Unfortunately nobody has been on it for decades - so there’s no data to measure.
1 Like
Ah, transplant patients?
1 Like
Yes, some transplant patients could be a little under three decades on it - it was first approved in 1999 - but transplant patients are a bad model to measure anything in healthy population.
5 Likes
They’re taking much higher doses (in addition to having other health problems), so those taking it for longevity benefits at lower, pulsed doses likely couldn’t extrapolate from that population.
That said, if we start seeing transplant patients with decades of rapamycin use living past 100, we will likely want to start using doses like those transplant patients 
5 Likes
3 Likes
Welcome back Peter Attia… who is off supposidly rapamycin?
Or, was that just a ploy to not seem so woo-woo to ABC networks to win a healthcare contributor role on the station… which is now a mute point.
2 Likes
Keep in mind that the Rapa group gained +28% chair stand reps, and the control group gained 46%. So even the 6mg/w Rapa didn’t negate all gains, and they still got a pretty big benefit from training.
Also, keep in mind that the sample size is TINY. Looking at the plot in Figure 2B, there are two placebo group participants who seem to have DOUBLED their performance in 13 weeks. That has a massive effect on the group means. @LukeMV I reckon you and I have been training a while, and I bet you can’t recall the last time when you doubled the number of reps to failure in 13 weeks!
For myself, I am totally unconcerned that Rapamycin is in any way getting in the way of my training. (That said, I take 2mg/wk, which is a low dose but has been enough to move several biomarkers).
Extremely well said!!
Interestingly, Rapa shortened lifespan in obese diabetic mice. (Sataranatarajan et al 2016)
So there might be something to be said for underlying metabolic health to also play a role.
It should be noted that the pneumonia case was in a patient who had taken one dose of Rapa. I feel that is more likely to just be a coincidence than immunosuppression.
6 Likes
@relaxedmeatball thank you for the comments and they make a lot of sense. I’ll consider going back to weekly, but in the meantime, I did try my first larger 14 day dose of 14mg.
HOLY MOLY!!! I took it on Thursday night and have felt like the energizer bunny ever since!
I did start an experiment of taking the Synthroid brand of t4 at the same time, and I assumed that was the source of my euphoria, but Claude said nah, it was the rapa (which is unfortunate because that means this is fleeting).
I was so nervous about taking this dose but it turned out to be a very pleasant surprise. I’m used to most people saying how they get tired.
There is still a small chance it was Synthroid… I’ll know soon enough.
2 Likes
Reading the past 200 comments… I need to caution against fooling ourselves. I’m not saying most commenters are coping. The criticism of the trial design is mostly valid.
But ask yourself: would you be equally critical of the design and consequently the results, if the trial would have been favorable for Rapa? Would the shortcomings be discussed to the same extend?
We are biased in favor of Rapa and similar interventions (Telmisarta, Ezetimib, SGLT2i etc.). Therefore we have to be particularly honest to ourselves.
Saying that - to give the results a more uplifting interpretation:
as discussed here, there is the open question how to bridge the rather large dose in mice and monkeys with the small dose in human volunteers (often 5 mg to 10 mg once a week). What this trial indicates: the typical dose in volunteers can produce a notable side effect seen in mice with much larger intake of Rapa. If we believe, that you can’t get the benefits of Rapa without getting at least some of the side effects - this study could be supportive of the current dose used in anti-aging.
To confirm this, someone would need to dig up a study in mice with a low dose of rapa, that didn’t result in muscle effects (demonstrating, that the trial result indeed mimics are large-dose-equivalent in mice).
2 Likes
A Scott Carney interview with Brad talking about his study.
Nothing you don’t know in here, but we rarely get to see Brand in these long form conversations. He seems like such a nice human.
