When we are younger, the basal mTOR rate is low, but it spikes given stress, food, etc.
As we get older it seems that mTOR becomes increasingly disregulated and higher, and does not return to the low level after spikes (as quickly or consistently as when young). So the theory is that as you get older you want to suppress mTOR more (though still allow spikes and periodic increases as “appropriate”. See this video with Brian Kennedy here: Make your arguments for Rapamycin dosed weekly vs. biweekly - #12 by RapAdmin
But we are still in the early days of identifying the optimal dosing for people, age groups, weights, etc… so its all more trial and error. What most of us are doing here is starting low, slowly increasing, and doing regular blood testing to see how things are going (and hopefully working with your doctor to try to optimize things).
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As noted in another rapamycin forum:
"Dr Green has moved up from 10mg a week, then to 20mg every 2 weeks. Technically that is the same dose, he just doubles it up and waits twice as long before redosing.
I am shocked that he isnt getting the mouth sores at that kind of dose. I wonder if the older you are and the slower your cell division is that maybe you can tolerate these higher doses without side effects?
Is anyone else experimenting with extreme doses or what is your limit?
Here is the clip discussing it.
008-Alan Green MD: Rapamycin for Longevity in Clinical Practice - YouTube "
*Note: It appears that Dr. Green was on 6mg 1x / week for 3Y (unk cycling), he then went to 10mg 1x / week for one year. As of the date of the YouTube I/V he had titrated up to 20mg every other week with no side effects. Dr. Green is 80 years old.
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the mouth sores issue is a strange side effect. I’m not sure what exactly is driving it. I had one at around 4mg or 5mg/week, and never again, despite going over 28mg dosing. For some people it may be dose related, but for many of us it has no relation at all to dosing. You’ll see many people in the forums dosing very high, with no mouth sores at all.
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sol
#209
For myself, I observed side-effects at dose changes, even at 1mg the first time, that don’t repeat. I speculate that there’s some sort of start-up effect.
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I am currently on 5 mg + GFJ + EVOO + Metformin bi-weekly, and I developed a new canker sore on the inside of my cheek after the first week. The rash on my hand has also come back mildly as is the rash on my neck. I had hoped to go up to 6 mg next week, so with the GFJ, I’d expect that to be about 20 mg standard without.
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I, for one, have been looking for data points for dosage to older adults. Say 75 y o and above. There aren’t as many, so I was glad to see that the Kraig 2018 paper was mentioned (“An RCT to establish the feasibility and safety…”).
I think it’s been mentioned on this site, but --I think-- also in an early Attia interview, that older individuals may not need to take vacations from dosing.
My interest in the older cohort has to do with cachexia and sarcopenia so if anyone’s got insights around rapa’s use there I’d welcome it. Perhaps dosage could need to be altered.
(If it would take us too far off topic message me.)
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Sirt6
#212
I wonder if women with a cycle have to dose rapamycin in different pulses than men. So e.g. Dr. Mindi Pelz teaches fasting in women. According to her, women have to pause fasting in the 2nd half of their cycle, so when progesterone rises. I thought that you need an egg to hop, which then builds the progesterone. So I would expect low progesterone after fasting in the 1st half of my cycle, if the egg doesn’t jump. A lot of guessing here…
So question to the women, how do you dose rapamycin and fast in accordance to your cycle?
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What most of us are doing here is starting low, slowly increasing, and doing regular blood testing to see how things are going (and hopefully working with your doctor to try to optimize things).
Could you please point to a post or thread that explains what blood testing will tell you? Do we in fact know what level of rapa in the blood is optimal? And how do we know that?
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Not rapa, but my favorite goto on health in general:
Aerobic exercise provides at least a partial solution to sarcopenia as it ameliorates mitochondria-derived problems, and resistance exercise strengthens muscle mass and function.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165967/
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Here is a good thread about rapamycin blood testing: How to get a Rapamycin (sirolimus) Blood Level Test
We do not know what the optimal dosing for rapamycin is for longevity. Its hard to do longevity studies of drugs because humans live so long, and the FDA doesn’t recognize aging as a disease so no drugs are going to be approved for “aging” anytime soon.
Additionally, rapamycin is a generic drug now (cheap) so nobody is going to invest the money for longer term clinical trials.
Generally, what we’ve seen in the mammal studies so far is the higher the dose, the longer the animal lives. See: List of all the Mouse Studies Showing Rapamycin Lifespan Extension
But mice live in pathogen-free cages, so what works for mice may not work for humans.
So - we are all working to figure this out ourselves.
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Hi, Elizabeth, I couldn’t agree more.
Here’s an article from 2016 that looks at rapa among other interventions including exercise countering cachexia from colon cancer in mice. Aerobic Exercise and Pharmacological Treatments Counteract Cachexia by Modulating Autophagy in Colon Cancer | Scientific Reports
Cachexia, sarcopenia, and other muscle loss have in common the (upregulation?) of a couple ligases that are directly involved in protein degradation in skeletal muscle. Rapamycin significantly reduces the expression of these two. As did another intervention also tested that also targets AMPK. The article did spend a lot of time on voluntary exercise too.
Nevertheless, what 75-and-older humans may want to consume is what I’m going to keep thinking about. Similarly those coming back from significant health challenges. I think this will lead me into more cancer literature.
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Sirt6
#217
As far as I remember, female mice could overdose rapamycin, so there was a sweet spot for dosing.
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Yes - In one study ( of the 45+ studies of rapamycin in mice) they did finally find an upper dose of rapamycin that no longer increased lifespan in those female mice. It was an extremely high dose though.
I should note that in mice there is a significant dose / response difference between male mice and female mice. This difference is not seen in humans.
Most of people currently using rapamycin seem to be (in mouse equivalent dosing) in the low levels tested (note: mice were dosed rapamycin in their food, daily, so that is another difference - vs. us using rapamycin dosed once weekly or so).
Here are the National Institutes on Aging Results from their rapamycin studies (these are the best rapamycin studies):
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% |
Here are results from all the higher dose studies I could find:
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 |
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.
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DrM
#219
What is the mouse equivalent of a human week? One day?
Based on the above half-life information, about 2 days mouse = 1 week human. So the mice were dosing 4x a week in human translation based on the half-life of Rapamycin. So for maximal longevity, should we even consider dosing every other day? The mice must have had their MTOR pathways completely shutdown.
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DrM
#221
That what I was thinking!
DrM
#222
Based on my body weight (245 lb), at the lowest of the high dose ranges (4.7ppm ∼2.24 3 to 4 ng/mL 0.182 mg/kg 10.92 mg 2.73 mg), I should take 20 mg of sirolimus per week, divided by 4, so 5mg every other day. When you add grapefruit juice with each dose, I am guessing 2mg (roughly 3-6X) every other day? Very rough approximation and probably very incorrect
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My target is 6 mg + GFJ each week to get 20 mg weekly equivalency. I also add EVOO and metformin which increase absorption beyond 3.5X.
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DrM
#224
Me too, same dose. I am not ready to go to every-other-day dosing unless I find some strong evidence.
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