FoundMyFitness - #027 Valter Longo, Ph.D. on the Fasting-Mimicking Diet & Fasting for Longevity, Cancer & Multiple Sclerosis

Episode Date: September 30, 2016

 Dr. Valter Longo This episode of the FoundMyFitness podcast features 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 this podcast, Valter and I discuss... (00:00) Introduction (03:30) The fasting-mimicking diet makes fasting accessible to more people (08:10) Prolonged fasting stimulates stem cell regeneration (12:57) Does inflammation cause aging or is it the other way around? (17:59) Using the fasting-mimicking diet in a hospital setting (22:18) Fasting prior to chemotherapy preps cancer cells for death and protects healthy cells from damage (36:05) Using fasting and time-restricted feeding to control weight gain (42:08) How long do you need to fast to induce autophagy? (45:32) A fasting-mimicking diet reversed a multiple sclerosis-like autoimmune condition in mice (52:09) What are the cellular mechanisms that underlie the regenerative benefits of fasting? (58:27) Are fasting-mimicking drugs, such as spermidine and resveratrol, safe and effective? What about metformin? (01:07:03) Blocking the growth hormone/IGF-1 axis protects from cancer and diabetes in people with Laron's syndrome (01:14:23) Exercise is essential for healthy metabolism and longevity If you're interested in learning more, you can read the full show notes here: https://www.foundmyfitness.com/episodes/valter-longo Join over 300,000 people and get the latest distilled information straight to your inbox weekly: https://www.foundmyfitness.com/newsletter Become a FoundMyFitness premium member to get access to exclusive episodes, emails, live Q+A's with Rhonda and more: https://www.foundmyfitness.com/crowdsponsor

Welcome back, friends. I hope your mitochondria are running at maximum capacity because today's guest is a great one. Today, I bring you Dr. Walter Longo, who is director of the USC Longevity Institute at the University of Southern California. I've been really excited about this one for a while because I have a great deal of respect for the translational nature of Dr. Longo's research. What makes his work so profoundly unique is that it spans from lower organisms such as yeast, where he has teased out basic mechanisms of longevity to animals such as mice and finally translates the research into actual clinical practice in humans. Many scientists spend their entire career of specializing in just one model organism. In this podcast, Volta and I discuss the effects of prolonged fasting, which

refers to two to three days in mice or four to five days in humans, Dr. Longo's work on the fasting mimicking diet, which is a five-day restricted diet that is meant to simulate some of the biological effects of prolonged fasting while still allowing some food, how clinical trials have demonstrated efficacy for this diet for type 2 diabetes, multiple sclerosis, and cancer patients, fasting as an inducer of differential stress resistance, where it can simultaneously make cancer cells more sensitive to death stimuli, while also making healthy cells more resistant to the same death stimuli, such as chemotherapy and radiation, which might otherwise induce death among healthy cells as collateral damage. Fasting as a biological state which humans historically

experienced with extreme regularity and we may ultimately need in order to mitigate various disease states. The effects of prolonged fasting on the immune system, namely how it clears away damaged white blood cells via itophagy and how this causes hematipoetic stem cells to self-renew and make more stem cells and also produce new blood cells to fully replenish the white blood cell population. How prolonged fasting causes a shift in the immune cell population towards one that is more representative of youth by normalizing the ratio of myeloid cells to lymphoid cells. The positive effects of prolonged fasting and the fasting mimicking diet on markers of inflammation, blood glucose levels, and other aging biomarkers, the conclusions of Dr. Longo and Dr. Marcus Box research comparing one week of the fasting mimicking diet, followed by six months of the Mediterranean diet to six months of the ketogenic diet in people with multiple sclerosis. The strange and somewhat paradoxical role of autophagy genes in cancer progression and some of the open questions surrounding the exact role that these genes are playing.

Dr. Longo's high-level thoughts on metformin as an anti-aging drug. How the growth hormone IGF-1 access is one of the most important genetic pathways in aging from yeast to worms to mice to humans. Dr. Longo's upcoming book, and believe it or not, we talk about so much more. But before we get started, I want to mention a couple of things. First of all, if you were interested in the topics discussed in this podcast, I highly recommend checking out the accompanying video for this podcast. The video is loaded with annotations, definitions, definitions,

graphs and figures from some of the papers we discuss and other useful explanations. You can check that out by going to my YouTube channel at YouTube.com forward slash found my fitness, F-O-U-N-D-M-Y-F-F-I-T-N-E-S. When you're done with that, get on my email newsletter list. You can find that at foundmyfitness.com. I use the newsletter to announce podcasts, share interesting studies, informative articles, and much more. And now, on to the podcast. Hello, everyone.

