Valter Longo, Ph.D. on Fasting-Mimicking Diet & Fasting for Longevity, Cancer & Multiple Sclerosis

[Rhonda]: Hello, everyone. I'm very excited to be sitting here with Valter
Longo, who's a professor of Gerontology and Biological Sciences at the University of Southern
California. He's also Director of the Longevity Institute. Dr. Longo has made huge contributions to the
field of aging. He has made significant contributions looking
at the effects of fasting and other diets in the role of human aging, and lifespan,
and biomarkers of health span, as well as looking at other metabolic fasting therapies
for the treatment of human diseases. So, Valter, on the podcast, we've talked a
lot about time restrictive eating from Dr. Satchin Panda's work, and what the effects
are of eating within a certain time frame, like at least a 12-hour time window, where
that corresponds with the circadian rhythm.

And how that's really important for a variety
of different metabolic factors because our metabolism is on a circadian rhythm, but also
looking at the effects of having a longer fasting period when we're resting. So, maybe you can tell us. You've done a significant amount of research
on fasting in animals and humans. [Valter]: Yes, yes. So, we are very interested in aging, and really
what are the interventions that extend longevity in a safe way. And in fasting, periodic fasting, or better
yet, fasting-mimicking diets, so these diets that are designed to sorta trick the system
and make it think that it's fasting when you're not fasting, so that's what we focus on. And the idea really came from trying to substitute
the calorie restriction, these interventions which require the people are restricted from
calories permanently essentially. And I always thought, I was a student of Roy
Walford, who was one of the pioneers of our calorie restriction back in the early 90s. And, in fact, I was there when they went into
Biosphere 2, which was this bubble, essentially, in Arizona, where they did the first human
study and calorie restriction.

And in the group, when they came out, it was
a very stressed out group, very thin, right? So, from then, I wanted to come up with something
that was really for everybody, right? So, how can you take that, have something
as powerful, but everybody can do? And that's where this fasting-mimicking diet
came about. And, really, about, you know, anywhere from
four to one week or longer of this changing to these diets, which is usually low in protein,
low in sugar, and high in good fats. [Rhonda]: Is that, sort of, so it's low…we're
kinda talking about this fasting-mimetic diet, but the fasting itself is also something. So, there's the fasting-mimetic diet, which
you've done a lot of research on in animals and also humans, but the fasting itself is
different from caloric restriction, right? There's a lot of overlap between looking at
the effects of different biomarkers for healthspan, but there's also some differences, right? [Valter]: Well, it's very different, right? I mean, calorie restriction is, say, 20% to
30% restriction in calories, so you're basically eating all the time, and you just happen to
eat less calories.

Fasting and periodic fasting are much more
extreme, and we really use them to trick, or manipulate the system, orchestrate a lot
of genes to get it to do things like increase protection a lot or turn on stem cells. And so, a lot of these things you can't get
by calorie restriction, but you can get them by these more extreme interventions. And, yeah, so calorie restriction also is
missing the biggest component of the periodic fasting, which is not fast in itself, but
it's refeeding, right? So, most people think of the restriction as
what's working, but it turns out, as we've shown in a number of papers, that is the refeeding
that is doing most of the work, right? So, they're doing that. For example, when we publish on regeneration,
the stem cells are turned on during fasting, but it is the refeeding that causes the rebuilding
of the system.

And so, the most important part is the refeeding,
and in calorie restriction, of course, you never have that. So, it's really interesting how this works,
and it's a very coordinated effect based on cycles of fasting and refeeding. [Rhonda]: You mentioned the regeneration of
the stem cells, so that's the study that you're referring to. You did this prolonged fasting for, I think
it was like 48 to 72 hours in animals, and you showed that during that fasting state
the white blood cells were…basically their populations decreased. And the reason they had decreased was because
something was being activated called autophagy, which is the clearing away of damaged cells. And somehow, so the autophagy that happened,
you're saying that after that occurred, that was the signal for the regeneration of the
stem cells or the refeeding after? [Valter]: Yeah.

Autophagy is clearly occurring, and this is
established for fasting. But we don't think, I mean…what we've done
so far was…now we're focusing more on autophagy, but what we done so far was more about, if
you have an immune system, a complete immune system, that immune system has a lot of cells
that you don't really need, right? [Rhonda]: Mm-hmm. [Valter]: So, during starvation, whether you're
a mouse, and now we know the same to be true for people, you have to get rid of a lot of
cells, a lot of things that you don't need.

And that's what's happening, it's not so much
about autophagy, but it's more about apoptosis, and so, a program cell diet. You're killing, essentially giving rid of
a lot of cells, and then you stand by, you wait until food comes around again, and you
rebuild it. So, for example, in a mouse, about 40% of
the white blood cells are destroyed during this period of four days of fasting or so.

And then, that 40% is rebuilt within a few
days of refeeding, right? So, it's really extraordinary and probably
the most powerful regeneration or generation program that you have since birth, essentially,
right? So, when a baby is first born, of course,
you're generating all these systems. But then, that never happens again, right? Not in that way. Like, for example, the liver being generated,
and the lungs being generated, and the heart, etc.

So, fasting is probably the most powerful,
at least, that we could think of. The most powerful way, particularly if it's
prolonged, to shrink a system, let's say, make the liver a lot smaller, make all these
organs a lot smaller, the immune system, and then regenerate it, right? And so, this is why we think it's so powerful
because it is not really the fasting that is doing anything, it is the body that is
doing everything. The fasting just tells the body, "I need you
to kill all these cells," and then, the refeeding gives the message, "I need you to rebuild
all the systems cells." [Rhonda]: Mm-hmm. This seems like it has, I mean, implications
for human aging because, you know, if you're talking about humans as we age, something
occurs called immunosenescence, where we start to lose some of our, you know… We don't we don't make as many lymphocytes,
actually, it's the lymphoid population that decreases with age. And so, if you're able to then be able to
activate these hematopoietic stem cells to regenerate, you know, the blood cell population,
that seems like it would have implications for aging.

But, also, I thought you found something very
interesting in that paper, and that was what we talked about with the regenerating the
hematopoietic stem cells, which also increased in cell number if I remember correctly. [Valter]: Mm-hmm. [Rhonda]: You also did this experiment in
older mice, and you showed something very interesting, I thought because as we age,
the immunosenescence seems to be happening. And I may be doing a huge oversimplification
here, but it seems to be happening in the lymphoid cells, which are mostly B and T cells
as opposed to the other blood cells we have, the myeloid lineages, which are composed of
neutrophils, macrophages, platelets, and things like monocytes. So, as we age, we have more of those types
of immune cells. But you actually found that if you fasted
those animals, something happened with their populations, correct? [Valter]: Yes, so we found that the lymphocytes
number goes back to the more youthful level, and the ratio of myeloid cells to lymphocytes
because they're also back not to the same level as during youth, but certainly it moves
in that direction.

And so, the profile of the immune system is
much more similar to the young one, so essentially, we see a rejuvenation of the system. [Rhonda]: See, that was really cool for me
when I was reading that because I started thinking about, you know, not only with the
immunosenescence, how that seems relevant, because when you're older, you become, you
know, more susceptible to infections, cancer, obviously your immune cells play, you know,
the first line of defense against killing cancer cells. But the other thing I thought about that was
very interesting, and I'm not sure if you've…you've probably read this paper, but it came out
of Japan a few months ago, I don't remember the group, but they were looking at a variety
of different biomarkers in the elderly population, in centenarians, in semi-supercentenarians,
and in supercentenarians.

