#637

Whether it didn’t increase his aging speed is besides the point, what matters is longevity and worsening of cholesterol, glucose, soft tissue infections, and RHR is not good for longevity.

Nobody is debating these points other than you. Even Bryan Johnson was aware of these things—it was the laughable aging clocks preprint that was the turning point for him.

Him calling rapamycin poison and saying it accelerated his aging for clicks is not “besides the point.” He’s promoting misinformation to millions of people. Most of us here have caught onto his grift for awhile now, but many of these people on YouTube and X are quite credulous (thinking he’s a hero, God, etc). It’s a real problem.

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#638

Johnson just upload a new piece on Rapamycin (made him older)

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#639

Nicely produced video. It certainly raises my concern about taking rapamycin. Especially the cancer risk. But he was taking pretty high doses and was already doing a bunch of other stuff with likely overlapping mechanisms.

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#640

From a lover to a hater. It seems as if he wants to keep the secrets of longevity to himself. Besides, Rapamycin can’t make him any money anyways. He’s just in it for the fame and money now.

He’s peddling supplements and common sense that will help people live their normal lifespans.

Honestly, I don’t trust any expert that doesn’t first address the CVD elephant in the room. If you can’t dodge heart disease, you’re not serious about longevity. And you can’t do that without talking about Bempedoic Acid, Ezetemibe and statins.

That’s why I give Peter Attia high marks.

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#642

It isn’t. Transplant patients on mTOR inhibitors are associated to have higher rates of CVD compared to other drugs. I don’t know about marmosets, but mice don’t die from CVD, while that’s the primary cause of death in humans. Mice die from cancer, and mTOR can be used to treat cancer. So as far as mice are concerned, they are not informative whether it will be a net benefit in humans concurrent with such side effects.

Of course, but if you don’t then it is expected to be a net negative. Even young people get CVD, so whether someone is the biologically youngest patient with CVD like stroke or MI isn’t incompatible.

You explicitly said that it didn’t increase his speed of aging, and I told you that what matters is longevity, and listed the different side effects on longevity. So do you agree that it’s longevity that matters now and not speed of aging (geroprotection) per se?

It was explicitly said in the video that they learned about the preprint 1 month after cessation of rapamycin. Unless you define the turning point anything other than actually quitting rapamycin.

Not sure what you did in this discussion. If you didn’t pay attention to the video while you watched it, or if it’s bias, or something else. Consider refuting a steelman of the video instead.

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#643

Well, you might be right, as I am not familiar with all the transplant literature. However, sticking to rapamycin rather than all mTOR inhibitors, and to heart transplants specifically, since you highlight CVD, rapamycin appears to actually be superior to other drugs, resulting in lower all cause mortality, longer survival and fewer events compared to another class of drugs used in this setting (calcineurin inhibitors).

Long-Term Sirolimus for Primary Immunosuppression in Heart Transplant Recipients

https://www.jacc.org/doi/10.1016/j.jacc.2017.12.005

“Results:

The progression in plaque volume (2.8 ± 2.3 mm3/mm vs. 0.46 ± 1.8 mm3/mm; p < 0.0001) and plaque index (plaque volume–to–vessel volume ratio) (12.2 ± 9.6% vs. 1.1 ± 7.9%; p < 0.0001) were significantly attenuated when treated with SRL compared with CNI. Over a mean follow-up period of 8.9 years from time of HT, all-cause mortality occurred in 25.6% of the patients and was lower during treatment with SRL compared with CNI (adjusted hazard ratio: 0.47; 95% confidence interval: 0.31 to 0.70; p = 0.0002), and CAV-related events were also less frequent during treatment with SRL (adjusted hazard ratio: 0.35; 95% confidence interval: 0.21 to 0.59; p < 0.0001). Further analyses suggested more attenuation of CAV and more favorable clinical outcomes with earlier conversion to SRL (≤2 years) compared with late conversion (>2 years) after HT.

Conclusions:

Early conversion to SRL is associated with attenuated CAV progression and with lower long-term mortality and fewer CAV-related events compared with continued CNI use.”

Plaque formation is a significant factor in CVD, and is attenuated by rapamycin compared to other drugs, resulting in lower all cause mortality.