I'm very excited to be sitting here with Dr. Walter 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, Walter, on the podcast, we've talked a lot about time-restricted eating from Dr. Sotchen

Panda's work and how, what the effects are of eating within a certain time frame, like a 12-hour, at least a 12-hour time window that's in, where that corresponds with a certain certain 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 that you've done a significant amount of research on fasting and animals and humans. Yes, yes. So we are very interested in aging and really what are the interventions that extend longevity in a safe way. And fasting, periodic fasting, or better yet, fasting mimicking diets.

So these diets that are designed to sort of trick the system and make it think that'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 that 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 color restriction back in the early 90s. And in fact, I was there when they went into biosphere two, which was this bubble essentially

in Arizona where they did the first human study on color restriction. And the group, when they came out, there 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 possible? powerful, but everybody can do, and that's where this fasting-emicking diet came about, and really about, you know, anywhere from four to one week or longer of this change into these diets, which is usually low in protein, low in sugar, and high in good fats. Is that sort of, so it's low, we're kind of talking about this fasting memetic diet, but

the fasting itself is also something, so there's the fasting mimetic diet, which you've done a lot of research 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 health span, but there's also some differences, right? Well, it's very different, right? I mean, calorie restriction is, say, 20 to 30 percent 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 increased protection a lot or turn-on stem cells. And so a lot of these things you can't get by color restriction, but you can get them by these more extreme interventions. And yeah, so color restriction also is missing the biggest component of the periodic fasting, which is not fasting itself, but it's refeating, 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 during the, 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 refeeing. And in color 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. 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 clear. They 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 the autophagy that happened, you're saying that after that occurred, that was the signal for the regeneration of the stem cells or we're eating after? Autophagy is clearly occurring. 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've done so far, it 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? 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, getting 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. of refeeding, right? So it's really extraordinary and probably the most powerful regeneration or generation program that you have since birth, essentially. 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, et cetera. 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. It's not really the fasting that is doing anything, is the body that is doing everything. The fasting just tells the body, I need you to kill all the cells, and then the the refeeding gives the message, I need to rebuild all the systems. This seems like it has, I mean, implications for human aging, because, you know, if you're talking about humans as we age,

we something occurs called immunosinessence, where we start to lose some of our, you know, 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 hematopoetic 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 regenerating the hematopoetic stem cells, which also

increased in cell number, if I remember correctly. You also did this experiment in older mice, and you showed something very interesting, I thought, because as we age, the immunosonecence 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&T cells, as opposed to the other blood cells we have, the myloid lineages, which are composed of neutrophils, macrophages, platelets, things like monocytes. So as we age, we have more of those types of immune cells, unless the other, but you actually found that if you fasted those animals, something happened with that population, correct?

Yes, so we found that the lymphocytes number goes back to the more youthful level and the ratio of myeloid cells to lymphocytes goes 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 rejuvenation of the system. See, that was really cool for me when I was reading that because I started thinking about, you know, not only with the immunosin essence, how that seems relevant because when you're older, it become, you know, more susceptible to infections.

Cancer, obviously, your immune cells are, 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-scentenarians, and in supercentenarians. And they looked at all sorts of biomarkers that are related to aging. They looked at telomere length. They looked at senescence, immunosinensensensis.

They looked at all sorts of inflammatory biomarkers. They looked at metabolic markers, glucose regularly, you know, insulin sensitivity. They looked like kidney function, you know, just tons of different biomarkers. And they were trying to find which biomarkers were consistent with healthy aging. 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, and I was thinking about how monocytes, macrophages, 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 myloid lineage is producing lots of nasty inflammatory chemicals. So it would be kind of interesting to look and see. I mean, I'm totally just speculating here, but if there's some way, if you were to make a, if you could regenerate the immune system to resemble more of a youthful phenotype. First of all, it would be interesting to look at Centenarians to see if they have more balanced, 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 age. Yeah, I think we need to be careful with the inflammation and the, as a cause of aging. I see it the other way around. I see it is the aging is the cause of inflammation. And that makes sense, right? Because inflammation is really can come from this regulation of immune cells and other cells in the body. So yeah, so I think it's really the evidence that inflammation is 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. 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 this centenary 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 an intervention that you do, you want to see them coming down and this is a good indication, as we've done for our fasting mimicking diet, where we show that almost every patient that, I mean, we showed a decrease in inflammation in the mice that were given the fasting immune diet started in middle age, but we also saw it in the population, in the human population, age 20 to 70,

where everybody that had high C-reactive protein came back down, after three cycles of the FMD, came back down to the normal levels. So, but again, that's probably indicating that the systems were not working properly, and now you bring them back to, you know, so maybe you're regenerating part of the, you know, bone marrow, and maybe also you kill some bad cells in the spleen, et cetera, et cetera. And so the result of that is the last inflammatory markers that are being released. The liver also, we've shown that undergo cycles of, you know, atrophy. and regeneration. So all of these organs are contributing to inflammation. And so,

