As i have said previously, the trough matters. mTOR has a role to play and should be uninhibited from time to time.
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I wouldn’t dare go near him as an example of having benefited from RAPA. I don’t usually like anecdotes that are based on oh if he didn’t take Rapa he would have died way earlier. How would you/I know that? How about playing devil’s advocate and saying if he didn’t take Rappa he would have easily lived another 10 or so years by watching his lipids and doing SGLT2, Eze, and Pita and maybe metformin as an example. While his ills to start may have had nothing to do with Rapa, perhaps RAPA signed off his demise by wrecking his immune system? Who knows - right. Bottom line the guy dropped dead before he was even 80? I think (and was taking RAPA). That is NOT a very good sign if you were to ask me. Find me an example of a guy/gal that was taking Rapa regularly and they are (or lived) at least to a 100, then I’ll accept it. As a rule of thumb, I’d say that every time someone whose taking Rappa dies before reaching 90 (regardless of the cause) we should call that a very bad sign and every time someone that’s taking Rappa dies and is over 100 we should consider that a very good sign. If’s and but’s and other scenarios can fly around and every conceivable direction LOL. The best we have so far is @desertshores which his case is very promising, I’ll admit to that, but regardless of how much I search and search all over I have yet to come with a concrete case of a human being past 90 that has been taking rapa say in last 10 years, or even 5. Until that becomes the norm (meaning there is a lot of people that fit the category, I’m going to be VERY skeptical while still continuing to take RAPA.
Having said that I do take RAPA myself but I’m not the one to make up stories in my own mind to convince myself that RAPA will help me live longer. I’m gonna be brutally honest, while I think RAPA has probably helped some with inflammation and joint discomfort, I can also attest that couple times I have had very nasty cold like symptoms (way worse than what I would normally have when used to get sick pre RAPA days) which actually were so bad that I was thinking to myself, imagine if I’m in advance age (77+) and getting this kind of symptoms most likely won’t be able to make it. I’m almost certain that RAPA was the culprit of the worsened symptoms via destruction of the immune system, while the cold itself might or might not have been affected by it. So, keep that at the back of your mind that in case you might get hit with some nasty virus or cold etc. RAPA may not be your best friend. I’m even tempted to think that RAPA will be a contributor to one’s demise should a nasty viral infection were to occur when you are in advance age. I do however believe that for those lucky ones that have never had any bad side effects from RAPA then the benefits should far out way the risks. For unlucky ones (unfortunately I tend to be in this group) that we tend to often get side effects the opposite may be true.
Again, I’m not giving up on RAPA yet, but I’ll be very open minded and watching it closely as I go along.
I don’t know why and this is entirely based on anecdotal and how I feel but I am starting to think that a combination of PITA, EZE, EMPA, TELMISARTAN, and perhaps Metformin may offer WAYYYYYYYYYYYYYYYYYYY more benefits for longevity than Rapa(which to me means reaching about 105 years old, because beyond that there is nothing that we know of as of now that can subjectively help). I take them all and can attest to NOT being able to identify any side effects at all while absolutely getting HUGE benefits in way of lower glucose, lower inflammation, and lower lipids. Just my unbiased and untainted (by euphoria and placebo LOL) opinion. BTW, this is my earnest opinion, and it is absolutely not meant to be argumentative in any way shape or form.
If I may ask, was your renal failure due to antiphospholipid syndrome (APS) by any chance? There are several case reports of stellar improvement in the microangiopathy of APS patients when rapamycin is added to the drug regimen of these trasplant patients. The Reader’s Digest version is APS antibodies attack the intimal lining of renal microvasculature => mTOR overactivety => thickening of the intima => sluggishness of blood flow in these tiny vessels => clots forming => tissue death. Rapamycin knocks that overactivity down, the intimal thickness regresses, and blood flow is restored.
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Keep in mind that regarding heart health specifically, rapamycin is heart protective. We know this from validated studies in pets. To the point that a rapamycin formulation is actually FDA approved for a heart condition in cats (HCM) - that’s about as rigorous as it gets. Matt Kaeberlein’s idea of testing rapamycin in dogs was that dogs age similarly to people, suffer from a similar range of diseases and share our exact environment, and so are an excellent model for human aging. From preliminary results (the sudy is ongoing), there are reports that rapamycin actually reverses aging of the heart, and brings it back to more youthful functionality. Therefore it seems eminently sensible that Dr. Green would select rapamycin to treat his heart condition, which he claimed helped him greatly. We all are gambling, but regarding heart health, I personally am pretty sanguine about the impact of rapamycin on my heart health. YMMV.
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Agreed it’s a gamble, but I view it a as semi-informed gamble that can be mitigated with pauses etc.
