#50

I don’t think there is evidence to support either of these.

2 Likes
#51

I suggest you Google Rapamycin MTor2

The impact on MTor2 is well documented.

#52

We do know that doses below 20 mg equivalent we don’t see MTOR rebound in humans. At 40 mg, 50% of people had MTOR rebound. So the magic number for MTOR rebound is between 20-40 mg. That’s why I recommend not going above 20 mg or 6 mg + GFJ.

We’ve had people take a 500 mg equivalent dose (100 mg + Ketaconazole) and they turned out fine. So we know you can’t OD. Also, look at the marmoset colonies. They did just fine on a higher dose.

Rapamycin, IMHO, is incredibly safe but not perfect. You can die from a bacterial infection which is probably the worst case. Other side effects can be controlled with other medications (hyperglycemia and hyperlipidemia).

And to be honest, my “high dose” is not actually that high and I am willing to put up with apthous ulcers, slow wound healing, and diarrhea in exchange for a healthier and longer life.

Of course if additional information comes out, that will alter my course of action just as this marmoset data has.

The marmoset data is probably the best data we are going to get for a long time. Human studies will be too short term to be conclusive and there are no other long term studies in the pipeline. Waiting for more data is like waiting for Godot at this point.

The data is in. It’s time to make a decision on what we have. It’s neither perfect nor guaranteed, but it’s enough for me.

10 Likes
#53

Really?? 100mg of rapamycin pills…that’s a lot of pills!! And a CYP3A4 inhibitor?? Were they suicidal? Are you sure that it didn’t cause brain damage? Was it @SNK ?

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#54

May I ask what this is based on, Chris?

#55

Please see these excellent posts by @McAlister on dosing. As always, I welcome other people’s opinions. We need to work together to find the best possible outcome.

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#56

Thanks Chris / @DeStrider .

  1. I read read the first post and while it very helpful to understand rebound risks and layers out the case that <20mg equivalent rapa ranges may not lead to rebound dynamics, I’m not sure I follow how that answers the question about risks of decreasing mTORC2 from taking rapa in the first place?

It seems that rebound is about mTOR and mTORC1 (and perhaps mTORC2) going UP - but what we are worried about with regards tk mTORC2 is it being inhibited and hence going down.

What am I missing? Please do help me understand if in incorrectly understanding things here.

  1. I also read the second post and it was also a good, valuable read. However the take away there seems to be that the lower range to target is not 20mg but might be much lower than that.

The post concludes

Personally, a 12 mg dose of rapamycin taken with food yielded an approximate peak of 17.9 ng/mL three hours later. The blood level (ng/mL) achieved by a given dose (mg) varies widely from person to person, so everyone needs to get their own blood work done.

Takeaways

  • Unless human clinical data eventually says otherwise, design your dosing schedule to avoid inhibiting mTORC2. You’ll need some personal data points to assist with that. A peak rapamycin level of 10 ng/mL probably avoids inhibiting mTORC2.*

Where as you can see he is saying from at least his own data that 12mg yields at least a 17 ng/mL peak which is above the 10 ng/mL peak to be “safe from mTORC2 effects” and hence 12mg is too high so 20mg is not a “safe limit” for mTORC2 (even if it perhaps is “safe” for avoidance of mTORC1 rebound).

Please let me know if I misunderstood anything above or in some other ways am getting something wrong here also.

In that second link you posted @McAlister also says

Based on rapamycin’s half-life, I expect most people to have detectable levels at 7 days. I suspect that matters less for lower doses, as the ng/mL amount of rapamycin would likely be below the mTORC2 inhibition threshold. But for higher doses, 14 days is probably wiser. But personal blood work is necessary to determine those parameters.

Given that first bolded part people who do weekly rapa - without breaks - might over the course of weeks keep slowly building up higher and higher doses in their system.

(The second bolded part on doing 14 day cycles might help solve that issue)

1 Like
#57

I was looking at this part:

What do we know about when rapamycin begins affecting mTORC2?

In male and female C57BL/6 mice, 16 weeks of oral rapamycin (2.24 mg/kg body weight/day ≈ 22.7 mg at 75 kg body weight) had no effect on the phosphorylation of Akt (Ser473) and PKCα (Ser657)—both targets of mTORC2—but decreased the phosphorylation of p70S6K (an mTORC1 target) by ~34% in whole brain lysates (Halloran et al. 2012) 1. This indicates that, at least in the brain, concerns over rapamycin’s capacity to suppress of mTORC2 are not warranted.

16 weeks of daily high dose Rapamycin did not affect MTOR2. That’s why I also included the mouse measurements.