and so it's important that with an intervention, you see also an effect and inflammation, because it tells you that the intervention is working. The system is being reset back to a more useful state. Yeah, I do agree that that's definitely a good marker. So you were talking about this fasting meomatic diet in humans, this clinical study in humans that you had, or pilot trial that you had done humans where you're, is there, so with the, with the mouse studies and the fasting and the atophagy and 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 fast

emimetic diet because the amount of time would have to be like a week or five days or or something that seems a lot more difficult for humans to do. Yeah, so it's not just about difficulty. It's also about safety. And so when we first started with the fasting and 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 gave you a fasting making diet? Then 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 of medicine.

And then everything turned around. So people were much more likely to do it. They felt like psychologically, we give them something. They also, of course, they're eating almost normally. I mean, normally in the sense, at the right times, they're not being normally. Obviously, the diet is very different than the normal diet. And the doctors felt good about it. So I think it was really important to get the fasting-meinicine diet going.

And, you know, so now we have a number of trials, both in cancer patient, in diabetes patients, soon enough we'll start with, well, we finish one in 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 that's good and bad, I guess, but I think that it's got real potential, as we're seeing now, that we're talking to doctors, and now we're seeing a lot of doctors, cardiologists, endocrinologist, a gynecologist, and prescribing it, right, or recommending it. They're not prescribed it.

It's not a drug, but they're recommending it to a patient, and I, I, I, I, I, I, It's been great. You know, now we have a couple hundred doctors that we're talking to, but 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, World War, why these type of interventions are going to be standard in the doctor's office.

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, being sedentary, they all increase the chance of eating cancer. And, you know, these 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. In Europe, it's the same way in a lot of places. In Europe. Really? People smoke a lot in Europe. But, you know, the cancer treatments of the standard of care, you know, chemotherapy, radiation, surgical, you know, 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. But you did a clinical trial, so you were involved in this clinical trial that you kind of mentioned briefly, which I thought was very interesting in 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. 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. Can you explain that a little bit? Like, why that is? Yeah. Well, that is, again, because the, almost every organism, you can start with e-collide, 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 shield the 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 mice and now we think humans, chemotherapy is also one of the toxins that they're resistant to. So you starve them, the normal cells go into the protected mode.

When you starve a cancer cell, though, because the oncogenes are the regulatory genes of this protection, cancer cells by definition can never respond, right? So they're just normal cells respond, no matter what normal cell it is, from a muscle cell to a 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 underappreciated, 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 evolved in all this high nourishment environment, right? So it's evolved 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 oncologists mean well, right? But by making all this available during chemotherapy, you're really helping one thing more than anything else is the cancers, right? What's you're referring to as them telling people to eat a lot of calories. Yeah, of course. Yeah, so they tell, they tell me. And so, you know, because the cancer loves sugar and loves amino acids,

right, and depends on sugar and amino acids. The more you give it, the happier it is. And so, and also these nutrients basically, you know, make the normal cells sensitive, right? So you're making the normal sense sensitive and you're making the cancer happy, right? Instead of the opposite, which is make 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, be 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 very low IQ and you, you know, you put it in front of food all around it and it's going to 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's a lot of the same monkey. And you're going to have no problem, right? As soon as you take the same monkey with a very low IQ, and you make it's really difficult to find the food. Now, that that monkey is going to have a problem. And that's how we see the cancer cells. Once the amino acids are low, the growth factors in the sugar law, the cancer is going to struggle. 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 that mice are 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? We and many of the labs have tried that. You see, which is great, often the fasting,

the fasting in the way can't do it is good as chemo, but you never see 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, both of them are very important. And when you combine it, particularly the alternative integrity medicine that's got a deep scientific foundation, when you combine it, now you have a very powerful system in your hands. And, you know, whereas each alone doesn't work very well. Yeah, so it's kind of like what you're explaining, at least the way I'm understanding it, is that you need.

So 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. Yeah, I don't see it. I mean, I don't really see it as a stress. Fasting? 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 last medieval times in Italy and even after. And it's amazing how many times they were with.

food at all, right? It could be without food for months. And this was very, very common for everybody. Imagine before then, you know, imagine tens of thousands of years ago. We must have gone without food for 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 fasting. But you have to respond to that and you respond by having, you know, 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. Yeah, I see what you're saying, but I think what I kind of 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, you know, it is part of our normal biology, I guess. But I think that because it activates all these stress response pathways in a way. I mean, worldwide, technically, yeah, it is, it is a stress. I mean, it's viewed as a stress. But I guess that's- Like a hormetic type of stress is what I'm talking about. Yeah, but that's the one that I have a problem with, meaning that the hormetic stress is really a, 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?

