Hi John
I agree. I think the PEARL study is reflective of what we can expect with human rapamycin use - mild benefits but unlike the preceding mouse, worm and fly studies, no longevity benefits from rapamycin alone. Doesn’t mean that rapamycin shouldn’t be a part of our long term longevity plan but we should temper our expectations of it
I disagree with that. I think intermittent Rapamycin can produce longevity benefits. The dosing in PEARL (which was driven by the need to have a placebo that could not be distinguished from rapamycin itself) was too low to be able to measure any real effects.
As people know I think the mechanism through which Rapamycin has its main benefit could be called a “spring clean”. I would say of mitochondria, but I am happy to agree on a general metabolic improvement. The frequency and depth of such cleans are things for experimentation. I go for deeper and less frequent. However, there are potentially other negative side effects from going too deep.
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A lot of this is supposedly due to loss of neuromuscular junctions (how your brain talks to the muscle). Strength is a function of muscle mass, but also how well you can activate it. That’s why a 60kg trained lifter can be stronger than an untrained 100kg guy. However, the 100kg guy will likely have a higher ceiling if he trained.
Hmm, I think the glucose and lipid effects are well known, minor, and expected. They’re also very easily managed.
Grip strength though at least has some plausibility. In the animal studies, mice treated with Rapa have better performance in the various tests of physical fitness. There is a plausible mechanism where aged cells, including satellite cells, are cleared, basically allowing muscles to recover better. But that’s where this sort of study is just way too short to tell us anything. As I pointed out early, untrained elderly lifters will have a big lag time and learning curve when it comes to any sort of exercise intervention. Even a young healthy guy will make fairly negligible gains in hypertrophy or strength over the first few weeks of lifting, simply because you need to recover and adapt to the new stimulus. The greatest gains usually come in the 3-12 month window.
And again, you have two participants in the placebo group who DOUBLED their performance during the course of the study. Any of the gym bros here will tell you that that isn’t something you should expect in anything except untrained people who probably didn’t push very hard in the first baseline test. So it’s really very limited data to draw any sort of conclusions.
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“I disagree with that. I think intermittent Rapamycin can produce longevity benefits.”
John, let me qualify that statement - I believe that rapamycin and other autophagy stimulators will have profound benefits in extending the healthspan of humans. However, I do not think that rapamycin alone will extend lifespan. For maximum effect, rapamucin needs to be pulsed along with 12 week anabolic phases. I am waiting for the study to show that this pulsing will, in the long run (after 1 year and not at the end of 13 weeks) give an improvement to both muscle hypertrophy and muscle strength, compared to the arm that just drives muscle anabolism for a month. To extend lifespan a rapalogue may need to be combined with SIRT support, senescent cell reduction and epigenetic reprogramming.
So in the mean time, this is what i am doing - a 3 month block of rapamycin, plus an autophagy lifestyle (zone 2 training, ice-baths, spermidine, Urolithin-A, fasting). This is followed by 3 months of an anabolic lifestyle (heavy weights, HIIT, high protein, high Leucine, higher calories, saunas). What I am finding is that the gains in the anabolic cycles are noticeably greater and the body inflammation is reduced (no stiffness, no injuries) than just by pushing hard on a continuous basis.
There has been a mouse study done showing the histological muscle quality improvement from using sirolimus for i think 12 weeks, but not to my knowledge a human study. As far as I am aware there has been no study on pulsing autophagy and then anabolism. In honour of Yoshinori Ohsumi and his 2016 Nobel acceptance speech for his contribution to autophagy research, I think this aught to be done.
Any thoughts on this approach?
I like the term “a rapamycin spring clean”. Please explain in what way you are going deep?
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The key point is that mitophagy is selective. Although there will be a limited stochastic element you can consider it for example as going for the least efficient say 1% or 2% of mitochondria. 2% is going deeper than 1%.
I am assuming also that the fission, mitophagy, fusion process is working.
Looks like Brad started taking 1.25mg Tirzepatide and 6.25mg Empagliflozin if you scroll to the bottom.
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Nice catch! Thanks for sharing. Soon everyone will be on statin + ezetimibe (+ obicetrapib?) + GLP-1RA + SGLT2i. Easy win.
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I know of Yurpeak, which is sold at about the same price as Mounjaroo in the US.
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I don’t think that’s true. The mouse studies show greater benefits with higher doses and we haven’t even found the dose that is too high for mice. Since they take a lot relative to humans I don’t think that’s suggestive of small margin of error. I don’t think rapamycin has a narrow therapeutic range, and for people that are concerned about getting in the range of taking too much, just stay on the safe side and take a very moderate dose.
