Dr. Valter Longo on Resetting Autoimmunity and Rejuvenating Systems with Prolonged Fasting & the FMD

Dr. Valter Longo on Resetting Autoimmunity and Rejuvenating Systems with Prolonged Fasting & the FMD

[Rhonda]: Hello everyone, I’m sitting here
with Dr. Valter Longo, for a round two podcast. I’m pretty excited to be back, it’s been a
couple of years since our last discussion, Valter. In my mind, you are one of the leading experts
in this realm of how diet and lifestyle all regulate longevity, particularly when it comes
to fasting. So, there’s been a really big interest in
fasting and also in limiting food intake, and limiting food intake is actually one of
the probably most, I would say, reproducible interventions that’s been shown to modulate
the aging process across multiple organisms. So, I was wondering if you could maybe describe…define
and sort of describe some of the common denominators between various modalities of limiting food
intake like caloric restriction, intermittent fasting, prolonged fasting. [Valter]: Right. Yes. So, I think that we’re at the point where
we have to start…we have to stop using terms like intermittent fasting, because it covers
almost everything, right? I mean, at least in the journalist mind, when
they talk about intermittent fasting, it covers from two hours food…not eating, to one month. And of course they’re completely different
practices and they have completely different effects. And so I think it’s important to start qualifying
what it is that we’re talking about. So, intermittent fasting, I guess it could
be a way to include let’s say alternate day fasting, and include what’s called the five-two,
so having two days a week of a very restricted diet, and maybe it could also include the
one day a week of fasting, of complete fasting. I think it would be fair to include those
three in intermittent fasting, even though they can have very different effects. Now, of course time-restricted feeding is
time-restricted feeding, which refers to let’s say how long of a time you eat per day. So 8 a.m., 8 p.m., that would be 12 hours
of feeding and 12 hours of fasting. And then calorie restriction is that…of
course you can say some people use calorie restriction to define everything that is calorie
restricted, but the people in the field talk about calorie restriction, when they hear
calorie restriction, they think of chronic reduction of calories below the normal level. So, below the level that will allow you to
maintain a normal weight, and so chronically, so if you do this all the time. And then periodic prolonged fasting instead
is what we mostly work on, and it’s very different, and it’s not intermittent in the sense that
it’s not something that has to happen in any type of cycles, frequent cycles. It can be done once a year, it can be done
10 times a year, it can be done 20 times a year, and it refers to let’s say at least
2 days of fasting or longer, or 2 days of a fasting-mimicking diet or longer. So, what do they have in common? I mean, some things may be in common, but
they are very different interventions, and they each do something different. I mean, I think we know now from the calorie
restriction field that the diet…I mean, the restriction of calories like that can
have incredible effects on diseases, diabetes particularly, but also cancer, cardiovascular
diseases. So this is really unbelievable effects. I mean, the monkeys, we know that it can wipe
out diabetes completely. It can reduce cardiovascular disease and cancer
by 50%. But the monkeys either live a little bit longer,
or don’t live longer at all. And this is what we and others, a few at least
suspected for a long time. I was a student of Roy Walford back in the
early ’90s, and it was…I mean, being around calorie-restricted people, it was very clear
to me that this was going to have problems, but it was also very clear that this was going
to have huge effects on health. [Rhonda]: For the monkey studies that you’re
referring to, there were two published, correct? One from the University of Madison and one
from the NIH? [Valter]: Right. [Rhonda]: And neither of them increased lifespan,
but they increased healthspan? [Valter]: No, no, no. The Wisconsin increased lifespan. Richard Weindruch was also a student of Roy
Walford. So, yeah, that increased lifespan. But if you look at the lifespan that is based
on the disease-dependent lifespan, so the mortality caused by major age-related diseases,
that was…there was a huge effect. If you look at the overall survival due to
where all causes of mortality were taken into consideration, then the survival curves are
very close to each other. [Rhonda]: Would that be considered maximum
lifespan? This one [inaudible 00:05:39] [Valter]: No, this will be mean lifespan,
mean and maximum, right? [Rhonda]: Okay. [Valter]: So, small effect. They don’t have maximum because I think they
will have taken…at some point they had to stop it so they couldn’t really get to full
lengths. It already took 25 years to do that. So, I think it would have been difficult to
get maximum lifespan. But the mean lifespan was extended in Wisconsin,
it was not extended at the NIA. Of course the Wisconsin study had a controlled
diet that was much worse than the NIA-controlled diet. So the NIA had somewhat of an ideal diet,
at least ideal monkey diet, and the Wisconsin didn’t. The Wisconsin was a reasonably good model
for the western diet. [Rhonda]: That’s interesting. Okay, so there’s no really…I think there
was also maybe some different genetic backgrounds as well from the monkeys but who knows? [Valter]: Yes, probably genetic… [Rhonda]: Do you know if in these studies
did they see common pathways…and I want to talk about this with you. Genetic pathways that are known to be modulated
by caloric restriction, were those changed? For example, did IGF…were IGF-1 lowered
or mTOR? [Valter]: Yeah, now I haven’t looked at those
papers in a while, but almost for sure, I mean, those were affected. I mean, calories are cut by 30%, so that would
mean 30% less proteins and 30% less sugars. So, yes, I will assume that both of them showed
effects on the nutrient-signaling pathways and including TOR and IGF-1. [Rhonda]: And I guess so that’s probably something
that’s also a common denominator between these other modalities of limiting food such as
the periodic prolonged fasting. I guess one of the major differences would
be the shift in metabolism to, when you’re fasting, to beta-oxidation, to…because that’s…is
that something that occurs during caloric restriction? [Valter]: That probably occurs. There’s probably a minimal switch to a ketogenic
mode, depending on who it is and what the restriction is. So, it is possible that chronically, when
you’re chronically restricted, it also depends how you restrict it. So for example there are human studies where
they show that because the people that are restricted were eating high protein, a high
vegetable protein diet, and the IGF-1 was not affected. So, it is possible that some of these individuals
have a diet that would block entry into even a small ketogenic mode. But overall they’re probably not, they’re
relatively in a standard metabolic mode as far as ketone bodies and fatty acids are concerned. [Rhonda]: That’s interesting because you said
the diet was a high vegetable protein diet, and I was thinking the study from I think
it was Dr. Fontana’s lab that showed that humans that undergo caloric restriction naturally
gravitate towards eating more protein because it’s more satiating, and so people that were
eating a higher animal protein diet, even though they were caloric restricted, so they
were eating about 30% less normal food than they normally would, their IGF-1 levels were
higher because the… [Valter]: Were normal, yeah… [Rhonda]: Yeah, they were. And they didn’t go lower like they do in animal
studies. [Valter]: Right, until they restricted the
proteins. [Rhonda]: Until they restricted the proteins. [Valter]: So they actually did a second study,
Fontana and colleagues did the second study, the follow-up in which they restricted the
proteins, and then the IGF-1 went down. [Rhonda]: I haven’t seen that one, okay. Yeah, I should definitely take a look at that. But for people that are listening and kind
of wondering, we’re talking about one of the major dietary regulators of the IGF-1 pathway
which maybe you can mention a little bit about the role of IGF-1 in the aging process. [Valter]: Yeah. So, proteins, and particularly certain amino
acids, methionine, cysteine, etc., they regulate IGF-1 levels, and IGF-1 in simple organisms,
at least the orthologs of IGF-1, as well as in mammals seem to have an important role
in aging. It is not clear how much is IGF-1 versus insulin
versus growth hormone receptor-dependent signaling, which is independent of IGF-1 and insulin,
but most likely it is the growth hormone receptor. Growth hormone and growth hormone receptor,
they are the sort of master controllers, and IGF-1 seems to be one of the axis that regulates
or accelerates aging in multiple cell types. [Rhonda]: And from humans there are some,
there’s some evidence with polymorphisms and various like growth hormone…? [Valter]: Yeah, that’s actually our work with
not polymorphism but mutations in the growth hormone receptor, something called E180 mutation. And the people…Well, we knew from mice,
from the work of John Kopchick and Andrzej Bartke, that mice that have either a growth
hormone receptor, or growth hormone deficiency, live longer, about 40% longer, they also live
much healthier. That’s probably, you know, I think one of
the most important observations made in the aging field, that you could live 40% longer,
and yet about half of the mice get to the end of life without any obvious pathological
lesions, so they don’t develop diseases. And that the control of disease is less than
10%. So, and these… [Rhonda]: It’s pretty significant. [Valter]: I’m pointing these out…Well, it’s
a huge effect right there. I’m pointing these out because obviously people
think that if we extend the lifespan of, human lifespan, then it’s going to come with a lot
of more problems. And instead, in the mice, but also in our
work in humans, where we’ve been following these people with growth hormone receptor
deficiency down in Ecuador, and they’re called, there’s a syndrome there, a syndrome called
Laron’s syndrome. So they’re very much the equivalent to the
mice, and they don’t have a very long lifespan, they may live a few years more than their
relatives, they don’t have homozygous growth hormone receptor deficiency, but they’re protected
from cancer, they’re protected from diabetes, and a recent paper showed that they seem to
be protected from age-dependent cognitive decline, and all of these are matched by the
mouse work. So that makes you feel a lot more confident,
having the mouse data suggesting that this is concern the fact of having low growth hormone,
of course and then low IGF-1, low insulin, and low TOR, and also I think low Ras, at
least expression activities a little bit harder to figure out in people. [Rhonda]: Have you measured the IGF-1 levels
in these people with Laron’s syndrome? You’ve measured their IGF-1 levels, is that
