Valter Longo, Ph.D. on the Fasting-Mimicking Diet & Fasting for Longevity, Cancer & Multiple Sclerosis
Posted on October 4th 2016 (over 2 years)
Dr. Rhonda Patrick speaks with Dr. Valter Longo, a professor of gerontology and biological sciences and director of the longevity institute at the University of Southern California. Dr. Longo has made huge contributions to the field of aging, including the role of fasting and diet in longevity and healthspan in humans as well as metabolic fasting therapies for the treatment of human diseases."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." - Dr. Valter Longo Click To Tweet
- Andrew Dillin
- Andrzej Bartke
- David Sabatini
- Eric Verdin - episode with Dr. Verdin
- Frank Madeo
- Guido Kroemer - episode with Dr. Kroemer
- Jaime Guevara-Aguirre
- John Kopchick
- Roy Walford
- Satchin Panda - episodes with Dr. Panda: Episode 1, Episode 2
- Markus Bock
- Michael Hall
- Nir Barzilai
Learn more about Dr. Valter Longo
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?
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 death. 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.
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.
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?
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.
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?
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?
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?
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?
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.
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?
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?
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...
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 pyruvate. 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?
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 population.
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?
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 ago. 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?
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.
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?
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.
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?
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.
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.
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 l-nutra.com.
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, fmd.com. 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.
AMP Kinase (AMPK)
An enzyme that plays a role in cellular energy homeostasis. The net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, skeletal muscle fatty acid oxidation, and glucose uptake; inhibition of cholesterol synthesis, lipogenesis, triglyceride synthesis, adipocyte lipolysis, and lipogenesis; and modulation of insulin secretion by pancreatic beta-cells.
Cellular program that causes a cell to kill itself after damage has occurred. This is one of the ways that multicellular organisms protect themselves from cancer.
An intracellular degradation system involved in the disassembly and recycling of unnecessary or dysfunctional cellular components. Autophagy participates in cell death, a process known as **autophagic dell death**. Prolonged fasting is a robust initiator of autophagy and is thought to help protect against cancer and even aging by reducing the burden of abnormal cells. **However, the relationship between autophagy and cancer is complex**. Autophagy may prevent the survival of pre-malignant cells, but can also be hijacked as a malignant adaptation by cancer, providing a useful means to scavenge resources needed for further growth.
A chemical produced in the liver via the breakdown of fatty acids. Beta-hydroxybutyrate is a type of ketone body. It can be used to produce energy inside the mitochondria and acts as a signaling molecule that alters gene expression by inhibiting a class of enzymes known as histone deacetylases.
A highly selective semi-permeable barrier in the brain made up of endothelial cells, which are connected by tight junctions. The blood-brain barrier separates the circulating blood from the brain's extracellular fluid in the central nervous system. Whereas water, lipid-soluble molecules, and some gases can pass through the blood-brain barrier via passive diffusion, molecules such as glucose and amino acids that are crucial to neural function enter via selective transport. The barrier prevents the entry of lipophilic substances that may be neurotoxic via an active transport mechanism.
Restricting caloric intake by 30% has been shown to extend lifespan in some animals.
C-reactive protein (CRP)
A ring-shaped protein found in blood plasma. CRP levels rise in response to inflammation and infection, or following a heart attack, surgery, or trauma. CRP is one of several proteins often referred to as acute phase reactants. It binds to the phosphocholine expressed on the surface of dead or dying cells and some bacteria, activating the complement system and promoting phagocytosis by macrophages, which clears necrotic and apoptotic cells and bacteria. The high-sensitivity CRP test (hsCRP) measures low levels of CRP in the blood to identify low levels of inflammation that are associated with risk of developing cardiovascular disease.
An inflammatory bowel disease that causes inflammation of the lining of the digestive tract, which can lead to abdominal pain, diarrhea, fatigue, weight loss and malnutrition.
Cytotoxic T Lymphocytes
A type of white blood cell that kills cancer cells, cells that are infected (particularly with viruses) or are otherwise damaged.
Differential Stress Resistance (DSR)
A property that is characteristic of **prolonged fasting**. During a prolonged fast normal cells have the tendency of becoming more resilient to stress, whereas cancer cells are unable to do this as a consequence of oncogenic signaling. Mounting evidence suggests that exploiting this property may be useful for reducing the toxicity of chemotherapeutics while also maximizing their impact in the treatment of cancer.
Fasting-mimicking Diet (FMD)
A diet that mimics the effects of fasting on markers associated with the stress resistance induced by prolonged fasting, including low levels of glucose and IGF-1, and high levels of ketone bodies and IGFBP-1. More importantly, evidence suggests these changes in the cellular milieu are associated with a sensitization of cancer cells to chemotherapeutic drugs while simultaneously also conferring greater stress resistance to healthy cells. Evidence also continues to emerge that properties of the fasting-mimicking diet, particularly its ability to cause immune cell turnover, may also make it useful in the amelioration of auto-immune diseases like multiple sclerosis. ## Fasting-Mimicking Diet Breakdown - Day 1 - consists of 1,090 total calories (10% protein, 55% fat and 34% carbohydrate) - Days 2 through 5 - consists of 725 total calories (9% protein, 44% fat and 47% carbohydrate)  Cheng, Chia-Wei, et al. "Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression." _Cell Stem Cell_ 14.6 (2014): 810-823.  Choi, In Young, et al. "A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms." _Cell Reports_ 15.10 (2016): 2136-2146.
