTrials.gov, but here are some tweets about it.

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https://twitter.com/user/status/1851632219812516135

Amy Proal:
[...] We may also add an arm of ME/CFS patients to our trial, but want to first see how the drug is tolerated in LongCovid, and get back some immune system data to best design the potential ME/CFS arm

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https://twitter.com/user/status/1851625941778198738

PolyBio:
We are excited to announce an $800,000 donation to Mount Sinai to support a clinical trial of the drug rapamycin in patients with long COVID. The trial will be conducted at CoRE: a clinic directed by Dr. David Putrino and PolyBio's Dr. Amy Proal:
https://polybio.org/polybio-supports-helps-conceptualize-long-covid-rapamycin-clinical-trial/

2/ "We extremely motivated to run a clinical trial for an affordable, generic drug with the potential to help long COVID patients" says Dr. Proal, who serves as PolyBio's President and Scientific Director of CoRE.

3/ Blood samples from trial participants will be sent to Dr. Akiko Iwasaki's laboratory at Yale University where analysis will determine how use of rapamycin impacts parts of the immune response.

4/ Rapamycin is an FDA approved, generic drug that regulates immune and growth- inhibitory signaling. Increasingly, it is being tested or prescribed in a low, once-weekly dose in an effort to improve immune function.

5/ For example, one clinical trial found that low-dose analogs of rapamycin increased interferon-induced antiviral gene expression in elderly adults:
https://pubmed.ncbi.nlm.nih.gov/29997249/

6/ Long COVID is increasingly connected to persistence of the SARS-CoV-2 virus in tissue, Epstein-Barr virus reactivation, and immune exhaustion. It follows that low-dose rapamycin may benefit patients with long COVID.

7/ With such effects in mind, one clinical trial found that continuous rapamycin use throughout the SARS-CoV-2 infection period was associated with a significant reduction in moderate or severe COVID-19 cases:
https://pmc.ncbi.nlm.nih.gov/articles/PMC10187519/

8/ Rapamycin users also did not report any cases of long COVID, despite being an average of 7.5 years older than non-users.

9/ In another study, once-weekly dosing of a rapamycin analog was found to improve signs of T cell exhaustion and to boost influenza vaccine immune response in otherwise healthy older adults without significant side effects:
https://pubmed.ncbi.nlm.nih.gov/25540326/

10/ The dose of rapamycin used for immune modulation is much lower than that used for rapamycin’s conventional use as an organ transplant rejection or cancer therapy drug.

11/ "From the discoveries we have published regarding the biological features of people with long COVID with our collaborator Dr Akiko Iwasaki, low-dose rapamycin is an exciting drug target that has the potential to directly address some of the immune (cont. in next)

12/ “or infection-related dysfunction that many people are experiencing," says David Putrino, the Nash Family Director of CoRE. We are hopeful that this will be a first step in validating a cheap, safe and effective long COVID treatment."
 
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Someone on Reddit in the ME/CFS trial said Simmaron just finished the study. Their doctor told them most of her patients didn't benefit from it. This person had pretty minor improvements in brain fog and fatigue. They didn't say if they know which group (evidence of authophagy disruption or not) they were in.

From another comment they made, referring to their doctor: "She said people that benefit from Rapamycin are few, but for the few, it usually helps a lot and fairly early on."
 
Some info on the immunostimulatory properties of rapamycin.

Sirolimus (rapamycin) on Wikipedia:
Sirolimus has complex effects on the immune system—while IL-12 goes up and IL-10 decreases, which suggests an immunostimulatory response, TNF and IL-6 are decreased, which suggests an immunosuppressive response. The duration of the inhibition and the exact extent to which mTORC1 and mTORC2 are inhibited play a role, but were not yet well understood according to a 2015 paper.[75]

It cites the following paper (which is from a different year than Wikipedia says, not sure why). I added line breaks for easier reading.