3 Likes
#58

Ok, I see that subpart, but @McAlister does not seem to use it the way you are doing, he is sharing it as one data point that he then puts in context with mice data on lower levels leading to mTORC2 inhibition

and (if I understand it correctly, perhaps not as this is not my area of expertise) he also explains that one cannot only look at the direct mTORC2 lowering pathway (that the section from the one mouse study you decided to point to), but also that if mTOR / mTORC1 overall is lowered, then mTORC2 can be lowered through that in an indirect way

In 26-week-old male psPten–/– mice (n = 15), eight weeks of 3x weekly oral doses of a highly bioavailable nanoformulation of rapamycin called Rapatar appeared to increase the amount of phosphorylated Akt at both a low (~0.1 mg/kg rapamycin) and a high (~0.5 mg/kg rapamycin) dose, but only the high dose was significant (p = 0.02) (Antoch et al. 2020). The increase in pAkt could result from releasing mTORC1’s inhibition of IRS1/2 and mTORC2 (Rozengurt et al. 2014). Direct inhibition of mTORC2 has previously required higher doses: e.g. 10 mg/kg in (Halloran et al. 2012) and 8 mg/kg in (Schreiber et al. 2015). These results indicate that rapamycin causes a compensatory activation of Akt at doses below the threshold of mTORC2 inhibition.

3 Likes
#59

Any comment on what I wrote in (1) above?

And on how to weigh (2) above in the context of thinking of threshold for mTORC2 risks starting to be relevant?

#60

Getting into the finer details of dosing is going to vary a lot due to individual differences. For instance, the 6 mg + GFJ I plan take as a 95 kg male will probably be equivalent to a 4-5 mg + GFJ dose that a smaller 75 kg person would. Therefore my dose and @desertshores dose will probably yield the same blood concentration due to our size difference. For most people here, a high dose would probably fit in the 4-6 mg + GFJ range.

I also am taking into account anecdotal evidence from Bryan Johnson as he is constantly monitored by his medical team and if something is going off the rails, he’d be able to detect it and change. He takes the equivalent of a 4 mg + GFJ dose. And of course we have the amazing @Agetron and @desertshores who have taken and are currently taking relatively similar doses.

Based on my research and experience gained from this board and looking at my own lab work, I feel confident in my current higher dosing schedule of 6 mg + GFJ every two weeks. I am thinking of taking an extra dose of 3 mg + GFJ the second week.

4 Likes
#61

AIUI and I have not checked the references, mTORC2 inhibition comes in after a period of inhibiting mTORC1. Hence if you keep the lower thresholds sufficiently low between doses either
a) You won’t inhibit mTORC2 or
b) You will only temporarily inhibit it.

It strikes me it may be a measure of a greater shortage of nutrients than mTORC1.

3 Likes
#62

SGLT2 inhibitors are expensive in the US. What about remogliflozin out of India as 100mg BID? It showed essentially a 20mg/dl and 40mg/dl drop in blood glucose in fasting and postprandial states respectively. Released in 2019 in India. Any experience with it?

#63

You can buy empagliflozin Jardiance from India and have it shipped to the USA. That’s what I do.

1 Like
#64

Good to know. I am discouraged by the ~10mg/dl rise in my fasting glucose on just 1mg weekly of rapamycin (and not happy with my fasting glucose before rapamycin, to be honest). Regarding my BS, the thought, “It doesn’t seem fair” has crossed my mind since I climb 4500 up steps (and 4500 down) each morning, have a healthy 22.8 BMI, and work hard at keeping my carb intake really low-- I stress over 2 gm added sugar! Thank you for the info. By the way, I had a pt some years ago with Fournier’s gangrene, not on an SGLT2 inhibitor, and that is a nasty disease.

2 Likes
#65

BMI is not a reliable marker of healthy body composition. If you really want to know, get a Dexa body comp scan to see how much and where you have body fat stored. I am 16.3% body fat but have too much visceral fat. My BMI is 26.8.

6 Likes
#66

I think reasonable people can disagree with this. Obviously we don’t have good dose/response information on rapamycin in healthy humans with regard to longevity. But I suspect we may never get this, given the problems with funding such studies and the timescales involved. So then the issue becomes “how much do we know, in what organisms, and can we may educated guesses from that data and then cautiously (with a lot of testing and monitoring) work towards acting on the best knowledge we have?”.

I would posit that some people may want to take this approach, depending on your personal risk profile, and access to testing facilities, etc.

Its not like we have zero data on this.

  • We know the dose response profile of rapamycin in longevity in mice from the many ITP and other studies on this (see below).
  • We have some early data from the marmoset study with approximately the equivalent to the mouse studies of 14PPM, which equates (by Adam Salmon’s estimate) to around 30mg per day (or perhaps every two days - need clarification from Adam on this, given the approx. 24 hour half-life for rapamycin in marmosets) for a typical 60kg human. This seems to be providing close to the mouse longevity benefit of 10% to 15% healthy lifespan improvement.
  • If we see the same dose response for healthy longevity in mice and marmosets (e.g. 14ppm translates into a healthy lifespan benefit of around 10% to 15%, it seems that there is a reasonable chance it would also translate to humans, all things being equal).
  • And, I think we may be able to measure the “failure of the dosing regiment”, by doing frequent and regular blood testing to track key variables. If they get too far out of wack, I would just the dosing level a failure. See this related thread: Ideas on Protocols for Testing Higher Rapamycin Doses

Assuming a starting level of 6mg dosing once per week, it seems like it might be feasible to slowly increase that dosing level safetly by regularly monitoring all the key blood measures that might indicate negative side effects, like LDL, APOB, blood sugar and insulin levels, and markers of immune suppression, like white blood cell levels, TREGs, etc.

