Yeah - nutrient deprivation is what really gets autophagy going, but it’s not only proteins - autophagy is regulated by mTOR, AMPK, insulin and glucagon (and perhaps other things), and eating any protein or carbohydrate greatly affects the picture, there. While leucine is the most potent inhibitor of autophagy, any increase in mTOR activity works to slow or stop autophagy.
The association with the ‘Fast Mimicking Diet’ came from an overzealous marketer, as far as I can tell - I’ve never seen Dr. Longo insist that the FMD starts or increases autophagy like actual fasting, and rightly so. For autophagy, we want mTOR and insulin to be low, relatively down-regulated, etc., and AMPK and glucagon to be high. Eating any carbohydrate or protein works against autophagy, there. Fats have much less effect - to the point that I think an argument can be made for a small amount, like butter in coffee, likely not hurting us much if we want autophagy.
Dr. Longo developed the supplement that is marketed with his direct involvement (he says in his book) to be taken for a one week “fasting mimicking diet” to reduce disease risk and increase longevity.
It finances research, he says with his profit being directed into research funding.
mTor is stimulated by exercise amongst various things… and has a different effect depending whether it is in the bloodstream or the muscles.
Certainly - and I don’t think there is any question that those health benefits you mention, there, take effect for most people in general, the same as the “Newcastle Diet” or ‘Protocol,’ i.e. Dr. Roy Taylor et al. where prevalent betterment is observable. It’s calorie restriction, but over a time frame that seems to avoid metabolic slowdown. This is not autophagy, however.
‘Newcastle’ is ~800 calories per day, and FMD is often generalized to ~1000 on the first day and ~700 thereafter. The marketed ‘Prolon’ for the FMD is a package deal whereas one could (and probably should?) adjust for one’s body mass. Prolon is also brutally expensive - one can buy one’s own ingredients for a very small fraction of the price.
If mTOR is stimulated by exercise, that would be working against autophagy, yet we know that exercise increases autophagy in some muscle tissue, to an extent.
This…anxiety…seems like a critical factor to me. No data or reports to cite (though I hope they are out there). Anxiety triggers the sympathetic nervous system, which triggers first adrenaline and then cortisol production. Both have a slowing affect on the digestive system, telling the body to use available energy for getting ready to fight or run. For me, FWIW, choosing to be less stressed and anxious is as good (if not better, given the variety of effects) keeps the body running better than worrying …about a bit of cream or anything else for that matter. I fast for weight loss and for helping my metabolism. If I get to the stage of wanting more autophagy, will need to rethink.
Exactly the point…so the generalizations about mTor and autophagy are not helpful imo and I think will soon be proven wrong.
Longo in his book has FMD in about 6 chapter headings (from memory not certain) so I think he is pretty focussed on it. The Italian edition came out in 2016 US first edition 2018.
I am not interested in taking the weeklong Fasting Mimicking support, I am able to water fast personally.
I just think people should have all the options available, not only the ones I personally prefer or that suit me.
It may be helpful for those who are not metabolically disordered and are not insulin resistant. Keto particularly helps those who are insulin resistant but not everyone who is metabolically healthy benefits from keto I believe.
With the popularization of keto as a weight loss tool, more healthy people will be trying it and possibly many of them will not lose weight with keto. Or so I have heard. Those are the people who would possibly wish to use the FMD and may benefit from it. imo
I’m just noting that even if that is true - exercise activating mTOR - that it does not entirely override the effects of exercise on muscles as far as autophagy. In muscle tissue, there is no reason that both processes - anabolism and catabolism - cannot be going on at the same time, to some extent. Some people do seem to be able to build muscle tissue, even while outright fasting - almost surely affected by increased growth hormone secretion.
We know that exercise does stimulate autophagy in at least some muscle tissue, and we know that increased mTOR is anabolic in nature - it’s involved with building, not tearing down. If the body builds stronger, in response to stress (exercise in this case), then it would fit that increased mTOR activity is present.
Yet in no way does this mean that generalizations about mTOR and autophagy are wrong. Decreased mTOR signalling/increased AMPK activity is crucial for increased autophagy, just as are lower insulin/glucagon ratios and lower insulin levels on an absolute basis. Down at the cellular level, glucagon and lowered amino acid concentration are directly involved in the beginning steps for the formation of autophagic vacuoles. mTOR is very sensitive to protein (amino acid) levels, and is a primary regulator of autophagy.
I think Longo is doing great research. In one of his interviews, he says he wanted to study people who were fasting, not just restricting calories and nutrients, but there was little interest and much less financial support available. So, he decided to look at “the next best thing,” so to speak. Totally agree that a FMD approach or similar can be of great value to some people, even if they cannot or will not fast. But again - this does not mean they should expect autophagy, as one would when outright fasting.
Yes, hence the omission of essential amino acids in Longos fasting mimicking food I assume?
And the oft repeated generalization that mTor is suppressing autophagy is simplistic and is just a recent meme, it is more complicated as you mentioned, muscles. Exercise stimulates mTor in them. And does not stop autophagy so that implies a dichotomy to me at least.
I am not a chemist, just an interested consumer attempting to take charge of my health cause I have had to, so do take what I say with a grain or several of salt flakes.