I’ll note that he says if we have other studies showing rapa blunts muscle growth than he would think it’s nothing we should use for longevity. I think that overlooks the other potential benefits it has… for example, IF IF IF it can prevent heart failure/cancer/fill-in-the-blank, then having a little less muscle might be an excellent trade off. And on that note, as someone who is newly experimenting with every 14 day dosing, I wish we knew how infrequently we can take it while not sacrificing the other potential health benefits… I realize we may never have these answers.
3 Likes
Rapamycin’s biggest use case is slowing down cancer progression but we don’t actually know whether low to moderate doses taken once weekly or even less frequently actually do anything in that regard. Worst case, rapamycin only temporarily weakens your immune system and blunts exercise recovery effects without providing any benefit.
With SGLT2i we at least have good reason to believe that it helps with slowing down CKD progression in addition to lowering the risk of heart failure even if we were to completely disregard the ITP study.
1 Like
Stanfield’s study has degenerated into clickbait for YouTube influencers.
Someday, we will look back and think how meaningless and inadequate this small, short study was.
On the bright side, it will slow down the number of people jumping on the bandwagon and drying up or raising prices on our Indian sources.
11 Likes
One thing i still don’t get is the way this study is being portrayed though. Everyone is acting/reacting to it as if RAPA was supposed to help with muscle growth. No body is taking RAPA to grow muscles; there is steroids for that LOL. what is this obsession with longevity and big muscles. If anything, it is almost common knowledge that things that help grow muscle are usually bad for longevity, otherwise we would all be jumping on the roid wagon LOL. Plus, last time I checked not many people in body building crowd are practicing calorie restriction (another longevity intervention). This study means nothing to me, and I think we should stop mentioning it unless something new comes out.
As far as I’m concerned, I’m happy with this study. Basically, It implies (indirectly) that it mimics calorie restriction and that is a good thing for longevity, But If somebody else likes to read it differently go right ahead, do as you please. So to finalize. the study is fine and implicitly showed RAPA is good for longevity, the problem is people have decided to attach their own stories to it. LOL
I haven’t changed my weekly dosing and do not intend to.
7 Likes
Muscle mass is pretty important for longevity though. So if this study did in fact suggest that rapamycin inhibits muscle growth over the long term (and it did not) that would be a real downside
1 Like
Yes, but where do you guys get it that muscles continue (or should continue) to grow as people get older? It is a MUTE point; it is detrimental to growth of something that it is not supposed to grow. I think the only thing that grows as people get old it is ears. So, if someone were to be worried that RAPA won’t let their ears grow then by all mean stop using it LOL.
BTW, not only did this study suggests that RAPA inhibits muscle growth but the mechanism by which RAPA works does in itself inhibit growth, any growth, not just muscle, so yes please don’t go give RAPA to your kids and grandkids LOL. and yes, RAPA does in fact inhibit muscle growth in long term, intermediate term, short term and for as long as one will be using it, but that fact alone has nothing to do with longevity.
Muscle is important for longevity and healthy aging (no brainer there) but maintaining muscle is what it is important, NOT GROWING MUSCLE. Excuse my French but after 25 you’re growing shit, not muscle and not anything else, naturally, and if people decide they want to grow muscle that is all fine, but growing muscle has no relation to longevity.
Again, this study has nothing to do with longevity and everything to do with muscle growth, two very distinct and two very different things. How people mix them up or confuse them, it is totally beyond me.
5 Likes
Keep in mind that the Rapa group gained 28% strength improvement, and the control group gained 46%. So even the 6mg/w Rapa (in untrained old noob lifter) didn’t negate all gains.
Yes. And interestingly, Rapa shortened lifespan in obese diabetic mice. (
So there might be something to be said for underlying metabolic health to also play a role.
It should be noted that the pneumonia case was in a patient who had taken one dose of Rapa. I feel that is more likely to just be coincidence than immunosuppression.
