I wasn’t sure how to search for this information, so I’m asking. I know how to change the dosing in mice to dosing in humans by dividing the dose per kilogram by 12 (I think it is 6 for rats and 4 for dogs? There is a chart; I know how to find it; I know how to use it). But what about timing? By which I mean two things. Mice only live around two years. Therefore should daily dosing in mice be translated to daily dosing in humans or roughly once monthly dosing in humans? I’m pretty sure the answer for that is daily. But, what about duration of treatment? If a result is produced in mice after four weeks of daily treatment, do we expect to see a similar result, with appropriate dosing adjustment, in four weeks in humans? Or should we expect it to take 40 times as long since humans live roughly 40 times as long as mice? Trying something for a month versus trying it for three years is a huge difference in effort and makes doing n=1 trials consecutively more difficult.
Here are the dose translations from the other rapamycin studies - mice metabolize rapamycin much faster. I would say we really don’t know the details of how the ITP and other trials showing the longevity impacts of rapamycin on mice lifespans translate to humans… the tests just haven’t been done (and may never, given that rapamycin is a generic medication so unless a government or nonprofit steps up to do the clinical trials, there is no financial incentive for a company to do the clinical trials).
My belief is that the best we can do is test different dosing levels and timing approaches on our own bodies, track blood test and functional results closely - and modulate in a way that we think will optimize results.
If you have not done it yet, I recommend you read the entire “Rapamycin Dosing” thread - it has a lot of good information in it and feedback from different people: What is the Rapamycin Dose / Dosage for Anti-Aging or Longevity?
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.
Wouldn’t that mean as an adult male weighting 70-90kg, you’d need 9-12mg for significant increases in median lifespan?
Well, yes. The issue is that in all the Mouse studies are done with mice, the mice are raised in pathogen-free environment, with carefully controlled environmental conditions, food, antiseptic air flow, etc. which is very different from your human environments.
As you increase your dosing and frequency of rapamycin you increase the likelihood that mTORC2 gets inhibited, and that increases the immune system supression. So - while that might be fine for mice in pathogen free environments who don’t get infections, we are not so lucky.
In general, the research studies in mice suggest that the higher the dosing, the greater the longevity effect. But that is in mice, in unique conditions. We really don’t know the risk/benefit tradeoffs at any significant granularity for humans, of this type of thing.
See past discussions on this general topic:
Here: Ideas on Protocols for Testing Higher Rapamycin Doses
Here: Poll: Would You Participate in a Higher Rapamycin Dose Clinical Trial?
Here: More Rapamycin Might Not Be Better
I’ve only seen one really bad outcome of high dose rapamycin use, in this case in the clinical trial the woman was 27 years old, taking 10mg/day of everolimus (a “rapalog”) in a clinical trial.
Rapamycin is not a risk-free drug, especially as you increase doses above the regular 5 to 8mg dosing once per week level. Below is an example of high dosing (10mg/day, so about 10X what most people here are taking) clinical trial for tuberous sclerosis complex, see Tuberous sclerosis - Wikipedia
See below the high dose (10mg/day) clinical trial:
The most common Adverse Effects (AEs) of everolimus therapy were laboratory abnormalities (100% of patients) and infection complications (83 episodes in 15 patients). Infectious episodes of pharyngitis (67%), diarrhea (44%), stomatitis (39%), and bronchitis (39%) were the most common infections. They were mostly mild or moderate in severity (grade 1–2).
In two cases, life-threatening conditions related to mTOR inhibitor treatment were encountered. The first was classified as grade 4 pleuropneumonia and Streptococcus pneumoniae sepsis, whereas the second was classified as death related to AE (grade 5) Escherichia coli sepsis.