And they looked at all sorts of biomarkers
that are related to aging, so it looked at telomere length, they looked at senescence,
immunosenescence, they looked at all sorts of inflammatory biomarkers. They looked at metabolic markers, glucose
regularly, you know, insulin sensitivity, they looked at kidney function, you know,
the whole pack, just tons of different biomarkers. And they were trying to find which biomarkers
were consistent with healthy aging in all populations. So, not just, you know, to make it to centenarians,
but to make it to every single age group. And what was identified was the only biomarker
that was consistent with all the age groups was inflammation. So, lower inflammation was predictive of vitality,
and cognitive function, and it was considered to be the only thing that was driving the
aging process, or that could predict mortality aside from age itself.

And I was thinking about how monocytes, macrophages,
and neutrophils, these are the parts of the immune system that are the myeloid lineage,
which is, you know, we have more of them when we're older. They actually produce a lot of really nasty
chemicals, hypochlorite, hydrogen peroxide. So, the myeloid lineage is producing lots
of nasty inflammatory chemicals, so it'll be kind of interesting to look and see. I mean, I'm totally just speculating here,
but if there's some way…if you to make a…if you could regenerate the immune system to
resemble more of a youthful phenotype, first of all, it'll be interesting look at centenarians
to see if they have more balance, right, if they have more of an immune system that has
more lymphoid and myeloid, so it's not so asymmetric.

That would be interesting to see, but also,
whether or not, if that plays a role in healthy aging. [Valter]: Yeah. I think we need to be careful with the inflammation
as a cause of aging. I see it the other way around, I see it as
the aging is the cause of inflammation. And that makes sense, right, because inflammation
is really can come from dysregulation of immune cells and other cells in the body. So, yeah, so I think it's really the evidence,
the inflammation is the driving…the driver is not there. There's very few studies actually showing
that, you know, by increasing a little bit of inflammation, increase in aging, they're
not there. It's possible but this doesn't seem likely,
you know. I look at it as much more in the sense of
program, meaning that all organisms have a program, and this program is there to keep
them healthy, and young up to a certain point, and now, there are ways to make these programs
longer, or shorter, and I think the centenarian just happened to have programs that are stronger
and longer.

And then, when these programs fail, the inflammation
is one of the things that you see as well, and it happens together with a lot of other
problems. But certainly, inflammation, I mean, as a
marker, is a very important one. So, if you look at C-reactive protein, for
example, or Interleukin-6, in any intervention, they should do, you wanna see them coming
down, and this is a good indication. As we've done for our fasting-mimicking diet,
where we've showed that almost every patient that…I mean, we showed a decrease in inflammation
in the mice that were given the fasting-mimicking diet started at middle-aged. But we also saw it in the human population
aged 20 to 70, where everybody they had high C-reactive protein came back down after 3
cycles the FMD, came back down to their normal levels. But again, that's probably indicating that
the systems were not working properly, and now you bringing them back to a prior…you
know, maybe you're regenerating part of the, you know, bone marrow and maybe also you killed
some bad cells in the spleen, etc., etc.

And so, the result of that is the last inflammatory
markers that are being released. The liver, also, we've shown they undergo
cycles of atrophy and regeneration. So, all of these organs are contributing to
information, and so, it's important that with an intervention, you see also an effect in
an inflammation, because it tells you that the intervention is working, the system is
being reset back to a more youthful state. [Rhonda]: Yeah, I do agree that that's definitely
a good marker. So, you were talking about this fasting-mimicking
diet in humans this clinical study in humans that you have a pilot trial that you had done
in humans, where you're… So, with the mouse studies into fasting, and
their autophagy in the regenerating of the stem cells, and, you know, that stuff's all
very exciting and has relevance for, you know, for cancer, and for aging, in general. But how can you translate like a 48-hour fast
to humans, and is that, sort of, why you've come up with this fasting-mimicking diet because
the amount of time would have to be like a week, or five days, or something that seems
a lot more difficult for humans to do? [Valter]: Yeah.

So, it's not just about difficulty, it's also
about safety. And so, when we first started with the fasting
in cancer patients, basically the patients didn't want to do it, and the doctors didn't
want to do it, so it's really a struggle. And it took us forever here at the Norris
Cancer Center, our own University, to get 18 patients to go through it, it took us like
five or six years. So, it was very difficult.

And then, we started asking people, "What
if we give you a fasting-mimicking diet?" And we started asking doctors, "What if we
give patients a box, and it has all the foods that they need?" So, it's more of a medicine, right? You just hand over to the patient a medicine. And then, everything turned around, so people
were much more likely to do it, they felt like… [Rhonda]: It's more compliance. [Valter]: …psychologically, we give them
something, they also, of course, they're eating almost normal…I mean, normally in the sense
at the right times, they're not eating normally, but obviously, the diet is very different
than the normal diet. And the doctors felt so good about it. So, I think, it was really important to get
to get the fasting-mimicking diet going, and, you know, so now we have a number of trials
in cancer patient, in diabetes patients. Soon enough, we'll start with…well, we finished
one multiple sclerosis, and so, now, we're ready to start talking to the FDA about moving
to the next level.

I think people are underestimating the power
of this, and there's good and bad, I guess, but I think that it's got a real potential
as we're seeing now that we're talking to doctors. And now we're seeing a lot of doctors, cardiologists,
and endocrinologists, gynecologists prescribing it, right? Or recommending, and they're not prescribing,
it's not a drug. But they're recommending it to a patient,
and it's been great, you know. And now we have a couple of hundred doctors
that we're been talking to see this group of people changed from this drug-centered
mentality to, maybe there are things that we didn't realize could be very powerful,
and much more able to, again, let the body fix itself.

And so, I would not be surprised if in 10
years, worldwide, these type of interventions are gonna be standard in the doctor's office. [Rhonda]: Wow, that's really cool. You know, it's really diet lifestyle they
play a really big role in cancer. I mean, it's pretty well known that things
like obesity, smoking, you know, that being sedentary, they all increase the chance of
getting cancer. And, you know, people are getting cancer more
and more these days, I know that it's the second leading cause of death in the United
States. And I think, actually, recently, according
to the newest CDC data, the state of California, it's the leading cause of death, it trumped
a heart disease in the state of California.

So… [Valter]: In Europe, it is the same way, in
a lot of places, it is number one. [Rhonda]: In Europe, really? People smoke a lot in Europe. But, you know, the cancer treatments of standard
of care, you know, chemotherapy, radiation, surgical interventions have, sort of, been
the same for quite some time, several decades, at least. So, I can't think of a better time than now
for these metabolic types of interventions to make their way, hopefully, into standard
care, either with standard care or possibly replacing it to some degree in the future. [Valter]: Yeah. [Rhonda]: But you did a clinical trial, so
are you involved in this clinical trial that you kind of mentioned, like, briefly, which
I thought was very interesting? The actual one with fasting, where the cancer
patients fasted either before or after the chemo treatment, and I thought it was very
interesting that you found, maybe you can talk about it, but you found that their normal
cells were more resistant to the stresses of chemo, whereas the cancer cells were more
sensitized to that.

[Valter]: Right, right. So, of course, all of these starts in mice. And in mice, we were able to show very strong
effects, what we call differential stress resistance, which is you protect the normal
cells, but not the cancer cells. And then, something called differential stress
sensitization, where you kill the cancer cells, but not the normal cells. [Rhonda]: Can you explain that a little bit,
like why that is? [Valter]: Yeah. Well, that is, again, because almost every
organism, you can start with E. coli, actually, bacteria, and then move to simple organism
like yeast, and all the way up to mice, they have starvation responses, right? So, if you starve any system, virtually any
system, they'll go into this shielding mode, protected mode, and then, they sit there until
food comes around again. So, in this protective mode, they're very
resistant to all kinds of things. They're resistant probably because they have
to be resistant to the sun, and to chemical produced by other microorganisms that might
be surrounding them.

