Purely coincidental I expect
Yes - that is true.
The higher the dose, the longer the lifespan increase (at least in males, but at 8mg/kg in females they reached the dose level for mice that lifespan was no longer increased). In males they’ve gone up to 378ppm with still good results.
So I agree - low doses are unlikely to increase lifespan, but may be individualized in terms of responses.
But the big issue is that the mouse studies are done in largely pathogen-free environments for the mice, whereas we humans don’t live in such environments… so we can’t pursue the exact same dosing levels or strategies.
See mouse study list here: List of all the Mouse Studies Showing Rapamycin Lifespan Extension
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Thanks for the insightful post, RapAdmin. That paper written by Dudley Lamming is incredibly interesting. Albeit I’m left with so many questions.
Do we have lifespan studies wherein both selective mTORc1-inhibitors and Rapa where compared? Or rather: do we know if when mTORc1 is more selectively targeted this results in an additional increase in lifespan versus when both mTORc1 and mTORc2 are inhibited?
The list of studies Lamming cites is fascinating for sure. You mentioned that “at 8mg/kg in females they reached the dose level for mice that lifespan was no longer increased”. I’m currently trying to look up that study, but do you happen to know: at 8mg/kg in females was there ‘no further increase’ in lifespan, or actually a less long lifespan compared to the lifespan at a lower dose of Rapa? Or perhaps even a decrease in lifespan compared to the non-treated, control group (I would assume not)?
Do we know where that gender-specific difference stems from? I believe the female rodents had higher serum levels of Rapa than male rodents, while receiving the same dose, is that correct? So could it be due to toxicity issues/mTORc2 inhibition?
I think it is incredibly interesting that Lamming suggests that in male rodents fed acarbose or 17-alpha estradiol that experienced an increase in lifespan, mTORc2-activation was established. Albeit I’m not sure at all what to make out of everything and admittedly my head is spinning.
As to potentially deleterious mTORc2-inhibition; would it be sufficient to keep an eye on neutrophils, lymphocytes, and potential insulin resistance as well as hyperlipidemia? And if theoretically glucose metabolism and lipid markers would be affected only for a few days after dosing Rapamycin: would that still be deleterious if we were to dose only intermittently? (I assume even suppression of neutrophils or lymphocytes for a few days may potentially be problematic?)
Sorry for all the questions. I feel a bit overwhelmed reading that paper from Lamming.
@RapAdmin. You mentioned that “at 8mg/kg in females they reached the dose level for mice that lifespan was no longer increased”.
Sorry but do you happen to know if this was intermittent dosing or daily dosing. How would 8mg/kg translate to dosing for humans?
See here:
After receiving the lower dose, both male and female mice lived about 50% longer than untreated mice, and showed improvements in their muscle strength and motor coordination. When given the higher dose, male mice showed an even greater increase in life expectancy, but the female mice did not. These female mice had an increased risk of developing rare and aggressive forms of blood cancer, but were protected from other types of cancer.
In this study:
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See this post for information on translating mouse dosing to human dosing:
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Generally, I believe people only see mTORC2 inhibition if dosing daily for many weeks. I think that is the most common situation. But there may be outliers.
Not a bad idea to track neutrophils, etc. - but I seem to recall that you have a hard time getting blood tests, so not sure how you would do it.
Dudley Lamming mentioned to me that he thought we should be tracking TREGS (T-regulatory) cell test, but I have yet to find that for people to be able to get (in the USA) easily at reasonable cost… If anyone finds some good options, please post:
** TREGs (T-cell Regulatory Test)** (Test details ), Labcorp TREGs test
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Thanks, I can’t get a Rapamycin blood level test performed here. (Albeit someone recently pointed out a lab abroad where I may be able to get my blood levels of Sirolimus tested). I am able to get my other blood work, such as lipid values, CBC, etc.
Either way, thank you very much for posting that study: very interesting for sure! The female rodents had similar serum levels of Sirolimus to the male rodents in this study when 8mg/kg/day of Rapa was administrated IP. (I thought to have read previously that the same dose of Sirolimus can result in higher serum levels of Sirolimus in female rodents. But this was not the case in this study). So the female rodents experienced a decreased lifespan at a dose of 8mg/kg while male rodents experienced a significant increase in lifespan. Remarkable, once again. Did Kaeberlein or Blagosklonny (or anyone) ever suggest what may be a possible explanation for such a gender difference?
No - its unknown, and not seen in humans.
And yes - as you mentioned, The ITP studies of rapamycin (14ppm and 42ppm) done earlier did see the differential effect in male/female response with higher blood levels for the same dose in female mice.
The study mentioned above at 8mg/kg was injection, so different delivery method than the NIA ITP rapamycin studies which are all oral/feed based.