A 27-year-old woman with TSC was started on everolimus
treatment because of AML of the left kidney
(60 Å~ 48 Å~ 36mm in size). The other signs of TSC were
facial angiofibroma, hypomelanotic macules of the skin,
and shagreen patch. The diagnosis of TSC was made
12 years earlier when the patient underwent nephrectomy
because of a large tumor of the right kidney. The
patient received everolimus at a dose 10 mg/day and the
trough concentrations of the drug ranged from 4.08 to
5.08 ng/ml. After 3 months of everolimus therapy, a
reduction in AML was observed (40 Å~ 31 Å~ 20mm in
size). During treatment, hypercholesterolemia (309 mg/
dl) and transient leukopenia (3.2 Å~ 109/l) with neutropenia
(1.34 Å~ 109/l) was observed. She also reported
oligomenorrhea. After a gynecological consultation, a
functional ovarian cyst was identified and contraceptives
were prescribed. However, 2 weeks later, she was
admitted to the gynecological unit because of subabdominal
pain and an ovarian cyst (64 Å~ 53mm in seize)
on ultrasound examination. Torsion of the ovarian cyst
was suspected. On the day of admission, WBC was
9.2 Å~ 109/l, the absolute neutrophil count (ANC) was
6.6 Å~ 109/l, the hemoglobin level was 10.8 mg/dl, the
PLT count was − 275 Å~ 109/l, and the C-reactive protein
concentration was 8.0 mg/dl (normal < 5.0 mg/dl). The
patient was advised to continue intake of contraceptives
and everolimus. The next day, the general condition of
the patient aggravated. Her blood pressure was low (85-
/50mmHg). Her WBC and ANC decreased (WBC
−2.4 Å~ 109/l, ANC − 1.8 Å~ 109/l), whereas the hemoglobin
level (11.0 g/dl), the PLT count (185 Å~ 109/l), and coagulation
tests were normal. Computed tomography of the
abdomen and pelvis showed AML of the left kidney (size
as in the previous examination), an ovarian cyst measuring
65 Å~ 50 Å~ 40 mm, and fluid in the retroperitoneal
space with density of the blood. Further aggravation of
her general condition was observed. The patient was
transferred to the ICU and she died after 2 h with
symptoms of shock and multiorgan failure. Blood and
urine cultures collected when she was in the ICU were
positive for Escherichia coli.
Complications of mammalian target of rapamycin inhibitor anticancer treatment among patients with tuberous sclerosis complex are common and occasionally life-threatening
Thank you for this.
I was meaning to ask in a broader sense.
Do I care how long it takes before my rapamycin effects kick in? Sure, but I’m ramping up painfully slowly, so I know it’s going to be a good long while - Started with 1 mg/wk on April 25. I was up to 5 mg/9 days on June 27.
I guess the dosing part of the question would be addressed by the relative half-lives in mice and humans for any given drug/supplement. That’s the practical need.
But, how long to give it before giving up on getting a benefit is a worthy question.
It’s easy to pick for things that have been tested in humans. It’s not so clear for animal only studies.
Its interesting… probably about 50% of people notice no difference in the short term of taking rapamycin. But if its slowing aging as it does in all the other organisms its been tested in, I don’t see why we would “feel it”. Its not like you feel the loss of function and strength, etc. over time that aging does to you. Do you feel any different over 6 months or a year of time due to natural aging? I think most people do not, until you get really old or have some major decrease in function due to an accident or something.
So - that reduction in speed of aging slowed, why would we notice it when we haven’t noticed even the faster rate of aging.
And if you haven’t seen them already - I encourage you to review the results of our user surveys here:
The million dollar question. 10 years? 20? 30? Reflects why we don’t haven’t had a good study done on humans. In theory, if it’s working, you won’t notice anything. This applies to many of the supplements we take.
For me, I started having positive effects within a month. I just felt healthier like my body had been completely refreshed. The feeling is best at a 6 mg equivalent (2 mg + GFJ)
Yup, I read all of that before I started.
For rapa, I suspect I could see a difference in how often I have to do my roots. I’ve had documented improvements and deteriorations in the density of greys, all linked to abhorrent diet and sleep patterns, since I was 23. But, I now have some consistent grey hair even when not living on beer, ramen, and 3 hours of sleep a night. I have very dark brown hair, so greys are easy to notice.
But, I’m also thinking about all the other things people here are trying. I have plenty of time to think it over since I don’t want to add anything else until I’ve given rapa 3 months at 10 mg/14 days and I won’t even get up to that dose for a couple more months.