And so, then, they happen to also, at least
in mice and now we think humans, chemotherapy is also one of the toxins that they're resistant
to. So, you starve the normal cells going to the
protected mode when you starve a cancer cell though because the oncogenes are the regulatory
genes of this protection. The cancer cells, by definition, can never
respond, right? So, they just, normal cells respond no matter
what normal cell is, from a muscle cell to hepatocytes, to a brain cell, but the cancer
cells don't respond. And that's really what's called differential
stress resistance. In the differential stress sensitization,
instead, it really has to do with something that, I think, was under-appreciated, which
is a cancer cell is viewed as a smart cell. In fact, the cancer cell is a very dumb cell.

And why is it dumb? Because it is involved in all this high nourishment
environment, right? So, it's involved with a lot of proteins,
a lot of amino acids, a lot of sugars, a lot of growth factors, all these things are around
all the time. So, by making them available I know the oncologist
means well, right? But by making all this available during chemotherapy,
you really helping one thing more than anything else, is the cancer, right? [Rhonda]: What you're referring to is them
telling people to eat a lot of calories. [Valter]: Yeah, of course, yes, so they tell
them to eat. And so, you know, because the cancer loves
sugar, and loves amino acids, right, and depends on sugar and amino acid, the more you give
it, the happier it is.

And also these nutrients basically, make the
normal cells sensitive, right? So, you're making the normal cell sensitive,
and you're making the cancer happy, right? Instead of the opposite, which is making the
normal cells protected, and make the cancer cells miserable. Why are the cancer cells miserable? Well, because, again, having evolved in this
abundance, once you take the abundance away, it's like almost saying imagine somebody that
had a very low IQ, you know, been looking for food, you know, and if you make it available,
it's easy. Let's say, thinking about a monkey, let's
say a monkey that has got a very low IQ, and, you know, you put it in front of food all
around it, and it's gonna have no problem, right? As soon as you take the same monkey with a
very low IQ, and you make it extremely difficult to find the food, now that monkey is gonna
have a problem. And, you know, and that's how we see the cancer
cells. You know, once the amino acids are low, the
growth factors and the sugar are low, the cancer is gonna starve.

And then, if on top of that, you hit it with
chemotherapy, it just has a very low chance of escaping. This is why, in mice, we see cancer-free survival,
meaning myself free of cancer only when we combine the starvation or the fasting-mimicking
diets with the chemotherapy. We almost never see it when we use each one
alone, right? [Rhonda]: Mm-hmm. [Valter]: We, and many other labs have tried
that. You see, which is great, often the fasting,
the first thing we can say it's as good as chemo, but you never see, you know, alone,
each intervention alone being curative. So, it's very interesting, and this is also
very important to point out because a lot of people, tend to either be in the camp of
traditional medicine, or in the camp of alternative medicine. And people don't understand that, you know,
that both of them are very important, and when you combine it, particularly the alternative
integrative medicine that's got a deep scientific foundation, when you combine it, now you have
a very powerful system, you know, in your hands.

And, you know, whereas each alone doesn't
work very well. [Rhonda]: Yes. It's kind of, like, what you're explaining
it, at least, the way I'm understanding it is that you need, so that the fasting itself
is a stressor, but you need another stressor because the stress plus the stress is what
can push the cancer cells to the death, right? So, they're, in a way… [Valter]: Yeah, I don't see it, I mean, I
don't really see it as a stress. [Rhonda]: Fasting? [Valter]: Yeah. I really don't see it as a stress, I see it
more as an environment that is very common, right? It's very common to bacteria, it's more common,
in fact than food, right? So, you can see food is a bigger stress than
fasting, right? Because food really puts you in a weak position,
right? And fasting puts you in a strong position. So, if you look at most organisms on the planet,
they're much more under starvation condition that they are, including humans, right? Historically, if you look at, there's some
really nice books about, you know, the medieval times in Italy, and even after, and it's amazing
how many times they were with our food at all, right? [Rhonda]: Mm-hmm, yeah.

[Valter]: They could be without food for months,
and this was very common for everybody. Imagine before then, imagine in tens of thousands
of years ago, we must have gone without food for a really long time. So, fasting is part of the normal world, it
is the normal world. And food comes around once in a while, and
then you go back to the fasting. But you have to respond to that, and you respond
by having a entering a mode of survival that is very different from the one that you enter
or you stay in when you have plenty of food around.

[Rhonda]: Yeah. I see what you're saying, but, I think, though,
what I, kinda, was trying to convey was that it activates stress response pathways because,
you know, even though it is part of our normal, you know… Obviously, throughout human evolution, we've
been through periods of time with, you know, no food and starvation. That is normal, it is part of our normal,
it is part of our normal biology, I guess. But, I think that because it activates all
these stress response pathways in a way… [Valter]: Yeah. I mean, word-wise, technically, yeah, it is
a stress, I mean, it's viewed as a stress. But I guess that… [Rhonda]: Like the hormetic type of stress
is what I'm talking about. [Valter]: Yeah, but that's the one that I
have a problem with, meaning that, the hormetic stress is really, you know, something that
you activate by having some type of damage or problem that activates a response. And then, that response makes the system more
protected against the bigger problem, right? But, here, I view it more as program A, program
B, type of thing, right? So, program A, the major program is the starvation
program, where you are in a shielded mode, right? Your decision is, "Let's be in a long-term
protective mode." And program B is when the organism makes the
decision that it doesn't need to be in a productive mode because they really want to focus on
reproduction, and growth, and reproduction.

And so, I think it's better to view it this
way because I think a lot of people, by going into the hormesis theory, maybe you missed
a little bit of the point. And I know a lot of people would disagree
with me on this, but, really, by doing the work like we've done in E. coli, in yeast,
in human cells, in mice, and in humans, you start getting, you know, a more clear picture
of what's going on. And I really see this as A and B, you know,
the environment decides which program you adopt. [Rhonda]: Mm-hmm, that's an interesting way
to think about it. Getting back to the cancer with the fasting
and this…kinda we got sidetracked. But the fasting, the cancer cells itself are
doing this in animals. And also, you've been involved in a clinical
trial, where it was shown to lower markers of damage in human blood cells, DNA damage
was lower, but the cancer cells were more sensitized to death.

In animal studies, you showed that because
of the fasting lowers glucose levels, and… Like you mentioned, cancer cells love glucose,
that's called the Warburg effect, where they're predominantly using glucose, of course, they
also use glutamine and amino acids. But I thought it was also very interesting
because I've often thought about cancer cells as being primed to die. You mentioned how oncogenic signaling is all
screwed up all sorts of…they're damaged, they're messed up cells, they're not normal. And they have high levels of, you know, pro-apoptotic
proteins that are causing them…they're supposed to cause them to die, but they've countered
that with the anti-apoptotics.

So, it's almost like they're primed to die,
but they need that just extra stress, whether that's from chemo or possibly from activating
mitochondria, which are the largest producers of reactive oxygen species. So, do you think that part of the fasting
of the cancer cells, and, sort of, causing them to then use fatty acids, which can only
be used by the mitochondria to generate energy as a byproduct, then making reactive oxygen
species, do you think that's part of the killing, I mean, in addition to the immune system,
which you also showed…

[Valter]: Yeah, I think it's all connected. You know, I think it's all connected. So, yes, yes we publish a paper calling the
fasting-dependent anti-Warburg effect. And so, basically, normally, the cancer cells
can rely on glucose, and once that glucose is lower, they have no choice but to try to
go back to oxidative phosphorylation, and using the mitochondria to get energy, because
there's no other way around, right? And that's great because, then, they become
desperate, essentially, and that condition makes them undergo suicide. Because now, like you said, you know, you
produce a lot of free radicals, but the cell is not set up to be protected.

