#64

Individuals often fixate on a certain item causing their adverse reaction or outcome. The majority of the time, in my experience, they end up being mistaken, but solidly convinced.
We’d need to know the details on such an individual’s claim, their full medical history, other meds, supplements, and importantly what % of the time were they under mTORC1 inhibition.
For all that we know, this individual could have been taking it daily.
There are adverse reactions to everything, from foods to environmental exposures, supplements and medications. It’s not a reason to have no one take what one person has an adverse reaction to.
I’m yet to have anyone have a significant adverse effect of rapamycin - and hope it stays that way.

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#65

Yes.This is always the challenge with evaluating adverse events…

What (in the myriad number of things in our “environment” (food, supplements, medications, etc.) is causing the given issue. I know its a hard issue, made even more difficult because we have such extremely limited information and just was there is a placebo effect on the “positive” side of things, there is also the false attribution issue or coincidence issue that convinces people that X caused Y.

Maybe if we develop an “Adverse incidence” database for longevity drugs / therapeutics - as well as a positive / benefits incidents reporting mechanism, perhaps we can get a better handle on this - with the type of detail that you might see in a clinical study.

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#66

I continue to be amazed by this story - even as low-key, cautionary and underselling of rapamycin as it was.

I didn’t realize it, but I just found out it was on the front page of The NY Times print edition. Wow - this will, I hope, help move longevity drugs and treatment more into the mainstream.

While I know many people here are disappointed the story was not as enthusiastic as most of us are about the potential for rapamycin to greatly improve people’s healthy lifespans… (and I fully agree with that sentiment) - I’m still glad that everyone here pitched in and share their stories and spoke with the reporter.

There is no question in my mind that the increased attention this type of story brings to field of longevity science will ultimately result in more investment in the field, more people working in the field, and faster progress. With a little luck even a rapamycin / longevity clinical trial might get done. Thank you everyone!

And yes, as you might expect, we’re getting more news media enquiries… so word seems to be spreading even faster now.

NYTimesSept25Rapamycin.pdf (2.6 MB)

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#67

I told my family about rapa and its potential help with neurodegenerative diseases (for some people some of the time). So, my sis in law asked her father’s doc about it for her father who has advanced parkinson’s. The doc refused and said it can make Parkinson’s worse and have negative side effects. So very frustrating when they don’t know that isn’t even true. What side effect for this immobile person are they even worried about. Makes me want to scream!

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#68

The story hit my instagram feed. I scrolled through some of the comments, and WHOA! There are so many unhappy people out there, which is pretty sad (who wants to live longer in this awful world, etc). Many more who seem angry and assume they know the details (only for rich people, etc). I didn’t see one person saying, hmmm, tell me more about this, I’m not convinced… etc.

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#69

Thanks for being willing to be in the article and sharing some of your story with us here. We all have different bodies, and we all can use therapies to help us with health - since many of us here take rapa.

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#70

Thanks for sharing your experience. A young (25yo) friend of mine, who has never used rapa, had the same (also shingles… Regular outbreaks of both for a few years now…). His first outbreak was just after he got his COVID vaccine. He never got COVID on the other hand. By any chance: did your first outbreak happen shortly after a COVID infection or vaccination?

1 Like
#71

If anything, T cell immunity is enhanced by Rapamycin, so I’d personally be happy that I was on Rapamycin - same thing for any of the viral illnesses.

I asked Vera-Health.ai … and got a good answer on this:
Rapamycin, also known as sirolimus, has a complex role in modulating T cell immunity. Its effects are context-dependent and can vary based on dosage and specific immune conditions.

Rapamycin primarily functions by inhibiting the mammalian target of rapamycin (mTOR) pathway, which is crucial for T cell activation, proliferation, and differentiation. This inhibition can lead to both immunosuppressive and immune-enhancing effects, depending on the circumstances.

One of the key ways rapamycin enhances T cell immunity is by promoting the generation of memory CD8+ T cells. These cells are essential for long-term immune protection and are particularly beneficial in the context of vaccinations, where a robust memory T cell response is desired for effective adaptive immunity. Rapamycin has been shown to improve the quality and longevity of antigen-specific CD8+ T cell responses, which can enhance the efficacy of various vaccines.