And 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 protected mode. And program B is when you say, when the organism makes the decision, that it doesn't need to be in a protected mode because they really want to focus on reproduction, on growth and reproduction. So I think it's better to view it this way

because I think a lot of people, by going into the Ormises theory, maybe miss 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 I coli and yeast, in human cells, in mice, and in humans, you started getting a more clear picture of what's going on. And I really see it as A&B, you know, the environment decides which program you adopt. That's an interesting way to think about it. Getting back to the cancer with the fasting and this kind of we got sidetracked, but the fasting,

the fasting, the cancer cells itself, so doing this in animals and also you've been, involved in a clinical trial where it was shown to lower, you know, 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 the, 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, you know, very interesting because I've often thought about cancer cells as being primed to die. You mentioned how oncogenic signaling is all screwing 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-apapotic proteins that are causing them. They're supposed to cause them to die, but they've countered that with the anti-apoptotics. And all it really, 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 the immune system? Yeah, I think it's all connected. I think it's all connected. So yes, yes, we published a paper calling it. the fasting dependent, anti-Worberg effect. And so basically the, and 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 is no other way around it, right? And that's great because then that is, they become desperate, essentially, and that condition makes them undergrowing. go 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 leads to, we believe, leads to the extensive death 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 that now they're easier to be recognized by the enderitic cell, et cetera, and to be set up to cause an immune response than normal. Yeah, I think you actually showed that maybe it was the fasting memetic diet itself

was able to increase cytotoxic tyloctocyte, number, and play an important role in killing cancer cells. Yeah, not just increase the fasting. number, which that is very much consistent with our older paper, but more so making the cancer cells exposed to it, right? So it was, it's more about making the cancer cell more unable, like you were saying, now, normally the cancer cell figures out how to deal with the immune system and says, 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 it is this coordinated, a 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, of pre-cancer cells, right? Because fasting was something that was normal for human beings, kind of 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 exposed to this very high incidence of diseases that we earlier did not have. Do you practice fasting?

yourself? Do you... Yes, of course, I practice fasting. I don't normally eat lunch, but I just want to finish a book, which was published in Italy, and it's going to 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 going to have to be the future of nutrition. And I think nutritionists and the dietitians and doctors are going to have to get used to this.

So, 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, like breakfast and lunch or breakfast and dinner, okay, as I did for 15 years. Then if you underweight, though, 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 restrictive feeding, such in Panda's work, which I also utilize, for that purpose, you know? And so keep the feed-in to 12 hours or less

and then decide the meal frequency and Sachin and I just wrote an article on this and to control the weight. It's really important, particularly control visceral fat. So we hope that that's what doctors start doing and say instead of... It 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 going to 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 much higher control. and that can serve to, in time restriction and two meals a day, they can serve to, you know, regulate the amount of calories as such and it's shown for the time restriction. And so now we, you know, we need to do more studies on a meal frequency. But, but of course, this is likely to get the same similar effects. Do you think it's more important? So within, if you're eating within this 12-hour window, which is coordinated with the circadian rhythm,

then, and if you're eating two meals, do you think that, you'd get more benefits if you had the two mills closer together because then you, there would be fasting for longer. You'd have, you know, more beta-hydroxybutyrate, ketone bodies, things that are, you know, you know, being produced upon a prolonged fasting. Or do you think it doesn't... I would say, you know, I spend, you know, almost 25 years since the wall for days. And I would say I learned one thing and also be in Italian and spend a lot of time around world. I learned that you cannot take happiness away from people, you know. So I always stayed away

from trying to regulate too much, you know, too close, two hours apart, you know, what do you got to 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 going to do it, just like color restriction. Color restriction has been around for 100 years and nobody does, right? I mean, maybe one in a thousand. I'd be surprised if it's even that, right?

Maybe one in 10,000, right? So after 100 years of color restriction research, one in 10,000 American maybe are doing color 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. they're wrong, right? 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, I eat twice a day. That's okay. And so that told me that from the beginning that there was something that was doable

and people even doing it in a voluntary, voluntary way. And anything else, you start regulating, you should eat at four. And also 12 hours, I think a lot of people did that kind of time restriction, right? You know, so that's when I grew up, That's how we did it. You know, maybe at breakfast at 8 a.m. And then 8.30 at the most, you finished. You know, that was it. And so, yeah, so I think that that's important to not try to push for every inch of the longevity plan.

And really, because people will abandon it. That's another thing we show up, you know. If you tell them to do things that are very much, you know, 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 it all the rest of your life. And then the periodic fasting-immulking diets, because also it's not very invasive, and people

say, 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 it's, 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, you know, rather than trying to, you know, regulate everything, you know, how people do everything. Yeah, compliance is very important.