Agreed. We simply don’t know. One thing I have in mind is that there’s a potential “risk” in that some cancers are very ‘sensitive’ to immunosuppression. For example, risk of skin cancers rises dramatically with immunosuppression. I found a paper saying that squamous cell carcinoma risk is 100x (yes, one hundred fold) increased in chronically immunosuppressed patients. In someone like a transplant patient, the immunosuppression raises SCC risk by up to 250-fold. Obviously a weekly (or bi-weekly) dose of Rapamycin isn’t at this level, but it’s also not nothing.
Well, that’s taking two extremes though, isn’t it?
I don’t think people expected Rapa to be anabolic. And again, the Rapa group did produce significant gains in strength etc. It’s not like Rapa prevented them making any gains at all.
But also these were old, untrained patients, not bodybuilders. If you’re striving for maximum muscle mass, that’s clearly not pro-longevity. But at the same time, frailty is a huge deal in ageing humans, and I would wager that moderate amounts of exercise to induce hypertrophy, strength, bone density etc should be pro-longevity. If you’re using steroids to the point where you get sleep apnea, cardiac hypertrophy etc, clearly it’s not pro-longevity any more.
I also don’t quite get how you think the study shows Rapa is good for longevity? Can you explain? It shows there is an effect of the 6mg/w dose, but I think we knew that already.
2 Likes
What I am not clear on is the argument for not exercising whilst there are highish levels of rapamycin in your system. I am planning on taking a dose of rapamycin tomorrow. I have delayed from 6->7 weeks for practical reasons related to the elections in Birmingham.
I will, however, continue using my exercise routine (which is not a big one) after taking it.
What we should know is that the response to exercise will be inhibited in the short term by Rapamycin. I think the response links to mitochondrial efficiency hence any increases in mitochondrial efficiency from Rapamycin will mean a greater long term response to exercise. However, that is really hard to measure as there are so many confounding factors.
If we think more generally about anabolic processes there are three components:
a) Nutrition - without the right inputs you cannot make proteins
b) Stimulus - not just exercise, but other stimuli tell cells to make proteins
c) Genomic Function - the genes need to function although this is a response to a range of post translational modifications I would argue that the key variant is acetylation.
The key driver for acetylation under normal circumstances is citrate efflux from mitochondria which follows from membrane potential/efficiency.
2 Likes
I got a few DMs asking for commentary about the results of Brad’s study, and I’m happy to oblige, but as I have not read the whole thread since the study came out, I apologize if any of my points cover arguments made by other posters. I’ll try to compensate by taking a broader view of the methodology and general approaches in the biohacking space.
I read the study, but have not taken a microscope to it, because I did not find the study personally particularly relevant or rewarding further examination. This is not a criticism of the author, Dr. Brad is a very likeable character, and he certainly means well, and I think it’s highly commendable that he undertook a rapamycin study at all. In general, I think the study has a decent design, but unfortunately the problem is with the interpretation of the results, including the interpretation made by Dr. Brad within the text of the study and outside of the study (as in the video commentary posted above).
The very first issue is a pretty prevalent one in all of science, and that is overinterpreting the results, with faulty extrapolation from the results. We must always keep in mind what it is that a study has actually shown, vs the conclusions we draw from these results.
What this study has shown is that (1) rapamycin at 6mg (2) once a week (3) over a period of 13 weeks (4) blunted exercise performance improvement (5) in select measures of select domains (sit-stand, walk, grip) (6) in older individuals 65-85 of age (7) who underwent a regular exercise program (8) and who were intially largely sedentary at baseline (9) and the study included some bloodwork biomarker results. That’s it. Sum total. Anything we extrapolate from this and any conclusions beyond the one outlined in points from (1) to (9) are speculation, whether reasonable speculation or not. It’s speculation, period, end of story.
Now, it is understandable that scientists speculate and extrapolate based on a particular model, because that’s how we refine models and try to build further hypothesis with explanatory power. But there are scientifically valid extrapolations and ones that are faulty. The valid ones are built on the totality of the contextual data and the faulty ones are those which are contradicted by other extant data. In the case of Dr. Brad, we are dealing with the latter - his explanations of the results are built on a faulty model and so his extrapolations are scientifically invalid.