something that’s achievable from doing the caloric-protein restriction or the fasting,
which we should probably start talking about? [Valter]: Yeah, we measure the IGF-1, it’s
very low in these subjects. [Rhonda]: Very low. Okay. [Valter]: Yeah, it’s like 10% of the normal
IGF-1, circulating IGF-1 levels. So there’s extremely low IGF-1, low insulin,
and also we have…What we’ve done is we’ve taken the…this of course we can measure
in their serum, right? But then we’ve taken the serum and we took
human epithelial cells, and we expose the human epithelial cells either to control serum,
or to the serum in the Laron’s, and then we looked at the gene expression. And that showed that not only the TOR was
down-regulated, so was Ras, at least gene expression-wise, and a number of other genes
that are associated with accelerated aging. [Rhonda]: And cancer. Wow… So maybe we can…I kind of took us off into
the tangent here, but the fasting, you’ve done a lot of work on both, doing periodic
fasting, water fasting, and also a fasting-mimicking diet which you can explain in a minute. So I was kind of…I found it kind of interesting,
like the reason why you developed the fasting-mimicking diet, at least I read in your recent book,
“The Longevity Diet,” was if I’m correct, because you were doing some studies on cancer
patients. And, is that correct, the… [Valter]: Yes. So we…Well, first of all for a long time
I had been thinking about how to get the benefits of calorie restriction without the problems
of calorie restriction, and so that was something that I was looking for. And also I, you know, back in the days in
my graduate work, you know, we were starving yeast and bacteria, and we had shown that
this was very beneficial. So I was really…I wanted to look at the
possibility that prolonged fasting will be beneficial. And so…then also the point when we discovered
that the proto-oncogenes, so the normal versions of the oncogenes that are so central in cancer,
they are the genes that control cellular protection. And so from that came the idea that…and
maybe we discussed that already in the first interview. But that came the idea that if you starve
a system, the normal cells would become protected, and the cancer cells will remain sensitive,
so then we started testing this in cancer patients, but realized that they didn’t want
to fast. And then I think they gave us an opportunity
and the motivation to look for a fasting-mimicking diet, so a diet that works as well as fasting,
but allows patients to eat. And this was funded by the National Cancer
Institute first, and then by the National Institute on Aging. And so it’s of course exploring all these
understanding, all the understanding of the connection between let’s say amino acids and
TOR and IGF-1, sugars or certain sugars, and PKA actually we’d shown that, as we had shown
for yeast, we now shown in mammalian cells that glucose levels activate PKA, and so that’s
part of the…that’s a lot of what went into the development of a diet that can nourish
the patient and yet have effects on IGF-1, IGFBP-1, ketone bodies, and glucose that is
equivalent to that of water-only fasting. [Rhonda]: So you basically looked at all these
known genetic pathways from your work and others that…so IGF-1, mTOR, PKA, Ras? [Valter]: Yeah, Ras. Although Ras may or may not be conserved. The role of Ras, we didn’t really see it in
mammalian cells yet. I mean, it’s probably there, but we didn’t
see it at least in the cells that we looked at so far, you know? It looks like IGF-1 and glucose can directly
feed into PKA, and IGF-1 can feed into PKA. So we think that PKA is very central, maybe
handling both the protein signaling and the sugar signaling. [Rhonda]: Interesting. Yeah, that’s…the interesting…what are
your thoughts on…and I’m going on a tangent here, I’m going to come back to it, but the…because
you just mentioned this. The role of insulin in regulating IGF-1, I
guess both function and also level. So there were some studies that I…and I’m
not sure if this was Fontana or who did these studies, but there are studies showing that
limiting the glucose intake was important for bioavailability of IGF-1 through some
of the insulin…IGF-1-binding proteins like IGF-1 binding protein 1, and also for regulating
transcription of IGF-1. So, it’s kind of… [Valter]: So it’s all interconnected. Obviously we don’t know enough, you know,
the association between…I mean, insulin and IGF-1 are very similar, they can interchangeably
bind to the receptor, each other’s receptor with different affinity of course, and so
yeah, we…how are they connected? I don’t know and I’m not sure that that is
very well understood, but those are certainly connected and they’re certainly linked, both
linked to growth hormone signaling. [Rhonda]: I think there was another study,
and this was in animals, and this is what really piqued my interest. I’ll look up the reference and send it to
you if you haven’t seen it already, where I think the protein, limiting the protein
intake, essential amino acids specifically, wasn’t as key if the total kilocals were kept
under a certain level, in terms of activating IGF-1. So that there was like this sort of energy
threshold where if you had low enough energy specifically from like glucose, then your
protein, your essential amino acids can go a little bit higher than they’d otherwise
go. [Valter]: Right. And this will be consistent with our work
in yeast. Yeast when you have, when you look at the
aging rate, it’s very clear that there is a network, and it’s not really a pathway. And the network is very much interconnected,
you know, PKA and TOR, and everything else and AMP kinase. And so actually in yeast, the sugar seems
to dominate, and the proteins seem to be second most important. So if you remove sugar and you increase the
protein consistent to what we were just saying, that’s not so, then it’s not so bad. But if you have both the sugars and the protein,
then you see much more the protein-dependent sensitization. [Rhonda]: Yeah, it’s extremely interesting. So, I’ll look up the reference too in case
you haven’t seen it… [Valter]: And of course in the case of yeast
is individual amino acids, there’s no protein. [Rhonda]: So, we went out back on a tangent,
but this is why these discussions are so interesting. But so you were talking about the development
of the fasting-mimicking diet, and how you were looking at all these genetic pathways,
and also you mentioned the ketone bodies and…what was the last thing for… [Valter]: Ketone bodies and glucose. [Rhonda]: And glucose, right. [Valter]: IGF-1, IGFBP-1, glucose, and ketone
bodies. [Rhonda]: And these are all things that regulate
cancer growth as well? [Valter]: Yes, they can regulate cancer, they
do regulate many cancers in different ways. I mean, ketone bodies, you know, some will
argue that they hurt cancer cells, but some cancers actually love to use both ketone bodies
and sugar. [Rhonda]: Yeah, there was a recent publication
I think. [Valter]: So you can actually accelerate cancer
growth with ketone bodies, but you can also hurt cancer cells with ketone bodies. This is why ketogenic diet, you know, I wouldn’t
get too confident about using ketogenic diet alone against cancer cells because of course
even fasting, a lot of cancer cells can adapt to the changed environment. So… [Rhonda]: Yeah, cancer is a very…it’s so…it’s
so complicated when it comes to cancer and it seems like really…you really have to
be careful when you’re trying to treat the cancer. [Valter]: Yeah. And I think that there is a lot of, of course
interest on the ketogenic diets and cancer treatment, and it’s good, I think it can do…there
are situations where the ketogenic diet can hurt the cancer growth. But as for fasting, we see that you need to
have in most cases the powerful target intervention with the fasting. So like fasting and chemo, fasting and kinase
inhibitors, fasting and immunotherapy for example. So, I will assume that the ketogenic diet
alone is going to be a complementary intervention. So now for example we’re very interested in
what happens if you do fasting, ketogenic diet, and cancer treatment together, you know? That I think is very promising. Particularly if you do it in the sense of…And
we have patients that, with very aggressive phenotypes that are doing this. So they do the periodic fasting-mimicking
diet, then in between the ketogenic diet, and then they keep doing the radiotherapy,
and particularly like gliomas, radiotherapies and chemotherapy. And this seems to be working, or certainly
very promising what we’re seeing. [Rhonda]: Is this an ongoing trial you’re
talking about, or is it just… [Valter]: We haven’t started…I mean, we
have trials on cancer, a number of trials on cancer. We don’t have one on glioma yet, but I know
that some groups in Arizona, they are…But then mostly they have just done it with a
ketogenic diet. But because it’s so aggressive, and most people…you
cannot tell like glioma patient, wait until the clinical trial is ready, right? Because it’s a very quick-moving cancer. So, in some cases we just say, look, go to
your oncologist and ask them if they’re okay letting you follow a fasting plus ketogenic
diet plus standard of care. So they’re just adding ketogenic diet and
fasting to the standard of care. [Rhonda]: Yeah, okay. And that’s, so the, for the periodic fasting,
is that also including the fasting-mimicking diet which they can talk to… [Valter]: Yeah. The fasting-mimicking diet, I mean, not water-only
fasting, but FMD, ketogenic diet, and standard of care. [Rhonda]: So I do remember that at least with…there’s
been a couple of studies that you were involved on with water fasting, you showed a combination
with standard of care treatment, it seemed to be safe, and also to some degree you seemed
to sensitize some of the cancer cells to death, and also maybe even protect some of the normal
cells and some of these blood cells. They weren’t getting neutropenia or the myelotoxicity
quite as significant as people that didn’t do the fast. Do you have any…Now, I know you’ve published
studies on the fasting-mimicking diet in animals and cancer, in combination with standard of
care. Is there any clinical trials that you’re planning
on doing with fasting-mimicking diet on humans? [Valter]: Yeah. No, we’re doing it, right. So, we’re going a little bit slower than predicted,
in part because we didn’t see coming the food aversion. So patients, when you give them any food with
something that is toxic, they develop a food aversion. So, anything that you give them with a toxicity,
is now recognized as toxic also. And so now we’re having to develop a number
of new foods specifically to avoid the repetition. You cannot repeat anything twice essentially
for…So if somebody has eight cycles of chemotherapy, you know, we may have to give him eight different
things, all respecting the formulation requirements. So, yeah, that surprised us little bit. But we already, couple hundred patients have
already been involved in these multiple randomized clinical trials. And then the good news is that there is no
problems, we don’t see any problems with the fasting-mimicking diet in cancer treatment,