I’m not a doctor, chemist, biologist, etc., either. Yet autophagy is a fascinating subject. Yes, there are dichotomies and complications all over the place, but there are also straightforward applications like possibly being very preventative of Alzheimer’s Disease - where a lot of evidence is building up that it’s at least partially caused by the failure of autophagy in nervous system cells.
Perhaps that was the intent, but in practice it’s not going to get us to much autophagy. Of the amino acids, leucine is the most potent inhibitor of autophagy. In some cells (like most of the nervous system), a low level of autophagy is always going on (or should be), and with muscle tissue it can be stimulated by exercise. So, here we have some autophagy already occurring.
Also, let us assume that deprivation of essential amino acids causes some autophagy in general. Now we have three pathways for autophagy to be occurring. To the extent that it is occurring, it is releasing leucine as parts of cells are catabolized. The bad part about having any protein in the diet at all for autophagy is that leucine becomes very anabolic and greatly up-regulates the mTOR pathway in the presence of other amino acids, even non-essential ones, and it does not take much dietary protein to make this happen: 2 or 3 grams is enough.
This raises the specter of autophagy down-regulating itself, by chewing up old proteins and voilà - now there are amino acids that result from it. This may happen - I don’t know - but the amount of a cell that is being consumed by autophagy is normally very tiny. Leucine is so strong of an inhibitor to autophagy that it does not take much. The amounts of other amino acids due to autophagy in a cell is very low, and I am guessing that at any one time they are inconsequential, compared to protein from the diet (if we eat any), i.e. they will not bring about the anabolic effect of leucine and the increase in mTOR activity.
There is more than just “mTOR and autophagy” to be sure. However, even as simple as it is to say it, the relative activity of mTOR/AMPK and the relative levels of insulin/glucagon do weigh very heavily on autophagy. Under certain conditions, genes do certain things. Kinases like mTOR and AMPK tell genes what to do, and in this case they are saying “Go” or “No go” on autophagy.
Added in are factors like muscle tissue autophagy being stimulated by exercise. Exercise may have an effect on mTOR, but it is not sufficient to counteract the autophagy-stimulating effect of exercise on certain muscle tissue, in many people anyway.
Perhaps if you actually read Longo’s book then you would be able to understand that is exactly what he is saying and exactly what he has formulated. Fasting mimicking is autophagy creating. That is the whole point and what he has developed and spent all these years researching. The man is not a fool and knows what he is doing. Unfortunately, if you don’t read his book you don’t know what he is writing…and keep missing the point entirely.
The point is, to repeat, his fasting mimicking diet is creating autophagy, that is what he is selling.
I though autophagy is constantly happening in the body to some very small extent.
FMD enhances that to levels that help weight loss, lower blood pressure and can make several blood markers go in the right direction.
Salt water fasting moves it to its maximal level - where you might want to be if fighting certain cancers or for some quarterly / semi-annual / annual cancer prevention and reset 5-day fast.
But, I would not characterize FMD and fasting as equal - part of the reason for FMD was because concessions had to be made because, in a hospital setting, you can’t just ask patients to outright fast (even if that is best for them). I am pretty sure Dr. Longo pointed this out specifically in one of his YouTube videos.
I’ve watched some videos of interviews with Dr. Longo, and I have not seen him talk about autophagy much. I have not read his book, but we do know just how suppressive of autophagy protein and carbohydrates are.
Some benefits of fasting can be had with calorie-restriction, no question about it. That cannot be logically extended to autophagy, however, due to the amount of protein and carbohydrates in the FMD.
I don’t think he’s a fool, but I have yet to see him actually say that the FMD induces autophagy or increases it like outright fasting does (and this makes total sense to me, since it cannot) - and if he claims that in his book, then as of 2019 I’d have to say he’s wrong about that.
I hope to see some good studies on fasting and autophagy in humans - we definitely need more there.
“The Fasting Mimicking Diet allows the natural process of starvation (autophagy, protection, stem cell regeneration) to occur. You don’t interfere with the natural process. That’s a key of the Fasting Mimicking Diet.” – Dr. Valter Longo.
Robert, if that is a direct quote from Dr. Longo, I suspect that it’s taken out of context to some extent, and that the matter of degree to which autophagy is induced or increased, if any, by the FMD, is still in play.
It seems to me that ‘autophagy’ has been thrown into association with the FMD because it sounds good, not because anything really backs it up, necessarily. Longo and the CEO of L-Nutra - the company that licenses ProLon the Fasting Mimicking Diet - have both said that the trials were not focused on autophagy, but rather on proving that the FMD is safe for people and that it works to make some commonly age-related markers get better.
It’s true there is a spectrum of autophagy, but yes - very heavily weighted to zero or exceedingly low nutrient levels.
As far as autophagy and the FMD, here’s the study - authored by Longo himself, et al.
There’s hardly anything in there about autophagy, other than general comments about it. Only the barest, most tenuous connection can be made, and I’ve already argued this, above:
The science of autophagy is still in its infancy so even the great Dr “Mouse Study” Longo “please buy my product” has no idea of exactly what he is talking about. There’s currently no way of measuring it so he simply cannot “know” anything. Like a lot of scientists though he seems incapable of saying "I have no idea’ possibly because his funding depends on it…?