In general, the lower the dose you take the lower the chances that any benefits will be small enough to not reach significance. However the lower the dose, the higher the chances of the benefit/risk ratio being higher.
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Sirolimus is associated with impaired spermatogenesis and, as a corollary, may reduce male fertility.Moreover, the fathered pregnancy rate (pregnancies/1000 patient years) was 5.9 (95% CI, 0.8-42.1) and 92.9 (95% CI, 66.4-130.0) in patients receiving sirolimus-based and sirolimus-free regimens, respectively (p = 0.007).
Adverse effects of mTOR inhibitors on spermatogenesis are poorly evaluated but hypogonadism is described under sirolimus. We report the case of a renal transplant 30 years old patient in whom azoospermia was discovered while he was being treated by everolimus.
Rapamycin administration in mice has been shown to cause testicular atrophy, and hypogonadism has been observed in humans as well; the therapeutic window for this drug is quite narrow.
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I agree that we need to test higher doses to truly demonstrate rapamycin’s clinical efficacy. Since both 1mg and 6mg doses have failed to show results, we need clinical data for 10mg, 15mg, and 20mg. I recall there are already relevant clinical trials underway for these.
Furthermore, the current once-weekly dosing regimen is quite flawed; we need to rethink not only the dosage but also the dosing interval.
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We could even conduct an N-of-1 trial on our own to determine an truly effective protocol. This would require your current anti-aging stack to remain constant while you adjust the rapamycin dosage and dosing interval, followed by rigorous monitoring. For instance, those with tumors could track whether tumor progression is suppressed, while elderly individuals could monitor gait speed, inflammatory markers, vascular health, cardiac function, and frailty indices. Patients with Type 2 diabetes could track insulin sensitivity. Whether we see deterioration or improvement, sharing these findings would be invaluable.
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Well if 6mg per week is enough to suppress exercise benefits, I wouldn’t want to take more. Also, dose frequency is probably the biggest mystery here.
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Yes - caloric restriction does the same thing, (evolution prioritizes survival over fertility during times of scarce food - no big surprise there), and rapamycin mimics many aspects of caloric restriction, and everything comes back when food level rises again (caloric restriction goes away).
There are lots of papers about organ transplant patients going off rapamycin (moving to other drugs) and then having children.
More details here: Possible Rapamycin Risks for Healthy Humans (Part 2)
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How would we even measure successful results when it comes to Rapamycin if longer lifespan is the goal? It doesn’t seem to improve many lab markers. And for what it’s worth, it doesn’t seem to make people younger on those biological age tests from what I have observed.
Yes, it’s impossible right now for the individual person, given the tools we have today. All we can do is measure our biomarkers and make sure things are not going out of whack, and at the same time wait for the larger clinical trials now under way.
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Cancer survival and prevention rates. If rapamycin doesn’t provide a statistically strong benefit there, I’d consider that conclusive evidence. Ideally you have several groups taking 6mg, 10mg, 20mg and 30mg once weekly, once biweekly and once per month.
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Exactly correct. Unless you are planning on having children imminently, this is a desired effect, exactly as in CR - it indicates the drug is at a dose where it is having an actual effect. Of course, transplant patient dosing protocols are rather different from the way people take it for life/health purposes.
The rat testicle atrophy was a talking point for Chris Masterjohn in his article deprecating rapamycin a couple of years ago, and we discussed it on the site at the time (overall unfortunately the article was poorly written and unconvincing). So the whole thing is old, old news with rapamycin, regularly rediscovered by people who only started reading up on rapamycin/yawn/.
The fertility tradeoff is very common for a lot of longevity interventions, which doesn’t mean we should always welcome it (eunuchs, anyone, lol?), but it’s a bog standard mechanism. That said, in CR it was always a matter of intense discussion. I remember some 20-25 years ago on the email list for CRONies, there was extensive discussion when the men on more severe CR reported a drop or outright disappearance of the sex drive. The group broke into two camps - for some it was a regrettable side effect. For others it was a genuine benefit, they felt peaceful without the intrusive sexual thoughts and urges, generally lower aggression levels and a big jump in QOL. But one very prominent CR practitioner and advocate, a founding member of the CR list actually abandoned CR altogether, because his wife gave him an ultimatum: her or CR. He chose his wife. Perhaps rapamycin might split people into similar camps😂.
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My N=1 Inflammation level is that of someone in their mid-40’s – taking 6mg weekly with water. No other additives. Mostly same dose 5 years. Biological age 22 years younger than my 68 chronological age.
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Valid. It’ll take a very long time to run these studies though.