Dr. Brad is aware of some of the limitations of the study, the primary one being the short duration. If anyone has any doubts about this, just look at the story of SGLT2i drugs. This is highly relevant to muscle specifically as I’ll show later. There are tons of well conducted studies showing overwhelmingly renoprotective effects of these drugs in both diabetics and non-diabetics. But what does the short term data show? There are many markers of kidney health, but the most commonly used one is a global one of eGFR. Kidney health as measured by eGFR declines with age - the eGFR number declines. SGLT2i were initially prescribed in diabetics and diabetics are particularly vulnerable to a faster decline in eGFR - guess what happens when you put that cohort on SGLT2i drugs: the eGFR number drops compared to controls not on SGLT2i. The SGLT2i drugs cause an immediate drop in eGFR in a substantial number of those diabetics. Over time however, while both the SGLT2i and the controls see an age related decline in eGFR, the SGLT2i group declines much slower (and sometimes bounces back to the initial eGFR number measured before taking the SGLT2i drug) - over time, the controls catch up with the decline of SGLT2i, and then continue declining faster, and over time, the controls keep getting further down in eGFR compared to the rate of decline in SGLT2i. Guess how long it takes for this effect to occur? It can take some 52 weeks - a year. So a Dr. Brad who did a 13 weeks study, would conclude that SGLT2i cause a decline in kidney function, when the exact opposite is true. This is a very relevant example for muscle - and I’ll cite a study showing that.
But Dr. Brad, despite knowing that 13 weeks is a limitation, nonetheless keeps extrapolating from that to conclude - illegitimately - that 6mg/1-week blunts muscle health longer term. No. That’s speculation. Look at what was actually shown in the study as outlined in point (3) - over 13 weeks, not over the long term leading to sarcopenia. Again - stick to the study, the study showed an effect over (3) 13 weeks, not 14 weeks, 2 years or 10 years. It’s 13 weeks, and that’s ALL you can claim based on the study. That’s like saying based on 13 weeks of SGLT2i eGFR number that these drugs are harmful to kidneys longer term. He even states - in the video - that he’d never prescribe rapamycin to the elderly because of fears of sarcopenia. But again, that’s ignoring the limitation he himself acknowledges - the 13 week duration, and extrapolates beyond what the study shows. Now, is this a legitimate extrapolation? Legitimate does not mean “correct”. An extrapolation may be legitimate based on all we know, it’s a reasonable extrapolation. As I outlined above, it must be based on the totality of the data in this context - if there is no contradictory data, it’s a reasonable (even if not necessarily correct) extrapolation. But here it is not - there is contradictory data on muscles that Dr. Brad does not take into account. Therefore, his extrapolation is scientifically illegitimate.
This is such an important methodological point, that I want to take an extra beat looking at this, because this happens over and over and over again in the literature - a real plague.
What is SHOWN in the study by the data is a defined set. However, authors frequently already in the discussion and most often conclusion portions extrapolate from that data and speculate. When is it legitimate, and when is it illegitimate?
In the SGLT2i, let’s imagine that all we have is 13 week data. Based on that, it is legitimate extrapolation that SGLT2i are harmful to the kidneys, because based on the totality of what we know, there is nothing to contradict such extrapolation. Obviously, while it’s legitimate, it is not necessarily correct - indeed we happen now to know it’s not correct. But it’s legitimate based on the totality of the data in this context. Now let’s imagine that we have studies showing that after week 52, the decline flips, and now the SGLT2i show a slower eGFR decline than the controls. If we still claim harm based on the 13 week study, then our extrapolation is now illegitimate based on the totality of the data context (in this case the 52+ week results). Funnily enough we see this even now with some people on this list: those who based on the initial dip in eGFR refuse SGLT2i, even though we also have the contradictory 52+ week data! They extrapolate illegitimately.