You know, so do you, the, eating within a certain time frame and eating two meals a day actually is what? What I do, I eat, 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, you know, being able to make more hematopoetic stem cells. And I'm wondering what a human would have to do to get, like, is my 14 hours of fast every night doing that or do I have to do a four-day prolonged fast, which I can't, I mean, I wouldn't do that, like, unless I have. had some sort of supervision or possibly this fasting mimetic diet, which you mentioned, you've shown in several different studies in many different ways, mimics fasting. And it's this low-strigger, low-protein, high-fat diet. So, you know, is that something that's...

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 pescatarian diet, low protein, high nourishment, and then, like, I do all this. this, like two meals a day, 12-hour restriction, and then the rest that I just said, if you're on that, you're not going to need as many fasting-immiric diets, right? But the fasting-emic diet 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. And I shouldn't go over that because it's just a continuous thing. You know, you don't want to push the system too much into these extreme modes all the time. It's different from the fasting and making diet because, as I said, you know,

the fasting making diet 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 you're a major source of energy. Your brain starts moving from burning sugar to burning ketone bodies, you know, beta-droxybutyrate. So as I said, everything starts shrinking. The immune system starts shrinking. The liver, the heart, the, even the oligodendrocytes, as we've shown in our multiple sclerosis paper.

So, yeah, so that you're not going to get with anything else. And you're only going to get it with this prolonged fasting making diet. Now, is it possible that if you did some of these things many, many times, that this will be equivalent to a fascinating thing that? Yes, possible. But again, we've seen that we don't know, you know, because theoretically there shouldn't be enough because you're never going to get to this shrinking and rebuild them.

But even if it was like that, then I think that it'd be, again, it's hard to change people's behavior all the time. So we felt that by doing this periodic interventions, we got a much better chance of getting there. You mentioned the multiple sclerosis with your fasting pneumatic diet and also the fact that this diet sort of shifts you to a more fat-burning state.

which is sort of in line with, 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, say, one of the studies you had, I think it was the human study, you want to talk about that? You had a ketogenic diet, you had the fast mimetic diet. 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 something.

and this is very clear effects, which was the fasting mimicking diet causes the Yblah cells. So the immune cells, as I mentioned earlier, to be destroyed, partially destroyed. And then it turns out the stem cells. And when you make new cells, of course, they're no longer autoimmune. 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 this leads to about 20% of the mice being disease-free, right?

So, meaning 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 meaning the general inflammatory state around the spinal cord, particularly, goes down. And so this is very important because, allows the progenital cells, so 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, well, this is incredible. This is magic, right? 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? 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? That's, if you want to see fasting, you can see it like that. And that's why it looks so magic is because it is an evolved process that has been, you know, been evolving for billions of years.

And so I knows exactly what to do to fix a series of problems. Yeah. I mean, if you can see the wound as, you know, in the spinal cord, as you will see as a cut, you would think of as the cut in the skin. So. I wonder, I had this thought I want to say. Also, you showed, the people with multiple sclerosis had improvements according to some test or something as well, right, with the fasting mnematic diet and also the ketogenic diet, which... Yeah, and also the ketogenic diet.

And this is Marcus Bock in Berlin that was the lead person in the study. And, but, I mean, the amazing thing is that a week of fasting followed by Mediterranean diet, which is really a regular diet. diet did better than six months of ketogenic diet, right? Oh, wow. So, continues, right? Okay. And that's what makes it very impressive. So wait, it was one week of fast-mimetic diet and then...

One single time, right. Five days, and then 25 days. Seven days. Seven days. And then the rest of the six months, a regular Mediterranean diet with much the... Really? Just one? Yeah.

Wow. That is... This is what makes it remarkable. And so now we're approaching the FDA, and I think we're going to propose a... one cycle every two months. And, you know, so, so hopefully that. For another trial? For another clinical trial?

Yeah, a much larger trial. Is this something that it 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 the new fully functional ones, it can be applied to a lot of diseases. Yeah, there is no doubt. Yeah. So we're now doing mouse work in many autoimmune diseases, for example, we're doing cognitive diseases. So yes, I think that 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 or another autoimmunity, or a degenerative disease, or diabetes, or cardiovascular disease, I mean, all these things 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 I say at least a thousand, right? And then you have to look at the statistics, you have to look at the response, et cetera, et cetera. 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 your 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 got to be a decision made by the clinicians

together with the patient saying, you know, should we take a risk in adding to this fasting mimicking diet to the treatment? And that's, you know, together they have to come up with an answer is a word at 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 being died. So we haven't published that, yeah. But, and so I think same for multiple carosis and all these diseases. You have to see where you're at. Can you wait? Can you not? Is there something that is working and they make the decision on, is it for now or is it for, you know, five years from now? Yeah, I think that makes a lot of sense, Walter.