That’s the heart transplant. What about the much more common kidney transplants? Well actually it’s entirely the same story. Rapamycin compared to other drugs is cardio protective in kidney transplant patients through a variety of mechanisms, and as I posited, the elevated lipids can in fact be effectively treated with lipid lowering drugs.

Cardiovascular risk profile in patients treated with sirolimus after renal transplantation

https://www.kidney-international.org/article/S0085-2538(15)50764-3/fulltext

“Renal transplant patients are inherently predisposed to cardiovascular disease (CVD) as a result of prolonged exposure to multiple cardiovascular risk factors. Approximately one half of all late graft losses are due to death with a functioning graft, and CVD is the most frequent cause of death with a functioning graft among these patients. Immunosuppressive therapies associated with a reduced burden of risk for CVD would therefore greatly decrease post-transplantation morbidity and mortality. The nephrotoxic effects observed with the use of calcineurin inhibitors (CNIs), such as cyclosporine (CsA), run counter to the goal of renal transplant therapy. Sirolimus, a more recent immunosuppressive agent with a unique mechanism of action, offers an alternative to CsA. Recent data from a 4-year study investigating early CsA withdrawal from a sirolimus-CsA-steroid (SRL-CsA-ST) combination demonstrated significantly better renal function, lower blood pressure, and improved graft survival after CsA withdrawal. During that trial, the increase in serum lipids induced by sirolimus was generally manageable with lipid-lowering therapy.”

There is reason to believe that rapamycin can lower the progress of atherosclerotic plaque despite raising lipids - this was demonstrated in the first paper I cited, where plaque volume was comparatively lower by rapamycin. The reason being, that while elevated lipids are a definite cause of plaque and CVD, elevated lipids do not always result in those pathologies even in familiar hypercholesterolimia, as some other factors can protect the CV system from high lipids. Rapamycin comparatively resulting in lower progress in plaque volume, hints at such protection.

What about liver transplant patients? Again, rapamycin does not appear to be a CVD negative compared to other drugs, contrary to your claim.

The Effect of Sirolimus Immunosuppression on Cardiovascular Outcomes in Liver Transplantation

https://www.sciencedirect.com/science/article/pii/S2666967624000126

“Conclusions

Our analysis shows that in both the NASH and non-NASH cohorts, liver transplant patients on sirolimusdid not have a significantly higher risk of developing cardiovascular disease after transplant compared to immunosuppression with calcineurin inhibitors.”

Again, rapamycin might result in worse CVD outcomes in transplant patients, but I didn’t find much evidence for that.

But, moving from transplant patients, how does rapamycin do with other heart pathologies? You mention mice not being a good model as they don’t tend to die of CVD - fair enough (although BJ was concerned about cancer and mice die a lot from it - but less on rapamycin). However, I mentioned animal models - and looking at those, we also have cats. Rapamycin has just been cleared by the FDA as a drug that prolongs the life of cats suffering from heart hypertrophy, a very common condition that cats tend to die from. So again, rapamycin tends to prolong life in an animal model of this CVD. But we have another animal model with other CVD conditions - dogs, particularly large dogs tend to die of CVD. Here, in research conducted by Matt Kaeberlein, it seems rapamycin has a remarkably strong effect in making the heart functionally younger, improving ejection fraction and other clinical measures, in the words of MK, rapamycin appears to reverse the aging of the heart in dogs. The general health of dogs seems to have been improved leading to a new trial that will look at lifespan effects of rapamycin in dogs - we shall see, but I wouldn’t bet on rapamycin shortening their lifespan through CVD.

In short, while rapamycin might be a net negative for CVD in humans, I can’t find particularly strong evidence that this is so. If I had to place my bets, I’d bet on the opposite.

The lipid disregulation is one mechanistic speculation for why rapamycin might be a CVD negative. And perhaps, as you say, rapamycin might not net out to be a net positive because of that. But if higher rapamycin LDL in some people is the basis of this mechanistic speculation (sadly we don’t have lifespan studies in humans), then we do have very effective drugs to lower that LDL in those people, hence that mechanistic objection seems can be met very effectively by such a drug combination. Thus, looking at this concern (CVD) in some people on rapamycin, I see grounds for optimism that such drug combinations could entirely dispose of this biomarker worry.

Bottom line, I still don’t see why the hypothesis that rapamycin might be a net life prolonging intervention in humans despite some side effects has to be wrong. Not based on your CVD objection, met with drug combinations.

