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