FoundMyFitness - #042 Dr. Valter Longo on Resetting Autoimmunity and Rejuvenating Systems with Prolonged Fasting & the FMD

Episode Date: July 9, 2018

Dr. Valter Longo Dr. Longo is the current director of the longevity institute at the University of Southern California and also director of the Oncology and Longevity Program at the Institute of Molecular Oncology Foundation in Milan, Italy. Dr. Longo's research focuses understanding the biological mechanisms that regulate the aging process, 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 episode, we discuss... (00:00) Introduction (09:30) Defining fasting (16:10) Insulin/growth hormone axis and aging (21:37) Growth hormone deficiency protects from some diseases (30:55) Fasting vs a ketogenic diet for cancer (40:13) The fasting-mimicking diet (FMD) (48:28) "Yo-yo" fasting once per month (52:21) Fasting does not reduce muscle mass  (57:03) Autophagy and apoptosis are our repair mechanisms (01:02:33) Refeeding is necessary to rebuild healthy cells (01:05:31) Top 5 biomarkers of healthy aging If you're interested in learning more, you can read the full show notes here. 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

Howdy folks, welcome back to another round of the Found My Fitness podcast. Today's podcast is a spectacular round two podcast with Dr. Walter Longo. If you miss the first episode featuring Dr. Longo, throw your podcast player in reverse and grab that episode to also listen to you when you get a moment. That said, this bad boy is totally standalone, so don't go anywhere just yet. First, the street cred. Dr. Longo is the current director of the Longevity Institute at the University of Southern California and is also the director of Oncology and Langell. longevity program at the Institute of Molecular Oncology Foundation in Milan, Italy. Volter is, in a word, a giant, both himself a pioneer in the field of aging and has an extremely

dynamic and prolific publishing history that's moved the field forward. Many scientists can spend most of their career working only in one animal model. His work, however, is profoundly translational, ranging from yeast to rodent and back to where it actually counts to the clinic. In this episode, he takes us on a journey, or a voyage, if you will, back to where it all began with caloric restriction. Caloric restriction has long been the focus of promising aging research and research into the amelioration of age-related diseases. Research in animals has shown impressive results with studies in mice and rats, showing chronic caloric restriction and able to extend the lifespan up to 40%, also showing the ability in some animal studies to virtually eliminate type 2 diabetes and dramatically reduce cancer incidents. Chronic caloric restriction, perhaps unsurprisingly, is not wholly without undesirable qualities,

such as slowed wound healing and a weakened immune system and other related effects, not to mention being notoriously hard to practice with long-term caloric restrictors ultimately failing at reproducing some of the cellular signaling changes that seem to be important. But what if we could achieve some of the benefits of caloric restriction without living a life of constant chronic deficit? That is a special question that Dr. Longo's research is especially poised to answer through his research into periodic, prolonged fasting, and more recently, a fasting-mimicking diet that has been shown to achieve many of the same effects of multiple days of water fasting only. What sets this approach apart from that of chronic caloric restriction is that rather than

undergoing constant restriction, we approach it as something that can be cycled periodically to achieve a persistency of effects, which Volter's research indicates can last for at least several months after a four- or five-day cycle. The utility of periodic prolonged fasting and the fasting-mimicking diet, fall into a few broader areas of interest, including relevance for cancer prevention and possibly treatment as well via a quality known as differential stress resistance, as a tool against autoimmunity as a whole, and as a general systemic multi-tissue reset with implications for aging, or at least age-related diseases. One very large, likely contributor to all the important effects of multi-day fasting or fasting

mimicking are the changes that happen to a cell signaling pathway known as the growth hormone IGF1 axis. The IGF1 axis is an extremely important pathway that is activated potently when we consume essential amino acids and protein, but is reduced by up to 50% after just a few days of fasting in humans. When this happens during fasting in animals, it is associated with a shrinking of entire organ systems like the heart, liver, and kidneys, and a breakdown of the immune system with white blood cells rapidly being turned over and reduced by up to 40 to 50 percent. Upon refeeding, a normalization of these growth signaling pathways occurs, and this causes the same organ systems to re-expand to their original size. This may have implications for autoimmunity,

where immune cells that, when renewed from their progenitor cells, have been shown in an animal model of multiple sclerosis to be restored to a naive, non-automune state, resulting in either a reduction in clinical severity, or in some cases to a complete reversal of multiple sclerosis symptoms in these animal models. And there's some early evidence in humans as well. It is the sophisticated nature of this process of breakdown and rapid rebuilding that suggests it might be a way of tapping into an ancient program of self-repair, mostly lost to us because of the general abundance of food and utter lack of famine that most of us enjoy. The temporary reduction of growth signals may be relevant to the treatment of cancer as well.

The growth hormone IGF1 axis and its downstream elements, as it turns out, are a hotspot from cancer mutation. To put another way, cancer likes to grow. And as a consequence, mutations in genes that tell the cells not to die and instead proliferate are particularly common, especially in the IGF1 receptor and some of the signaling proteins downstream of IGF1 that also participate in growth and cellular proliferation and differentiation, such as AKT and RAS. RAS, for example, is found to be mutated in 20 to 30% of human cancers.