So what do we have here? Dr. Brad’s extrapolation of the data is not only speculation, but scientifically illegitimate, based on contradictory data. What that data is, I’ll discuss further down. For now, let’s look at the other big assumption of Dr. Brad’s which is simply wrong.
More in part II.
3 Likes
Part II
The endpoint of the study is exercise performance. That’s what’s actually shown in the study (over 13 weeks {3}) in point (4) “blunted exercise performace”. OK. But what Dr. Brad does now, is claim - through unsupported extrapolation - that (4) is an unambiguous marker of muscle health and performance long term. That extrapolated claim is simply wrong. First, exercise is not a good marker of longevity in and of itself - there are many studies (for the sake of time, I’m not citing them here, but I’ve posted them before on this site) showing that exercise lowers mortality but does not extend max longevity (i.e. squares the survival curve, but does not extend it). More importantly, short term exercise performance is not a longevity marker, nor a marker of muscle tissue health or performance long term. We have multiple examples, including from countless caloric restriction (CR) studies. In those studies, we see the effect of CR as promoting longevity, but resulting in lower muscle performance and bone density in the period before the decline of old age (same as short term effects of fasting on exercise induced muscle hypertrophy).
However, here we need to make a critical distinction which many people miss. It’s the distinction of (1) a tradeoff of muscle health for longevity and (2) short term performance hit on certain markers vs long term actual benefit for muscle health. That’s extremely important.
As an example we can look at statins and their effect on muscles. There have been studies showing that most statins have a negative effect on muscle health based on calcium channel handling. Whether that has a long term negative effect mediated through subpar exercise adaptation is unclear - I posted a study to the effect that there is no long term negative exercise effect shown for the 75+ year olds. Be that as it may, let’s assume that in fact statins do have a negative effect on muscle health. We may still opt to take statins, based on their overall effect - in which case we take the tradeoff, slightly worse muscle health/performance for better cardiovascular health, and we net out to the taking of statins. The same for the effect of statins on glucose control, where most statins (except pitavastatin) can induce T2 diabetes in a portion of statin taking population - we trade off this negative aspect of statins for the overall health benefit.
But is that what’s happening with CR (and rapamycin)? Is it a trade off? Do we say: both CR and rapamycin extend max lifespan (in animal models) and therefore I am willing to trade off worse muscle health/performance for longevity?
Actually, no. There is no long term trade off. Instead, it’s the SGLT2i model. We have a short term performance hit (blunted exercise benefit), but long term better performance, exactly as in SGLT2i initally taking a hit in eGFR, but later showing a SLOWER decline of eGFR. So, in effect, you have healthier and better performing muscles long term than controls. It’s not a tradeoff, but a preservation of function, superior to the declining muscle health and function of controls.
How does that happen in the case of SGLT2i? The reason eGFR dips in diabetics upon the introduction of an SGLT2i, is that in diabetics we have impaired nephrons doing more work to compensate, filtering more to compensate for the damage - so called hyperfiltration. This hyperfiltration gives you a higher eGFR number, but longer term, this extra work, the hyperfiltration exhausts the nephrons resulting ultimately in more damage and a rapid decline in filtration ability. Now you introduce SGLT2i and their effect is to eliminate the hyperfiltration - as a result, without hyperfiltration, the amount of filtering drops, and so eGFR drops. But longer term, look what you gain - you no longer have the intense exhaustion and damage to nephrons and in the long run they last longer, it’s a slower decline. It’s a win for SGLT2i, you end up not with a trade off, but with healthier kidneys compared to controls.