but it’s been slower than expected because of these, you know, A, because of course you
cannot promise, you cannot go to a patient and say, oh, this is going to make you feel
better. And if you give them a pill, it’s much easier
because there is no effort on the part of the patient. With the fasting-mimicking diet, if you knew
it was going to be much better for you and somebody told you, I don’t think it would
be a problem because we see it with a healthy subject. But if you don’t know you have cancer, and
then you have this food aversion, altogether, it makes it very tough for people. So we had about a 40% thus far compliance,
and so now we need to tweak it so we get to maybe 70%. [Rhonda]: Yeah, it sounds like a challenge. But if there are oncologists right now that
are interested in using the fasting-mimicking diet in combination with their standard of
care treatment, that is something that they can do. Correct? [Valter]: Well, yeah. The way we’ve been putting it is that they
can, if the patient cannot wait for the end of the clinical trials, and the oncologist
agrees, you know, for whatever reason that they cannot wait, then they can certainly
do it with the standard of care. So they do a standard of care, and then the
fasting-mimicking diet along with that. Now, the FDA prohibits any product or any
claim related to disease prevention or treatment for something that has not been FDA-approved. So then, you know, I think an oncologist should
be very careful in presenting it to the patient. So it has to be presented as something experimental,
that could be good for them or could be bad for them. So that said, of course in mice we have incredible
results, we and many labs now have repeated this, so works very, very well. And so, you know, if somebody cannot wait,
I think then it’s fair to go to an oncologist and say, “Obviously, I’m running out of options. Shall we consider this one?” [Rhonda]: What does it take to for…how many
like clinical trials does it take for FDA to approve something? Is it… [Valter]: No, the FDA is a specific process. So you have to enter, you have to file, it’s
an IND application, and there is…it’s a very expensive and long process, and it’s
not just trial. So, it’s three phases, phase one, two, three,
and in the end you probably have between 500 and 1,000 people, 1,000 patients, and then
they make a decision based on the data, whether it’s approved or not. The whole process usually costs about $50
million. And so, you know, this is what makes it complicated,
right? Because, yeah, it’s not easy to justify this
kind of investment on a diet, you know? [Rhonda]: So you do have evidence, and this
is a recent publication of yours, that the fasting-mimicking diet in healthy subjects
can, it seems, affect biomarkers that are related to aging in a positive way. [Valter]: Yes, aging and as well biomarkers
for aging, as well as risk factors for diseases, right? So this was a clinical trial, a randomized
clinical trial with three cycles of the fasting-mimicking diet once a month for five days, for three
months in a row, and then of course we looked at baseline and it was a randomized crossover. So, in each case you’ll have a group of controls,
a group on a control diet and a group on the fasting-mimicking diet, and then the crossover. And yeah, the results are remarkable. I mean, first of all, if you are a healthy
person with say a healthy or a low blood pressure, nothing happens to you. And this is a really nice distinction with
calorie restriction for example, right? Earlier we were talking about, you know, are
they all going to the same place? I don’t think so. So calorie restriction, chronic, it keeps
driving your markers down. Right? So, even if you started…I mean, if you look
at Biosphere 2, and these were then confirmed by Fontana and others, if you look at Biosphere
2, even people that had at the beginning a low blood pressure, they kept dropping, and
by the end of it, they had pressure like 85/55. And same thing for cholesterol, same thing
for triglycerides, almost everything, usually drop to very low levels. Fasting glucose. The fasting-mimicking diet itself, it seems
to…you know, if you have a blood glucose of 75, nothing changes, it doesn’t drop it
even more. If you had a fasting glucose of 106, almost
in every case, it brings you back to normal. This is very interesting, and also very good
for doctors. So now we have close to 3,000 doctors just
in the U.S. that are recommending the prolonged fasting-mimicking diet, what was tested in
the clinical trial, and this is a very important feature. So, the three cycles decreased, in normal
people did nothing, in people that had…I mean, I shouldn’t say did nothing. Did nothing that you can see in terms of markers,
because they already had good levels of these markers. But in people that had elevated cholesterol,
it decreased cholesterol. The people that had the elevated triglycerides,
it decreased triglycerides. People that had the elevated IGF-1, probably
people eating on a high protein diet, it dropped IGF-1. And the highest people dropped dramatically,
you know, it came down about 60 points. And the people that had the high fasting glucose,
came down. People with blood pressure that was elevated,
both the systolic and diastolic, had major effects. The people that had CRP, systemic inflammation,
in almost every case they moved back to the normal range. So it’s really powerful I think in resetting
the system somehow, that it’s getting out of the…its functional ideal state, it resets
it, and I think it really rejuvenates. Now we’re doing…we’re trying to calculate
based on published profiles, and also methylation profiles, is this rejuvenating you? And also A and B, after three cycles, what
is your risk for diseases in the next 10 years at baseline, and what is your risk after three
cycles? And we suspect there’s going to be a drastic
change, just…You know, if you think about it, it’s three months, right? Is just… [Rhonda]: And this was a five-day fast each? It was one week… [Valter]: Yeah, five days of…three cycles
of a five-day fasting-mimicking diet, and then we measured again, and of course all
these things that I just say change. But what if we go to the databases and we
plug in the numbers, and we say, tell me, you tell me, what is the risk now compared
to before? So we haven’t finished that yet, but I think
soon enough. And I’ll just say there’s very…the results
look very promising. [Rhonda]: I have a couple of questions. So first the…you measure these biomarkers
at baseline and then after the three cycles. Do you think if you were to have measured…you
measured them immediately after the third cycle, or…? [Valter]: One week. [Rhonda]: One week? Okay. So, do you think… [Valter]: And three months. And we also measured again three months [Rhonda]: Oh you did? And how were they…that was my question. So, what were they like three months later? Do you have to keep doing it every, you know,
month? [Valter]: Yes. I mean, there were, about 60% of the effects
were still there. So you could tell that they were smaller,
but 60% of the changes were still significant. So, yes. So this is why we say that on average people
probably need to do it once every four months, and it’s also important to point out that,
you know, until millions of people do it, it should be on a need-to-do-it basis, right? So, if you are an athlete, you have a great
diet, you know, low protein, pescetarian, and you do all the right things, you exercise,
etc., you probably only need to do it once or twice a year. It’s not very many people in that category,
maybe like 5% of the population. And then as you move to a problem state of
course, then, you know, the minimal risk that is associated with doing a fasting-mimicking
diet is a good risk to take, because of course any drug that you take, any intervention that
you do is going to have risks. And so now I think people, there’s over 25,000
people that have done the fasting-mimicking diet, the prolon, the same diet that was tested
clinically. We’ve had very few severe side effect reports,
right? And even the ones that had severe side effects,
they fully recovered and there was no evidence that it was the diet that caused them, right? So, it’s very good news, right? Then when you get to, this is what in the
FDA terms would be considered a phase four, when you say, well, let’s keep monitoring
this once it’s out in the market and see, you know, are there people that eventually
show side effects that we didn’t see in the FDA trials, right? Of course we didn’t do FDA trials, but…So
we have done phase one and phase two, and skipped phase three, and now we’re in phase
four. [Rhonda]: Wow, that’s really great. Twenty-five thousand people, that’s a lot. So you were mentioning the frequency changes,
the frequency of doing this fasting-mimicking diet may change according to someone’s health
status and how, what their lifestyle is. So someone that’s obese or has high cholesterol,
high triglycerides, high fasting blood glucose, all these markers that you mentioned, may
want to do it more frequently like… [Valter]: Well much more frequently, yeah. So, somebody that has those problems, say
obese, multiple markers for disease, or risk factor for disease, then once a month, yeah. And that’s what the doctors have been doing. So they put them on once a month, and then
monitor the changes. If it works, then you can keep it going. It doesn’t mean they’re going to do it once
a month for their entire life. The hope is that you slowly…And that’s also
very important, this idea, especially with obese people, we’ll see how it works, but
this idea that you can go back to your diet after five days, right? This is very mentally, to people is very important. Say, “Well, struggle for 5 days, but then
leave me alone for the next 25.” That I think is both potentially at the mechanistic
level, but also the psychological level it could be a good way to go. [Rhonda]: So I’ll just tell you, I have a
friend of mine who was morbidly overweight, I mean, he was morbidly obese, he was, I think
at his highest weight was about 400 pounds, and had tried all sorts of types of diets,
you know, and never could really get anything to work and the compliance was low. But then he started doing these prolonged
water fasts. Now he was doing, you know, five, seven days,
and he was doing it frequently, like once a month, and he’s lost 200 pounds. And I think for him, and he does exactly what
you said. He likes food. He likes food, and he likes to eat certain
foods, but he’s found something that works for him, where he can, he just, you know,
once a month he does a five-day fast, and then he goes back and he eats his… [Valter]: I want to talk to this guy. [Rhonda]: Yeah, I would absolutely like to
put you in touch with him. He’s actually applying to medical school now,
but he’s a very smart guy. He’s a lawyer, and now he’s going back to
medical school because he’s become very interested in obesity and all this stuff. [Valter]: So we’re running our trial in Holland
on diabetes patients, many of which are going to be obese, and yeah. So, that’s our hope, that hey, you know, people
always ask, you know, there’s famous papers that have shown what they call the yo-yo diets,