While these mutations may be to the cancer cells advantage in a high nutrient environment, it is the low nutrient environment, in other words, the fasted environment, that suppresses this so-called oncogenic signaling where things get interesting. Dr. Longo's group has found evidence that fasting may produce in cancer cells a sensitivity to stress while actually conferring greater resilience to stress in healthy cells and tissues. This may be because the same mutations that cancer has accumulated to promote their growth, ultimately make them less flexible. The advantage of this should be obvious.

Fasting may make cancer more vulnerable to standard of care treatments while also making the side effects less severe for healthy tissues, something still being validated but holding great promise. Okay, so that's just a few broad strokes of some of the enormous potential impact of Dr. Longo's work and gives a great hint as to why I'm so excited about it. Additionally, we also discuss the difference between intermittent fasting, prolonged fasting, time-restricted eating, the fasting-mimicking diet and caloric restriction. How the shift between normal metabolism and what Dr. Longo refers to ketogenic mode is subject to individual variation and the type

of restriction practiced. How the beneficial metabolic effects and short duration of the fasting-mimicking diet may help people overcome both the physiological and psychological hurdles of losing weight. how the fasting-mimicking diet causes a person to temporarily lose muscle, which gets restored upon refeating, but also seems to cause a preferential loss in visceral fat rather than subcutaneous fat. Visceral fat is the fat that is stored in and around your major organs in the admonum and is linked with an increased risk of a number of health problems, including type 2 diabetes, heart disease, and cancer. What some of the most promising lifespan extending strategies are and how they may have the potential

to improve life and old age by reducing the prevalence of age-related diseases that actually make up what we think of as the decreptitude of old age. How massive cell death occurs during the fasting-mimicking diet, but refeating enables healthy stem cell proliferation and potential differentiation. In the context of aging, how the fasting-mimicking diet has been shown to reset metabolism driving down biomarkers associated with poor metabolic health, inflammation, and cardiovascular disease in humans. How shorter fast may fail to approach some of the effects of periodic prolonged fasting and the fasting-mimicking diet by failing to achieve adequate glycogen depletion and ketogenicis. Some of the early but promising pretrial clinical antigenic data suggesting potential complementary roles for the ketogenic diet and the

fasting mimicking diet used in conjunction with conventional treatments like chemotherapy and radiotherapy for certain cancers like gliomas. How oncologists might approach incorporating the fasting mimicking diet, which is still seeking further clinical validation and approval into their patient's care if they choose to. Dr. Longo's top picks for assessing biological age markers, a person can ask their doctor to measure to gauge how well they're aging, a sneak peek at what's covered in Dr. Longo's new book, The Longevity Diet, and so much more. We're almost ready to get this show started, but first, Hey You, Yeah You, the person that's constantly finding themselves Googling things like Emtor and Rath, wanting to know everything there is to know about.

the growth hormone IGF1 axis and its downstream growth signaling pals. You're the reason we put these episodes together. You have to admit that it's pretty niche, which is exactly why we're in a pretty special situation. This podcast exists because people like you even exist. Because to everyone else, none of it matters. Therefore, if this stuff really hits the spot for you, you should absolutely consider becoming a monthly supporter of the show. We sort of do it like NPR around here, which is to say this podcast is viewer and listener supported. My goal is to make a better each and every episode, and the pay-what-you-can support from fans allows me to keep putting a lot of blood, sweat, and ketones into getting them out without cutting corners.

To learn more about how you can help me keep it going through a pay-what-you-can pledge or the equivalent to a monthly coffee date, head over to foundmyfitness.com forward-slash-crout-sponsor. That's found-my-fitness.com forward-slash-c-R-O-W-D-S-P-O-N-S-O-R, crowd-sponsor. Are you interested in the genetics of longevity? If you have used one of the consumer genetic testing services like 23 and me, you can find out if you have some of the unique genetic polymorphisms research has shown might provide an edge when aging. The good news is that while at least part of aging is genetic, a whole lot of it, as you may learn in this interview, is environmentally influenceable. That caveat aside, to learn more, head over to foundmyfitness.com forward slash genetics. That's found my fitness.com forward slash genetics, G-E-N-E-T-I-C-S. You'll find these polymorphisms in a report. at the bottom of the page called The Longevity Report. Now to the podcast. Hello, everyone.

I'm sitting here with Dr. Walter Longo for a round two podcast. I'm pretty excited to be back. It's been a couple of years since our last discussion, Walter. In my mind, you're one of the leading experts in this realm of how diet and lifestyle regulate longevity, particularly when it comes to fasting. So there's been a really big interest in fasting and also in limiting food intake. And limiting food intake is actually one of the probably most, I would say, reproducible interventions that's been shown to modulate the aging process across multiple organisms.