So, it's a very bad combination, and this,
we believe, leads to the extent of that, and then, in mice, can cause cancer-free survival. But also, we think that probably that is involved
in allowing the immune cells to move in and kill them, or it allows the cells to become
more immunogenic, so, then, now, they're easier to be recognized by the dendritic cell, etc.,
and to be set up to cause an immune response, the normal. [Rhonda]: Yeah. I think you actually showed that the…maybe
it was the fasting-mimetic diet itself was able to increase cytotoxic T lymphocyte number,
and play an important role in killing cancer cells. [Valter]: Yeah. Not just increase the number, which is very
much consistent with our older paper, but more or so making the cancer cells exposed
to it, right? So, it's more about making the cancer cell
more unable, like you were saying now, than normally, the cancer cell figures out how
to deal with the immune system, and has proteins that say, "I'm one of yours," right? And tricks the immune system in that sense.

And so, the fasting takes that away, and this
is really, again, interesting because this is coordinated multi-level approach that the
fasting is causing. Which makes you think, again, that some of
these programs, some of these effects may have been evolved effects to get rid of, let's
say, precancerous cells, right? [Rhonda]: Right. [Valter]: Because fasting was something that
was normal for human beings, kinda like sleep. And then, maybe it was utilized for protection. And then, eventually when we stopped doing
it, we lost this feature, we lost this help that the fasting had always given us.

And maybe, that also caused us to be now,
you know, exposed to this very high incidence of diseases that we earlier did not have. [Rhonda]: Do you practice fasting yourself,
do you? [Valter]: Yes, of course, I practice fasting,
I don't normally eat lunch. But also, I just, sort of, finished a book,
which was published in Italy, and it's gonna follow here in the U.S. And in it, I talk about the need to use this
in a flexible way, right? And this is gonna have to be the future of
nutrition, and I think nutritionists, and dietitian, and doctors are gonna have to get
used to this. So that, for example, I say, if you're overweight,
or obese, or you tend to gain weight, then you have to go to this two-meal-a-day program,
with breakfast and lunch, or breakfast and dinner, okay, as I did for 15 years. Then if you're underweight, you can't do that
anymore, so you have to go back to three meals a day, right? So, you have to use fasting and time-restricted
feeding, and such in Panda's work, which I also utilize, for that purpose, you know.

So, keep the feeding to 12 hours or less,
and then decide the meal frequency. And Satchin and I just wrote an article on
this, and to control the weight, it's really important, particularly control, you know,
visceral fat. So, we hope that that's what doctors start
doing, and say, instead of…gives simple solution because two meals a day may not be
easy to follow, but it's a clear rule, right? And that's what people need. You can say, "I go for it, or I don't. But if I do go for it, it's gonna work," right? Whereas, now we have a system, where it's
almost impossible for anybody to regulate. When you tell somebody, "Eats five or six
times a day," it's almost impossible to regulate what somebody eats, right? By making it two meals a day, then you have
a much higher control. In time restriction and two meals a day, they
can serve to, you know, regulate the amount of calories as such and as shown for the time
restriction. And so now, we know, we need to do more studies
on meal frequency, but, of course, this is likely to get the same similar effects.

[Rhonda]: Do you think it's more important,
so if you're eating within this 12-hour window, which is coordinated with circadian rhythm? Then if you're eating two meals, do you think
that you'd get more benefits if you had the two meals closer together, because then you
in theory would be fasting for longer, you'd have, you know more, beta-hydroxybutyrate,
ketone bodies, things that are being produced upon a prolonged fasting? [Valter]: I would say, you know, I spent,
you know, almost 25 years since the Walford days, and I would say I had learned one thing. And also being Italian, and I spend a lot
of time around the world, I learned that you cannot take happiness away from people, you
know? So, I always stayed away from trying to regulate
too much, to close, two hours apart what do you gotta eat.

So, I think we always start with how can we
keep you as close as possible to what makes you happy, while optimizing the longevity
aspect? So, I never started doing that because I know
that people are not gonna do it, just like calorie restriction. Calorie restriction has been around for 100
years, and nobody does it, right? I mean, maybe 1 in 1,000. I'll be surprised if it's even that, right? Maybe 1 in 10,000, right? So, after 100 years of calorie restriction
research, 1 in 10,000 American, maybe, are doing calorie restriction. So, I think that it's important, you know? For example, with the two meals a day, there's
a lot of people that have done that on their own, right? [Rhonda]: Yeah. [Valter]: There's a lot of centenarians if
you go to Loma Linda, or you go to Okinawa, or you go to Southern Italy, a lot of people
say, "Yeah, eat twice a day, that's okay." So, that told me that, from the beginning,
that that was something that was doable, and people are even doing it in a voluntary way.

Anything else, we start regulating, no, you
should eat [inaudible 00:36:56]. And also 12 hours, I think a lot of people
did that kind of time restriction, right? You know, so when I grew up, that's how we
did it, you know? Maybe at breakfast at 8:00 a.m., and then
8:00, 8:30, the most, you're finished, you know, that was it. And so, yeah, so I think that that's important
not try to push for every inch of the longevity plan. Because people will abandon it, that's another
thing we're sure of, you know? If you tell them to do things that are very
much not in tune with what they're used to, they'll do it for six months, and then they'll
never do it again.

So, you know, this is why the skipping meals
because a lot of people do it, and when you switch to it, that's just an easy thing to
do, and you can do a lot the rest of your life. And then, the periodic fasting-mimicking diets
because also it's not very invasive, and people say, "Yeah, you know, every three or four
months, I'll give you five days," like that.

You know, "Make it simple for me, don't make
me, you know, don't make it too low-calorie, make me eat, but I can do it." So, I think, if we want the masses to do it,
it has to be the technology, and the safety, etc., etc., has to match their needs. And I think that that's where the effort should
be put in, rather than trying to regulate everything, how people do everything. [Rhonda]: Yeah, compliance is very important,
you know. So eating within a certain time frame, and
eating two meals a day, actually is what I do.

I usually try to eat within a 10-hour, and
I fast for about, you know, 14 hours. But I'm really interested in the autophagy
benefits, and in the stem cell, being able to make more hematopoietic stem cells, and
I'm wondering what a human would have to do to get it? Like is my 14 hours of fast every night doing
that, or do I have to do a 4-day prolonged fast, which I can't? I mean, I wouldn't do that, like, unless I
had some, sort of, supervision, or possibly this fasting-mimetic diet, which you mentioned. You've shown in several different studies
and many different ways, it mimics fasting, and it's this low-sugar, low-protein, high-fat
diet. So, you know, is that something that… [Valter]: Yeah. I think there are different advantages. I mean, there's obviously some overlap, so
I would say if you're on the perfect diet, which is a vegan pescetarian diet, low-protein,
high-nourishment like I do always.