right? They’ve shown that these can actually lower
your metabolism. If you have this prolonged starvation period,
it can lower your metabolism and then you tend to gain weight. But in mice and in humans we’re seeing really
the opposite, you know? Doing it this way. So if you take somebody and you put him like
say two months on a very low calorie diet, and you make him exercise, that seems to be
a problem. Why? Because of course they can’t keep doing that. And then when you eventually go back to a
normal diet, your metabolism is now slow. But doing it like this for these five days,
particularly in the fasting-mimicking diet, seem to be not doing that. So the body doesn’t quite ever switch to a
slower metabolism because it’s so short. So I think, we’ll see, but I think it may
very well represent a very good way to psychologically and also physiologically get the people to
help them have a long-term plan to lose weight. [Rhonda]: For me I would almost think that
you’d have the opposite effect that these yo-yo diets that people are claiming lower
your metabolism, I would think because you’re spending five days in more of a fasting state,
or a fasting-mimicking state, that you are becoming more metabolically flexible because
you’re switching to being able to oxidize fatty acids and then…so you’re being able
to kind of switch between carbohydrate, you know, using glucose as the main source of
energy and using fatty acids… [Valter]: Not only switch, but what we suspect
is happening…in mice we’ve shown that per month, if you take mice and you put it on
a fasting-mimicking diet, they of course have less calories during the five days, the four
days in the case of mice, but then their metabolism seems to be speed up to the point that per
month they eat the same calories. So they over-eat everything they under-ate
during the four days, right? [Rhonda]: Okay. [Valter]: So they eat exactly the same, but
they lose a lot of weight. So we suspect that what’s happening is that
fat-burning mode keeps them going. So they never quite…I mean, they probably
get back to a relatively normal metabolism, but not quite the same. So they keep burning fat a little bit, to
the point…I mean, we’re investigating this now at the molecular level, but that’s where
we suspect that… And of course people we saw the abdominal
fat loss and we saw the weight loss, and so we suspect that the same is happening. Another interesting thing which makes a lot
of sense, we didn’t think about it too much at the beginning, but the muscle is…So almost
every diet, including calorie restriction, you lose fat, water, and muscle. Right? And almost every diet is the same way. And in this case it’s really interesting because
you now temporarily lose muscle, and of course you lose abdominal fat because after a few
days this becomes your reservoir. I mean, all the…it doesn’t touch subcutaneous
fat for some reason, and only goes to the main depot, the visceral fat. So that’s great news. But the muscle is also decreased. But then, when you refeed, the muscle is rebuilt. I mean, we have evidence for regeneration
in mice, we don’t know yet in humans. But certainly the people go back to their
normal muscle mass. So now you have a specific effect on visceral
fat, no effect on subcutaneous fat, and no or very little effect on even absolute lean
body mass. In fact the relative lean body mass goes up. Right? [Rhonda]: Yeah, because in your study the
lean body mass… [Valter]: Relative goes up. Absolute, either in one arm wasn’t affected,
in one arm was just slightly decreased. So, good news because it’s probably one of
the very few methods to maintain normal lean body mass while losing fat. [Rhonda]: And that’s very important to a lot
of people. I mean, you don’t want to lose muscle mass. Muscle mass is also very important for longevity. And that’s actually a question I was going
to ask you because I wasn’t sure what the mechanism was, but the shrinking of the organs
and then sort of in the refeeding phase the re-growing, is kind of something I wanted
to talk to you about as well, this rejuvenation process, because you’ve obviously shown this
now in several different studies both with fasting and fasting-mimicking diet in animals,
where they lose a significant amount of their different organs, right? And I think that you…maybe you want to talk
about this, the…what… [Valter]: Yes. So in mice for example, if you look at the
weight of most organs, and this of course was known for calorie restriction long term. But with fasting, and fasting-mimicking diet,
this happens much more rapidly. So the organs will be smaller, and at the
end of the days of fasting-mimicking diet, and then you refeed and of course they go
back to the normal level, right? So there is really, there is this shrinking
and re-expanding effect. Now, we don’t know how much of it is cells
becoming smaller, versus cells being killed, but clearly there is killing of cells. And certainly of course we are also very interested
in, is there preferential killing of the damaged cells? And we’ve started to show that in our multiple
sclerosis mouse model, and also the human study, there was evidence that the white blood
cell level temporarily was reduced during the, at the end of the fasting cycles and
then went back to normal. So yeah, so we suspect that there are these
fasting-dependent, depletion of both intracellular components, you know, autophagy, and cellular
components, and then we’ve shown the stem cell to be activated, and then the stem cell
during the refeeding part. And that’s another very important point, is
that differentiates it to most of other interventions, right? All of a sudden…even the intermittent fasting. Because you don’t have enough time. If you do like even one day, it barely even
gets you into the ketogenic mode, right? And of course if you do it for one day, you
wouldn’t want to break down too many of the components. That’s probably…having all the glycogen
and having all the digestion takes 30 hours to complete the food digestion, from the time
you eat to the time that all the calories have been taken up, it takes probably over
a day. So that’s a very important distinction between
the prolonged fasting and everything else, including calorie restriction, which does
not have the refeeding moment, right? So, if the rebuilding happens during refeeding
and you never have it, then of course you’re missing out the reconstruction part, which
is as important as the destruction part. [Rhonda]: You brought up so many different
interesting points that I kind of want to touch on. So first the threshold between, you know,
like you’re mentioning the threshold between when you’re actually getting rid of intracellular
compartments through autophagy, clearing away protein aggregates, pieces of DNA and things
like that, but also, and damaged mitochondria, but also the clearing away of complete cells,
and particularly damaged cells, which is very interesting to me, because as you mentioned,
you’ve shown this now and there’s two different animal models for autoimmune disease, one
was multiple sclerosis and the other was the, I think type 1 diabetes. [Valter]: Yeah, ours was not, that one particularly
wasn’t, was not autoimmune. We’re doing the autoimmune. There’s type 1 induced by, pharmacological
induced. [Rhonda]: Okay. So it has potential for… [Valter]: Yeah, but I can tell you, we’ve
now confirmed it with all the autoimmune diseases. So I think it’s going to be applicable to
many autoimmune diseases. [Rhonda]: So this is what’s so cool because,
I mean, the, you know, the potential for this type of fasting to cause cells that are preferentially
damaged to be cleared away by apoptosis, which makes sense. I mean, I spent six years studying apoptosis
and cells that are damaged preferentially die, I can tell you from doing multiple, multiple
experiments. [Valter]: Even during development, right? In development. I mean, that’s the way that the good and the
bad are… [Rhonda]: Right. It’s also how cancer cells are primed to die
as well, because cancer cells are damaged. They are mutated and completely damaged, and
that may be also why they’re very sensitive to stress. [Valter]: Yeah, and also, I mean, something
that is a speculation but we’re starting to think more and more, or at least I’m starting
to think more and more, is that…You know, I always say if you cut yourself, it doesn’t
matter where you cut yourself or if you hurt your head, the system repairs it, right? Or repairs almost anything. And so what about the inside? You know, is it possible that we never developed
a way to fix damaged organs and various systems? So we’re starting to think that maybe fasting
represents that opportunity to fix the inside, right? And maybe, and just maybe, because everybody
had to do it by force, they were forced to do it because there was no food at some point
of your month, almost unavoidably you probably were with no food. And so because it was almost unavoidable,
it was probably something that…you know, I always also think about sleep, right? And in sleep you feel so tired that you have
to sleep. Because obviously people wouldn’t have gone
to sleep just on their own right? But in the case of fasting, because it was
imposed by the environment, I suspect that maybe we never developed something that forces
you to fast. And so now that we eat all the time, which
completely lost this auto-repair mode, right? And this could be remarkable because imagine
if we had this ability if you have damaged liver, that fixes it. If you have damaged immune cells that are
autoimmune, that clears it. And so you never develop defense against autoimmunity
because fasting always took care of it. Now all of a sudden you get rid of fasting,
and all these things start building up, whether it’s insulin resistance, or liver damage,
fatty liver, etc., etc., right? So, this could be really…and people always
are surprised when we say, you know, we’re publishing on all these different diseases,
but if that’s true, then that make sense, right? [Rhonda]: Right. [Valter]: Because for example, in multiple
sclerosis, you see on one side it kills the immune cells. It then turns on the stem cells, then turns
on the oligodendrocytes, progenitor, and replace…I mean, it’s very…it’s like, how the hell
does it know how to do all of this? And it does it all in such a sophisticated
manner. But if it was an evolved process, that would
make a lot of sense. [Rhonda]: The thing that’s so interesting
is how the stem cells, you know, the clearing away of these damaged cells through apoptosis,
activating these stem cells which then have to repopulate whatever organ or tissue we’re
talking about, how they actually can make normal life cell. You’re talking about in the case at least
for autoimmunity or type 1 diabetes or multiple sclerosis, how they make their immune cells
normal, that is so… [Valter]: Yeah, but that makes sense, right? Because if you turn on a stem cell, you imagine
now that the…you’re not going to turn on a damaged stem cell, there’s got to be a selection
process to pick the…So the stem cell is now of course going to give rise to normal
white blood cells, right? They wouldn’t have any way to make an autoimmune
