I regularly think about the drug portfolio that was being developed by Tornado Therapeutics when Mannick was in charge (she left a while ago). She did a presentation you can find on youtube (and which I posted on this site), wherein she presented a rapalogue with unusually focused mTORC1 inhibition that entirely spared mTORC2. She contrasted that with rapamycin which in prolonged use at higher doses does lead to mTORC2 inhibition. The rapalogue she was developing apparently could be dosed extremely high without notable side effects, unlike rapamycin. She pointed to the promise of much safer and more potent and effective rapalogues, than the original rapamycin.
The inhibitory effects were undoubtedly selective and arguably superior to rapamycin. But, the presentation never quite got to the actual outcome benefits in a fully satisfactory way. I figured they needed more time and application studies. However, I have not heard much since, leaving me dissatisfied with the lack of a progress report on the promised wonderful world of superior rapalogues. I was left hanging.
Meanwhile, the world of mTOR inhibition is very complex. One kind of inhibition is not equivalent to a different inhibition in its downstream health effects. You can have mTOR inhibition, but no longevity benefits, as the paper below says. So rapamycin is doing something special when it inhibits mTOR, which results in longevity benefits where another mTOR inhibitor does not show that benefit. That makes me rather cautious with regard to the supposedly wonderfully strong mTOR inhibitors developed in some lab (including Tornado Therapeutics) - I need to see more than “it inhibits mTOR” before I get excited - OK, that’s great, but what is the outcome - does it show specific benefit like life extension, or superior outcomes compared to rapamycin?
This also shines a skeptical light on claims for any given molecule being beneficial just “because it inhibits mTOR” - we see such claims on the regular, for example “metformin inhibits mTOR” - the immediate question becomes “so what, are there beneficial outcomes?”.
That said the mechanism is key - if say metformin does it through AMPK activation? Because drugs that activate AMPK can have beneficial effects, as the second paper describes.
Two papers that are food for thought:
Caenorhabditis Intervention Testing Program: the putative mTOR inhibitors Cinnarizine and Meclizine do not extend lifespan in C. elegans
https://www.micropublication.org/journals/biology/micropub-biology-002198
" The mechanistic target of rapamycin (mTOR), a protein kinase and master cell regulator, is one of the most validated longevity drug targets: mTOR inhibition by compounds like rapamycin has been shown to significantly extend lifespan in numerous model organisms. Here, we tested whether the novel putative mTOR-inhibiting compounds cinnarizine and meclizine could likewise increase lifespan in the nematode C. elegans , following standardized protocols from the Caenorhabditis Intervention Testing Program (CITP). Our results indicate that cinnarizine and meclizine have no effect on C. elegans lifespan at lower doses, and that both compounds exert a toxic effect at higher doses, significantly shortening lifespan."
Direct Pharmacological Activation of AMPK Extends Lifespan in Yeast, Worms and Flies
https://onlinelibrary.wiley.com/doi/10.1111/acel.70721
" AMP-activated protein kinase (AMPK) is a key evolutionarily conserved sensor of energy homeostasis and plays a central role in metabolic health and disease. AMPK has also been implicated in ageing; however, most in vivo drug studies rely on the use of indirect activators, such as metformin, which have complex modes-of-action, therefore making conclusions on the specific role of AMPK more challenging. Here, we demonstrate that direct activation of AMPK with the compound 991 extends lifespan in Drosophila melanogaster , Caenorhabditis elegans and Schizosaccharomyces pombe . In mice, 991 treatment induces a pro-longevity proteomic profile, highlighting the potential for translation to mammals. Overall, our study provides important proof-of-principle for AMPK as a pharmacological target with longevity benefits."
Note the emphasis on direct activation vs more unclear indirect activation as in metformin. The direct activators show unambiguously benefits in lifespan extension (which metformin by itself does not). Worth keeping in mind - it’s not just about mediated suppression or activation, because you are introducing intermediate steps which might decisively affect the outcome (as in a recent discussion of empagliflozin both upregulating and suppressing mTORC1 in different cell types - why the question of direct bonding vs indirect is so critical).