It's like two meals a day, 12-hour restriction,
and then, the rest that I just said, if you're on that, you're not gonna need as many fasting-mimicking
diets, right? But the fasting-mimicking pushes you into
a mode that you don't normally get with all these interventions. Why? Because overnight, most of that 14 hours,
you got some glycogen to burn, right? So, you're not really needing to do much of
a switch to anything else. And that's fine, and I think it's good, you
know, shouldn't go over that because it's just a continuous thing, you know. You don't wanna push the system too much into
these extreme modes all the time. It's different from the fasting-mimicking
diet because, as I said, you know, the fasting-mimicking diet I really, by day two of the diet, and
only by day two or so of the diet, the system starts switching to a ketogenic mode. You start burning visceral fat as your major
source of energy. Your brain starts moving from burning sugar,
to burning ketone bodies, beta-hydroxybutyrate.

So, as I said, everything starts shrinking,
the immune system starts shrinking, the liver, the heart, even the oligodendrocytes, as we've
shown in our multiple sclerosis paper. So, yeah, so, that, you're not gonna get with
anything else, and you're only gonna get it with these prolong fasting-mimicking diet. Now, is it possible that if you did some of
these things many, many times that this would be equivalent to a fasting-mimicking diet? Yes, it's possible, but again, we don't know
because, theoretically, that shouldn't be enough because you're never gonna get to this
shrinking and rebuilding. But even if it was like that, then I think
that, again, it's hard to change people's behavior all the time, so we felt that by
doing these periodic interventions, we get a much better chance of getting there. [Rhonda]: You mentioned the multiple sclerosis
with your fasting-mimicking diet, and also the fact that this diet, sort of, shifted
to a more fat-burning state, which is, sort of, it's definitely in line with ketosis,
which you can get from fasting, but also in line with people that are doing a more ketogenic
type of diet.

And in your clinical study with people with
multiple sclerosis, or was it in the mouse, one of the studies you had. I think it was the human study, do you wanna
talk about that? You had a ketogenic diet, you had the fasting-mimicking
diet. [Valter]: Yeah, we did the same in mice and
human, right? So, it was a fasting-mimicking diet and ketogenic
diet in both cases. And in the mice, of course, we could demonstrate
some things, and there's very clear effects. Which was, the fasting-mimicking diet causes
the white blood cells, so the immune cells, as I mentioned earlier, to be destroyed, partially
destroyed. And then, it turns on the stem cells. And when you make new cells, of course, they're
no longer autoimmune, right? So, the original cells are autoimmune, they're
attacking the oligodendrocytes in the spinal cord. The new cells, we've shown they're no longer
immune. And these leads to about 20% of the mice being
disease-free, right? So, I mean, 20% of mice are cured from this
autoimmunity, which is very much like multiple sclerosis.

And the other thing that happens is that the
oligodendrocytes with the inflammation goes down, right? So, I mean, the general inflammatory state,
around the spinal cord particularly, goes down. And so, this is very important because it
allows the progenitor cells or the ones that give rise to new myelin, so they rebuild the
spinal cord. They can now do their job and regenerate the
system. So, now, again, as I mentioned earlier, for
cancer, you have this coordinated effect, which you take the bad cells, replace them
with the new cells, and then block the inflammation, rebuild the spinal cord. Now, you can say this is incredible, this
is magic, right? [Rhonda]: Right. [Valter]: Well, again, it's not, it's just
that the body has to have this ability. Like you cut yourself, the system that goes
to work is incredible, right? [Rhonda]: Mm-hmm.

[Valter]: And so, it's like saying, you know,
if I found a way to regenerate part of my arm by fooling the system into thinking that
it just got cut everywhere, right? If you wanna see fasting, you can see it like
that. And that's why it looks so magical, is because
it is an evolved process that has been, you know, been evolving for billions of years,
and so, it knows exactly what to do to fix a series of problems. [Rhonda]: Yeah. [Valter]: I mean, if you can see the wound,
you know, in the spinal cord as you would think of as the cut in the skin, so… [Rhonda]: I have this thought I wanna say,
but also you should the people with multiple sclerosis had improvements according to some
tests or something as well, right, with the fasting-mimicking diet, and also the ketogenic
diet, which… [Valter]: Yeah, and also the ketogenic. Last saw with the ketogenic diet, and this
is Markus Bock, in Berlin, that was the lead person in the study. But, I mean, the amazing thing is that a week
of fasting, followed by Mediterranean diet, which is really a regular diet, did better
than six months of ketogenic diet, right? [Rhonda]: Oh, wow.

[Valter]: So, continuous, right? [Rhonda]: Okay. [Valter]: And that's what makes it very impressive… [Rhonda]: So wait, it was one week of fasting-mimicking
diet. [Valter]: One single time, right. [Rhonda]: Five days, and then 25… [Valter]: Seven days. [Rhonda]: Seven days, and then the rest of
Mediterranean… [Valter]: And then, the rest of the six months,
a regular Mediterranean diet. [Rhonda]: Oh, really, just one? [Valter]: Yeah. [Rhonda]: Wow, that is… [Valter]: This is what makes it remarkable,
you know. So, now, we're approaching the FDA, and I
think we're going to propose one cycle every two months.

And, you know, so hopefully that… [Rhonda]: For another trial, for another clinical? [Valter]: Yeah, a much larger trial. [Rhonda]: Is this something that can be available
to physicians that are treating people with multiple sclerosis, or oncologists that are
treating cancer patients? Because you've, kind of, shown, you know,
you've shown that this is a very powerful metabolic therapy that can be used to…honestly,
it seems like if we're talking about getting rid of damaged cells and replacing them with
a new fully functional ones, it can be applied to a lot of diseases.

[Valter]: Yeah, there is no doubt, yeah. So, we're now doing mouse working many autoimmune
diseases. For example, we're doing in cognitive diseases,
and so, yes. What we're saying now to clinicians is the
following, and to patient is the following, and sometimes we get attacked for this, but
I really feel that this is the way to do it. Which is, if you feel, if there is a treatment,
whether it's multiple sclerosis, another autoimmunity, or a degenerative disease, or diabetes, or
cardiovascular disease, I mean, all these things that we tested in some way clinically.

But if you can wait because there's something
that works already very well for you, then wait, right? You shouldn't try something, "This is not
fully tested," meaning that we don't have a, "Yes, this works." You only get that when you do 2,000 patients,
or, you know, let's say at least 1,000, right? And then, you have to look at the statistics,
you have to look at the response, etc., etc. We're not there yet. So, we're saying, "If you can wait, wait." If you cannot wait because, you know, you
have multiple sclerosis, and you cannot take it anymore, or you have cancer, and you're
stage four, or even you're stage one and you're getting devastated by the side effects, so
go to your oncologist, your cardiologist, your diabetologist, your immunologist, whatever,
and say," I can't take this anymore. This is not working." And, of course, there's gotta be a decision
made by the clinicians together with the patient saying, you know, "Should we take a risk,
you know, in adding to this fasting-mimicking diet to the treatment?" And that's together, they have to come up
with an answer, is a worth the risk? And to some people, it is.

You know, we've had some people with Crohn's
disease, they said, you know, "I can't wait anymore," and they did it, and they did extremely
well, you know, after the fasting-mimicking diet. So, we haven't published that yet. And so, I think same for multiple sclerosis
and all these diseases, you have to see where you're at, can you wait, can you not, is there
something that is working that they make the decision, and is it for now or is it for five
years from now? [Rhonda]: Yeah, I think that makes a lot of
sense, Valter. I wanna kinda go back to this thought that
you instigated in my mind when you're talking about this, sort of, like wound healing sort
of analogy.