Regulation of innate immune cell function by mTOR, 2018, Weichhart et al
Treatment of human monocytes or primary myeloid DCs with rapamycin or ATP-competitive mTOR inhibitors (Box 1) enhances their production of IL-12p40 and IL-12p70 after stimulation with TLR ligands3,8,9,11,53,54. Mycobacteria- or LPS-induced production of IL-23 by human monocyte-derived macrophages and monocytes is also enhanced by rapamycin8,55.

An immunostimulatory effect of mTOR inhibitors is also seen in human transplant patients in vivo9,56,57. Two human studies showed activation of IL-12-induced signalling and increased inflammatory responses by blood leukocytes from rapamycin-treated transplant recipients56,57.

Inhibition of the mTOR pathway with rapamycin can also have immunostimulatory effects in mouse cells and models after bacterial infections8,18,58. Inactivation of mTORC1 by genetic deletion of Rptor (which encodes regulatory-associated protein of mTOR (RAPTOR)) in mouse intestinal DCs induces a severe inflammatory response to enteric bacteria following treatment with dextran sulfate sodium (DSS)59. Genetic inactivation of PI3K and pharmacological inhibition of mTORC1 promotes IL-12 production by mouse immune cells6,8,58,60, although this seems to be more cell-type dependent than mTORC1-mediated enhancement of IL-12 expression by primary human immune cells.

Accordingly, deletion of Tsc1 reduces IL-12 production by mouse bone marrow-derived DCs, but promotes IL-12 production by mouse macrophages via activation of Janus kinase 1 (JNK1) and/or JNK214,35,36,61. Interestingly, rapamycin treatment or genetic deletion of mTORC1 does not prevent and still increases IL-12 production by TSC1-deficient macrophages14, suggesting that some TSC1-mediated effects are independent of mTORC1 and that some of the effects of mTOR inhibitors are mediated by inhibition of mTORC2 (Box 1). Indeed, deletion of the mTORC2 component Rictor enhances IL-12 production by macrophages and DCs6264, potentially through the inactivation of an AKT-dependent inflammatory feedback pathway.

After LPS stimulation, mTORC2 directly phosphorylates AKT, which phosphorylates and limits the activation of the pro-inflammatory transcription factor FOXO162. Hence, deletion of mTORC2 activates FOXO1, which augments inflammatory gene expression and IL-12 production62,65. Inactivation of TSC1 and TSC2 could therefore promote inflammatory responses by inhibiting mTORC2, which in turn activates FOXO1.

There are several more paragraphs about immunostimulation after this one in the paper.
 
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Old video of Ron Davis, mentions mTOR inhibitors. (Starts at 5:05)



Question: Are you able to say anything about the involvement of the enzyme mTOR, or the complex mTOR C1, and the disease?

Well this is a very interesting question. We have found two patients - and we haven't looked at that many - that have a mutation in mTOR. The mutation that we have found is fairly rare in the population, according to the literature, so this is a little odd. And that would imply that mTOR is an important part of establishing this disease.

One reason why that's actually important would be that you don't want to take something that inhibits mTOR, and there are a number of drugs out there that are used for other purposes that are inhibitors for mTOR, and this may actually cause you to get chronic fatigue syndrome or in fact might make it worse.

Some of the antibiotics are drugs that will inhibit mTOR and so that could actually be making you worse by taking an antibiotic that you think is actually clearing you of an infection. That's why I've often said it's very very important to know that you have an infection before you try antibiotics.

I don't see why a mutation in mTOR implies that inhibiting it will make you worse. Is his thinking that a mutation is probably making it work less effectively, so inhibiting it would be adding to the problem? Isn't it possible a mutation is making it do too much of some process, so turning it down would be helpful?

I've read probably 10-15 anecdotes of rapamycin use in ME/CFS. I don't recall anyone saying they've gotten significantly worse. Mostly no change, with a few that had improvements.

Also, anyone know off hand if mTOR genes have popped up in any studies?
 