cell. So, I mean…yeah. So because that happens I think in the differentiated
cell, the clonal, so you expand already the differentiated cell. So even I think theoretically that makes perfect
sense that once you turn on the stem cell, the hematopoietic stem cell, you will make
a healthy…Now, you can always turn the healthy cells into autoimmune cell, but at least initially
you will make a healthy one, and that’s exactly what we see happening. [Rhonda]: So the refeeding phase is really
important for, I recall in our last discussion you mentioned the refeeding phase was really
important for the stem cell proliferation, so after you activate them, you want them
to proliferate and continue to grow. And you had mentioned, if I remember correctly,
that IGF-1 played a major role in that proliferation because it is after all a growth signal, you
know? [Valter]: Yes, so there’s no doubt. We haven’t spent too much time on it but it’s
pretty obvious that, you know, you’ll need growth factors to do that. So, this also makes us think about for example
the clinical trial, the multiple clinical trials that were done on IGF-1, in cancer,
that failed, right? And we thought, well maybe they failed because
the IGF-1 was also needed for example for the immune system to be built or rebuilt,
and, in those trials, right? So then the generation of healthy cells is
as important as the low IGF-1…generation of healthy cells is IGF-1-dependent, is probably
as important as the killing of damaged cells that is low IGF-1-dependent, and the turning
on of stem cells, which is also low IGF-1-dependent. So… [Rhonda]: Oh, it’s low? I thought it was higher, the…turning on
the stem cell…not turning on, the proliferation of them is high IGF-1, correct? [Valter]: Yeah, no, but the turning on, the
initial one is low. So low now is the signal to self-renew, you
know? [Rhonda]: Yeah. [Valter]: So now you have a population, a
small population of stem cells that are just active and standing by. Then probably when IGF-1 goes back up, now
they are the ones that are pushed by IGF-1 to proliferate and to differentiate, probably
also to differentiate. Proliferate and differentiate. Because now you want to rapidly make… [Rhonda]: Make new cells. [Valter]: …a lot of white blood cell for
example or whatever it is. [Rhonda]: So that’s my question about, my
question to you then is for the refeeding phase then, you may…is that…do you think
then for example having some protein would be a little more important because you want…protein
being essential amino acids…because you want a little more IGF-1 activated during
that specific time window? Is that something that you… [Valter]: Yeah, there is no doubt that when
you refeed, you have to have sufficient protein to rebuild. And if you don’t, I mean, you really don’t
have the bricks to rebuild whatever system you partially broke down. So yeah, protein…and also protein are going
to drive the IGF-1. So the whole system of course is set up to…the
sugar and the protein is set up to give the signals to rebuild, which is probably through
IGF-1. Insulin and IGF-1. [Rhonda]: Excellent. So just, since we’re running close to out
of time here, what are your top five biomarkers that you think are indicative of something
that people can…that are indicative of healthy aging that people can maybe go to their clinic
and measure? [Valter]: So if you…I went to the clinic…I
mean, if you’re talking to the masses, and you’re talking about health or you’re talking
about pure longevity? [Rhonda]: Well, I mean, I’m talking about,
you know, maybe both. If there’s…I don’t know if there are other
longevity markers that people can do now that are clinically available? [Valter]: I mean, yeah, I think there are
things that you can measure, that may predict your… [Rhonda]: Okay, let’s do longevity, let’s
do, yeah, biological age, let’s say. [Valter]: Yeah, biological age I will certainly…you
know, this is what are markers, certainly IGF-1, insulin, glucose, inflammation, systemic
inflammation, so CRP, most doctors can measure that. You could also, if you wanted to add, I mean,
triglyceride. And then you could add things such as for
example fatty liver. These are more pathological or pathology-oriented,
but certainly they can be major determinants of, or certainly can influence cellular functions
like insulin resistance. And so those are some of the things that I
would, I want to see in the ideal range. Of course blood pressure is another one. Then Morgan Levine, she’s now at Yale, she
has, she and others have a set of markers that are taken from large population and they
seem to be predictive of biological age, and I don’t…some of the ones that are overlapping
were the ones that I said, but there are other ones that are not, that I didn’t list. So, people can look up her papers. And also of course, you know, the methylation
profile, that seems to be predictive of…I mean, nobody does it now I think to the public… [Rhonda]: That’s Steve Horvath’s work you’re
talking about? [Valter]: Yes, but I’m assuming that soon
enough it is going to be available. [Rhonda]: Is it? Oh cool. Please let me know when it is, because I’m
very interested. [Valter]: I saw there are commercials now
about telomere measurement at home, right? [Rhonda]: Yeah. [Valter]: So now I’m assuming that soon enough
people are…at least a doctor will have the ability to assess methylation patterns. [Rhonda]: Cool. So you have a new book out, called “The Longevity
Diet,” which is the longevity diet… [Valter]: Yeah, “The Longevity Diet,” and
it’s divided into two sections, the first half is all about everyday diet, and in this
everyday diet I talk about five pillars of longevity. I basically say let’s base the decision on
diet on epidemiological studies, centenarian studies, basic research focus on longevity,
clinical studies, and studies of complex systems. And complex system being cars and planes. And I always thought that it’s very, a very
good way to remove, I mean, together with the other four pillars, to remove all the
uncertainties and say, well how do systems that we build age? To just get a fundamental understanding of
the environment and how the environment affects the complex systems. So the first health is that. And centenarian groups, the ones that have
record longevity from around the world who were really important. You know, for example I always say to people
the ketogenic diet, well let’s look at groups that have record longevity that use the ketogenic
diet. None of them. Right? So, that’s very important to say for the safety
component once you make a decision about what the science tells you, it’s always good to
look around the world and say, how commonly used is this diet? And if the answer is, it’s not used at all,
you’re really taking a chance on this diet. And the other half of the book is about the
fasting-mimicking diet, and you know, on normal people, some of the things we discussed, and
then a chapter on diabetes type 1 and type 2, there is a chapter on autoimmunities, there’s
a chapter on Alzheimer’s and neurodegeneration, and a chapter on cancer. So it goes through all the major…and a chapter
on cardiovascular disease…all the major diseases, and tries to, you know, mostly based
on data out there, and combine it with what we learn, to try to provide people with complementary
intervention. So for example if you look at diabetes, basically
it says, well, here’s what you could do every day, but then you can introduce the periodic
fasting-mimicking diet. Of course you’re going to need your endocrinologist
to make the decision whether this is clinical trial type of intervention or they can actually
do it. That is very tricky, so probably best, be
best to keep it within a clinical trial. But you know, some endocrinologists may be
experienced enough to follow their own patients and allow them to do it. [Rhonda]: That’s very cool, I think that’s,
the fasting-mimicking diet being used as a metabolic treatment for various diseases that
you just mentioned. Obviously many of them need to be under the
care of a physician. Is a very promising field because, you know,
as we’re learning now, metabolism plays a major role in not only, you know, causing
these diseases, but also in the treatment and how some of them respond to treatment. [Valter]: And again, is not just metabolism. Really, we’re looking at the ability in evolved
self-repair mode, right? So, I mean, almost every disease, let’s say
that you have high cholesterol, what do we do? We block cholesterol synthesis, right? But is that sophisticated? Not very sophisticated, right? And all, you know, say, the great majority
of the drugs are like that. You know, if you have an autoimmune disorder,
you have something that blocks a cytokine or a receptor. Very unsophisticated, right? So if there is, and I’m not sure that there
is, but it looks like there is. If there is a self-repair mode that goes after
almost every damaged system, this is much more than metabolic intervention, this really
deals with three billion years of learning how to fix a liver. Of course starting with bacteria, but the
process of autophagy started back then in bacteria. Now you’re using it to let’s say a muscle
cell that is insulin resistant, now you might push it to undergo autophagy, mitophagy, etc.,
etc., and now just maybe that resistant cell is no longer resistant, right? So, that’s the power of this, I think, much
more than the metabolic, you know, pushing the cell into a different metabolic state. I think it’s pushing it into a different metabolic
state while it’s doing this reset. [Rhonda]: Right, reset. That’s a great way of explaining it. The reset is probably what I’m most excited
about, is that they’re clearing away the damaged cells and then rejuvenating or fixing things. But I do, I quickly want to just mention,
because I do recall now one of your studies that you, at least in the clinical studies
with the fasting-mimicking diet, I think you were trying to look whether or not there was
some stem cell activation and there was sort of a trend you had seen mesenchymal stem cells
are trying to…you know, increasing them, but are you looking…is that something now
you’re moving forward with, and are there clinical studies to look at? [Valter]: Yeah. Now, yeah, we’re looking at that. I mean, of course we never took biopsies. I always feel bad about taking people’s biopsies
because it’s very painful usually to take their skin. So we had blood and it’s not so easy to measure
stem, circulating stem cells. I mean, now, techniques are getting better,
and so I think hopefully now we can have a better look at the circulating one, but yeah,
we’re definitely going to look at…I think in the trial that we’re now doing, athletes,
we’re doing a trial with athletes in University of Verona in Italy, I think as part of that,
we have biopsies, muscle biopsy. And so that should give us a better idea about
at least some tissue, associated stem cells, satellite cells for example. [Rhonda]: I’m so excited. I’ll definitely be following your research. Thank you so much Valter for the discussion
and your, talking about your book, “The Longevity Diet.” I look forward to talking to you some more. [Valter]: Yeah, yeah. Thank you for all the very good questions.

