Chris Masterjohn makes valid points regarding potential side effects of rapamycin when used chronically at high doses. However, his perspective might be misleading as mentioned by @John_Hemming and @RapAdmin and @Joseph_Lavelle:
Dose Translation: He directly extrapolates high-dose rodent side effects to humans without adequately adjusting for dosing differences or intermittent use common in longevity protocols.
Chronic vs. Intermittent Use: Most severe adverse effects he highlights (e.g., testicular atrophy, cataracts) occur at doses or schedules significantly higher or more frequent than typical human longevity usage (weekly low-dose).
Ignoring Positive Human Data: Masterjohn emphasizes transplant and disease-treatment side effects, neglecting evidence from human trials.
Selective Evidence and Bias: The article strongly promotes his alternative protocols (glycine, sulfur) while dismissing rapamycin entirely, potentially reflecting bias …
Even if you do take rapa long term, and regularly, there may be times where it just makes sense to pause it temporarily. For example, next week, 04/16/25, I’m having dental surgery - bone augmentation and two titanium posts placed. That’s fairly serious work, with antibiotics and healing. I took my last dose 04/05/25, so it will be 11 days of no rapa when I have the surgery, and subsequently I plan on 3-4 weeks of no rapa. That means a month or so of no rapa. Rapamycin slows down wound healing, so it makes sense to avoid it around surgery and recovery.
The point being, is that the taking of rapa is not rigid, but rather adaptive to its characteristics. You take it when it makes sense and stop it when it makes sense. Many of us might have 2-3 times a year when we are on a rapa break. I’m having two dental implants installed, so likely a couple more surgeries, and I’ll be on a rapa break then too. If you are a woman who is planning a pregnancy, or is pregnant, odds are you’ll pause rapa, perhaps breastfeeding too. And so on.
It’s not all or nothing. You use any drug as your health demands.
Yes…I found out the hard way… that high doses without wash outs… slowly ate away my initial biological gains. Lower dose 6 mg works… regained lost gains returned. Yeah!
As to nut sac shrinage… never been an issue… the opposite actually.
From research. Age-related testicular atrophy
There are very few studies on rapamycin in male reproductive system aging. Only one study noted that rapamycin protected against age-caused testicular atrophy by increasing spermatid, spermatocyte, differentiating spermatogonia, and primary spermatogonia numbers ( Wilkinson et al., 2012 ). Overall, these studies suggest that rapamycin has the potential for protecting healthy aging of the reproductive system.
I have never heard of heart scarring either. However a simple Chat GPT search produced the following:
Rapamycin, also known as sirolimus, is an immunosuppressive drug that can have serious side effects, including pulmonary complications. Overdosing on rapamycin may increase the risk of lung-related issues such as interstitial pneumonitis (IP), which can lead to lung scarring.
Rapamycin’s effects on the heart are complex. While it is being studied for its potential to improve cardiac function and reduce inflammation, overdosing or inappropriate use could lead to adverse effects, including potential scarring or damage to heart tissue. Excessive inhibition of mTOR, the pathway targeted by rapamycin, might disrupt cellular repair processes, which could theoretically contribute to scarring.
In both examples, it’s OVERDOSING that creates scarring.
For the record, I’m a 73 year old Rapa user (6mg ~every other week). I want to believe it’s having a beneficial effect and may partially contribute to my excellent health and vitality. That said, (with the help of Gemini AI), let’s review the consistency of Chris Masterjohn’s article with other research and identify potential flaws or counterarguments.
Consistency with Other Research:
Lifespan Extension in Model Organisms: It’s highly consistent with research that rapamycin robustly extends lifespan in various model organisms, particularly mice. This is a foundational finding in geroscience.
Mechanism (mTOR Inhibition): It’s consistent that rapamycin works primarily by inhibiting mTOR (specifically mTORC1), a key nutrient-sensing pathway involved in growth, proliferation, and autophagy. The idea that inhibiting mTOR mimics aspects of caloric restriction or fasting is also widely discussed.
Reported Side Effects: The specific side effects Masterjohn highlights (impaired glucose metabolism/insulin resistance, dyslipidemia, testicular atrophy/lower testosterone, cataracts in mice, mouth sores/stomatitis, impaired wound healing, potential immune modulation) are consistent with side effects reported in both animal studies and human clinical use (especially in transplant patients receiving higher, continuous doses).
Intermittent Dosing Strategy: It’s consistent that intermittent dosing (e.g., weekly) is being actively researched and used precisely to mitigate the side effects seen with chronic dosing, while potentially preserving some or all of the benefits. His points about intermittent dosing not fully resolving all issues or potentially having sex-specific effects on lifespan are also reflected in specific studies (though the overall picture is still evolving).
Concerns about Translatability and Optimal Dosing: The concern that findings in mice (especially regarding dose-response and specific side effects) may not perfectly translate to humans, and that the optimal human dose/schedule for longevity is unknown, is consistent with the general scientific consensus. There’s active debate and research on this.
Importance of Nutrient Cycling: The biological principle that cycling between periods of nutrient scarcity (catabolism, autophagy) and nutrient abundance (anabolism, rebuilding) is beneficial for health is consistent with broader metabolic research. Many researchers agree perpetual inhibition of growth pathways might be detrimental.
Potential Flaws, Biases, or Counterarguments:
Strong Negative Framing & Tone: The title (“Worst Longevity Idea Ever Conceived”) and strong language (“shuddering,” “trashed testosterone”) signal a very firm negative stance from the outset. While based on data, this framing might lead to a less balanced interpretation, potentially overemphasizing negatives and downplaying potential positives or mitigation strategies.