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I'll make a list of anecdotal reports of rapamycin use in ME/CFS or long COVID. I'm sure if I kept going through Reddit search results for "rapamycin" I'd find more, but I'm tired now.

Worsened
  1. Phoenix Rising
  2. Phoenix Rising (temporary symptoms after stopping: Phoenix Rising)
  3. Phoenix Rising
No change in ME/CFS symptoms
  1. r/covidlonghaulers
  2. r/covidlonghaulers
  3. r/cfs
  4. r/cfs
  5. r/cfs
  6. r/cfs
  7. r/cfs
  8. r/cfs (same person: r/cfs)
  9. r/cfs
  10. r/cfs
  11. r/cfs (same person: r/cfs)
  12. r/cfs
  13. r/Rapamycin (Caused mild depression while on it)
  14. Phoenix Rising (slight improvement in exercise intolerance, slight worsening of short term memory, 2 weeks)
  15. Phoenix Rising
  16. Phoenix Rising
  17. Phoenix Rising
  18. Phoenix Rising
Temporary improvement
  1. r/covidlonghaulers (Update: r/Rapamycin)
  2. r/cfs
  3. r/cfs
  4. Phoenix Rising
Improvement (though some are only a few weeks after starting, so might have ended up in temporary improvement)
  1. r/cfs
  2. Health Rising (7 months)
  3. Health Rising (search comments for "physical and cognitive functionality")
  4. r/covidlonghaulers (update: r/covidlonghaulers) (9 months)
  5. r/covidlonghaulers (update: r/covidlonghaulers) (Over 1 year, but I'm not sure if it helped fatigue or PEM for them. They say it helped "inflammation" and "healed the brain".)
  6. r/cfs (updates: r/cfs, r/Rapamycin) (At least 4.5 months)
  7. r/cfs (5 months)
  8. r/cfs (Updates: r/cfs, r/covidlonghaulers) (Improved energy but worsened hyperadrenergic POTS and nonepileptic seizere frequency, so they stopped)
  9. r/covidlonghaulers (At least 6 weeks)
  10. r/covidlonghaulers (helped brain fog, but not PEM)
  11. Phoenix Rising (4 weeks)
  12. Phoenix Rising (Update: Phoenix Rising)
  13. Phoenix Rising
Four more improvements that I didn't include, in the collage here. It's the Twitter screenshots. r/cfs

Edit: Added posts from Phoenix Rising

Edit 2: Added one to Worsened and two to No Change.
 
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Unfortunately, I didn't respond to rapamycin. I took 5 mg/week for 4 weeks. It's been 3 weeks since my last dose.

I was planning to do 2 months, but I was worried it was making me worse. I was getting slightly worse but hard to say if rapamycin was the cause, as I've been declining for a while.

I got a canker sore a few days in for a very short time. I also had a pretty bad sore throat from around days 4-6, which then turned into a runny nose for a couple days. A milder sore throat the second week. And that's pretty much it for side effects.
 
'Simmaron has already found 130 age and gender-matched healthy controls over the past year, but they are not including a placebo arm in this trial because they’re seeking FDA approval for the drug in ME/CFS in another way.

They aim to develop a diagnostic panel using pATG13 and BECLIN-1 to predict who responds to Rapamycin. They’re using a “high-complexity lab” called Coppe Labs (Konstance Knox, PhD), which specializes in the development of FDA diagnostic panels.

(If I have it right, if the clinical trials go as hoped, people with high pATG13 (blocks the MTORC1 pathway, which upregulates autophagy) and low BECLIN-1 levels (indicating low autophagy) will probably fit this profile). Ultimately, general practitioners will be able to order these labs to determine which patients should try the drug.'

https://www.healthrising.org/blog/2025/02/01/simmarons-rapamycin-chronic-fatigue-fda-approval/

No placebo arm in their phase 2 sounds completely wrong headed to me! What are they playing at?
 
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