And that is, at least, with the hematopoietic
stem cells, like I'm not sure about with that, you know, others stem cells and other tissues. But I know that when they're quiescent, when
they're not dividing, they are glycolytic, meaning they use glucose for energy because
they don't want to damage themselves with reactive oxygen species being generated as
a byproduct of mitochondrial function, right? But I do know that when they come out of quiescence,
and they come out to either self-renew or differentiate into progenitor cells, oxidative
phosphorylation becomes their source of making energy. And so, I'm wondering what's the signal… I know you've published some studies on looking
at different signaling pathways that are required to cause this hematopoietic stem cells self-renewal
mechanisms, but I'm wondering if possibly just not having the glucose available, and
having just the fatty acids, the source of energy that can only be used by mitochondria,
if that's somehow also is playing a role in making them self-renew more, or differentiate
more? [Valter]: I think so, and this is the work
by David Sabatini, and others at MIT, and they're doing work on the fat, and the role
of fat and fatty acids, etc., and self-renewal and the activation of stem cells, particularly
in the gut.

So, yeah, there seems to be a role for fat
in that, and I think we're still beginning to understand it. I think, obviously, with fasting, you produce
fat, and you produce fatty acids, and glycerol, and ketone bodies. So, the environment is there, and, you know,
we need to maybe understand more, how each component that is changing is affecting the
program, so yeah. So, we made the decision to try to, I think,
things are going very slow, and we've always been very interested in people that have a
problem now, right, instead of, you know…

[Rhonda]: Right. [Valter]: A lot of people are always like,
wow, in 20 years we'll have this. And we always said, you know, "There's people
who have cancer now, they have multiple sclerosis now, so what do you do for them," right? And so, our decision has been always understand
enough the mechanisms to be able to not, or minimize the chance of making mistakes, get
to the clinical trial, and then, go back and fill it in, right? [Rhonda]: Mm-hmm, yeah. [Valter]: Rather than step, by step, by step,
by step, you know, and then it'll take you 15 years to get to clinical trial. [Rhonda]: Right. Yeah. [Valter]: So, I mean, I'm not criticizing
the other method, but I'm just saying that for us it has been get the mechanism, get
enough mechanism, move to the clinical trial, and then make sure it's safe, and… [Rhonda]: It's been fantastic. I mean, you've been able to translate so many
different studies, I mean, it's really quite phenomenal. I'm just, sort of, thinking, in fact I just
thought about it when you're mentioning the ketone bodies too. Well, ketone bodies are more, if you think
about the stem cells, and if they need energy to differentiate or self-renew, ketone bodies
would actually provide a very energetically favorable source because it takes less oxygen,
actually, to convert beta-hydroxybutyrate into Acetyl-CoA, as opposed to glucose into

So, if you think about it, it's more energetically
favorable to have ketone bodies, and so, maybe it also helps just because it takes less energy
to do this process. I mean, you know, it's possible, but… [Valter]: Yeah. I think, there's also mechanisms. Again, the fasting imposes this new metabolic
profile, and the new metabolic profile requires the stem cells for this regeneration that
I mentioned. So, if you got to get rid of the health of
your liver, let's say that you fast for a month-and-a-half, right? Then you must, you will produce tons of fatty
acids and tons of ketone bodies, and that environment is gonna require the stem cell
to be renewing, and being standing by for the day where you need to make a new liver,
essentially, or health for the liver, right? So, this is why, I think, it's all a part
of a coordinated response, where, you know, you have the fat…

And by then, the fat is one of the few abundant
sources of energy also for the stem cells, so they really have no choice but to be ready
to respond to fat metabolites so that they can self-renew. Because there's not much sugar around, and
the brain needs the sugar, by the way, right? So, the brain needs a lot of the sugar that
is available, a lot of is made by gluconeogenesis, so it makes sense… [Rhonda]: Red blood cells are needed since
they have no mitochondria. [Valter]: Right. And so it makes sense that you would have
a system like that, that is fat in fatty acid and ketone body… [Rhonda]: Yeah, yeah, absolutely. Not to mention that like, you know, beta-hydroxybutyrate
has been identified to be signaling molecule as well. I think Eric Verdin's work at UCSF has showed
it's a class one in histone deacetylase inhibitor, I mean, who knows what's going on.

But I wanted to ask you about…back to the
cancer, and, you know, this fasting cancer or fasting-mimicking diet cancer, a couple
of things. So one is I think you've shown without a doubt,
in both animals and also in some preliminary work in humans, that the fasting or the fasting-mimicking
diet can sensitize cancer cells to the standard of care, whether that's chemo, radiation,
whatever, you know, death, while still protecting the normal cells, which are upregulating all
sorts of protective pathways, as you mentioned. But there's this whole other field that I'm
familiar with, and I'm sure you're familiar with, and that is that cancer cells also upregulate
a lot of genes that are involved in autophagy, and they use this as a mechanism to help them
spread, metastasize.

I know that, you know, there's a very well-known
inhibitor of autophagy called chloroquine, which is used to kill cancer. So, what do you think…? I mean, you know, obviously fasting is not
just causing autophagy, it's like doing, it's this whole… Like you mentioned, there's lots of desensitizing
the cancer cells, and the stress response, but all these different things going on causing
the mitochondria to make more reactive oxygen species, and all that. Do you think there's some, sort of, like,
different stage of cancer where this is, you know, autophagy becomes more important like
later in cancer, when they'd actually that's when the metastasis occurs? Or what do you think of that whole field of,
you know, autophagy also playing a role in cancer? [Valter]: I think the autophagy, and I think
this was in the paper that was published together with ours by Guido Kroemer, and he showed…and
Frank Madeo has also being doing work on that. But Guido was showing that autophagy was very
important during the starvation, or using starvation mimicking drugs in causing the
exposure of cancer cells to the immune system, right? So, which probably means that the autophagy
is really part of this weakening and maybe death of the cancer cells.

So, autophagy turns from something good, in
a normal cell, that it does in a very coordinated way into something bad in a cancer cell, probably
because it might break down components that are needed. I mean, I don't know, but certainly, you know,
autophagy seems to be, you know, at least for this purpose, it seems to be very important,
and probably part of the desperate attempt of cancer cells to get what they need from
somewhere. And that's what we see that, in general, we've
seen that for almost everything else. I mean, even independent of autophagy, the
desperation seems to be key. Meaning that, for example, they try to increase
translation, to get more proteins, right? Instead of shutting down like a normal cell
would, they go and try to do things that they seem to be desperate.

And, of course, you can't do that, or you
can do it only for so long, and that's probably why they die. [Rhonda]: Yeah. I mean, I know it was something that kinda
was confusing to me at first, and then I thought about it for, you know, a little more in-depth. And I thought, well, fasting itself is doing
so much more than just autophagy as well, so it's not like that's the only mechanism
that's occurring, biological mechanism that's changing with fasting. But I just thought it was, kind of, interesting
how it seems to be theirs, sort of, this opposite end of the spectrum, you know, effects in
terms of cancer. But you mentioned fasting-mimetic drugs, or
what was it? Fasting-mimetic drugs or autophagy mimicking? [Valter]: I don't know.

Fasting-mimicking drugs, so Kroemer had a
series of drugs that… [Rhonda]: So, which one, like is there… [Valter]: I forgot now what drugs they had. But, for example, resveratrol, spermidine
are considered fasting-mimicking drugs. They may not have the power of fasting, but
certainly, they push the cells in that direction. [Rhonda]: They activate certain signaling
pathways… [Valter]: That are similar to fasting. And, you know, this one I had discussion with
people that do drugs, I mean, you have some benefits, but, of course, you have also potential
side effects. And usually, the benefits are weaker than
the ones that you get by doing the real thing. But that's okay, I mean, it's a reasonable
compromise if you can get some effects, let's say, by giving spermidine to cells and organisms,
and that makes life much easier than having to fast all the time. So, I think maybe a combination of the pharmaceutical
intervention, the ones we know that are very safe, and they're very effective, together
with this older type of intervention might be the way to go, you know.

