Rapamycin, when taking at high doses on a continual basis, is known to eventually start to inhibit mTORC2. One of the results of ongoing mTORC2 inhibition is immune system suppression (while this is considered a feature, not a bug, in organ transplant patients, in anti-aging its definitely a “bug” (negative). Research also suggests that mTORC2 inhibition shortens healthspan and lifespan in animals.
These are the reasons why, for rapamycin in anti-aging, we typically take rapamycin on a pulsed dosing schedule (e.g. once per week or once every two weeks).
Here is a twitter thread where one of the leading researchers on rapamycin and mTOR outlines the evidence on mTORC2 inhibition:
He also seems to say the jury is still out on whether all mTORC2 inhibition is detrimental, and there is plenty more to learn about the many downsides.
Lamming has developed new rapalogs that ONLY target mTORC1.
“DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system”
Looking into this study… More broadly (putting the mTORC1 vs mTORC2 distinction aside), isn’t it concerning that rapamycin shortens life in GHR-KO mice? Are these mice considered bad model organisms for humans, even for those who are healthy, lean, and insulin-sensitive?
You realize that GHR-KO mice are “Growth Hormone Receptor knock out” mice - right? They have no uptake of growth hormone in their bodies.
They are extremely different from 99.99999% of humans who have lots of growth hormone.
I mean there are about 250 people in the entire world who are like GHR-KO mice - they are called Laron Syndrome dwarfs, and yes - they should probably not use rapamycin based on this research. But all the mice who have regular growth hormone levels (like all but the 250 Laron dwarf humans) do very well with rapamycin.
The study was with “remarkably long-lived GHR-KO mice”.
They are comparing C57BL/6 mice with their study" Our longevity study was performed using the dose and injection protocol of rapamycin shown to extend the life span of C57BL/6 mice with normal GH signaling"
Even then they showed some beneficial results and explained the detrimental causes of the rapamycin treatment:
“Taken together, rapamycin-treated GHR-KO mice lost much of their functionally unique and “healthy” fat depots, which was accompanied by detrimental alterations in their circulating lipid profile. However, energy metabolism parameters remained stable, and some measurably beneficial responses occurred, such as increased spontaneous locomotor activity and increased circulating levels of total ketone bodies.”
Most of the papers I have read were only able to show mTORC2 suppression in high weekly doses given to kidney transplant patients.
This paper has been around for six years. I am sure the people studying life extension properties of rapamycin such as; Mike Kaeberlein, etc., have seen this paper.
The life extension properties in a multitude of everything from worms, mice, rats etc have shown rapamycin to extend lifespan, so I am not worried by this one outlier study with mice that have unusual qualities such as their “unique healthy fat deposits”.
As @RapAdmin wrote, GHR-KO mice are “Growth Hormone Receptor knockout” mice. This means that for example their mTOR activity will be low because mTOR is downstream of GHR. It makes the animals not grow as they should and they become quite small in size. So to add even more mTOR inhibition to such an animal will push things too far and lead to detrimental effects and life shortening. I like to compare things to exercise. There is a sweet spot in the amount of exercise to practice and if we go past this then the dose of exercise gets too high and leads to detrimental effects. More of something good is seldom better.
Here is an interview time clip with the researcher Brian Kennedy where he touches on the topic.
Yes - they give the mice rapamycin in the food, and they are fed “ad libitum” so they can eat anytime they want. And yes, they see mTOR2 inhibition but the mice still live a lot longer.
The issue is that for us, we don’t live in pathogen-free environments like the lab mice. With the lab mice the air is HEPA filtered, the cages are sterilized on a regular basis, researchers are in sanitized and protected.
We don’t live in a pathogen free environment; so immune suppression is a bigger issue for us (due to mTORC2 inhibition).
