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 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?
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 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?
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 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?
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 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.
Obviously that's for people with more money to burn than calories. So figuring out how to do it yourself would be worth the effort.