100 thoughts on “Dr. Valter Longo on Resetting Autoimmunity and Rejuvenating Systems with Prolonged Fasting & the FMD

  1. Have you thought about putting simplified bullet points in the drop bar, or giving a simplified breakdown at the end of these videos? I research nutrition more than the average bear, as well as other scientific topics and I haven’t been able to understand a good amount of any of these types of interviews. It would be nice if you could help those of us who don’t know certain language and certain assumptions of knowledge we may not have. I run my own business and simply don’t have time to research enough of all these interviews to fully understand what’s going on. This is why I love Joe Rogan interviewing you, he breaks things down for us. I’d love it if you’d consider this, I’d gain a lot more from your videos and I suspect others may too. Thx! I donate to you via your webpage because I appreciate you!

  2. This is perhaps the most interesting interviews of the many i have viewed of Dr. Longo.
    I reproduced the exact combination of fats, proteins, and carbohydrates of the the Prolon diet (for less than $1.50 per day), and extended it to 6 days. I also decreased the calories for days 2 through 6 to 550, in order to ensure positive effects. Five days later during my yearly health screening at work my glucose level was 73, 16 points lower than the past 4 years. This change occurred even though I had eaten a plant based diet (with no processed food) for more than a decade.

  3. Hi! We LOVE your podcast! We would love to sponsor it if possible? Can't seem to find a contact form on your website. Please advise 🙂 -Andy

  4. Rhonda te escribo desde CHILE. He visto varias de tus entrevistas muy interesantes y siempre intentas conectar con el CANCER. Luego de revisar algunos de los videos, puedo decir que hay un eslabón perdido que ha estado pasando frente a tus ojos, y no te has dado cuenta. SULFORAFANO, MORINGA, CURCUMINA Y PIPERINA, TE VERDE Y OTROS, proveen de efectos ANTICANCERIGENOS induciendo la generación de ESPECIES REACTIVAS DEL OXIGENO (ROS), que activan APOPTOSIS mediante ESTRES OXIDATIVO. Las células cancerígenas tienen niveles basales de ROS muy cerca del umbral tóxico. Una dieta alta en grasas o el ayuno, sensibilizan a las células cancerígenas al estrés oxidativo, ya que al disminuir los niveles de GLUCOSA, se deprime la PPP (VIA DE LA PENTOSA FOSFATO) que activa la respuesta ANTIOXIDANTE mediante NADPH, que es lo que permite a las células cancerígenas escapar de la muerte. LOS NIVELES BASALES DE OXIDANTES Y ANTIOXIDANTES son muy elevados en células cancerígenas, y cualquier intervención que favorezca el balance hacia ROS, producirá muerte por estrés oxidativo. Por otra parte, el metabolismo de las grasas (Beta Oxidación), evitará la excesiva generación de LACTATO que se produce al fermentar glucosa, y en consecuencia, el riesgo de METASTASIS será minimizado, ya que el entorno celular no recibirá la carga del ácido láctico exportado desde las células cancerígenas. Esto es sólo la punta del iceberg.