But we have to be very careful because, again,
in the future. And this, I think, is being underestimated
by the aging community, which is, to treat somebody sick, you can allow a certain degree
of toxicity by whatever treatment you're giving. But when you treat somebody healthy, really,
there should be no toxicity whatsoever, right? [Rhonda]: Yeah. [Valter]: Because now, you just generate,
even if it was 1% of the people that get a side effect. So, in moving forward with this fasting-mimicking
diets and these anti-aging drugs, I mean, we work on it ourselves, right? But certainly, you really got to get it to
the point where you say, "I know this will never be toxic to anybody." It's tough, right? [Rhonda]: Right, it is.

Especially in long-term, you're thinking,
"Well, feedback loops, all sorts of things happen." If you're perturbing one system that's gonna
have so many consequences, everything's connected, you know. And how you gonna know 20 years from now that… [Valter]: Exactly, it's impossible, right? [Rhonda]: It's impossible. [Valter]: So, you'll have to have the 20 years,
right? [Rhonda]: Right, yeah. [Valter]: You'll have the 20 years observation. For example, this is why metformin, now, is
starting to very slowly move into the candidate position for an anti-aging drug, you know. Nir Barzilai and others are talking to the
FDA about moving forward with it because there is so much observation. But that doesn't mean that even for metformin,
where all the observation is for diabetic patients and given to somebody that is completely
healthy, that may turn out to generate some problems that we did not see in the diabetic

[Rhonda]: Right, yeah. So metformin, in a way, sort of, one could
possibly say, in a way it's a fasting mimetic in the sense where it activates AMP kinase,
one of the signaling pathways that also activates…. Do you know if metformin increases autophagy,
or has that been looked at? [Valter]: I'm pretty sure it does, yeah, I'm
pretty sure it does.

So, metformin, in our view, seems to be acting
more in the sugar pathway, but then, of course, it's missing the effect on the amino acid
pathway, or it has a much weaker effect on their pathways. But metformin's got potential, but, then again,
will I take metformin knowing what I know? Absolutely not, you know. [Rhonda]: What about when you're 65 or 70,
would you start taking it? [Valter]: No way. [Rhonda]: No, really? [Valter]: No. [Rhonda]: Why is that? [Valter]: Well, because I just don't like
the, you know…our laboratory discovered the tyrosine kinase pathway in aging 15 years

And we used to work with rapamycin back in
the 90s, in the mid-90s, you know, while working with the cells from Mike Hall. But I always said that I never wanna work…I
mean, not never, but I really am not enthusiastic working by blocking something so central,
you know, in a cell, and its metabolism, and it's cerotic, etc., etc. And I think everybody got very excited in
the field, and instead of seeing, first, of all the positive results with rapamycin until,
of course, you start getting the negative, right? [Rhonda]: Right.

[Valter]: And it was hyperglycemia, testicular
degeneration, cataracts, and these are probably just some. And I think with any drug that intervenes,
is such a central inside of the cell. I always say that's kind of like taking a
car that it's got a problem, and just sticking things into it until you find, "Oh, the problem
stop," right? So, you can leave the knife in there, you
know, or leave the device in there. You know, that's not the way you do it, right? You have to somehow rebuild the car in a way
that works.

But pharmacology, a lot of times, or almost
always, blocks something. [Rhonda]: Right. [Valter]: When you block that, what happens
to everything else around it? Well, I don't know. But, well, and say, you know, 30 years of
all that. Let's just say, you activate an AMP kinase,
right? [Rhonda]: Yeah. [Valter]: And then, you change all these things,
well, what happens after 30 years of this interference? And then, you do it in all the cells. Is it possible that just disruption of all
these normal pathways it does nothing? I don't know. [Rhonda]: Yeah. [Valter]: So, we prefer, for example, we always
prefer to go with where we have human evidence, then there are no consequences and there's
a growth hormone receptor, right? [Rhonda]: Mm-hmm. [Valter]: So, we're not developing drugs against
growth hormone receptor, why? Because we have the Ecuadorean that we've
been following for 10 years, and Guevara, our colleagues, has been following them for
30 years.

And that's fine, they make it to very old
age. [Rhonda]: In years by now, so people like,
you know, the IGF-1, and growth hormone pathway… [Valter]: Right. So, essentially, proteins and amino acids
control two major pathways, right? One is the growth hormone IGF-1, which is
called an axis, it's not really a pathway, but an axis. And then, the other one is tyrosine kinase,
right? So, if you have a lot of amino acids, those
two are activated, and both are now widely recognized, it's very powerful pro-aging pathways.

And so, yeah, of course, you could do it by
food, or you could do it by mutations. So, if you take a mouse and you knock out
the growth hormone receptor, this mouse will live 40%, 50% longer. It's also, and in spite, and this is work
by John Kopchick and Andre Barkey, and in spite of living longer, it has much less diseases. So, almost half of these mice will get to
the end of life with no diseases that are visible, right? So, it's really remarkable. And as remarkable, I think, is our work with
humans that have the same mutation in the growth of more receptor, and these people
will live, maybe, a little bit longer.

Not 40% longer, for sure, but they have a
terrible diet, they smoke, they drink, they really don't watch anything they do. And in spite of all this, they almost never
get cancer, they almost never get diabetes, we really haven't seen any chronic disease
in these people, in the same household like a normal diseases, right? So, it's nothing to do with Ecuador, it has
to do with mutation. [Rhonda]: Mm-hmm. [Valter]: Which matches very well with the
mouse data. So, yeah, I think that that is a much better
target. I mean, I'm biased, but I think having all
of it available to us for a long time, and we picked the target that was the least likely
to cause any side effects also based on, you know, very long-term human data. [Rhonda]: There's also human data showing
that there's polymorphisms in, for example, the IGF-1 receptor, or that whole pathway,
you know, that are also consistent with longevity as well. [Valter]: Yeah, yeah. FOXO that are in communication and polymorphism.

And FOXO in the IGF-1 receptor, in the growth
hormone receptor, yeah. [Rhonda]: Right. It's all consistent, where, I mean… [Valter]: I think so, yeah. [Rhonda]: I remember, in fact, one of my first
experiments in biology was doing, you know, manipulating the IGF-1 signaling pathway in
worms, in Andrew Dillin's lab at the Salk Institute. And I remember when I saw, you know, when
you get rid of that pathway in these worms, they live 100% longer. I mean, it was like amazing to me that you
could change one genetic pathway and cause a worm to live like 100% longer.

I mean, that, to me, was mind-blowing. Like how is that…and these are genes that
are conserved in humans, nonetheless, so it really makes you think, "Well, if this can
happen to a worm, you know, what's the potential for humans?" And we know, centenarians have like, you said,
FOXOs. So IGF-1 just for people, so that IGF-1 is
a growth signaling pathway that…I don't, and maybe you can answer this question for
me. When I think about it, for human aging, I
always think about too much IGF-1 playing an important role in cancer, promoting cancer
growth. When I was studying it in worms, it was more
about not inhibiting this very important stress response pathway, the FOXO3 pathway, and how
that's important for turning on all these genes that are involved in stem cell, making
stem cells, and autophagy, and degrading proteins.