A story on Dr. Green piqued my interest in rapamycin many years ago, and started dosing 5+ years ago.
That said, I’ve taken breaks and now am coming off my longest break of about 6 months and looking for advice on reintroducing. I took up running and paused to not mess with Boston training. With the race last Monday, I’m looking to both start dosing and continue training (I’m hooked 
). I’ve liked my prior 6mg/10 day routine which I’d take on easy or off training days.
Would love feedback from the geniuses on this board.
Thanks
1. Primary and Secondary Efficacy Data: Functional Performance
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Primary Outcome (30-Second Chair-Stand Test): * Intention-to-Treat (ITT) Analysis: Both groups improved, but the rapamycin group completed an average of 2.13 fewer repetitions compared to the placebo group at 13 weeks (p=0.089).
- Per-Protocol (PP) Analysis: Among participants who strictly adhered to the exercise and dosing schedule, the negative impact was statistically significant, with the rapamycin group completing 3.44 fewer repetitions than the placebo group (p=0.007).
- Objective Takeaway: The data demonstrates a clear, negative dose-response relationship: strictly adhering to the rapamycin regimen resulted in significantly worse lower-body functional improvements compared to exercise alone.
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Secondary Functional Outcomes (6-Minute Walk and Grip Strength):
- The rapamycin group walked an average of 4.87 meters less than the placebo group.
- Grip strength in the rapamycin group was an average of 1.13 kg lower than in the placebo group.
- Objective Takeaway: While these specific secondary differences did not reach statistical significance (p>0.3), the directional trend is uniform across all physical metrics: rapamycin produced inferior functional outcomes compared to placebo.
2. Biological Aging and Systemic Inflammation Markers
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Epigenetic Clocks (DNA Methylation):
- Measurements across multiple epigenetic aging clocks (e.g., GrimAge, SystemsAge, OMICmAge) showed mixed, negligible differences between the groups that were not statistically significant.
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Systemic Inflammation (C-Reactive Protein):
- The mean CRP level in the rapamycin group increased by 4.26 mg/L compared to placebo (p=0.152).
- This numerical increase was entirely driven by two extreme outliers in the treatment group (17 mg/L and 50 mg/L).
- Objective Takeaway: There is zero quantitative evidence in this 13-week timeframe that 6 mg of weekly rapamycin reduces biological age or systemic inflammation.
3. Safety, Adverse Events, and Metabolic Data
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Adverse Events (AEs):
- While 85% of participants in both arms reported at least one adverse event, the total volume of events was notably higher in the rapamycin arm (99 events) compared to the placebo arm (63 events).
- Events adjudicated as “possibly or probably related” to the drug were more than twice as frequent in the rapamycin group (35%) compared to the placebo group (15%).
- The only serious adverse event (SAE) in the trial—a case of community-acquired pneumonia requiring hospitalization—occurred in the rapamycin arm.
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Laboratory Safety Parameters: * Glucose Metabolism: Rapamycin caused a statistically significant increase in HbA1c (+1.74 mmol/mol, p=0.030).
- Lipid Metabolism: Rapamycin caused a statistically significant increase in LDL (“bad”) cholesterol (+0.32 mmol/L, p=0.036).
- Hematology: Rapamycin caused a statistically significant decrease in Mean Corpuscular Volume (MCV) (-2.90 fL, p<0.001).
- Objective Takeaway: Beyond mere symptoms, the bloodwork objectively proves that 13 weeks of weekly 6 mg rapamycin induces measurable degradation in lipid profiles, glucose regulation, and red blood cell parameters in this demographic.
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No, it was because of food poisoning.
I hear you, but apparently, it either didn’t help him much (but he thought it did), or it wasn’t enough help. Either way he’s dead and he was taking RAPA. Not good in my books regardless of what anyone thinks. I definitely need to see cases of people being in their late 90’s and hopefully 100’s that seem relatively healthy and have been take RAPA for a while to be convinced. Until such time count me as being very sceptical, while I am still taking it though, which is to say I’m not against it yet. But instead of being say 100% pro, I’m more like 60-65 pro and 35-40 against. Everything else I take I’m 100% pro, not even a 1% doubt that I’m benefiting (greatly) by taking them.
Again, I think Rapa is a perfect case of reward vs risk. For some people there seems to be no risks (or very low) for others there are risks of lipid and glucose moving in wrong direction plus infections and other sides. I always love it when I take something and don’t feel any negative side effects while reaping the benefits. and, for people with no side effects from RAPA I do think they are benefiting from it overall. But if you happened to have to take other meds to counter the side effects of RAPA as an example (or any other med for that matter) then to me it beats the purpose. Why not stick with the substances/meds that you know are not negatively affecting you, yet they are benefiting you greatly with better markers, while still showing pretty convincingly longevity benefits, i.e. SGLT2i’s, Acarbose and many others.
