How Strong an Immunosuppressant is Rapamycin, Really?

[RapAdmin]

I’ve seen Matt Kaeberlein mention that he doesn’t think that rapamycin is a very strong immune suppressant. I was wondering if anyone has seen any specific data related to the dose/response relationship of rapamycin in terms of immune suppression, especially compared to the most popular immunosupressant cyclosporin: https://en.wikipedia.org/wiki/Ciclosporin

Obviously this is an important issue as the primary theory on why we shouldn’t be dosing at high levels (over a long period of time) is that eventually these high and regular dosing of rapamycin will cause mTORC2 inhibition and then immune suppression. I don’t doubt that this is true at some level, but what I’m wondering is specifically how much immune supression we will actually see, and what that means in the real world.

Part of the reason I’m asking this is because I’ve recently communicated with an independent researcher who is doing testing with high dose rapamycin in rat communities at his own home. And by “high dose” I’m talking 100mg/kg to 200mg/kg per day (by IP / SC injection), in very non-sterile environmental conditions, and he’s not seeing any issues with regard to immune system related issues. To put this in perspective, this is the highest ongoing dosing level experiment I’ve ever heard of or seen. I’ve looked in all the literature and the highest dosing ongoing experiment I’ve ever seen is 100mg/kg for a few weeks in mice and rats. So, short of doing LD50 experiments (testing dosing levels to find the point that is lethal for 50% of the population), this is one of the highest dosing levels ever done in rats.

This is a small and low-cost personal project by this individual working with a large number of rats in a garage. This is not a typical lab-like environment with its pathogen free environment (purified air cycled through HEPA filters, autoclaved cages and equipment, purified water, etc.).

This experiment is comprised of rats from a local vivarium purchased for $3 each (vs. $60 per sterile rat from Jackson Labs for true lab rats), no autoclaving of cages and equipment, no masks, no sterile food, etc… The environment these high dose rats are living in are pretty similar to a human environment… a regular garage, plastic crates from Costco, being fed regular dogfood and left over old vegetables, tap water for drinking, etc. And these rats are living in relatively crowded environments; up to 14 rats in a crate. So if there are any immune system issues, you’d expect him to see them in this type of environment.

So - I’m starting to wonder, how truly immunosuppressant is rapamycin? Is there some agreed to classification or measure of immunosupressants? Does anyone have any information on this, before I start doing a deep dive into the issue?

How exactly is risk quantified with regard to immunosuppressants? Are there some general benchmarks that they might use in transplant patients - e.g. T-cell counts, or other mechanism or ranges?

[Arhu]

That’s like 15g per day for an average human but iirc there’s a conversion factor too from rat to human of 1 to 7, so still 2g per day🫨

[RapAdmin]

Please explain how you get these calculations.

I know about the typical animal to human conversion factor https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804402/

And this is a little complex from what I can see… did you go through these calculations?

The dose by factor method is an empirical approach and use the no observed adverse effect levels (NOAEL) of drug from preclinical toxicological studies to estimate human equivalent dose (HED)
…

For example, for a newly developed drug molecule, the NOAEL value in rat weighing approximately 150 g is 18 mg/kg. To calculate the starting dose for human studies, use Equation 1.

HED (mg / kg = 18 × (0.15 / 60)(0.33) = 2.5 mg / kg

Thus, for a 60 kg human, the dose is 150 mg. This HED value is further divided by a factor value of 10; thus, the initial dose in entry into man studies is 15 mg.

Dose is equally related to body weight although it is not the lone factor which influences the scaling for dose calculation. The correction factor (Km) is estimated by dividing the average body weight (kg) of species to its body surface area (m2). For example, the average human body weight is 60 kg, and the body surface area is 1.62 m2. Therefore, the Km factor for human is calculated by dividing 60 by 1.62, which is 37 [Table 1]. The Km factor values of various animal species [Table 1] is used to estimate the HED as:

HED (mg / kg) = Animal does (mg / kg) × (Animal Km / Human Km) Eq. (2)

As the Km factor for each species is constant, the Km ratio is used to simplify calculations. Hence, Equation 2 is modified as:

HED (mg / kg) = Animal does (mg / kg) × Km ratio Eq. (3)

The Km ratio values provided in Table 1 is easily obtained by dividing human Km factor by animal Km factor or vice versa. For instance, the Km ratio values for rat is 6.2 and 0.162, obtained by dividing 37 (human Km factor) by 6 (animal Km factor) and vice versa, respectively. Thus, usually to obtain the HED values (mg/kg), one can either divide or multiply the animal dose (mg/kg) by the Km ratio provided in Table 1. For example, for a particular drug, the NOAEL in rats is 50 mg/kg. Using Equation 3, HED is calculated either by multiplying or dividing the animal dose with the Km ratio values given in Table 1. Accordingly, divide the rat dose (50 mg/kg) by 6.2 or multiply by 0.162, the HED is –8.1 mg/kg.