A protein that provides the instructions for genes responsible for the regulation of cellular replication, resistance to oxidative stress, metabolism, and DNA repair. FOXO3 may play an integral part in both longevity and tumor suppression. Variants of FOXO3 are associated with longevity in humans. Humans with a more active version of this gene have a 2.7-fold increased chance of living to be a centenarian.
A metabolic pathway in which the liver produces glucose from non-carbohydrate substrates including glycogenic amino acids (from protein) and glycerol (from lipids).
A sugar-alcohol compound that is the backbone of the triglycerides.
The ability of a particular substance, such as an antigen or epitope, to provoke an immune response in the body of a human or animal.
The gradual deterioration of the immune system brought on by natural age advancement. Immunosenescence is considered the most important reason for the increased rate of infections (and cancers) in the elderly and is believed to be the diminished or exhausted function of the immune system that naturally occurs with aging.
Insulin-like growth factor 1 (IGF-1)
One of the most potent natural activators of the AKT signaling pathway, stimulator of cell growth and proliferation, potent inhibitor of programmed cell death, primary mediator of the effects of growth hormone, and has been implicated in contributing to aging and enhancing the growth of cancer after it has been initiated. Similar in molecular structure to insulin, IGF-1 plays a role during childhood for growth and continues later in life to have anabolic, as well as neurotrophic effects. Protein intake increases IGF-1 levels in humans, independent of total caloric consumption.
Molecules (often simply called “ketones”) produced by the liver during the breakdown of fatty acids. Ketone production occurs during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, or prolonged intense exercise. There are three types of ketone bodies: acetoacetate, beta-hydroxybutyrate, and acetone. Ketone bodies are readily used as energy by a diverse array of cell types, including neurons.
A drug commonly used for the treatment of type 2 diabetes that works by decreasing gluconeogenesis in the liver, reducing the amount of sugar absorbed in the gut, and increasing insulin sensitivity. Some animal research has been published indicating that metformin may lengthen lifespan.
A type of glial cell that is involved in the production of myelin, providing support and insulation to axons in the central nervous system. A single oligodendrocyte can extend its processes to 50 axons, wrapping approximately 1 micrometer of myelin sheath around each axon.
A gene that has the potential to cause cancer. A proto-oncogene is a normal gene that regulates cell growth and proliferation but if it acquires a mutation that keeps it active all the time it can become an oncogene that allows cancer cells to survive when they otherwise would have died.
The process of generating energy that occurs when mitochondria couple oxygen with electrons that have been derived from different food sources including glucose, fatty acids, and amino acids.
Resveratrol falls into a category of compounds known as stilbenoids, which includes another notable compound known as pterostilbene, and is produced naturally by several plants in response to injury or when the plant is under attack by pathogens such as bacteria or fungi. Resveratrol exerts its effects through sirtuin 1 (SIRT1), which is an enzyme that deacetylates proteins and thereby contributes to cellular regulation (including autophagy). **Food sources include**: the skin of grapes, blueberries, raspberries, and mulberries. **Resveratrol Autophagy** ↑ Detacetylases (especially SIRT1) → ↓ Protein Acetylation → Autophagy
Single nucleotide polymorphism (SNP)
A change in one nucleotide DNA sequence in a gene that may or may not alter the function of the gene. SNPs, commonly called "snips," can affect phenotype such as hair and eye color, but they can also affect a person's disease risk, absorption and metabolism of nutrients, and much more. SNPs differ from mutations in terms of their frequency within a population: SNPs are detectable in >1 % of the population, while mutations are detectable in <1 %.
A polyamine (an organic compound having more than two amino groups) named for having been isolated in semen. Spermidine has since been found in a variety of different tissue types, as well as foods. It is best known for its role as a potential autophagy and longevity promoter with its effects having been demonstrated in yeast, flies, worms, and human immune cells. ↓ Acetyltransferase activity (especially EP300) → ↓ cytosolic Acetyl CoA → Autophagy  Tobias Eisenberg, et al. (4 October 2009). "Induction of autophagy by spermidine promotes longevity,". Nature Cell Biology. 11 (11): 1305–14. PMID 19801973. doi:10.1038/ncb1975. **↓ mitochondrial transmembrane potential → ↑ ubiquitination → mitophagy (preferentially targeted)**
Fasting results in ketogenesis, promotes potent changes in metabolic pathways and cellular processes such as stress resistance, lipolysis and autophagy. It induces cancer cell death by the production of reactive oxygen species (ROS) through mitochondrial activation.
Time-restricted eating (TRE)
Eating within an 8- to 12-hour time window that begins with the first food or non-water drink. TRE has health benefits that may include reductions in fat mass, increases in lean muscle mass, lower inflammation, improved heart function with age, increased mitochondrial volume, ketone body production, improved repair processes, and aerobic endurance improvements.
A large family of integral components of actin filaments that play a critical role in regulating the function of actin filaments in both muscle and nonmuscle cells. The study of tropomyosin has relevance for muscle diseases, autoimmunity, and cancer.
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