    Rhonda I write to you from CHILE. I have seen several of your interviews very interesting and always try to connect with the CANCER. After reviewing some of the videos, I can say that there is a missing link that has been happening before your eyes, and you have not noticed. SULFORAPHANE, MORINGA, CURCUMIN AND PIPERINE, GREEN TEA AND OTHERS, provide ANTICANCERIGENOS effects inducing the generation of REACTIVE OXYGEN SPECIES (ROS), that activate APOPTOSIS through OXIDATIVE STRESS. Cancer cells have basal levels of ROS very close to the toxic threshold. A diet high in fats or fasting, sensitize cancer cells to oxidative stress, since by lowering GLUCOSE levels, PPP (PENTOSE PHOSPHATE PATHWAY) is depressed, which activates the ANTIOXIDANT response through NADPH, which is what allows cancer cells to escape death. BASAL LEVELS OF OXIDIZERS AND ANTIOXIDANTS are very high in cancer cells, and any intervention that favors the balance towards ROS, will produce death due to oxidative stress. On the other hand, the metabolism of fats (Beta Oxidation), will avoid the excessive generation of LACTATE that occurs when fermenting glucose, and consequently, the risk of METASTASIS will be minimized, since the cellular environment will not receive the load of lactic acid exported from cancer cells. This is just the tip of the iceberg.

    Rodrigo in [email protected]

  5. incredible quality video with the studies and citation edited, really made it amazing!!! what program was used to achieve this?

  6. Dear Dr. Rhonda Patrick. What if you throw exercise in the mix? I mean if many of the benefits is due to a big calorie restriction. Then instead of fasting 2-5 days, what if you then just did fasted exercise after sleeping. So for example – No food 2-3 hours before sleep, then sleeping. That would be around 10-12 hours of fasting, then exercising, for example riding a bike – for 3 hours. That would create a huge calorie deficit/calorie restriction. 15 hours of fasting, + around 1500-2000 calorie deficit from the exercise. Would this bring some of the same health benefits, in terms of cancer risk and neurological diseases? I guess my question is, is it the severe/huge calorie restriction/deficit that is the key here? Best wishes Malte

  7. Ask your doctor before you try it….I told my doctor that my knees are in so much pain I cannot run anymore, and his response was "why do you need to run?"

    The Extraordinary Benefits of ASTRAGALUS ROOT: The Ancient Herb of Longevity and Strength

  9. Summary:
    He promotes caloric restriction, fasting: alternate day fasting, prolonged fasting, intermittent fasting, (just fast!!!)

    Proteins, especially the amino acid methionine (found mainly in animal flesh), upregulate IGF-1 (Insulin-like Growth Factor 1), which is a growth pathway. Studies have shown that animals that experience minimal IGF-1 upregulation (by minimizing/eliminating animal protein consumption) live significantly longer.

    He promotes the "Fasting Mimicking Diet" (low calorie, low protein, low carb, high fat), gives the benefits of fasting, without fasting. He promotes that you use this diet for 5 days in a row, a couple of times a year. For very healthy people, maybe only twice a year. For most people, more than twice a year.

    The fasting-mimicking diet had a positive effect on cholesterol, triglycerides, blood pressure, IGF-1, inflammatory biomarkers, etc. in people who had unhealthy levels of those things. But in people who already had healthy levels, the diet had no measurable effects.

    Some cancer can adapt to using ketones for fuel, also they can adapt to fasting. So fasting and ketogenic diets can not be used to cure cancer, but he does think they can be used in addition to traditional cancer therapy.

    He says that pescatarian (eating only plants and fish) is a very healthy way to eat.

    In almost every other calorie restriction diet, you lose fat, water, and muscle. In the fasting-mimicking diet, you virtually don't lose any muscle, muscle loss is very minimized, and the relative lean body mass actually increases.

    During the FMD, you lose a lot of organ mass, but after refeeding, your organs become larger than they were before you ever did the diet. So overall your organs get larger (but temporarily shrink during the diet).

    FMD can help cure auto-immune diseases.

  10. Here's a study where they seem to state that autophagy is related to the progression, not relief from, atrial fibrillation (https://www.ncbi.nlm.nih.gov/pubmed/29066441) But here's reference to a study wherein they find that autophagy is impaired in those who have atrial fibrillation (https://www.researchgate.net/publication/284929894_Autophagy_in_the_Onset_of_Atrial_Fibrillation) and that the impaired autophagy may be a causal factor for the disorder. Here's one more that says Carvedilol, a beta-blocker, increases autophagy in the heart, and that could be therapeutic (https://www.ncbi.nlm.nih.gov/pubmed/30186288). So what does one make of these? Also, what about fasting-induced autophagy? Is it bad or good for those with atrial fibrillation?

  11. I'm confused. At 53:03 in the video, Dr. Patrick and Dr. Longo talk about the importance of consumption of Protein during the Re-Feeding Window to increase IGF1 and proliferate stem cells, but on Page 114 of Dr. Longo's book "The Longevity Diet", it says:

    "Day 6 – Transition diet For 24 hours following the end of the five-day FMD, patients should follow a diet based on complex carbohydrates (vegetables, cereals, pasta, rice, bread, fruit, etc.), and minimize the consumption of fish, meat, saturated fats, pastries, cheeses, milk, etc."

    So which is it? Is it better to consume complex carbohydrates or protein (or both) during the re-feeding day? What about bone broth? If we shouldn't eat fish or meat, should we eat some form of plant protein? Is protein powder OK? What is recommended?

    Appreciate any thoughts on this, because I want to make sure and maximize the effect of re-feeding during this short window.

  12. These interviews are exemplary! They push my non-clinical mind to integrate science in a manner that rewards my curiosity with very practical application from well-researched investigation. You guys are the new Carl Sagans – thank you!

  13. Is there a connection between nrf2 pathway and vegfc connection to lymphedema and can they work together in promoting bennefits in treatment of the condition

  14. Never listen to physicians for health advice use researchers… Physicians are always behind on information, always follow the scientists, these guys are researchers.

  15. If I eat that little protein I will disappear.. is it always a choice between looking young and beautiful and being healthy and live longer? 🙁

  16. Dr. Patrick – I have been doing every other day 24 hour fasting for a couple of weeks now and want to thank you for putting this information out. It has been the ONLY thing that helps me with weight loss. I've got several issues going on – heavy menstrual cycle and iron deficiency as well as hypothyroidism now. I am severely allergic to Fish AND Shellfish. I have an allergy to "man-made" iodine since it's mostly derived from the sea. Doctors argue with me about this all the time. I literally cannot touch a drop of iodine solution or I break out in hives. Anyhow, my question to you is – because I'm so highly allergic to fish and shellfish, what would you suggest I increase in my diet to get more DHA and Omegas? I tried taking flaxseed oil once and had to go to the ER because of an episode of PVC's, which the Dr. said Flaxseed oil can have that side effect on some people. Thank you!

  17. Hi Rhonda,
    Talk about 5G, and how it will kill us please next. You have enough "Egg-Head" friends out there, and followers who will believe and get to realize how we're about the go through a eugenics period in the US and elsewhere.

  18. Dr. Rhonda Patrick, Dr. Longo says that chronic food restriction beyond 12-13 hours is not good—that it causes problems. I recall you saying that you were restricting your eating window to 9 hours (a 15 hour fast, for lack of a better term). Can you speak to the conflicting views?

    Thank you.

  19. Subject : Alcar-L-Carnitine/I am a lung cancer survivor, (Lobectomy)did you say all amino acids including Alcar is NOT recommended for cancer patient/survivor? Q #2
    Dr Longo spoke of a vitamin C called "Ester C" is that ok for me, I thought you spoke of all anti-oxident supplement not good for cancer patients/survivor? Note# your information I follow like my life depends on it, I am so grateful, tools to fight ! ……….a sincere thanks you know I will check back for your reply:)

  20. The part where he talks about the FDA process and how much it all costs is so depressing to hear. I understand why the process is the way that it is, but it's obvious who will have $50 million of investment for a potential treatment, and those entities will not have an interest in investing that amount into a complementary, dietary treatment. Just shows how much more complicated the whole system is than just finding the "most effective" treatment. Even just research requires grant money to test less invasive alternatives that show no promise of making any money to anyone, but are solely for the benefit of treating the disease.

  21. so whats your take on this? https://academic.oup.com/ajcn/article/105/6/1351/4668664
    study saying skipping breakfast is a contributor to the onset of type 2 diabetes. bad info?

  22. Everyone blames MD's for not staying up to date on information like this, but that's not necessarily true. Some do stay very informed, and understand the benefits of some of these protocols. However, most patients will not comply.