However, it must be borne in mind that the km factor varies across animal species and increases proportional to W2/3 within a species as body weight increases. For example, the km value in rats varies from 5.2 (100 g rat), 6 (150 g rat), and 7 (250 g rat). Therefore, calculation of HED for a drug of NOAEL in rats is 50 mg/kg with an average weight of 250 g is as below:

HED(mg/kg)=50(mg/kg)×=9.5 mg/kg in humans

Using the standard km factor value of 6 for rats with average weight of 150 g [Table 1], the dose varies accordingly as seen below:

HED(mg/kg)=50(mg/kg)×=8.1 mg/kg in humans

Interchange of unit (mg/kg to mg/m2) of dose of animals or human is carried out using the Km factor [Table 1] as:

mg / m2 = Km × mg / kg Eq. (4)

[blsm]

I’ve been pretty shocked that I haven’t gotten sick considering my work exposure to very ill people. Most of my patients are in contact isolation for various superbugs and so far I haven’t contracted anything, felt sick or even like I was fighting something. Early on that was my greatest concern. I’m careful as always of course but it’s still a risky environment to work in if a person’s immune system is compromised.
I’m really glad someone is doing an experiment like this one.

[Arhu]

Ballpark estimates from memory. I wasn’t too far off, the actual dose equivalent for an average 75kg human would be 3.5kg/day according to that table

[Olafurpall]

Wasn’t there some study that showed that rapamycin, even at very high concentrations, could only inhibit mTORC1 partially (by 70% or something if I recall) and could never inhibit it close to 100%? (if anyone has the reference for this please share) If that is true that could explain why it doesn’t suppress immunity that much even at extreme intakes.

[BigSky]

I recall a study that showed an improved immune response in elderly people who had taken a flu vaccine.

[rivasp12]

I’ve posted comments on this in the past under rapamycin and infections. Rapamycin is a very selective immunosuppressant in that it suppresses naive T cells involved in organ transplant rejection while increasing T cell CD8 + populations which helps to fight off viral infections.

There’s little to no evidence that the standard weekly doses used by the anti aging population leads to bacterial infections , and the survey by MK in his recent study didn’t reveal such a risk. It’s unknown whether very high doses would lead to bacterial infections.

Selective Effects of mTOR Inhibitor Sirolimus on Naïve and CMV-Specific T...

[J0hn]

I must say, I have to applaud the independent researcher for at least trying

[Tim]

@RapAdmin Blagosklonny has argued that rapamycin is not an immunosupressant but rather an immunomodulator. He claims that it “stimulates” or “rejuvinates” immunity.

Rapamycin for longevity: opinion article | Aging

[RapAdmin]

Yes - Many researchers are now calling rapamycin an immunomodulator, based on the Mannick studies. But at higher doses, on a regular daily schedule, its well known for immune system suppression (historically, that is the primary use for the drug, in organ transplant patients).

My question that started this thread is really about the issue of the exact immune suppression profile of rapamycin at higher and regular dosing (anywhere from daily to every two weeks) of rapamycin (in healthy people).

The study hasn’t been done, but basically I’m talking about the need for an optimal dosing study for healthy humans on rapamycin. I’d like to understand better the exact trade-off on potential longevity benefits vs. potential reduction in immune suppression (and the risks associated with it).

There is little data on this really, other than a few cancer or related studies.

This is related to this thread: Ideas on Protocols for Testing Higher Rapamycin Doses

We do know that in a 10mg/day dosing study that there are records of fatalities (due to infections/Sepsis) and other life-threatening situations.

I’ve communicated with the researcher Dudley Lamming and he thinks we should be measuring TREGs (regulatory T cells, a measure of immune function), as people go up higher in doses: Regulatory T-cells: Purpose, Function & Development

And here is that case of a fatality with higher dose (10mg/day) Everolimus (a rapalog), see below:

Rapamycin is not a risk-free drug, especially as you increase doses above the regular 5 to 8mg dosing once per week level.

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

https://sci-hub.se/10.1097/CAD.0000000000000207

[LaraPo]

Do we know if Peter Diamandis is still taking doxycycline with his Rapa dose?

[AnUser]

No he is not. Not in his Fall longevity guide.