Rapamycin lead to the discovery of mTOR, the regulator of growth and proliferation at the lysosome, performing protein synthesis. Of note is mTOR Complex 1, which Rapamycin inhibits, leading to the proposed longevity in the studies linked. mTOR overactivation is one of the issues at hand, leading to increased protein synthesis, and inhibition of autophagy, causing the progression of cancer, diabetes, aging, and dysfunction. It’s proposed that Rapamycin is currently the only pharmacological treatment proven to extend lifespan, however as we’re all aware, diet should really be central to this conversation.
In our previous home on the RPF, poster Travis (may he rest in peace) had lots of information regarding cancer, and the importance of the polyamines, and therefore methionine, which links directly to Rapamycin and it’s proposed benefits. I’ll be paraphrasing a lot of his best material, and trying to expand on it. The polyamines are required for normal cell growth, so cancer cells are particularly sensitive to polyamine depletion due to their loss of growth control.
mTOR C1 is regulated by a few different things, however SAMTOR (and AMPK to a lesser extent, however I won’t speak about that currently) is really of importance. SAMTOR is a protein which controls mTOR C1 signaling based off of methionine, which many have likely seen as another key to longevity, in that methionine restriction increases lifespan.
mTOR complex 1 is just one part of the story, however methionine is incriminated in just about every part of this system. Methionine activates mTOR C1 via SAMTOR through the creation of S-adenosylmethionine (SAM), however the inverse is also true, in that methionine restriction deactivates mTOR by reducing SAM levels. SAM is also used in the formation of the polyamines, and their dysregulation is associated with almost all forms of cancer.
The synthesis of the polyamines begins with ornithine, which is then decarboxylated by ornithine decarboxylase in its committed step, leading to putrescine. Spermidine and spermine are synthesized by the sequential addition of an aminopropyl group, donated by S-adenosylmethionine.
This paper appears to have an incredibly clear picture, tying together both the polyamines and mTOR:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487480/
PI3K, which is upstream of mTOR, appears to control polyamine production as well:
“The loss of PTEN function results in aberrant response to growth factor stimuli through PI3K signalling pathway, thus activating mTOR complex 1 … mTOR complex 1 stabilizes pro-S-adenosylmethionine decarboxylase, leading to increased s-adenosylmethionine decarboxylase, and increased polyamine biosynthesis.”
Methionine restriction seems like a very obvious therapy, mimicking Rapamycin's function. As Travis noted, you would expect that with no methionine, you would have almost no growth, and that is true— depletion of the polyamines results in cytostasis. From Travis:
“This could be one of the main reasons why Koch and Gerson had noticed that cancer more‐or‐less stops growing on a certain diet. All vegan foods, with a few exceptions (i.e. soy), are relatively low in methionine. Why an amino acid is made limiting, most of it will be incorporated into muscle and enzymes with little remaining for it's secondary functions (many have secondary functions: tryptophan ⟶ serotonin, tyrosine ⟶ dopamine, histidine ⟶ histamine, cysteine ⟶ glutathione, arginine ⟶ nitric oxide, threonine ⟶ methylglyoxal, and methionine ⟶ polyamines + SAM.)”
Selenomethionine can substitute well, as is in Kale, as it does not form a polyamine, and it promotes the initiation of autophagy via AMPK-mTOR pathway:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596838/
I may continue on with AMPK later if I get the time.