I want to kind of go back to this thought that you instigate. in my mind when you're talking about this sort of like wound healing sort of analogy, and that is, at least with the hematopoic stem cells, I'm not sure about with other stem cells and other tissues, but I know that they, 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 from, you know, as a byproduct of mitochondrial function, right? But I do know that when they come out a quiescence and they come out to either self-renew or differentiate into progenitor cells, they become oxidative phosphorylation becomes their

source of making energy. And so I'm wondering if there's what the signal, I know you've published some studies on looking at different signaling pathways that are required to cause this hematipotic stem cell self-renewal mechanism, 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 somehow also is playing a role in making them self-renew more or differentiate more? I think so, and this is the work by Davy Sabatini and others at MIT, and they're doing

work on the fat and the role of fat and fatty acids, etc., on self-renewal. and on 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 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, a lot of people are like, well, in 20 years we'll have this.

And we always say, you know, there's people that have cancer now. They have multiple carosis now. So what do you do for them, right? And so our decision is being 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? Yeah, yeah. Rather than step by step by step, you know, and then it'll take you 15 years to get to the clinical trial.

So, I mean, I'm not saying. criticizing the other method, but I'm just saying that for us is being, get the mechanism, get enough mechanism, move to the clinical trial, and then make sure it's safe. 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 a more, if you think about the stem cells, and if they need energy to differentiate our self-renew, ketone bodies would actually provide a very energetically favorable source because it takes less oxygen, actually,

to convert beta-hydroxybutyrate into acetylchoe, 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. Yeah, I think there's also mechanisms, again, and 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 health of your liver, let's say you fast for a month and a half, right, then you must, you will produce tons of, of fatty acids and tons of ketone bodies. And that environment is going to require the stem cells to be renewing and being standing by for the day where you need to make a new liver, essentially, or health of 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 sources, 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 it is made by gluconeogenesis. So it makes sense.

So need it. Since they have no mitochondria. Right. And so it makes sense that you will have a. a system like that that is fat and fatty acid and ketome body base. Yeah, yeah, absolutely. Not to mention that, like, you know, beta-hydroxy beta-beterate's been identified to be signaling molecule as well.

I think Eric Friedin's work at DCSF showed it's a class one, his own 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, a fasting emetic diet and cancer, a couple of things. So one is, you know, I think you've shown without a doubt that this, that in both animals and also in some preliminary work in humans, that the fasting or the fasting of mosaic diet can sensitize cancer cells to a 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 there's a very well-known inhibitor of autophagy called chloroquin, which is used to kill cancer. So what do you think? I mean, obviously fasting is weight. It's not just causing atopathy. It's like doing it's this whole, like you mentioned, there's lots of the sensitizing 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, atopathy becomes more important like later in cancer when that actually that's when the metastasus. occurs or what do you think of that whole field of, you know, autophagy also playing a role in cancer? I think the autophagy, and I think this was in the paper that was published together with

ours by Guido Cromer. And he showed, and Frank Madero has also been doing work on that, but Guido was showing that autophagy was very, very important during the starvation. using starvation-mimicking drugs in causing the exposure of cancer cells to the immune system, right? So which probably means that 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 does in a very coordinated way into something bad in a cancer cell.

probably because it may 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. Even independently of autophagy, the desperation seem to be key, meaning, for example, they try to increase translation to get more proteins, right? Instead of shining down like a normal cell,

would they go and try to do things that they seem to be desperate. And, of course, you can do that. Or you can do it only for so long. and that's probably why they die. Yeah. I mean, it's, I know it was something that kind of was confusing to me at first, and then I thought about it for, you know, a little more in depth. And I thought, well, you know, fasting itself is doing so much more than just autophagy as well.

So it's not like, that's the only mechanism that, you know, that's a current, a biological mechanism that's changing with fasting. So, but I just thought it was kind of interesting how it seems to be there's sort of this opposite end of the spectrum, you know, effects in terms of cancer. But you mentioned fasting memetic drugs, or what was it, fasting mimetic drugs or autophagymetic? No, fasting mimicking drugs. So Cromer had a series of drugs. So which one, like, is there? I forget now what drugs they had. But for example, resveratrol is spermidine are considered fasting mimicking drugs. They, you know, They may not have the power of fasting, but certainly they push the cells in that direction.