The analogy would be to two houses, “blue” and “red”. Both have old plumbing that’s weakening from progressive rusting and constricting from mineral deposits - the rate of water flowing from the taps is falling like eGFR. The plumbing is declining with age. The “blue house” calls for a plumber and Matt Kaeberlein turns up - he says, ‘let me turn down this pressure valve’ (by using SGLT2i, rapamycin etc.), and what happens is that because the pressure is lower, the flow of water no longer being pressured so hard slows down - the tap goes from full force to a weaker stream. Meanwhile, the “red house” calls for a plumber and Brad Stanfield turns up and says “do not touch that pressure valve, your water flow will slow down!” - and sure enough, water comes down nicely from the tap, instead of weakly as in the blue house. A year later, in the “red house” where Brad proposed doing absolutely nothing (“will not prescribe rapamycin”), the high water pressure ruptures the progressively more corroded pipes and that’s the end of any water flow from the tap at all. That’s it, flooded basement and no water in the taps, the owner dies of thirst. Meanwhile, in the “blue house”, the weak flow is not stressing the corroded pipes and it keeps on ticking, the owner quenching thirst. The result is that the plumbing in the blue house is in a healthier state and lasts longer than the red house where the pipes burst.
This is basically what happens with a lot of tissues and systems in CR - we have studies (again, posted before, for the sake of time I won’t dig them up here) showing many aspects of muscle tissue benefitting from CR compared to ad lib controls, and ultimately at advanced ages performing better than controls, not just longer lasting. You take an old mouse and the one on CR will have stronger, healthier muscles than the old ad lib one, even though at middle age the ad lib one was stronger. It’s the same curve as in the SGLT2i case - as is the case with testosterone - animals (and humans) on CR take an initial hit on testosterone levels, a dip like eGFR and SGLT2i, but exactly the same way, in the long run the testosterone levels are higher in the CR’d animals compared to ad lib later in life. Same story for reproductive capacity on CR - like exercise capacity superior in old age compared to ad lib, despite the early dip. This is true of many tissues, including neural tissue on CR (and we see that in biomarkers in humans as in the CALERIE study), not merely longer lasting as a tradeoff, but actually healthier, no tradeoff, just straight better. Now, that doesn’t mean that there may not be actual trade offs with CR or rapamycin - the CALERIE study in humans showed lower bone density on CR. In animal models there were hints of CR causing an initial dip in bone density, but compensating for it with superior bone architecture ultimately resulting in superior bone strength in old age. But that is not proven in humans, so from an abundance of caution, I call bone density a genuine trade off in CR. Same way rapamycin can show glucose and lipid disregulation - even though MK claims that in mouse models this normalizes over time, several weeks - I still am cautious and allow that rapamycin may genuinely have a side effect of worse glucose and lipid control. But exercise performance? Nah.
There is one other - minor - aspect of rapamycin and exercise performance, which Dr. Brad is not taking account of. In the PEARL trial, we saw a tendency of women having superior muscle mass and skeletal effect from rapamycin over the long term (48 weeks). Anecdotally, we have reports from folks like Matt Kaeberlein that rapamycin can rescue conditions like frozen shoulder and better performance and recovery in the gym, and many people report fewer aches and pains when exercising with rapamycin (myself included - in fact, this is the only positive effect of rapamycin that I can subjectively FEEL - my endurance is better and I have fewer joint and tendon pains when exercising or post exercise). If this is a legitimate effect, then Brad might not be taking into account the effect of better capacity to exercise - rapamycin may have less of a performance growth with exercise, but because you can exercise MORE with rapamycin (due to muscoskeletal recovery) you might ultimately end up with better performce effects from being able to perform more exercise thanks to rapamycin - something not tested in the exercise program as structured in Brad’s study (a limitation of the study).
But is there a similar “hyperfiltration” effect in muscles as in the kidney nephrons? This is where the SGLT2i effect on kidneys is so relevant to the aging muscle. This is a vital effect which has monumental importance on our approach to the biohacking of the whole aging process - something that is sorely lacking in the approach of the vast majority of the people in this space.
More in part III.
2 Likes
I haven’t seen Part III, but I agree with your analysis in Parts I and II.
It remains, however, that given my understanding of the mechanism through which Rapamycin affects cells I think it should be taken less frequently than every week. I am taking it tomorrow 7 weeks after the last dose. A high dose, however.
1 Like