People With These Health Conditions Should Not Take Rapamycin?

It seems that rapamycin may be contra-indicated for some people with certain health conditions, and I wanted to get peoples thoughts on this and help build a list so as to raise awareness. Are there other conditions that people have come across that might make rapamycin inadvisable?

For example - this study seems to suggest that people who have diabetes may not benefit from rapamycin, and might be harmed (at least if the diabetes is poorly controlled):

Rapamycin Increases Mortality in db/db Mice, a Mouse Model of Type 2 Diabetes

We examined the effect of rapamycin on the life span of a mouse model of type 2 diabetes, db/db mice. At 4 months of age, male and female C57BLKSJ-lepr db/dbmice (db/db ) were placed on either a control diet, lacking rapamycin or a diet containing rapamycin and maintained on these diets over their life span. Rapamycin was found to reduce the life span of the db/db mice. The median survival of male db/db mice fed the control and rapamycin diets was 349 and 302 days, respectively, and the median survival of female db/db mice fed the control and rapamycin diets was 487 and 411 days, respectively. Adjusting for gender differences, rapamycin increased the mortality risk 1.7-fold in both male and female db/db mice. End-of-life pathological data showed that suppurative inflammation was the main cause of death in the db/db mice, which is enhanced slightly by rapamycin treatment.

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Flawed study.

Starts rapamycin at 4 months of age, equal to a human 13 year old.

They did a trial with a different strain of mice at the same time also starting at 4 months of age where rapamycin did increase lifespan

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No - that shouldn’t affect the lifespan of the mice. Harvard’s Gladyshev lab did a study last year where they started giving rapamycin immediately after birth for 45 days and the mice lived longer and were healthier:

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My bad, you two are right. I should’ve read further than the abstract.

I wouldn’t have thought that rapamycin would increase the lifespan of mice given at such a young age. :hushed:

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It seems db/db mice are leptin receptor deficient which not only causes them to be obese but also diabetic and dyslipedemic unlike the ob/ob mice which are leptin deficient but are only obese

I have noticed that when I take my 20mg Rapamycin, for the next 24-48 hours my CGM reports larger than expected increases in BG after meals. Given that Rapamycin increases Insulin resistance, this should not be surprising and may explain why continuous Rapamycin in the db/db mice was so bad. I may need to adjust the timing of my diabetes meds (particularly the once weekly Mounjaro injection) to make sure they are at peak levels before my 20mg Rapamycin dosage, to minimize this effect. Maybe also raise the Acarbose/Skullcap dosage before meals (and/or avoid all carbs) for 48 hours after taking Rapamycin

This study suggests that continuous Rapamycin dosage is a bad idea for Type II diabetics or anyone with Insulin resistance (metabolic syndrome). Hopefully the pulsed dosing recommended here is still OK.

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Definitely understand the risks if disease processes are underway. Liver fibrosis I can confirm, I didn’t know I had fibrosis & Rapa will not halt activated stellate cells, but actually helps the process run through various pathways.

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Mounjaro user here as well, this information makes me a little hesitant.

Mounjaro reaches peak levels 8-72 hours after injection, so I am thinking of using Rapamycin 24-48 hours after my weekly Mounjaro dose. Mounjaro decreases Insulin resistance, so should counteract the effect of Rapamycin on Insulin resistance.

The good news for Mounjaro users is that long term use of Mounjaro leads to sufficient weight loss to end any metabolic syndrome and returns insulin resistance to normal (non diabetic) levels, so eventually it should be completely safe to take Rapamycin.

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My fasting insulin level dropped from 6 to 2 during last 3 months when I was taking rapamycin 5 mg. HgA1c stayed the same. I have been taking metformin 850 mg 2 times a day and acarbose 100 mg 2 times a day.
There is no significant change in ApoB, Lipoprotein(a), LDL or lipid profile.
My ferritine level dropped dramatically. We are all different!

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I just stumbled into this paper, related to this topic of what health conditions are contra-indicated for rapamycin, and perhaps these citations give us some additional information:

Although the overwhelming majority of studies on the effect of rapamycin on longevity in mice have shown a significant increase in lifespan, there are five studies that have reported either no effect or reduced lifespan when treated with rapamycin. Two studies using transgenic mouse models of amyotrophic lateral sclerosis (G93A and H46R/H48Q) reported no increase in lifespan when given rapamycin [26, 27]. Sataranatarajan et al. [28] reported that 14 ppm, a dose of rapamycin that increases the lifespan of C57BL/6 mice, reduced the lifespan of the obese and diabetic C57BL/KsJlepr db/db mice, 13% in males and 15% in females. The reduced lifespan of the db/db mice by rapamycin was associated with an increase in suppurative inflammation, which was the primary cause of death in the db/db mice. Ferrara-Romeo et al. [29] reported that 42 ppm rapamycin reduced the lifespan of telomerase-deficient mice (G2-Terc −/−) 16% compared with over a 50% increase in the lifespan of the G2-Terc +/+ mice. Fang et al. [30] found that rapamycin reduced the lifespan of growth hormone receptor knockout (GHR-KO) mice (15% for males and 5% for females) even though the same dose of rapamycin increased the lifespan of the wild-type, control mice. The reduced lifespan of the GHR-KO mice was associated with impaired glucose and lipid homeostasis and increased inflammation.

So - ALS patients probably want to skip rapamycin. Not sure if the Telomerase-deficient mice apply at all to humans, and similarly with the growth hormone knockout mice … this seems irrelevant for human application.

Source: Effect of rapamycin on aging and age-related diseases—past and future (Oct., 2020)

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Obviously a very important subject considering the high number of people with type 2 DM. You would think Dr Green would have some patients with DM.

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