They activate certain signaling pathways that are similar to fasting. And, you know, this is one of the discussions with people that do drugs. I mean, we, yeah, 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 once we know that they're very safe and they're very effective together with this older type of intervention, maybe the way to go, 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? Yeah. Because now you just generate it, even if it was 1% of the people, they get a side effect. So in moving forward with this fasting,

making diets and these anti-aging drugs, I mean, we work on ourselves, right? But certainly you really got to get to a point where you say, I know this will never be toxic to anybody. It's tough, right? 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 going to have so many consequences,

everything's connected, you know, and how are you going to know 20 years from now? Yeah, exactly. It's impossible, right? So you love to have the 20 years, right? You love to have the 20 years observation. And for example, this is why metformin now is starting to very slowly move into the candidate position for an anti-aging drug, you know, near Barzilli 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, given to somebody that is completely healthy, that may not turn out to generate some problems that we did not see in the diabetic population. So metformin in a way sort of could, one could possibly say, in a way, to fasting memetic in the sense where it activates A&P, one of the signaling pathways at also. No doubt, yeah. Do you know if metformin increases autophagy, or has that been looked at?

I'm pretty sure it does, yeah, I'm pretty sure it does. So metformin seems to, in our view, seems to. to be acting more in the sugar pathway. And then, but then, of course, it's missing the effect on the amino acid pathway. Or it has a much weaker effect on that pathway. So, but yeah, metformin has got potential. But then again, will I take metformin knowing what I know?

Absolutely not, you know. What about when you're 65 or 70, would you start taking it? No way. No, really? No way. Why is that? Well, because it is, I just, don't like the, you know, our laboratory discovered the Torres-Syskinease pathway in aging 15 years ago.

And we used to work with Rapa Mycine back in the 90s, in the mid-90s, you know, working with the cells from Mike Hall. But I always said, I never want to work, I mean, not never, but I really am not enthusiastic working by em-blacking something so central, you know, in a cell and its metabolism and it's crow. et cetera, et cetera. And I think everybody got very excited in the field, and you started seeing first all the positive results with robomycin, until, of course, you started getting the negative. Right.

And it was hyperglycemia, testicular degeneration, cataracts, and this is probably just so. And I think with any drug that intervenes as such a central inside of the cell, I always say it's kind of like taking a car that it's got a problem and just sticking things into it, And so you find, oh, the problem is stopped, right?

It's like leave the knife in there, you know, or leave the device in there. You know, that's not the way to do it, right? You have to somehow rebuild the car in a way that works. But pharmacology a lot of times or almost always block something. Right. It's like, well, when you block that, what happens to everything else around? I don't know.

But, well, you know, 30 years of all that, let's say, you activate the AMP kinase, right? 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 this just disruption of all this normal pathways does nothing? I don't know. So we prefer, for example, we always prefer to go with where we have human evidence and there are no consequences.

And that's a growth hormone receptor, right? So we're now developing drugs against a grotormor receptor. Why? Because we have the Ecuadorians that we've been following for 10 years. And Guevara has been, our colleagues, been following them for, for 30 years, and they're fine. They make it a very old age. Can you explain that?

So people like, you know, the IGF1 and growth hormone pathway. Right, right. So essentially, essentially amino acids, proteins and amino acids control two major pathways, right? One is the growth hormone IGF1, which is called an axis. It's not really a pathway, but an axi. And then the other one is Torresis-Kinase, right? So if you have a lot of amino acids, those two are activated. And both are now widely recognized.

This is very powerful pro-aging pathways. And so, yeah, so that if you, of course, you can do it by food or you could do it by mutation. So if you take a mouse and you knock out the growth hormone receptor, this mouse will live 40, 50% longer. It's also, in spite, and this is worked by John Kapchik 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, the

growth hormone 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 households, like a normal disease, right? So it has nothing to do with Ecuador, has to do with the mutation,

which matches very well the mouse data. But 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 very long-term human data. 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. Right, yeah.

Foxo, there are mutations in polymorphisms in the IGF1 receptor, in the Grotormone receptor. Right. So all those. It's all consistent where, I mean, I remember, in fact, one of my first experiments in biology, was doing, you know, manipulating the IGF1 signaling pathway in worms in Andrew Dillon's lab at the Sulk Institute. And I remember when I saw, you know, when you get rid of that pathway and 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, 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 Centinarians have, like you said, Foxx, so IGF-1, just for people, said 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 being, playing an important role in cancer, promoting cancer growth. When I was studying it in the 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 etophagy and degrading proteins. And it's just like a master regulator of all these 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 IGF1 is going to have a more profound effect on human lifespan via not getting cancer, or do you think the FOXO, not inhibiting that FOXO3 pathway is just as important? Probably it's very much connected, meaning that the aging process is the driver for the cancer, both at the level of cancer cells and accumulation of mutation, but also at the level of the tissues getting more inflammation, being more permissive to the metastasis, and also the level of the immunosin essence and the immune system getting weaker.