The hypothesis might still be wrong, but we need stronger evidence for it being wrong than that which has been supplied by BJ (or yourself) thus far. BJ has placed his bet wrt. to rapamycin, and others (including myself) have placed the opposite bet. New evidence might surface which will change my mind, but the evidence supplied by BJ I don’t find personally compelling. YMMV.

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#644

We have to keep in mind that transplant patients were not healthy to start with. Most of them had previous life threatening complications that resulted in organ transplant. Therefore, imo it doesn’t help to compare transplant patients with (more or less) healthy group that uses Rapamycin for longevity.

But even for transplant patients mTOR inhibitors are known to reduce the risk of malignancies and renal dysfunction compared to other immunosuppressive drugs. They may also help prevent cardiac allograft vasculopathy, a common cause of late mortality in heart transplant patients.

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#645

The way I see it:

  1. He has supplements and other wellness stuff to sell. Back in the day, he was all-in on metformin, aspirin, acarbose etc - basically anything which had passed the ITP. He was also taking exogenous testosterone and estrogens, and he was taking a statin. Now he’s preaching more of the “all natural lifestyle” type of message. The guy ditched statins and let his ApoB go higher, and the only reason I can think of is because of the brand image. Rapamycin doesn’t fit with the brand either.

  2. His decision was largely based on metrics like HRV and RHR where we aren’t too confident about the importance.

  3. The biological clocks especially I don’t put much belief in, though he uses this more like a justification for already quitting.

  4. He was taking a pretty high dose IMO. Especially as a guy who probably didn’t have that much to gain from additional mTor inhibition, given that he’s already on calorie restriction. It’s interesting to me that rather than taking a lower dose, he just quit altogether. Again, that IMO is more of a “brand” decision than a scientific one.

  5. I hate clickbait. Though the content of the video is pretty much fine and fairly reasonable, the “poison” designation is a huge detriment to any sort of credibility IMO.

  6. Again, I am compelled to point out that these questions and controversies could be relatively easily answered, within a few years, if he threw a small fraction of his wealth towards a reputable lab to run an experiment. If he actually truly believes in DON’T DIE then that’s a far more likely way to get us there than amino acids and minerals found in blood orange flavoured “longevity mixture”.

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#646

LDL-c wasn’t different between groups in that study and increases in lipids lead to adjustments in statin therapy.

It’s not speculation since we know that LDL-C is causative of ASCVD. Atherosclerosis is expected to happen with a suboptimal LDL-C.

mTOR inhibitors had significantly higher incidences of cardiovascular (ROR 1.95, 95% CI 1.70, 2.23), dermatologic (ROR 1.34, 95% CI 1.04, 1.73), endocrine (ROR 1.52, 95% CI 1.26, 1.82), gastrointestinal (ROR 1.15, 95% CI 1.01, 1.30), infectious disease (ROR 1.35, 95% 1.20, 1.52), musculoskeletal (ROR 1.39, 95% CI 1.13, 1.70), pulmonary (ROR 3.46, 95% 2.97, 4.03), renal (ROR 1.27, 95% CI 1.10, 1.46), and vascular AEs (ROR 3.10, 95% CI 2.14, 4.49). Across every organ type, mTOR inhibitors had greater cardiovascular AEs compared to tacrolimus, specifically in arteriosclerosis, heart failure, hypotension, tachycardia, chest pain, edema, and pericardial disorders. mTOR inhibitors may be associated with higher cardiovascular AEs. Further investigation is required to determine the potential mechanism of this effect.

Here’s the study I referenced earlier, and there was an associated 12x increase in dyslipidemia. I don’t really believe this study results that much. but the point is that suboptimal lipids from rapamycin if they happen hasn’t been proven to have no negative effect if they aren’t reduced back to optimal. All of the current evidence points to the contrary.

Mtor inhibitors associated with higher cardiovascular adverse events—A large population database analysis 2021

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#647

The consequences of mTOR inhibitor dyslipidemiasper seare unknown, and there are no long-term studies with adequate statistical power to determine whether mTOR inhibitors alter the risk for CVD events. In the absence of data to the contrary, it should be assumed that dyslipidemia caused by mTOR inhibitors increases the risk of CVD in kidney transplant patients as much as it does in the general population. Dyslipidemia associated with mTOR inhibitors can be successfully managed with statin and/or ezetimibe therapy in kidney transplant patients (20,43), following the KDOQI and NCEP guidelines (1,37).

