Just to say that Montelukkast seems to reduce the risk of developing pulmonary fibrosis
P.S. I’m taking 5mg three times a day for neuro-inflammation (off label AND NOT MEDICAL ADVICE)
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May I inquire as to what dose you’re currently taking? Also, how did you arrive at that dose, what went into your thought process? I’ve often wondered whether it might make sense to take a low daily dose just to keep the mTOR pathway tamped down all the time rather than hit with a large dose once weekly, which has the effect of much larger fluctuations in the amount of Rap in your system. While I see the logic of doing senolytics in that way, rapamycin is a different kettle of fish, at least that’s how I presently view it.
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The dose I’m taking is for the purpose of immunosuppression (for kidney transplant). It is not for longevity. I arrived at my ideal dose by watching closely my blood biomarkers. I draw blood once a month. My dose most likely won’t help you bc our goals are different.
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You raise a good question @PLEIADES. My read a year ago was that the evidence was mixed but favored the positive. I queried GPT-4 a few minutes ago and got the response you see below. This information should be taken as potentially interesting subject to confirmation. My prompt was first pass with no validating drill down.
PROMPT
Does the preponderance of the research and clinical evidence suggest that rapamycin can halt or slow the progression of development of pulmonary fibrosis or that it can cause or accelerate the progression of fibrosis? Be specific in citing the research and clinical evidence.
ChatGPT
Rapamycin, also known as sirolimus, is a macrolide compound with immunosuppressive properties used to prevent organ transplant rejection and in the treatment of certain malignancies and genetic disorders. Its role in pulmonary fibrosis has been the subject of research due to its mechanism of action on the mTOR (mammalian target of rapamycin) pathway, which is involved in cell growth, proliferation, and survival. The mTOR pathway has been implicated in the pathogenesis of pulmonary fibrosis, suggesting that rapamycin could potentially influence the development or progression of this condition.
The evidence regarding rapamycin’s effect on pulmonary fibrosis is mixed, with studies indicating both potential beneficial and detrimental effects. Below, I’ll summarize key findings from research and clinical studies to date:
### Potential Benefits in Halting or Slowing Progression
- Antifibrotic Effects: Some preclinical studies have shown that rapamycin can exert antifibrotic effects in models of pulmonary fibrosis. For instance, Korfei et al. (2015) demonstrated that mTOR inhibitors, including rapamycin, can reduce fibroblast proliferation and collagen deposition in lung tissue, suggesting a potential therapeutic role in fibrotic diseases.
- Inhibition of mTOR Pathway: Research has indicated that the mTOR pathway is activated in fibrotic diseases, and its inhibition by rapamycin could mitigate fibrosis. A study by Selman et al. highlighted that mTOR inhibitors could attenuate the progression of pulmonary fibrosis by inhibiting cellular proliferation and promoting autophagy in fibrotic lung tissue.
- Clinical Observations: Some clinical observations have suggested that patients receiving rapamycin for other indications might have a lower incidence or progression rate of pulmonary fibrosis, though these findings are preliminary and require further validation through controlled studies.
### Potential Risks in Causing or Accelerating Progression
- Case Reports of Pulmonary Toxicity: There are case reports and series suggesting that rapamycin can cause pulmonary toxicity, including pneumonitis and interstitial lung disease, which can mimic or exacerbate pulmonary fibrosis. This indicates a potential risk factor for certain patients, especially at higher doses or with long-term use.
- Complex Role of mTOR Pathway: While inhibition of the mTOR pathway has potential antifibrotic effects, the pathway’s role in lung disease is complex. Its complete inhibition could disrupt normal lung homeostasis and repair mechanisms, potentially leading to adverse outcomes. The balance between beneficial suppression of fibrosis and maintenance of necessary cellular functions is critical.
- Variable Responses: Individual variability in response to rapamycin, based on genetic differences, underlying conditions, and concurrent medications, can also influence its effects on pulmonary fibrosis. This variability underscores the need for personalized approaches to treatment.
### Conclusion
The current body of research and clinical evidence presents a complex picture of rapamycin’s role in pulmonary fibrosis. While there is promising evidence that rapamycin may have antifibrotic properties and could potentially be beneficial in halting or slowing the progression of pulmonary fibrosis, there are also significant concerns regarding its capacity to cause or exacerbate lung fibrosis in certain contexts. The decision to use rapamycin as a treatment for pulmonary fibrosis should be made on a case-by-case basis, considering the specific characteristics and conditions of the patient, and should be closely monitored for potential adverse effects.
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Very interesting. It underscores my view that it’s really a crap shoot, although I remain open to hearing all points of view.
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You may want to review these threads if you have not already:
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I don’t see it like this at all… I see fibrosis risk as very low, given the current dosing programs that most of us undertake (low dose, once per week or less). With periodic breaks (rapamycin vacations) that many people take, it seems like a vanishing risk.
While there will be varying responses in any patient population, most of the research I’ve seen has never mentioned fibrosis as a significant concern or side effect in any of the literature.
At the same time, as I now do some research into this topic since you’ve brought it up, most of the research literature are studies looking at rapamycin (sirolimus) as a treatment for fibrosis (not the cause).
Some research here:
We sought to test the hypothesis that short-term treatment with sirolimus reduces the concentration of CXCR4+ circulating fibrocytes in patients with idiopathic pulmonary fibrosis (IPF).
RESULTS
In the 28 study participants, sirolimus resulted in a statistically significant 35% decline in the concentration of total fibrocytes, 34% decline in CXCR4+ fibrocytes, and 42% decline in fibrocytes expressing α-smooth muscle actin, but no significant change in these populations occurred on placebo.