And we know that if you have an immune deficient mouse, the cancer grows a lot faster. So then the aging process is really, and I think 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 we always look in terms of treat aging, and then the rest comes. Now, of course, yeah, there are other 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 IGF1 because it helps it prevent apoptosis. 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 may be independent of the aging process. Yeah. We should probably also mention the good parts of IGF1. You know, IGF1 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-derab neurotrophic factor for growing new brain cells. Yeah, this is why I was saying the fasting and refeeding, right? So during the fasting, the IGF-1 goes down, and so that's Thor and that does everything else. But during the refeeding, IGF-1 goes up, and IGF-1 is the driver of all this regeneration, most likely. I mean, we haven't looked there in depth, but other people have. And so almost in a lot of regenerative process, UCIF1 have been involved. And this is why I was saying that color 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. And that's why I think it may be only half of the solution. Yeah. Something else that comes to my mind as well is wanting the IGF1 to go where it's instead of sitting around in your serum and, you know, in 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 IGF1. And I think it's because it's to the muscle, but also to the brain, because in mice, it's been shown that exercise causes IGF1 to cross the blood and brain barrier and get into the brain.

So that's another good reason to exercise is because now the IGF1 that you have, you know, is going to the places where it's, you know, it should. Right, right, right. Yeah, so exercise obviously is 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 repair.

And that's also known that the repairs will build the muscle. So this may be maybe not as potent as the fasting, but if you do it all the time, it could be that you have all this small regenerative processes occurring every couple days, if you access every couple days. And then, you know, eventually those could be cumulatively, it could be actually very powerful. And, yeah. Particularly in combination with the fasting, too.

I mean, if you're going to eat your protein and activate IGF1, then it's good to exercise to make sure it's going to the right place, right? And so it's, I think. Yeah, yeah, yeah. And, yeah, absolutely. And in the book that I wrote, I really talk about exercise and the need to exercise to make sure that some of these restrictions. 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 you really, 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 temporary loss, but then rebuild. So it's really interesting. And this is why athletes are starting to become very interested in this fasting and making diets.

Right. Yeah, because most of our diets will get rid of water, muscle, and fat, right? Right. And you want to increase lean muscle mass and decrease fat mass. I mean, that's... Or at least leave alone the limb body mass and decrease the fat. You're switching to a state that is much more beneficial to your athletic performance.

Do you think, I don't know, have you looked at whether or not mitopathy or plays a role in any of this? Because I know that if you're clearing away damage mitochondria or, you know, mitopathy or mitophagy. I don't know which one I've heard both, but you're causing, once that happens, much like in the whole cellular system, it causes mitochondrial biogenesis. Yeah. So I'm wondering. Yeah, so we're looking at that right now, yeah. So that's our current project, and we'll see what happens. But we're optimistic.

Great. Very, very cool. We talked about so much, Walter. Thank you so much for talking with us. So with these fasting memetic diets that you were for. to, either for people that are, you know, doing this for, you know, disease treatment or they want, they want to talk about it with their clinician, their oncologist, their doctor, whatever, these are available for people.

Yes, so there's a company that I founded. It's called L-NU-N-R-N-R-N-R-N-U-T-C-C-M. L-N-U-T-R-A. N-U-T-R-A. And they produce a product called Prolon FMD, and the product, I think, is on ProlonfmD.com. And this is a fasting mimicking diet that is being tested clinically. Doctors are now prescribing it, and so you can contact El-NUra 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 have, you know, I just did it because the, basically the patients were asking, what can we do instead of fasting, right? So I, so I, you're not benefiting monetarily. Not at all. In fact, I think I lose money sometimes, you know, so, yeah. So, so I think.

That's really cool. Yeah, I mean, I think it was not a good position. to be in to be benefiting from things we're testing. But yeah, so the company does it, though. It's, 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.

And there's lots of information there, like on the protocols and all that. Yeah, all the information. so people usually have to go to a doctor, just get clearance from the doctor that they don't have a disease or a problem that otherwise prevent them from doing it. And then they get assigned a nutritionist or a dietitian and they just fall on for the five days from the distance.

You can do this at home. And the great majority of the people have no problem. But you just have to be a little bit careful. It is a powerful intervention. Yeah. 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 fast immunicking diet and yeah so there are some some warnings but the company and the doctor's okay folks thank you so much for listening i hope you found the discussion illuminating dr longo's work has made huge contributions to the understanding of basic biological mechanisms that regulate the aging process and how to translate this knowledge gained from basic research into practical solutions that improve disease prevention and treatment in humans. Did you like this podcast? Every single episode of Found My Fitness is brought forth with the earnest desire to rock

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