Mammalian Target of Rapamycin Inhibitor Dyslipidemia in Kidney Transplant Recipients 2008

#648

These aren’t independent data. Any speed of aging data has to take longevity data into account (excluding cases of getting hit by a train, of course, knowing how you like to argue).

If you have atherosclerotic plaques your vascular system is aging at an accelerated rate <-> reduced longevity.

Manage your LDL-C of course. It’s not complicated, and people should do it whether they’re taking rapa or not.

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#649

You misunderstood, but perhaps my writing was ambiguous. What I meant is not that elevated LDL being causative of ASCVD in general is speculative (which we all know is causative although not in every person), but rather that LDL elevation due to rapamycin specifically, causes ASCVD is speculative - we don’t have proof, but as I said, it is plausible. Which is why I said that this negative side effect can be controlled with other drugs. Which was done in some of these studies, and to the result that ACM was lowered compared to other immunosuppresive drugs. Thus showing that rapamycin falls within the category of drugs with side effects I mentioned in my earlier post - drugs with benefits, but that have side effects, which in turn are controllable (with other drugs) resulting in net benefits. I believe these studies demonstrate that.

However it is important to note that this effect of rapamycin driven dislipidemia occurs in compromised patients on dosages of rapamycin which are immunosuppresive. This is not the dose or protocol utilized by those aiming for life extension purposes. As always, it is the dose that makes the poison. It is rather disingenuous to argue that rapamycin causes harmful side effects at doses specifically designated to suppress organ rejection and that this therefore applies to rapamycin at completely different doses. Because at different doses and pulsed, we know from the Mannick study, rapamycin is immune system enhancing. Please note, that not everyone taking rapamycin for life extension purposes has the effect of lipid and glucose disregulation, and those that do have a choice of adjusting the dosage or abolishing the negative effects with combination drugs which have been shown to be additive in animal models when it comes to life extension (in the case of glucose control drugs). As the study you yourself quoted says:

“Dyslipidemia associated with mTOR inhibitors can be successfully managed with statin and/or ezetimibe therapy in kidney transplant patients.”

Soon I will have extensive blood tests to assess the impact of rapamycin in my case. I might have elevated lipids and glucose just as BJ had. BJ quit rapamycin due to this side effect, just as some patients quit statins when those have a glucose elevating effect. Others, and this will be my approach, persist in taking the drug, but attempt to offset the negative side effects (a course of action recommended by cardiologists in case a statin raises glucose as it nets out better). My course of action will be different from BJ’s even though both of us may have exactly the same side effect from rapamycin. I am placing a bet that just as in the case of statins, rapamycin will net out positively, since “Dyslipidemia associated with mTOR inhibitors can be successfully managed with statin and/or ezetimibe therapy”.

You pays yer money and you places yer bets. I am betting on the opposite side from BJ, because looking at the same evidence I come to the opposite conclusion. None of his reasoning in this respect do I find personally compelling. YMMV.

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#650

It’s not the correct way of framing this in my view, we know from every line of inquiry that the scentific process can muster that LDL-C/ApoB is an independent, causative, and significant factor in ASCVD. That means it doesn’t matter what increases it. What we don’t know is if rapamycin can offset this, so until that has been established, what we do know is it is causing damage. The null hypothesis is that there is no effect of rapamycin on ASCVD. The null hypothesis that there is no effect of LDL-C on ASCVD has been disproven, and there is a negative effect. The net result is that suboptimal lipids from rapamycin, carnivore diet, resveratrol analogue, and a hundred other things that elevate lipids in someone, but haven’t been proven to increase heart attacks in a clinical trial, are expected to be harmful via ASCVD. That’s also why it’s enough to lower LDL-C to get a drug approved while the outcome trials are underway.

That’s good, it’s an interesting study and a positive result, but I’m unsure how generalizable it is as I don’t know much about HF and that specific outcome.

It hasn’t been that uncommon for people to report having an increase in lipids and even hyperlipidemia on the typical doses and schedules people describe here, but they’re anecdotes. A statin and ezetimibe might totally offset that however.

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#651

Gee, from your last post it looks like we broadly agree. Glad we reached the point I originally stood at, even if we took a long and circuitous route.