And it's just like a master regulator of all
these, like, amazing genes that can help you if you smoke, or just help you deal with the
stresses of aging in general. For humans, do you think that lowering IGF-1
is going to have a more profound effect on human lifespan via, like, not getting cancer,
or do you think not inhibiting that FOXO3 pathway is just as important? [Valter]: Probably it's very much connected,
meaning that the aging process is the driver for the cancer, about to the level of a cancer
cells and accumulation of mutation, but also the level the tissues getting more inflammation,
be more permissive to the metastasis, and also the level of the immunosenescence, and
the immune system getting weaker. And we know that if you have an immune deficient
mouse, the cancer grows a lot faster. So, yeah, so then, the aging process is really
anything most of us agree, the primary driver of the age-related disease, which is cancer,
and, of course, all the other age-related diseases.

So, yeah, so we're always looking in terms
of, you know, treat aging, and then the rest comes. Now, of course, yeah, there are all the things
that might not be necessarily related to aging. For example, if you have a high IGF-1 in the
moment where the cancer cell is generated, that cancer cell might still love to have
a lot of IGF-1 because it helps prevent apoptosis. And so, yeah, there could be a dual role of
some of these growth factors in making sure that the cancer becomes a metastatic cancer,
that some of it maybe an independent of the aging process. [Rhonda]: Mm-hmm, yeah. We should probably also mention the good parts
of IGF-1, you know. IGF-1 plays an important role in muscle growth,
muscle repair, and also it crosses the blood-brain barrier, and plays an important role along
with brain-derived neurotrophic factor for growing new brain cells.

[Valter]: Yeah. This is why I was saying the fasting and refeeding,
right? So, doing the fasting, the IGF-1 goes down,
and so that store and that does everything else. But during the refeeding, IGF-1 goes up, and
IGF-1 is the driver of all this regeneration. And most likely, I mean, we haven't looked
in-depth, but, you know, other people have. And so, almost in a lot of regenerative process,
you see IGF-1 being involved in, you know, the… And this is why I was saying that calorie
restriction will have this chronic effect on lowering the factors, but never has the
part B, which is after you lower it, you have to rebuild it.

[Rhonda]: Oh, it makes sense. [Valter]: And that's why, I think, it may
be only half of the solution. [Rhonda]: Mm-hmm, yeah. Something else I that comes to my mind as
well as wanting the IGF-1 to go where it's supposed instead of sitting around in your
serum, and the bloodstream, but going to the muscle, going to the brain. And I know that it's been shown in humans
that IGF, yeah, it's been shown in humans that acute exercise, I think it was aerobic,
lowers serum IGF-1. And I think it's because it's going to the
muscle, also to the brain, because in mice, it's been shown that exercise causes IGF-1
to cross the blood-brain barrier and get into the brain.

So, that's another good reason to exercise
is because, now, the IGF-1 that you have, you know, is going to the places where it
should. [Valter]: Right. Yes. So exercise out, obviously there's no doubt
that it's very beneficial. And some of it may be related to the fasting,
meaning that exercise is known to do damage to the muscle, right? And so, that damage, and then it's known that
after the damage, you get repaired. And that's also known that the repair is what
builds the muscle, right? So, this may be not as potent as the fasting,
but if you do it all the time, it could be that you have all these small regenerative
processes occurring every couple of days, if you access every couple of days.

And then, you know, eventually, those cumulatively,
it could be actually very powerful, and, yeah, so… [Rhonda]: Really in combination with the fasting
too, I mean, if you're going to eat your protein and activate IGF-1, then it's good to exercise
to make sure it's going to the right place, right? And so, it's… [Valter]: Yeah. Yeah, yeah. And, yeah, absolutely.

And in the book that I wrote, I really talked
about exercise and the need to exercise to make sure that some of these restrictions
don't end up in loss of lean body mass. Because the exercise, especially the weight
training, is very important in sending the signals to the muscle to rebuild it. And this is really another very interesting
thing about fasting, which is it takes the energy from the visceral fat, but it also
takes energy from the muscle. But then, unlike other diets, it rebuilds
the muscle. And so, now, in clinically, we see a specific
loss of fat only significant in the visceral area, and then, no loss, or very minimal loss
of lean body mass, right? Because there is a temporary loss, but then
rebuild it.

So, it's really interesting, and is what athletes
are starting to become very interested in this fasting-mimicking diets because… [Rhonda]: Right. Yeah. [Valter]: Because, you know, most of the diets
will get rid of water, muscle, and fat, right? [Rhonda]: Right. And you wanna increase lean muscle mass, and
decrease fat mass, I mean, that's… [Valter]: Yeah. Or at least leave alone the lean body mass,
and decreasing fat. Where you have, you know, you're switching
to a state that is much more beneficial to your pro-athletic performance, yeah. [Rhonda]: Do you think, I don't know, have
you looked at whether or not mitophagy plays a role in any of this? Because I know that if you're clearing away
damaged mitochondria, or, you know, mitophagy or mitophagy, I don't know which one, I've
heard both.

But once that happens, much like in the whole
cellular system, it causes mitochondrial biogenesis. [Valter]: Yeah. [Rhonda]: So, I'm wondering… [Valter]: Yeah, so we're looking at that right
now, yes. So, that's our current project, and we'll
see what happens, but we're optimistic. [Rhonda]: Great. Very, very cool. So, we talked about so much Valter, thank
you so much for talking with us. So, with these fasting-mimetic diets that
you refer to either for people that are, you know, doing this for, you know, disease treatment
or they wanna talk about it with their clinician, their oncologist, their doctor, or whatever,
if these are available for people… [Valter]: Yes. So, there's a company that I founded, it's
called L-Nutra, and it's [Rhonda]: L-Nutra like L-N-U-T… [Valter]: L-Nutra, yeah, N-U-T-R-A. And they have they produce a product called
ProLon FMD, and the product, I think, is important, And this is a fasting-mimicking diet that
is being tested clinically, doctors are now prescribing it, and so you can contact L-Nutra
and ask for it.

I should say, for disclosure purposes, I don't
receive any salary from the company, I don't receive consulting, and my shares will be
donated to a foundation. So, I absolutely, you know, I just did it
because basically the patients were asking, "What can we do instead of fasting," right? [Rhonda]: Yeah. So, you're not benefiting monetarily for this… [Valter]: Not at all. In fact, I think I lose money sometimes. So, yeah. [Rhonda]: That's really cool. [Valter]: Yeah. I mean, I think that it was not a good position
to be in to be benefiting from things we're testing.

But yeah, so the company does it all. Of course, I help them a lot in trying to
get this out to patient, but also trying to get it as cheap as possible, you know. So as effective as possible, as cheap as possible. And yeah, we're there, and hopefully, soon
enough, we'll be there all over the planet, yeah. [Rhonda]: And there's lots of information
there, like, on the protocols, and all that. [Valter]: Yeah, all the information so people
usually have to go to a doctor or just get clearance from the doctor that they don't
have a disease or a problem they're otherwise prevent them from doing it. And then, they get assigned a nutritionist,
or a dietitian, and they just follow them for the five days. From the distance, you can do this at home. Yeah, and the great majority of people have
no problem.

But you just have to be a little bit careful,
these are powerful intervention, and you have to respect it as such. So, you know, people, diabetics, anorexic
people, people particularly with diseases taking drugs, they have to, really, the doctor
is the only person that can decide if somebody is taking drug whether this can be combined
with the fasting-mimicking diet. And yeah, so, there are some warnings, but
the company and the doctor will tell you about it. [Rhonda]: Thank you so much for watching. If you enjoyed this episode, make sure you
click like, and subscribe to my YouTube channel. You should also head over to my website at, and sign up for my email newsletter. I send out interesting articles, links to
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