As a funny aside, I talked to Allesandro Bitto about this study and the reason they did IP injections of the rapamycin was because they didn’t have the budget in this study for the high doses of eRapa, so they went for the cheaper option of the injections (IP). Its easy to forget that everyone has budget limitations… and the studies get modified as quotes for supplies come in!
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@RapAdmin. Thanks once again! Interesting, so based on these two studies it seems only oral Rapa administration may result in higher serum levels of Sirolimus in female rodents - and not IP administration. Do we have any other studies that support that notion? I should get my own serum levels tested either way; the more I read, the more I’m convinced of that.
Sorry for all the questions. I feel a bit stupid, but I still don’t understand how to translate those mouse doses to human doses based on the table you linked in your post. Do we have any ‘simple explanation’ anywhere for ignorant rodents :-)? And sorry, really last question: but do you happen to know what dose resulted in the highest increase in lifespan in female rodents in studies? Or should I not be so focused on this gender difference seen in rodent studies.
Check the list of all the rapamycin mouse studies here: List of all the Mouse Studies Showing Rapamycin Lifespan Extension
Since we don’t see the same differential effect in humans of rapamycin in terms of female blood / sirolimus levels vs. male blood/sirolimus levels, I don’t think its something to put a lot of emphasis on.
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One thing to keep in mind. Dr. Green prescribes more rapamycin I suspect than any other doctor. He is interested in longevity. And he recommends that his patients take 6 MG per week without grapefruit juice. Not 10, not 20, and not 30.
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You are very right.
And M Kaeberlein and P. Attia are taking 8mg/kg once a week for 8 weeks and then a whashout. Guessing their weights just by observing them, they might weight 85 kg, then their dose is ~0.09mg/kg
Kaeberlein decided to give 0.15 mg/kg to dogs (all of them of large size) in the TRIAD clinical trial for dog life extension. According to the table that @RapAdmin shared above 0.15mg/kg is equivalent to ~0.083mg/kg for humans. So there you go, I will stick to the ~0.08mg/kg for my weekly dose for the time being.
Unfortunately, there is still the problem of translation of times from rats/dogs to humans (1 week in dogs/rats = How many weeks in humans?)
Anecdotically, RapAdmin told here that his toe nail fungus went away after ~1year on Rapamicyn. Kaeberlein said his shoulder pain went away in 8 weeks. Can anyone share what is the recommendation of Dr. Green about how many weeks does he keeps his patients on and how many weeks off? Or are they using Rapa in a continuous manner (no whashout)?
Cheers,
There was one in vitro study that found rapamycin may start to become ototoxic at high levels.
“Our experiment demonstrates a dose dependent damage of the auditory HCs. Low-dose concentrations of rapamycin (10 μ M) had no toxic effect, while 50 μ M and 100 μ M rapamycin result in dose dependent HC loss.”
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Dr. Green recommend 6 mg per week. He did not make any recommendations for cycling off absent some reason to do so such as a bacterial infection.
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This is interesting, but it seems that this is a study being done on “5-day old rats” - so the effect you’re seeing is a developmental impact on very young mammals… and this is a well known problem; blocking mTOR during early development causes all kinds of problems; its extremely important in development to have activated mTOR.
Next, tissue explants of 5-day-old rats were treated with increasing concentrations of rapamycin to explore the effects of rapamycin on auditory hair cells and spiral ganglion neurons. Auditory hair cell survival, spiral ganglion neuron number, length of neurites, and neuronal survival were analyzed in vitro . Our data indicates that both mTOR complexes are expressed in the mammalian cochlea. We observed that inhibition of mTOR by rapamycin results in a dose dependent damage of auditory hair cells.
But this is not the same, nor is it relevant to, adult rats, or any other mammals.
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Do we have an indication as to dosing levels and molar concentration?
Hi Agetron, sorry for asking another wuestion. Was that 6mg with gfj?
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Yes… approximately from April 2022 until end of November 2022… I was taking 6mg in pills and one fresh red grapefruit that I would hand squeeze and take with pills.
Side effects seemed to be elevated Blood Pressure went from lower 130’s to mid- 150’s. With pulse up to 100… normal pulse 72
Watched it this way for months… figured it was rapamycin. Since dropping my dose to 2mg with grapefruit juice… approximately 12 mg in my blood. B/P and pulse back in the normal range.
On dose day…and the next day can feel my heart racing… beating through out my body… in my arms and chest and head… and ringing in ears.
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Take care buddy! Those don’t sound like good side effects! Ringing in the ears and higher BP may have cardiac effects.
I am taking 5 mg + GFJ, biweekly and I have noticed my wound healing has really slowed. I have a blister on my finger and it is taking a much longer time to heal than in the past.
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