Emphasis on High-Dose/Chronic/Disease Context Data: Masterjohn heavily cites side effects from mouse studies often using relatively high chronic doses needed to achieve maximum lifespan extension, and human data primarily from transplant recipients or patients with specific diseases (like LAM) who often receive higher daily doses and have underlying health issues/confounding medications. While relevant, this data may not fully represent the risk profile of the lower, intermittent doses (e.g., 5-7 mg once weekly) commonly explored for anti-aging in relatively healthy individuals. The article acknowledges dose differences but often draws strong conclusions from the higher-dose contexts.
Interpretation of Dose Comparison: While correctly noting that typical human anti-aging doses are often lower than effective mouse lifespan-extending doses (when adjusted), concluding they are therefore ineffective or only cause harm is an interpretation. The dose-response curve for longevity and healthspan benefits vs. risks in humans is simply not established. Lower doses might yield different benefit/risk profiles than higher doses.
Downplaying Intermittent Dosing Potential: While acknowledging intermittent dosing studies, the article emphasizes their limitations rather than their potential successes in mitigating side effects. The research landscape here is complex and ongoing, with some studies showing significant reduction in side effects with intermittent schedules.
Selectivity in Evidence: Like any viewpoint article, there might be selectivity in which studies are highlighted. For example, it focuses less on studies showing potential benefits of rapamycin or its analogs (rapalogs) for specific age-related conditions or improved immune function (e.g., response to vaccines) in older adults even at lower doses.
Extrapolation Certainty: While acknowledging the need for caution, the article makes strong negative assertions about human effects based heavily on mouse data (e.g., projecting mouse testicular atrophy directly onto human testosterone levels at anti-aging doses).
Promotion of Alternatives: The conclusion transitions into promoting the author’s own specific protocols and products. While authors often suggest alternatives, explicitly linking to paid protocols can be seen as a potential conflict of interest or bias.
Conclusion:
The article raises valid and important concerns about rapamycin, grounding them in published research regarding significant side effects observed in animal models and certain human contexts. The facts cited about specific adverse outcomes are generally consistent with the literature.
However, the article presents a particularly critical and arguably one-sided perspective. It heavily emphasizes the negatives, draws strong conclusions based often on high-dose or non-longevity contexts, and may downplay the potential for mitigation strategies like optimized intermittent dosing. The actual risk-benefit profile of low-dose, intermittent rapamycin for human aging is still an area of active research and considerable debate, with proponents believing the benefits can outweigh the risks with careful management, while critics like Masterjohn remain highly skeptical. His article represents a strong voice on the skeptical end of that spectrum.
It shows that “dosing” is pretty much individual. If and when you get your first side effect, it’s a sign that you overdosed and need to cut back instead of tolerating mouth ulcers.
I find that dosing at 4mg + GFJ per week has the best effect on my arthritis. No pain even in the colder months. I’m tempted to go 5mg or 6mg but for now no reason. My 36 hour blood work is about 12ng/mL. Residual of about 1.7ng/mL on day 7.
You guys are way too reliant on these LLM models, and you should be more careful. They are very easily “persuaded” by the way you ask the question, and they still tend to spout nonsense - usually telling you what you want to hear.
The study itself is great, and contains lots of information - both positive, neutral and negative. There is a brief mention of cardiac fibrosis (not “scarring”, just to be clear) in the text. The data is in supplemental figure 7, and there is some increase in “mild” fibrosis in the male mice, which looks like it was in 5% of old mice, and around 25% of old mice with Rapa. There was no difference in any of the female mice. So, is it interesting there male mice had fibrosis? Sure. Does it mean Rapa ‘scars your heart’ and shouldn’t be taken? That’s a very different question.
Luckily, the same paper actually investigated cardiac parameters and physical performance. They show that Rapa improved the motor endurance, allowed the male mice to run on the rotarod (like a moving balance beam) for longer. Rapa also improved a bunch of cardiac electrophysiological parameters, and it reduced ventricular hypertrophy. Together, it looks like functionally the mice were overall better off, plus they lived longer. So whether the fibrosis is truly a negative is not really known.
Writing “it scars your heart” is either very lazy writing, or a deliberate attempt to exaggerate negative effects.
In terms of lifespan data, this study is less convincing that the ITP data. And from the ITP, we already knew there’s a difference between male and female. However, what I learned from this study is that there is actually a huge difference between the responses of male and female mice, at organ-specific levels. We have these seemingly conflicting findings where biomarkers and actual function are divergent. For me, a study like this reminds me that we really don’t understand what’s going on here, and most of these observations can’t be explained. We also don’t know how much is just an anomaly of mouse studies, and we urgently need those macaque and dog trials to give us more useful data.
I largely agree with this article based on my experience using Rapamycin. I stopped using it after it made me anemic. I now will only use things that have shown some benefit in human trials. The TRIIM Trial protocol gave me good results.
I have seen this effect while taking rapamycin in high doses. That is one reason I dialed back my dosage.
This is a well-known effect. I think we have discussed it previously.
“Rapamycin (sirolimus) has been linked to microcytic anemia, characterized by small red blood cells (low mean corpuscular volume, MCV) and reduced hemoglobin levels”
“Bone Marrow Suppression: Rapamycin inhibits the mTOR pathway, which regulates cell proliferation. While this can suppress pathological T-cell activity (beneficial in autoimmune anemia), it may also reduce red blood cell production in healthy individuals, contributing to mild anemia”