Update on Brad Stanfield's Rapamycin Clinical Study in NZ

[Zac]

I just switched to 6mg every other week.

[Olafurpall]

@starspawn0

It would be interesting to see if like a year or two later the people who took Rapamycin are in better health, compared to the placebo group. i.e. it might be that a couple weeks of Rapamycin triggers long-term improvements in health.

That would be interesting and an improvement in design if they followed people up so much later. I still don’t think you would detect an effect. I think it’s a stretch to expect to detect some long-term benefits after just 12 weeks of treatment considering that that’s not even 0.25% of the lifespan of humans.

@L_H

I wonder, given this research and given the recent paper indicating that rapamycin’s benefits largely derive from autophagy…whether we should be inspired by fasting research when deciding the best rapa dosing schedule.

That’s not a bad idea. The problem with that idea is that we also don’t know what the optimal regimen of fasting is for longevity for humans.

@LukeMV

No, both groups actually did train the exact same amount so it was a well designed study.

I don’t think it was well designed to answer whether rapamycin is beneficial for longevity. I think it was well designed given the funding limitations. However, he didn’t have enough funding to do a study that gives more answers as to whether rapamycin slows down aging or not. For that he would have needed a longer duration study. Also, the training regimen was far from optimal but it would have been more complicated and expensive to have them on a proper resistance training program. The chair stand up test is practical but a poor test if the goal is to test an intervention that gives a strong stimulus for muscle growth and strength. For some of the participants, standing up from a chair may have been hard enough to recruit type II muscle fibers and sent a strong stimulus for muscle mass gains. For others it may have been too easy to send a strong stimulus and for them the exercise was largely endurance exercise.

@qBx123Yk

The long half-life makes weekly dosing too frequent for my purposes. I prefer to do short cycles now: taking 3-6mg of rapamycin every 2 weeks, for at most 2 months out of the year. My intuition is that measurable inhibition should be acute, short, and infrequent. The inhibition is only half of the equation, giving the body enough time to recover is the other half.

If we assume for the sake of the argument that enough time to recover is the other half, why would you assume that you need months of recovery between bouts of doses? The mouse lifespan studies certainly don’t have long periods without rapamycin for recovery between doses.

@John_Hemming

My basic argument is that we need an anabolic period as well as a catabolic period. All of these things are variable. It is not a switch between anabolic 100% and catabolic 100%, but variations between the two.

That I agree with, but that does not mean the period between doses needs to be 42 days (which you seem to have settled on) for it to count as fluctuations between anabolic and catabolic. Even with very high doses, levels typically drop below that which inhibits mTOR significantly within a week.

@John_Hemming

Ask yourself a question. How often do you want a period of enhanced catabolism?

We know that weekly is probably too frequent.

No we don’t. I would argue that weekly is not necessarily too frequent, depending on how many days the catabolism is enhanced. If you consider rodents in calorie restriction studies, they are basically strongly catabolic half of the day between their daily feeding periods and that certainly isn’t too frequent for them.

@LukeMV

First, we can’t ignore the fact that Rapamycin was shown to improve muscle gain in animals. Yes, the mechanism would suggest otherwise and we now finally have proof of that in humans. It makes sense I suppose since animals aren’t strength training the same way that humans are.

I think it’s a matter of different time frames. In the short term, rapamycin will likely reduce muscle mass. But over the long term it will have the opposite effect. That effect may not become apparent until after decades of taking it. It’s reducing the mTOR overactivation which is a part of what causes anabolic resistance later in life. If you’re looking at short term effects you’re looking at the wrong things.

@Beth

If one wants to consider dosing every two weeks vs weekly, how do we begin to figure out the right dose to try?

If you have been dosing weekly, without any problems, then the most obvoius simple starting point is to double the dose and take that every other week.

@LukeMV

Stanfield mysteriously said prior to the results being released that if someone were to use Rapamycin, every 6 week dosing might make the most sense.

I think he is being overly cautious, which makes perfect sense, since someone in his high status position wouldn’t want people copying his recommendations in case he turns out to be wrong.

@AgentSmith

I never added it back after I logged how it impacted my strength. My wife had the same experience - she also had to drop it.

Interesting. FYI anecdotally your experience is rare however. I’ve seen hundreds of anecdotes on the use of rapamycin and it’s not common for people to notice negative effects on muscle strength or gains. Of course the effect could be common but just too small for people to notice.

@DrFraser

I’ve mostly stopped doing the multiple levels required to hunt this down and taken the approach of getting a level of 3 ng/mL at ~30-35% of the dosing interval, such that we know the level is above this for approximately 1/3rd of the week.

I must commend you here by saying that I think your approach here is one of the most reasonable I have seen.

@Random_Task477

Maybe they were testing the hypothesis that the chronically activated MTOR signal in the elderly was actually what impaired their ability to put on muscle?

I’m pretty sure chronically activated mTOR does impair their ability to put on muscle, it just takes far longer than 12 weeks for that effect to appear. It’s years if not decades of overactive mTOR that appears to be a part of what ultimately leads to increasing anabolic resistance at old ages. I would be surprised if that would be reversed close to fully by suddenly blocking mTOR over the short term at old ages when much of the damage is already done.

[qBx123Yk]

@Olafurpall

why would you assume that you need months of recovery between bouts of doses? The mouse lifespan studies certainly don’t have long periods without rapamycin for recovery between doses.

My comment was specifically about weekly dosing for recovery. I don’t think you need months for recovery.

When looking at my health markers and physical performance over the last 3, 4 years, I think I’ve had enough mtor inhibition. At my age, I’m not sure that much inhibition is worth it yet. So now I’ve decided to try to compress my catabolic phase into 1 continuous block, and do the same with my anabolic phase for simplicity.

I’m also looking at the mannick study where they administered everolimus for only 6 weeks, and the effects on PD1 expression in cells stayed around weeks after administration. The follow-up PROTECT study also somewhat supports that.

[Beth]

For anyone switching to a 14 day schedule and is also on Repatha, it just occurred to me it might make sense to take them on the same day. AI agrees.

The only negative I could think of with a higher dosing schedule is the potential effect on lipids. If I take them on the same day, my repatha will be strongest to hopefully counteract any potential damage.

[Agetron]

Yes, I agree it’s a long term agent. Short studies don’t tell us much.

I remember when I started taking rapa, read to not expect any benefits to even start until after 3 months. Noticeable benefits start to show at 6 months.

I think it’s a matter of different time frames. In the short term, rapamycin will likely reduce muscle mass. But over the long term it will have the opposite effect. That effect may not become apparent until after decades of taking it. It’s reducing the mTOR overactivation which is a part of what causes anabolic resistance later in life. If you’re looking at short term effects you’re looking at the wrong things.

[LaraPo]

@Agetron

That effect may not become apparent until after decades of taking it.

Unfortunately nobody has been on it for decades - so there’s no data to measure.

[DavidCary]

Ah, transplant patients?

[LaraPo]

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.

[Ashley]

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