As has been said in other contexts - it is unlikely that a single drug will substantially affect a complex process like aging. Odds are that it will take a combination of many drugs to have any impact.

We don’t know if rapamycin can help human lifespan or healthspan. It might be a net negative. But if it is helpful, odds are that other drugs might be needed too for its full positive potential - and the ITP studies in mice seem to imply that. That’s my roll of the dice. As always I will continue to be alert to evidence for or against this hypothesis.

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#652

5mg once per week is the lowest amount he tried according to that video. That’s not a high dose by most metrics.

I thought I read once he took it every two weeks as well but that video seems to suggest otherwise unless he simply didn’t mention it.

#653

One problem with the epic number of supplements and interventions he’s taking, is that there is great chance of unpredictable interactions. For example, it’s possible that if he took the same dose of rapamycin, but didn’t simultaneously take some other drug/supplement(s), he might not have experienced the same side effects. There’s just no way to know. I’m a great fan and advocate of polypharmacy, as I think it absolutely necessary for substantive improvements, but that also requires massive research and experimentation to establish whether the interactions are additive or negative. Frankly, I spend even more time on researching interactions than on the primary drug indications. But BJ’s stack is beyond my computational capacity and research time available. Bottom line, I’d be cautious extrapolating too much from his experiencing. YMMV.

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#654

The one negative thing I see from using Rapamycin that I speculate could be causative is that I’ve seen some pretty large increases in A1C that I don’t know how else to explain. I can’t completely blame the Rapamycin but I just don’t see what else could cause it when I’m also taking Acarbose and Empagloflozin.

I took a month off it once and used Berberine and it went down pretty significantly. The problem is since I added Berberine, it could be that instead of the time off Rapamycin that helped to get it back down.

I then restarted Rapamycin without the Berberine and it went back up.

I’ve seen lower A1C’s in the past without Berberine, which is why I speculate it’s from Rapamycin.

Currently taking time off Rapamycin again WITHOUT Berberine this time to see what happens to my A1C.

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#655

But he seems to be tracking each thing he adds/removes individually, as he says he did in the recent Rapamycin video.

Honestly I think he is presenting a decent case against Rapamycin. His anecdotes actually do hold some water with me since he measures a lot more parameters than pretty much everyone else. I just would like to ask if he tried taking it bi weekly instead. I could have sworn when his original list of supplements was released just as he was becoming popular, it said 13mg bi weekly Rapamycin on it. This video seems to make it sound like he’s only done weekly doses unless I misunderstood something.

#656

Perhaps. But as the list of drugs, supplements and interventions grows into the hundreds, I am skeptical that you can adequately isolate all effects by testing. First many effects cannot be adequately quantified, and more importantly, as secondary and tertiary effects manifest they impact each other in unpredictable ways, especially because they are spread out in time. Some only become evident longer term. No way can you then do tests that can detect some effect that took months/years to manifest and pin it on the last drug, or one drug. I think this is highly unlikely.

That is why in addition to testing and observation, I rely heavily on research papers showing interactions and long term outcomes, which I am in no position to test ahead of time on my own body. I think it’s absurd. Naturally, there will be many unknowns, attempts at risk/reward calculation and a lot of speculation. That comes with the territory. But it’s the best we can do currently. That’s why it’s all playing the odds. I bet on rapa, he bets against. I’ve looked at his arguments and found them personally not convincing. So it goes.

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#657

If I’m going to be picky, we can say that Rapamycin sometimes makes LDL-C higher, but there is more to ASCVD than just LDL-C. Some people, for whatever reason, can have sky high LDL-C and never build any plaque. It is possible that Rapamycin, despite worsening circulating lipids, is actually beneficial for ASCVD, because it may have effects on the wider spectrum of inflammation, autophagy, and perhaps direct action on the plaque itself, reducing cell infiltration and growth, and contributing towards removal and resolving of soft plaque. That is what some studies seem to indicate, at least. The only way to conclusively disprove the hypothesis you posited would be to look at Rapamycin and actual ASCVD outcomes, which most likely will never be done.

However, I do agree with your overall point here, and I view higher LDL-C as a “cost” for being on Rapamycin, and I take other measures to control the LDL-C, since it’s known to be an essential part of ASCVD. If my HBA1C went up while taking it, I’d also manage that - as you say, just as you’d do for any other sort of intervention.

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