    For example, when someone who is overweight, eating a poor diet, making poor choices like alcohol, smoking, sedentary lifestyle, it's really in the patient's court to take corrective action. But they don't.

    They come to MD's for prescription medication and to fix the damage they've done to themselves. Pills and medical interventions are their only idea of healthcare. To them healthcare comes in a prescription bottle, or happens at their doctor's office, or a hospital. They fail to understand that most healthcare occurs during their regular life, NOT in their doctor's office, or the hospital. It's the choices they make, the food they eat that have MUCH more impact on their health. They have to educate themselves and make their own choices. They have to be their primary physician.

    If a doctor tells a patient some of these self-interventions, the vast majority will not comply.

  23. my cousin has a (very) serious lung disease (COPD last stage). Question: will the lungs during longtime-fasting also shrink and then rebuild? actually his nose is wired up with some oxygen supply which generates a 2nd question: can it be problematic to shrink the organ via fasting?

  24. If you try the fasting diet that is sold by Dr Longo for say a 1 year period and your BP reduces accordingly does the heart adjust to this lower pressure? And if so when you come of the diet does the increase in BP suddenly cause a sustained spike in stress on the heart and in a quicker time frame than normal progressive increases in BP due to the usual causes?

  25. For heaven's sake Rhonda,

    Even though you may have a scientific background, realize that your purpose and function is ultimately to help your brothers and sisters in the simplest and most direct way possible!

    This is what nature does, which is intimately complexion yet renters itself into the simplest often is manifestation.

    So in this since you and your colleagues need to quit lab talk and to speak the language of the rest of ordinary motels on the planet speak.

    You should be able, in a handful of simple directive, to share with your fellows what are the most beneficial actual life changes that cannot should be made despite the incredible diversity in complexity of your research!

    5 simple sentences should do it

  26. I want to go back to school and learn this. I'm in health care and I agree that Alopathic medicine has reached a wall in relation to treating chronic disease

  27. When do the benefits of these restrictive diets start to diminish as people age? If someone were to start, say, in their 60s or 70s, would there be appreciable benefits? And what about the potential downsides of enduring the recommended regimens? Is diet alone sufficient or must there be ongoing exercise and of what type? And, finally, one needs to look at QUALITY of life and not simply longevity. Suppose you live longer, but the asceticism essentially ruins the VALUE of the extended existence?

  28. So… keto is a no-no, because some miniscule fraction of cancers can metabolize ketones (though vast majority can't and die in glucose deprived environment), but chemo is a great way to go! Thanks dr Longo, but no thanks.

  29. The title is a bit misleading. I came here trying to help my sister's autoimmunity, and came away with basically nothing. Perhaps, I can ask here/now…"""how can an individual who suffers autoimmunity reset their autoimmunity?"". Thank you for your time. =D

  30. I have never seen a better informed, intelligent interviewer. All i can say is wow! So informative without being redundant.

  31. i have been trying to regulate my autoimmune diseases with diet(type 1 diabetes, Graves disease, celiac, and arthritis). what would be the ideal diet for autoimmune disease? I am currently eating in a 6-hour window and have played with my macronutrients in that window. i would be willing to make any further dietary modifications necessary to improve. i currently follow low lectin protocols cutting dairy, legumes, nightshades and grains with the exception of corn and peanuts and a little cream in my coffee.

  32. FMD was an answer for offering fasting to people who refused to do a water fast.
    Is FMD better than water fasting. Or just a substitute?

  33. Someone I love very much has an autoimmune disease (also prediabetic with liver issues) wants to try prolonged fasting. However, their need for daily medication means they need to eat everyday. Any advice for a situation like this? Thanks for the excellent content as always! 🖖

  34. I don't understand why the products in the Longo FMD diet series have starch in them(rice) when he says in every intervju that the carbs in the diet must come from vegetables, not from starch…

  35. Awesome content! I love that you include the citations as real time overlays so the audience can follow along while you discuss the data.

  36. Rhonda likes to invent ad hoc theories that fit her confirmation bias. No wonder he is not a scientist but a propagandist.

  37. Ok, what should i eath after 5 days of fasting, while refiding? Should i eath just soups for 2-3 days, or how that whole thing goes from there? Does anyone know?

  38. What about discovering potential igf1 receptor antagonists, would this be beneficial? Someone should look into cannabinoids in this regard.

    As in both mice and human tissue culture cancer studies, delta 9 THC has been shown to have; anti-angiogenic, anti-proliferative, anti-metastatic and pro-apoptotic effects on the non healthy cells exclusively.

    I hypothesized that some cannabinoids may work as an insulin receptor agonist, as my type 1 diabetic mother noted anecdotally that she could lower her blood glucose a little by smoking cannabis without having to inject insulin, also I get very hypoglycemic if i do strenuous exercise after smoking… evidence to me that some cannabinoids may work in similar fashion to insulin on a cellular level as far as glucose metabolism is concerned, without having elevated levels of serum insulin and the subsequent resistance or other more serious (inflamation & pro tumor etc.) side effects.

    This explanation of the igf1 receptor signaling pathways as related to cancer and aging really make me think that cannabinoids may also be taking an antagonistic role at the igf1 receptor (particularly in cells with a low immune response, such as old/damaged/cancerous cells). This might explain why and how cannabinods have and perform their selective anticancer properties.

    This seems like a workable hypothesis, and i presume there is little chance dr. Patrick will see this comment… But I would love to hear her thoughts on this, its possibilities, and maybe potential for therapeutic application.

    Thanks for reading 😉

  39. Keep these videos coming! It is helping empower me to educate myself and put me in control of my health. Thank you!

  40. 3rd day of my 5 days water fast, 2nd day was worst, now I'm feeling a lot better, hopefully I can push through the 5 days

  41. I can’t wait for Rhonda’s talk with David Sinclair. I’d love to get a round table with her + Longo + Sinclair.

  42. well im on day 2 of my water fast i drink 500ml of coconut water 110 calories a day because im not a moron and i know my body needs sodium and potassium.

  43. I am trying to find out how I upload my DNA report from Ancestry DNA in order to obtain reports from FMF. Has anyone succeeded in doing this from Ancestry.ca? Thank you

  44. Dr. Patrick please make a video on ways to manage or heal ulcerative colitis / Crohns Disease. I would love to hear your perspective!

  45. Curious if FMD has been studied on people that are already using metformin or berberine. I use berberine and sulforophane which has affects on ampk, mtor, glucose, atophagy among many other things. How much would I need to alter the FMD process?

  46. first 10 minutes are very interesting. protein , IGF1 and aging is something Dr Grundy writes about in the Longevity Paradox. i sense some myth busting going on in the world of protein needs, esp of the animal sourced.

  47. I always have a hard time trusting researchers who have a personal financial interest in the thing they are researching. I think researchers should be rewarded for discovery but when money becomes the driver then bias is almost inevitable. I get really suspect when the representative product doesn’t go through FDA approval because efficacy doesn’t need to be proven. Even “independent” studies are problematic because someone has to fund those and if you look at disclosures you can usually find something that is suspect.

  48. I want so much to believe but I always have a hard time trusting researchers who have a personal financial interest in the thing they are researching. I think researchers should be rewarded for discovery but when money becomes the driver then bias is almost inevitable. I get really suspect when the representative product doesn’t go through FDA approval because efficacy doesn’t need to be proven. Even “independent” studies are problematic because someone has to fund those and if you look at disclosures you can usually find something that is suspect.

  49. I wonder if Dr Patrick could give her opinion on GcMAF which is said to cure stage four cancer without side effects.

  50. Good podcast and interview, but just be careful on how you interpret some of the information he presents here because he makes information from both animal studies and human studies. Metabolisms, and how organisms respond to fasting is vastly different and what happens to one wont necessarily happen to other.

  51. Intermittent fasting occurs naturally when you have good circadian rhythms. Early to bed…sleep well, wake up hungry. 🙂

  52. If Dr Longo can abandon having to deal with the FDA or other powers that be, who don't want society healthy. We all win. There are products available without FDA aporoval that are changing pepoles lives for the better. Once people see his product works, they will use it. Anecdotal eveidence or not, if people see results they will use the product. I just hope he doesn't sell his soul, when the O.T.O. makes him the offer to come to the dark side. Who besides Big Pharmaceutical companies can afford $50 million for FDA approval?

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