Rapamycin (alternatively known as sirolimus) is a macrolide immunosuppressant commonly used for organ transplantation. It acts both on lymphocytes through the mechanistic target of rapamycin (mTOR) pathway to reduce their sensitivity to interleukin-2 (IL-2) and, importantly, also has anti-fibrotic properties by acting on myofibroblasts.
https://www.nature.com/articles/s41433-019-0340-3
Rapamycin Ameliorates Inflammation and Fibrosis
Potent antifibrotic activity of mTOR inhibitors sirolimus and everolimus
https://www.sciencedirect.com/science/article/abs/pii/S0168827810011797
When I search on “sirolimus and fibrosis” - the research seems very positive, though I have not done an exhaustive review as its not a significant concern of mine.
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That is my thinking as well. I am trying a new schedule since 5 months where I take 1mg daily for 3 weeks and take one week pause and restart. I have not seen any adverse effect (I am planning a yearly check-up including extensive list of blood tests in about a month). The observational positive effects are mostly related to controlling sterile inflammation / autoimmune issues (dermatitis, rhinitis, joint pain…). But I had surgery in January and had a longer pause not to mess with healing and took three weeks off and all the issues that improved in last months slowly creeped back. I copied and modified this 1mg daily protocol form Pankaj Kapahi, he has lab at Buck institute and he explained about his own rapamycin protocol (2 weeks 1mg daily two weeks pause) in one of the interviews and reading some studies on rapamycin and autoimmune diseases. If biomarkers wont support it I will probably change it back to weekly.
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Thank you! I’m happy to see there are studies which find encouraging results vis-a-vis the fibrosis issue and yet there remain many uncertainties. Then again, life itself is a crap shoot in countless respects. Our entire existence is a grand casino which we struggle to navigate, using our brains and our instincts to arrive at decisions which may or may not be to our benefit. Pardon my waxing philosophic. Anyway, you do an excellent job with the site and I hope it draws more and more members as the topics it covers are extremely important.
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One more thing: I’ve read journal articles that state that sirolimus has no effect on mTORC2 but that appears to contradict other studies and I’m frankly confused about it. What is your opinion?
I think you’re talking about this interview and this information (queued up for the part where he talks about his dosing):
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Yes, this is the interview.
Blagosklonny suggested it in his paper Towards disease-oriented dosing of rapamycin for longevity: does aging exist or only age-related diseases? - PubMed
Based on “side” and therapeutic effect-avoidance, the most popular schedule of rapamycin for longevity is 5–7 mg once a week. The schedule is well tolerated and lacks side effects except of rare mouth sores [40]. It is based on the assumption that the intermittent schedule has fewer side effects than everyday doses. But this never was compared. For example, treatment with 1 mg rapamycin every day lacks side effects in healthy elderly [41]. So, both schedules have negligible side effects. But are they equally effective for life extension? We do not know.
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Might I ask what underlying disease you have requiring both pulmonologist and nephrologist? If it’s scleroderma, you may react quite differently than others.
Still interesting to see any traditional doc recommending low dose rapa.
After a few years on Rapa, I developed lung fibroses (detected by X-ray), and was sent to a pulmonologist who pointed to Rapa as a culprit. I stopped Rapa, as he advised, and fibroses cleared without any medications after 4 months.
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a new study show even intermittent use of rapamycin induce fibrosis in mice’s heart : https://www.sciencedirect.com/science/article/pii/S2212877824000334?via%3Dihub
Yes - at very high dosing, and they still did well overall.
See: Yes, the Dose Really Does Make the Poison (Skeptoid Blog)
From 6 months of age, male and female C3B6F1 hybrid mice were either continuously fed with 42 mg/kg rapamycin, or intermittently fed by alternating weekly feeding of 42 mg/kg rapamycin food with weekly control feeding.
Results
Chronic rapamycin treatment induced glucose intolerance, which was partially ameliorated by intermittent treatment. Chronic and intermittent rapamycin treatments increased lifespan equally in males, while in females chronic treatment resulted in slightly higher survival. The two treatments had equivalent effects on testicular degeneration, heart fibrosis and liver lipidosis. In males, the two treatment regimes led to a similar increase in motor coordination, heart rate and Q-T interval, and reduction in spleen weight, while in females, they equally reduced BAT inflammation and spleen weight and maintained heart rate and Q-T interval. However, other health parameters, including age related pathologies, were better prevented by continuous treatment.
Conclusions
Intermittent rapamycin treatment is effective in prolonging lifespan and reduces some side-effects of chronic treatment, but chronic treatment is more beneficial to healthspan.
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So myocardial fibromyalgia is only a problem at extremely high doses of Rapamycin?
I’m not worried about it at my doses. It seems like at transplant patient levels (significantly higher than most of us are taking) it actually still seems associated with an alleviation of fibrosis, but I’m not a doctor:
Background
Myocardial fibrosis is an important contributor for development of diastolic dysfunction. We investigated the impact of sirolimus as primary immunosuppression on diastolic dysfunction and fibrosis progression among heart transplantation recipients.
Conclusions
Early conversion to sirolimus is associated with improvement in diastolic dysfunction and filling pressures as compared with CNI therapy. Whether this could be attributed to attenuation of myocardial fibrosis progression with sirolimus treatment warrants further investigation.
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That’s all I wanted to hear. Thanks.
There is no debate that rapamycin does more good than bad. However heart fibrosis increased is still a concern to me.
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