Again, I don’t call it a gamble at all if I take something and have ZERO side effects while the benefits show right away in the labs. As I said earlier been taking Empa, EZE, Telmi, Pita, ACA, and meftormin all of which have shown to increase lifespan (some more, some less) and I have absolutely no negative side effects. I love them! As far as RAPA, well can’t say I love it. One thing is for sure that If I get one more cold/flu case with symptoms near or as bad as last one I had couple weeks ago (it started two days after taking my Rapa dose) you can rest assured that all my 1000 pills of RAPA will be thrown in the garbage, but being that I’m a bit of vengeful type of guy, I might actually burn them first, and to NEVER look back at it again LOL. No, thank you I’m not going to continue taking something that continues to make me sick, and If I were to continue then I’d agree with you, that is pure gambling. As far as the other 5 or six I listed earlier and I love don’t see much gambling there. Even my anion GAP (whatever that is) that has persistently been higher for last five years dropped to “optimal” out of nowhere and i didn’t even expect it at all on my last test. Out of convenience, (and maybe a good guess) I dedicate that improvement to SGLT2i/EMPA even though I had started couple other substances at same time and after my last test (i.e. Telmi and Sele) but it definitely wasn’t Rapa because it kept showing as too high even long after I had started Rapa.
Just my unvarnished opinion but in all honesty if I were to have no side effects from it, or if my sides somehow disappear going forward, I will definitely continue using it.
The mice in the ITP study also appeared to have metabolic disfunction yet they lived longer, part of the answer is in the following study
And don’t know how many people got rapamycin in the Stanfield study but by now there are many of us here, taking it for many years now and I don’t think anyone of us got any serious side effects definitely attributed to rapamycin
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The ITP paper does not explicitly discuss or provide data to demonstrate whether rapamycin increases or improves specific metabolic dysfunctions. Could you please share your data source?
Moreover, even if both humans and mice(ITP) exhibit metabolic dysfunction, does that prove that this can be used to extend human lifespan?
I was mistaken, it wasn’t from the actual ITP studies but from other studies with rats/mice on a similar feeding regime, eg
but I don’t see how that would have been different for the ITP mice
Never mind. I had a feeling I might get a lot of criticism, so I deleted my original comment. I’ve watched all his interview videos, and there are quite a lot of outrageous things.
I think you are talking about “clinical trials” that use certain biological or epigenetic clocks, which we know are not ready for prime time and that do not measure all aspects of aging.
It’s hard to ascertain people’s motivations, but he seemed to genuinely want to help people. Cole, I think you’re jumping to conclusions as we have no evidence for his true motivations. And, you seem not to know that he died a few years ago: Dr. Alan Green, a great pioneer in Rapamycin usage, passed away yesterday in Little Neck, NY
Dr. Green worked with Matt Keaberlein, and many people here on the forum, to study and learn from his patients, which resulted in this paper: Evaluation of Off-label Rapamycin use to Promote Healthspan in 333 Adults (New Paper)
and: No Covid Hospitalizations or Deaths in Dr. Alan Green's 700+ Rapamycin Users
I hear you but need a small correction. I think you might need to use past tense when you refer to him. I doubt he “IS” any longer because he’s been dead for over a year now LOL, other than that I do get your point 
An analysis of Cole’s analysis…
Critical Analysis of the Trial Evaluation
The provided analysis of the 13-week human trial is heavily skewed toward a binary “pass/fail” interpretation of gerotherapeutics. While the raw data accurately reflects the outcomes of that specific trial, the conclusions drawn from it contain significant mechanistic blind spots and biological misconceptions.
Here are the primary flaws in the analysis, cross-referenced with the 2026 Hibbert et al. Science Advances data and broader pharmacological literature.
1. The Hypertrophy Fallacy: Conflating “Power” with “Adaptation”
The analysis concludes that rapamycin “blunts muscular strength adaptations” and provides “zero measurable physiological or functional benefits” because of lower repetitions in the 30-Second Chair-Stand Test. This is a profound misinterpretation of muscle biology.
- The Flaw: The chair-stand test primarily measures explosive concentric power, which is directly dictated by the cross-sectional area (thickness) of muscle fibers. The Hibbert et al. (2026) [cite_start]study definitively proves that this specific type of growth—radial growth—is mediated entirely by the rapamycin-sensitive mTORC1 pathway[cite: 13, 167]. By administering a 6 mg weekly dose, the trial successfully inhibited mTORC1, thereby predictably blunting radial hypertrophy and the resulting concentric power generation.