I suspect that as you increase your dose past 6mg once per week that the risks increase and so more and more care is required as you increase the dose. But it does seem conceivable that a protocol could be developed to balance the risk and potential reward, at an individual level. I’m not advocating this for anyone, it just seems that there is a potential pathway forward in this area with an approach that controls the risk.

Here is the mouse dose/response data we have:

I think daily dosing in mice is roughly equivalent to about once every 4 days or so in human terms given the speed that mice metabolize rapamycin is about 4 times faster.

Sirolimus
Dose		 Mouse
mg/kg/day
Dose		 Mouse:
Blood/Sirolimus
Level		 Human
mg/kg/day
Dose		 Dose for 60kg Human Daily Dose adjusted for longer half-life (/4)
4.7ppm ∼2.24 3 to 4 ng/mL 0.182 mg/kg 10.92 mg 2.73 mg
14ppm ~6.67 9-16 ng/mL 0.542 mg/kg 32.54 mg 8.135 mg
42ppm ~20 23-80 ng/mL 1.626 mg/kg 97.56 mg 24.39 mg
126ppm ~60 4.878 mg/kg 292.68 mg 73.17 mg
378ppm ~180 45 to 1800 ng/mL 14.634 mg/kg 878.04 mg 218 mg
Sirolimus
Dose		 mg/kg/day
Dose		 Blood/Sirolimus
Level		 Male Median LS Increase Female Median LS Increase
4.7ppm ∼2.24 3 to 4 ng/mL 3% 16%
14ppm ~6.67 9-16 ng/mL 13% 21%
42ppm ~20 23-80 ng/mL 23% 26%

Based on the FDA animal to human dosing conversion guide here.

Note: ½ life for sirolimus in mice is approx. 15 hours, vs. approx. 62 hours in humans. So, mice metabolize sirolimus approximately 4 times faster than humans.

6 Likes
#67

All the information you’re providing is excellent, but it’s not based on human trials and it doesn’t address the goal of delaying aging.

We simply don’t know whether more rapamycin is better for anti-aging.

It may be that more is worse.

Whether or not humans can tolerate a higher dose is not the point. We need to know whether more will result in a longer lifespan.

For example, there have been studies on the impacts of aerobic exercise on aging.

Analysis of runners has shown that the benefits of running plateau after 30 to 45 minutes of running.

People who run marathon distances regularly die younger than people who run 10K.

The effects of running on MTor are not dissimilar to the effects of rapamycin, so it’s entirely possible we’d see a similar result, if human trials were done on rapamycin.

I acknowledge that human trials aren’t practical, as they would take decades. But humans are not mice.

We’re only a couple of years away from data from the dog aging project. While that project won’t address dosing, it will hopefully confirm if the anti-aging effect in larger mammals mirrors what we’ve seen in mice.

Assuming dogs perform as well as mice, we may have a little more comfort in using mouse data to predict outcomes in humans.

3 Likes
#68

I would argue that the mouse and marmoset longevity data do address the goal of aging; as those are all based on rigorous academic studies on longevity with rapamycin across multiple species, getting closer and closer genetically to humans. Is it perfect? No, but I think its relevant data that allows us to make a reasonable hypothesis that increasing from our current dosing (say 6mg per week for a 60kg person, or about 0.1 mg/kg once per week) to a higher dose; perhaps 0.25 mg/kg once a week or more often, is likely to increase healthy lifespan if (and this is a big “if” right now), you can keep side effects at a low level). Obviously not a bet everyone would want to make nor could they without the proper medical / testing support. But not an unreasonable bet from my perspective.

While I love the dog aging study, and all the effort going into it, I anticipate that there will be a few issues with it. First of all they had their funding cancelled by the NIA/NIH this year, so its up in the air whether it will ever get completed. I hope so, but I’ve not heard of their funding status for some time now.

The second issue is that the dosing level in the dogs is very low (compared to the marmosets); only 0.15mg/kg, and that translates to a very low dose in mice, probably less than the 4.7 ppm the ITP has tried (perhaps someone with some time can do the calculations), which resulted in only a 3% median male lifespan increase. The Dog aging study is only powered enough to detect a 10% lifespan increase in the dogs currently (going from memory here), so if its as effective in dogs as mice, the study will not be able to come to any conclusions. More info on the dog aging study here: How Do I Get Rapamycin for My Dog?

So, I think the best data we will have for rapamycin over the next 5 years will most likely be the marmoset data. Adam Salmon says they are working on a number of papers on the marmoset longevity study, so I really look forward to the information these papers provide.

9 Likes
#69

Sheesh I’m near 71, female, 140pounds and started it to see if it helps my chronic fatigue. Everything I read before starting it said typical dose is 6mg/week so that’s what I’ve done the past 4 weeks. (Built up to that for 6 weeks.). Now I’m thinking that’s way too much, but I haven’t had any side effects, but haven’t had blood drawn. How soon should one have blood drawn? If it’s ok and no other side effects do you think I should stick with 6 or go to every 2 weeks?