Hey everyone, I haven’t started taking rapamycin or one of the anlogs but I’m very interested in doing so. However, I recently came across a variety of journal articles which describe their experimental results and they demonstrate that rapamycin has pro-fibrotic properties. Some lab results in some labs show it causing fibrosis which is of course not what we want to see whereas others show the opposite. It’s quite distressing to me as I want to take it but these lab results scare me. It has something to do with rapamycin promoting pathways which increase the EndMT transition, whereby endothelial or epithelial cells become mesenchymal with all sorts of pathological results. I would love to know if anyone has read these reports and is familiar with the concept. If anyone is curious I can post links to the articles to which I refer.
FWIW: Nothing that I have been worried about and I have been taking rapamycin for over two years.
Almost all of the negative side effects of rapamycin occur in a dose-dependent manner.
Most studies are of kidney transplant and cancer patients who normally would be taking higher doses than most members of this forum.
The current evidence overall suggests rapamycin has predominantly anti-fibrotic properties based on animal models and some human studies, though pro-fibrotic effects were observed in one in vitro liver model.Single-Dose Treatment with Rapamycin Preserves Post-Ischemic Cardiac Function through Attenuation of Fibrosis and Inflammation in Diabetic Rabbit - PubMed
The study found that rapamycin treatment reduced skin and lung fibrosis in mouse models of systemic sclerosis. This suggests rapamycin has anti-fibrotic rather than pro-fibrotic properties.
The animal study in showed single-dose rapamycin preserved cardiac function and reduced cardiac fibrosis after ischemia/reperfusion injury in diabetic rabbits
“Therefore, mTOR represents an attractive and unique therapeutic target in pulmonary fibrosis.”
Yes, I was happy to read those articles but then there are these articles which reach different, if not completely opposite conclusions:
Taken together, we speculated that rapamycin, a commonly used antirejection agent after liver transplantation, may have potential fibrotic effect through activating profibrotic TGF-β-Smad signaling and upregulating profibrotic factor CTGF expression in HPCs.
Results
A decrease in SA-β-Gal activity and the suppression of SASP factors were observed in HCAECs undergoing stress-induced premature senescence (SIPS) after rapamycin treatment. In contrast, ICAM-1 and ganglioside GM1 were upregulated by rapamycin treatment. In addition, leukocyte adhesion to HCAECs was promoted by this treatment. In rapamycin-treated HCAECs, morphological changes and the promotion of EndMT were also observed. Furthermore, we found that autophagy activation induced by rapamycin treatment, which led to activation of the TGF-β pathway, contributed to EndMT induction.
Conclusions
We revealed that although rapamycin functions to inhibit senescence and suppress SASP in HCAECs undergoing SIPS, EndMT is induced due to the activation of autophagy.
In primary airway epithelial cells, the unjamming transition is distinct from the epithelial-to-mesenchymal transition
More broadly, the Human Lung Cell Atlas now points not only to dramatic heterogeneities of airway cells and cell states, but also to strong proximal-to-distal gradients along the airway tree141. But we do not yet know how these heterogeneities and their spatial gradients might impact UJT locally, or, conversely, how UJT might impact these gradients. In that light, the third and last question raised by this work is the extent to which EMT/pEMT and UJT might work independently, sequentially, or cooperatively to effect morphogenesis, wound repair, and tissue remodeling, as well as fibrosis, cancer invasion, and metastasis142,143.
I guess my point is: who do you believe when labs around the world come up with opposing results? Is it common that this should be the case? When I read the journal articles that describe the pro-fibrotic effects of rapamycin, they certainly sound no less credible than the ones you cited which show anti-fibrotic effects. It is awfully difficult, as a layman, to follow the biochemical pathways they describe in their entirety. Is there some hidden agenda going on or are they honestly describing their results? I’m left with the impression that there is much that isn’t known yet about the full spectrum of effects that rapamycin can have. There will come a point where far more is known and far better analogs will be available with far more predictable effects. Until then, it seems to me it’s a crap shoot, one I will probably engage in and hope and pray I’m not making a giant mistake.
I’ve broken this discussion out to its own thread so more people see it and can evaluate the papers you’ve cited. I don’t think we’ve discussed this in the past, so it would be good to do a deep dive into this issue to see if there is much risk.
I hope others will jump in here and comment if they’ve looked at this issue in the past at all.
Neither of the two pro-fibrosis papers actually studied organ fibrosis in vivo. They were studying in vitro pathways that possibly could upregulate fibrosis in some cell lines. The first paper cited previous research that showed no fibrosis in “cultured liver cell lines,” but that found that the major fibrosis pathway was upregulated by rapamycin in hepatic progenitor cells.
The conclusion of the second paper showed that rapamycin might increase transdifferentiation of some cells during cellular stress, but seemed a long way from any conclusions about fibrosis.
This research does not allow one to draw any conclusion about possible negative effects of rapamycin. Still, one could conservatively interpret these as a caution not to use continuous high doses and to take breaks from even periodic use.
I received a response from Matt Kaeberlein, a research scientist who I’m sure many of you know has a great deal of expertise on the subject of rapamycin. Here is my question and Matt’s reply:
Hi Matt, I’ve been enjoying watching your podcasts and trying to educate myself about rapamycin by doing a lot of reading of various research papers. As a layman, it’s not easy to understand much of what I’m reading but I do my best. Recently, I’ve come upon quite a few papers that reach opposite conclusions regarding the issue of whether rapamycin, by inducing autophagy, has pro-fibrotic vs anti-fibrotic effects, via the promotion or inhibition of EndMT. If the former, that would be very bad and the exact opposite of what we want to happen. I wonder if it concerns you when different labs around the world reach discordant conclusions. I would appreciate anything you have to say on this issue. Thanks.
Matt’s response:
I’m not sure the data are discordant, but probably more reflect differences in the way the experiments were done (dose, duration, cell/tissue types, in vitro, in vivo, etc.). Unfortunately, people often mis/over-interpret their results and make blanket claims instead of appreciating the biological complexity of the system they are working in. mTOR is one of the most important gatekeepers regulating cell proliferation and growth in response to environmental stimuli. As such, mild inhibition can have far different - even opposite - effects from very strong chronic inhibition. Likewise, effects seen in cultured cells bathed in rapamycin are often quite different from what we see in vivo in animals/people. Consider muscle function for example - chronic low dose rapamycin preserves muscle function whereas ridiculously high dose rapamycin impairs muscle formation. The same thing is true for learning and memory. I don’t know of any data that rapamycin doses used for healthspan/lifespan in animal studies or off-label in people are pro-fibrotic. Even in organ transplant patients, my recollection is that the majority of the literature suggests protection against fibrosis in different organs. If you have specific references that you think run counter to this, please share them and I’ll take a look - MK
From my own experience, some 7 - 8 years ago, after taking rapamycin 1mg every day (without breaks), since 2014, I developed lung fibrosis. My pulmonologist immediately told me that it’s because of rapamycin and wanted me to stop taking it, however my nephrologists wanted me to continue and argued that they didn’t know for sure. I made a decision to stop rapamycin for 4 months and then retest for fibrosis. In 4 months fibrosis completely cleared. It was then when I restarted taking rapamycin, but only intermittently. So far so good. I’m very careful about my dose.
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)
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.
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.
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.
Very interesting. It underscores my view that it’s really a crap shoot, although I remain open to hearing all points of view.
You may want to review these threads if you have not already:
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.
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.
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.
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):
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.