- The Ignored Benefit: The analysis completely ignores the existence of longitudinal growth. [cite_start]Hibbert et al. demonstrated that mechanical loading induces the in-series addition of new sarcomeres (lengthening the muscle fiber) via a completely rapamycin-insensitive mechanism[cite: 13, 172, 703]. [cite_start]Claiming there are “zero physiological benefits” ignores that these subjects were likely still undergoing profound structural remodeling, increasing fascicle length and altering contraction velocity, even while their radial “power” adaptations were chemically locked[cite: 706, 770].
2. Mischaracterization of the “Starvation Phenotype” as Toxicity
The analysis points to elevated HbA1c (+1.74 mmol/mol) and LDL cholesterol (+0.32 mmol/L) as “objective proof” of “measurable degradation” and metabolic dysfunction.
- The Flaw: In the context of mTOR inhibition, these lipid and glucose shifts are not necessarily indicative of pathological toxicity; they are well-documented features of a state often called “pseudo-diabetes” or the “starvation phenotype.”
- When mTORC1 is inhibited, the body mimics a state of nutrient scarcity. It suppresses lipid storage (resulting in a transient rise in circulating LDL as lipids remain in the blood) and initiates peripheral insulin resistance to spare circulating glucose for the brain (slightly elevating HbA1c). Equating an adaptive survival phenotype to pathological metabolic disease is a common error in translating standard clinical biomarkers to longevity interventions.
3. The Epigenetic Time-Horizon Fallacy
The author asserts there is “zero quantitative evidence” of anti-aging benefits because epigenetic clocks (GrimAge, etc.) showed negligible differences over the 13 weeks.
- The Flaw: Epigenetic clocks track the long-term, cumulative methylation changes of cellular aging. Expecting a 13-week (91-day) protocol to yield statistically significant, systemic reversals in human DNA methylation is biologically naive. The absence of epigenetic age reversal in a single financial quarter is a limitation of the study’s duration, not definitive proof of the drug’s inefficacy as a geroprotector.
4. Statistical Misdirection Regarding Inflammation
The analysis states that mean C-Reactive Protein (CRP) increased by 4.26 mg/L, framing this as a failure of rapamycin’s anti-inflammatory properties, while simultaneously admitting the data was skewed by two massive outliers (17 mg/L and 50 mg/L).
- The Flaw: A CRP of 50 mg/L indicates an acute phase response—typically a severe bacterial infection (which perfectly aligns with the single reported Serious Adverse Event of community-acquired pneumonia). Allowing acute infection outliers to dictate the mathematical mean, and then using that skewed mean to declare the drug lacks basal systemic anti-inflammatory properties, represents poor data interpretation.
5. Protocol Failure vs. Mechanism Failure
The overarching conclusion strips away “theoretical optimism” to declare a “definitive negative result” for the drug.
- The Flaw: The trial does not prove that rapamycin is a failure; it proves that this specific protocol (combining an exercise intervention with a high-trough 6 mg weekly dose) creates a biological conflict of interest. You cannot maximally stimulate radial muscle hypertrophy (which requires mTORC1) while simultaneously dosing a compound designed to block it. The blunted functional gains are a failure of timing and pharmacokinetics, not a failure of the molecule’s longevity potential.
It’s hard to even know what to make of this AI-on-AI analysis. The study only looked at short-term data, and every conclusion is strictly qualified by that 13-week window. If I ran your critique through an AI again, it would just hallucinate even more errors.
You stated this in your analysis. Are you now saying you don’t agree with your post? Why post it if you don’t agree with it?
Your posting / analysis seems to largely be a “straw man” analysis. It was a short-term muscle study, it tell us nothing about the long-known benefits of longevity that rapamycin has demonstrated in dozens and dozens of studies.
The original commentary explicitly limited its conclusions to a 13-week or short-term timeframe, as that is what the raw data reflects.
I simply used Gemini Pro to analyze the data from this specific paper, using prompts strictly designed for objective analysis. Therefore, any conclusions are limited to the scope of this study alone. I am confident that the AI followed my instructions and did not extrapolate findings beyond the actual timeframe of the trial.
I guess the key thing we learned here is that 13 weeks is not an appropriate period to test a longevity drug.
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Exactly. The analysis was strictly limited to the data in that paper, and I certainly didn’t bias the prompts to favor any specific outcome. Gemini Pro’s use of ‘anti-aging’ was merely a description of the epigenetic clock, and ‘anti-inflammatory’ referred specifically to the C-Reactive Protein levels. If those terms are problematic, I’m happy to remove them and leave only the raw data. Since those descriptions seem to have touched a nerve, I’ll ensure the AI strips away any descriptive labels for the metrics next time.
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