However, rapamycin’s impact on the primary immune response is more nuanced. While it boosts memory T cell responses, it can impair the function of effector CD8 T cells and macrophages, which are critical for immediate defense against acute infections. This suggests a trade-off between enhancing long-term immunity and potentially dampening immediate effector functions.

In the context of cancer treatment, rapamycin can enhance the antitumor efficacy of immunotherapies by promoting memory CD8+ T cell generation. However, its immunosuppressive properties necessitate careful application to avoid hindering immune responses.

Additionally, rapamycin’s modulation of mTOR signaling is crucial in balancing T cell quiescence and activation, influencing T cell differentiation and homeostasis. Emerging evidence also suggests that rapamycin can reduce chronic inflammation and improve antiviral T cell responses, as seen in HIV-1 infection models.

In summary, rapamycin can enhance T cell immunity primarily by boosting memory T cell responses, though this comes with the trade-off of possibly dampening immediate effector functions. Its application requires careful consideration of therapeutic contexts and dosing regimens to balance these effects effectively.

References

  1. Autophagy inducer rapamycin treatment reduces IFN-I–mediated Inflammation and improves anti–HIV-1 T cell response in vivo
    JCI Insight
    Mu et al.
    10 citations
    2022
    It is demonstrated that autophagy is directly linked to IFN-I signaling, which is a key driver of immune activation and T cell exhaustion during chronic HIV infection, and therapeutically targeting autophagic is a promising approach to treat persistent inflammation and improve immune control of HIV replication.

Open Access
Influential Journal
Show more
2. Immune Memory–Boosting Dose of Rapamycin Impairs Macrophage Vesicle Acidification and Curtails Glycolysis in Effector CD8 Cells, Impairing Defense against Acute Infections
Journal of Immunology
Goldberg et al.
29 citations
2014
It is found that functional CD8 T cell and macrophage responses to both viral and intracellular bacterial pathogens were depressed in mice in vivo and in humans to phorbol ester and calcium ionophore stimulation in vitro in the face of low-dose Rapa treatment.

Open Access
Influential Journal
Show more
3. Regulating Mammalian Target of Rapamycin To Tune Vaccination-Induced CD8+ T Cell Responses for Tumor Immunity
Journal of Immunology
Li et al.
81 citations
2012
The ability of a variety of rapamycin treatment regimens to regulate virus vaccination-induced CD8+ T cell memory responses and tumor efficacy is demonstrated and indicates that judicious application ofRapamycin can augment vaccine efficacy for chronic challenges.

Open Access
Influential Journal
Show more
4. Combining mTOR Inhibitors and T Cell-Based Immunotherapies in Cancer Treatment
Cancers
Hage et al.
26 citations
2021
This review presents the different classes of mTOR inhibitors and discusses their effect on immune cells by focusing mainly on CD8+ T cells and provides an overview of the different preclinical studies that investigated the anticancer effects of m TOR inhibitors combined to immunotherapies.

Open Access
Influential Journal
Show more
5. mTOR Signaling in T Cell Immunity and Autoimmunity
International Reviews of Immunology
Liu et al.
69 citations
2015
The mammalian target of rapamycin, a phosphoinositide-3-kinase-related protein kinase, acts as a rheostat capable of integrating a variety of environmental cues in the form of nutrients, energy, and growth factors to modulate organismal processes and homeostasis.

Influential Journal
Show more
6. Effects of Sirolimus treatment on patients with β‐Thalassemia: Lymphocyte immunophenotype and biological activity of memory CD4 + and CD8 + T cells
Journal of Cellular and Molecular Medicine
Zurlo et al.
5 citations
2023
Treatment of β‐Thalassemia patients with Sirolimus has a positive impact on the biological activity and number of memory CD4+ and CD8+ T cells releasing IFN‐γ following stimulation with antigenic stimuli present in immunological memory.

