I’m very interested in the different mechanistic pathways of how for example mTOR can be inhibited rather than by just rapamycin. For example calorie restriction and fasting has been shown to inhibit mTOR but it is not as effective as rapamycin (mTOR Signaling in Growth, Metabolism, and Disease - PubMed). Protein restriction, ketogenic diet, vegan diet and other different ways can also inhibit mTOR. Even stress for example from highly intense exercise inhibit mTOR. Pharmalogical drugs such as metformin, berberine inhibit mTOR even if it’s indirectly. There are different natural compounds like garlic, cinnamon etc that has some mTOR inhibitation effect.
As we can see there are many ways to inhibit mTOR and this is most likely important to take in consideration when trying to find the right dose of rapamycin. Because every single thing a person does when it comes to mTOR inhibition it will be stacked which will end up as the total dose of mTOR inhibation. I would argue that it’s important to see the whole picture here of the dose regime and not just stare blindly on the rapamycin dose regime.
If for example a person is practicing prolonged fasting regularly, time-restricted eating, calorie restriction, ketogenic diet, taking metformin and rapamycin with dose X than that total dose of mTOR inhibition is higher than if that same person would only have taken the rapamycin dose X and skiped the other interventions. So when we talk about side effects we probably should more talk and look at the total mTOR inhibitation instead of just the dose of rapamycin. This because of that the total dose of mTOR inhibitation says more about what is happening than the dose of just rapamycin.This also means that blood tests which only look at the rapamycin levels in the blood can be misleading. The more interesting part that we should get a good biomarker on (in the future) is the total level of mTOR inhibitation. This way we also can start to compare our mTOR inhibition doses with each other in a better way and find what the optimal dose of mTOR inhibition is. Rapamycin is just one great tool for this purpose but we should not forget that we do other things to do inhibit mTOR.
This is an important issue - and of course you are right there are many ways to inhibit mTOR, and at some point its going to be possible to measure mTOR inhibition - or more likely, from what I’ve read, measure autophagy, which is what I think we are really after since that is the process that gives us the benefits that we seek.
I’ve read about a study that came out a year or more ago from a group in Australia that has successfully measured autophagy in the lab for the first time, and published a paper. The researcher’s name is Tim Seargent and he’s on twitter (see his twitter handle in the twitter post below by Agingdoc1) and I follow him. Here is the paper:
So, with any luck this lab test will at some point (who knows how long) will make it into the clinic so we can actually measure our autophagy levels, so we can figure out what the dose/response relationship is for all the different mTOR inhibition / autophagy producers like rapamycin, fasting, ketosis, etc., and how much the interpersonal variations are.
So - you are completely correct that there are many ways to inhibit mTOR, but while we might expect that a 5 day Fast will result in greater inhibition of mTOR and therefore increased autophagy than a 3-Day Fast, we really have no idea if its 10% more, or 500% more. And we have no idea how much autophagy we get from a dose of 10mg of rapamycin a week compares to a 3-Day Fast, etc…
So I’m not sure we are at a place where the science/measurements will allow us to get the granular / specific type of information we would like to have, that would help us guide our behaviors in this area.
Dr. Seargent has written a popular science article that suggests we are already running way ahead of the science when it comes to mTOR and autophagy (at least for some compounds, I don’t know if he believes that when it comes to rapamycin)…
Interesting that you lift up the measurement of autophagy. I agree that mTOR has as relation with AMPK and autophagy pathway and vice versa. Do you think that rapamycin is one of the most powerful autophagy stimulators? I would say that prolonged fasting probably is more powerful autophagy stimulator. The interesting thing is that fasting on the other hand is less powerful mTOR inhibitor compared to rapamycin. So I don’t really see how the mechanistic puzzle should be put together here.
Hmmm, if we look at both calorie restriction and extended fasting than these interventions (in mice) increase lifespan more than rapamycin. But the interesting thing is that they only seems to work good if they are started early in life. On the other hand rapamycin seems to have similiar effects (in mice) regardless if it is started early or late in life. I made this matrix quickly.
One way to try to explain this is that low mTOR has always good effect on lifespan and middle mTOR inhibition is not enough to impact lifespan if it’s started late in life. It would be very interesting to see lifespan impact if fasting and calorie restriction late in life could be stacked with other mTOR inhibition interventions other than rapamycin so that the decreases in mTOR gets to similiar levels as when only rapamycin is taken. If this will show similiar lifespan extension as rapamycin than mTOR inhibition is the key. If it will not show similiar lifespan extension as rapamycin than probably autophagy is more important parameter to regulate. It could for example be that fasting and calorie restriction regime if it’s started late in life needs to be less tough which lowers the autophagy to similiar levels as when taking rapamycin.