Open Access
Show more
7. mTORC1 and mTORC2 as regulators of cell metabolism in immunity
FEBS Letters
Linke et al.
183 citations
2017
Findings show that the mTOR pathway integrates spatiotemporal information of the environmental and cellular energy status by regulating cellular metabolic responses to guide immune cell activation and generate a systemic understanding of the immune system.

Open Access
Show more
8. Rapamycin: could it enhance vaccine efficacy?
Expert Review of Vaccines
Nam et al.
12 citations
2009
It was reported recently that rapamycin, which is used as an immunosuppressive drug for organ transplantation, stimulates the production of memory CD8 T cells, which means thatRapamycin or related drugs could be used to enhance the efficacy of many types of vaccines.

4 Likes
#72

Thanks for the tip.

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2 Likes
#73

Looks like one needs an invite. One can join a waitlist, however.

#74

It’s only for doctors.

1 Like
#75

Thank you for the response. I agree that it’s important to weigh both the benefits and risks associated with longevity therapeutics like rapamycin. When I encountered infections, I immediately stopped taking rapamycin. I had a comprehensive blood panel done (CBC, CMP, lipids, insulin, genetic testing) before starting, and everything was perfectly normal. During the infections, my blood work remained normal, though I did test positive for herpes and other infections.

I think tracking TREGs and other markers could offer insight into immune function during rapamycin use, but we should recognize that side effects may not always work with what theoretical models predict. It might be that a lower dose of an immunosuppressant would suppress the immune system less, but in my case, the timing of the initial herpes infection was critical. Because my immune system was compromised at that moment, it influenced the severity of the infection for the rest of my life.

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#76

Thank you for sharing your friend’s experience. In my case, I contracted genital herpes while taking rapamycin, not shortly after a COVID infection or vaccination. From what I understand, the initial infection plays a significant role in determining how severe the outbreaks will be throughout life, and since my immune system was likely compromised due to rapamycin at that time, it may have influenced the severity of my condition moving forward.

1 Like
#77

I appreciate your input, but I believe it’s important to recognize the real-world impact of immunosuppressants, particularly those with long half-lives like rapamycin. I took it once a week. While it’s true that adverse reactions can happen with anything, my point is that the immune-suppressing properties of rapamycin, especially when taken regularly, could increase susceptibility to infections like herpes, as I personally experienced.

I’m not suggesting that rapamycin is unsafe for everyone, but my case highlights that immune suppression, even in low doses, can have significant consequences for certain individuals.

3 Likes
#78

Is it just a coincidence that while you were taking Rapamycin you contracted (got infected with) genital herpes (HSV-2) or do you think you got infected because of Rapamycin?

#79

Agree. But she is not your normal person, as she is very smart and into the field directly.

1 Like
#80

That’s all fine and I was speaking in generalities - again without knowing all the specifics difficult to know their situation.
The concept that this is an immunosuppressant taken cyclically at reasonable doses isn’t consistent with my interpretation of the situation. It is definitely immunomodulatory. It probably slightly hurts humoral immunity (which is related to bacterial/parasitic/fungal infections) and helps T cell immunity.

3 Likes
#81

I get it and I don’t understand it as well.

From my personal anedoctal point, I get less sick than before (3 kids at school age, I’d normally get down once or twice a year with some nasty flu)

After starting rapa, I don’t feel anything when people at home are sick or get milder symptons than my wife - who is yet to use rapa - and my kids. Used to be the other way around.

And while I am aware of the possible effects on humoral immunity and I don’t have developed anything that I could link to rapamycin intake.

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#82

Matt (and others) weigh in: x.com

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#83

Seems to me there’s an asymmetrical response to n=1 reports of positive or negative outcomes around this neighborhood.

Imagine the following response to a positive correlative report:

‘Individuals often fixate on a certain item causing their positive reaction or outcome. The majority of the time, in my experience, they end up being mistaken, but solidly convinced.’

A loud round of boos would likely ensue.

Yes, let’s make this same demand next time someone reports something favorable.

They said they were taking it weekly, didn’t they?

I don’t believe this was stated anywhere.

All that said, I agree Matterhorn displays an unwarranted level of certainty about the impacts of rapa in this case. I just think it’s interesting to contrast the level of reaction here, vs. positive reports.

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