It could also be that both parameters needs to be adjusted if fasting and calorie restriction is started late in life. So that mTOR inhibition is high and autophagy stimulation is low so that it matches more how rapamycin works.
All the above is really quess work but it would be really interesting to make this kind of experiments. If for example ITP could do non drug interventions like the above that would give very interesting insights to the topic.
I suspect that rapamycin is a more powerful autophagy stimulator simply because when rapamycin is used in middle age mice it extends lifespan quite significantly, whereas caloric restriction (CR) does not (in mice).
But - there may be other reasons why rapamycin increases lifespan besides autophagy, and we have no real data comparing the two - so I can’t prove it.
But how do you explain for example why calorie restriction started early in life is superior to both rapamycin started early or late in life (in mice)? It most be some missing puzzle piece here that we don’t see.
I think that rapamycin is much more focused in terms of what it does - it only blocks mTORC1 really well. I think that calorie restriction does many other things besides partially blocking mTORC1…
But I have no explanation as to why calorie restriction does not work in mid-life, as rapamycin does.
For anyone interested for work in the direction of explaining why old mice don’t benefit from CR, at ARDD2021 Karl Rudolph discussed work suggesting that NR supplementation can enable old mice to benefit from caloric restriction, including a signficant lifespan benefit.
This was probably one of the best videos in science that I have ever seen! Really good explanation and they did solve the puzzle in a smart way. Big thums up for that!
It’s also fun that you recommended this video and in the video they mentioned metformin, In my morning walking today I was thinking about metformin and I thought I would write a post here about it because it’s a ampk stimulator (autophagy stimulator) and if it is taken late in life it dose not have as good effect as if it’s taken early in life.
I really like that this video explains one possible reason for why this is the case and also why calorie restriction and most likely fasting late in life does not work that good in lifespan extension. The great part is that the researcher did not stop there. Instead he and his team looked at a way to tweak that process so that it also leads to lifespan extension late in life. This made me see the NAD area in a totally new way than I did before. So big thanks for sharing this video! It helped me a lot in understanding things more and this understanding fits very well with my current mechanistic puzzle of how things work.
what is DR in his presentation? Metformin? He is talking about combining Metformin and NR? nicotinamide riboside is a supplement easy to obtain.
He mentioned a 35% extension of lifespan in mice, which is pretty big and I wonder why we have not heard much from the media. (Metformin+nicotinamide riboside)
I am on Keto diet and calories restriction for a long time. If I only take 1mg sirolimus a week, do you think that it will have any postive effect on my mTOR? because its long-term adverse effect is still unknown and I don’t want to take too much of it for now.
I ask you because you read every message here and are knowledgable in this field. Other members are welcome to jump in to make comments.
Even 1mg/week is going to inhibit mTOR to some degree. And, since you’re on a Keto diet (I’m not sure what exactly your diet is, but if it has substantial meat in the diet, that will activate mTOR quite a bit). I would say its highly unlikely to hurt you - so if it was me I’d take it. We still have little idea on the optimal levels for rapamycin for longevity in healthy people, so I really can’t comment on how beneficial 1mg dosing would be, but its likely to be better than no dosing, the current data suggests.
Just to clarify I believe it’s actually a low glycemic diet and BCAA restricted diet are less likely to activate mTOR, the diets don’t actually INHIBIT mTOR like rapamycin.
Exercise is a selective mTOR inhibitor - probably best of all inhibitors including rapamycin.
Multiple agents were implicated in m-TOR inhibition but I don’t think any were actually validated properly. So I would use them only if they serve another purpose, like Asthaxanthin for purported prevention of macular degeneration.
Thanks for reminding me of this main post and I really like my thoughts about that it’s important to take to whole mTOR inhibition dose inconsideration. This reminds me also about something similar which Brian Kennedy said in a podcast when I interviewed him. Here is a timeclip from that part.
Exactly. I remember there was a study on monkeys and caloric restriction. The monkeys that were fed a typical American garbage diet lived longer on caloric restriction. However monkeys who had a healthy diet did not benefit from caloric restriction. So, restricting calories only works if you have a poor diet. Also too much caloric restriction led to an earlier death. You have to get it just right. See study link below.
Rapamycin works no matter what you eat, so it is probably better than caloric restriction. And you don’t have to worry about an overdose as a 500 mg equivalent dosage will not kill you. (Just don’t do it all the time!)
Controls lived longer than CR monkeys in the NIA trial.
I can be good to highlight one important thing about the CR monkey studies. Here is a timeclip what Nir Barzilai found out. Someone was feeding the CR monkeys extra food