So I was wondering if you could maybe define and sort of describe some of the common denominators between various modalities of limiting food intake. caloric restriction, intermittent fasting, prolonged fasting. Right. Yes. So I think that we're at the point where we have to stop using terms like intermittent fasting because it covers almost everything, right? I mean, at least in the journalist's mind, when they talk about intermittent fasting,

it covers from two hours food not eating to one month. And of course, there are completely different practices, and they have completely different effects. And so I think it's important to start qualifying what it is that we're talking about. So intermittent fasting, I guess it could be a way to include, let's say, alternate day fasting and include what's called the fight two, so having two days a week of a color, a very restricted diet.

And maybe it could also include the one day a week of fasting, of complete fasting. I think it would be fair to include those three in intermittent fasting, even though they can have very different effects. Now, of course, time-restrictive feeding is time-restricted feeding, which refers to, let's say, how long of a time you eat per day? So 8 a.m., 8 p.m. That would be 12 hours of feeding and 12 hours of fasting.

So, and then color restriction instead, I mean, of course you can say some people use colorization to define everything that is color restricted. But the people in the field talk about color restriction, when they hear color restriction, they think of chronic reduction of calories below the normal levels. So below the level, they will allow you to maintain a normal weight. And so chronically, so if you do this all the time. And then periodic prolonged fasting instead is what we mostly work on, and it's very different, and it's not intermittent,

in the sense that it's not something that has to happen in any type of cycles, frequent cycles. It can be done once a year. It can be done 10 times a year. It can be done 20 times a year. And it refers to, say, at least two days of fasting or longer. Or two days of a fasting mimicking diet or longer. And so what do they have in common?

I mean, some things may be in common, but they are very different. interventions and they each do something different. I mean, I think we know now from the calorie restriction field that the diet, I mean, the restriction of calories like that can have incredible effects on diseases, diabetes particularly, but also cancer, cardiovascular diseases. This is really unbelievable effects. I mean, the monkeys, we know that it can wipe out diabetes, completely. It can reduce cardiovascular disease and cancer by 50%. But the monkeys either live

a little bit longer or don't live longer at all. So, and this is what we and know there's a few, at least suspected for a long time. I was a student of Roy Walford back in the early 90s. And it was, I mean, being around Carous of the people, it was very clear to me that this was going to have problems. But it was also very clear that this was going to have huge effects and health. Yeah. For the monkey studies that you're referring to, there were two published, correct? One from the University of Madison and one from the NIH. Right. And neither of them increased lifespan, but they increased health span. No, no, no. The Wisconsin increased lifespan. Richard Weindrück was also student of Roy Welford. So, yeah, that increased lifespan. But if you

look at the lifespan that is based on... the disease-dependent lifespan. So the mortality caused by major age-related diseases, there was a huge effect. If you look at the overall survival, so survival due to where all causes of mortality were taken into consideration, then the survival curves are very close to each other.

Would that be considered maximum lifespan? No, this would mean lifespan, mean and maximum, right? So a small effect. They don't have maximum because I think they will have taken, at some point, they had to stop it, so they couldn't really get to, you know, full lengths. It already took 25 years to do that. So I think it would have been difficult to get maximum lifespan. But the mean lifespan was extended in Wisconsin.

It was not extended at the NIA. Of course, the Wisconsin study had a controlled diet that was much worse than the NIA, control diet. So the NIA had somewhat of an ideal diet, at least an ideal monkey diet, and the Wisconsin didn't. The Wisconsin was a reasonably good model for the Western diet. Oh, that's interesting. Okay. So there's no really, I think there was also maybe some different genetic backgrounds as well from the monkeys, but who knows? Yes, probably genetic. Do you know if they, In these studies, did they see common pathways? And I want to talk about this with you.

Genetic pathways that are known to be modulated by caloric restriction. Were those changed? For example, did IGF more, IGF1 lowered or MTOR? Yeah, now I haven't looked at those paper in a while, but almost for sure. I mean, those were affected. I mean, calories are cut by 30%. So that would mean 30% less proteins and 30% percent. and less sugars. So yes, I will assume that both of them showed the effects on the nutrient

signaling pathways, including Tor and IGF1. And I guess that's probably something that's also a common denominator between these other modalities of limiting food, such as the periodic prolonged fasting. I guess one of the major differences would be the shift in metabolism when you're fasting to beta oxidation to, because is that something that occurs during Kellogg restriction? That probably occurs. There's probably a minimal switch to a ketogenic mode depending on who it is and what the restriction is.

So it is possible that, you know, chronically, when you're chronically restricted, it also depends how you're restricted. So, for example, there are human studies where they show that because the, you the people that are restricted were eating high protein, a high vegetable protein diet, and the IGF1 was not affected. So it is possible that some of these individuals have a diet that would block entry into even a small ketogenic mode. But overall, they're probably not.

They're relatively in a standard metabolic mode as far as ketone. these and fatty acids are concerned. You said, oh, that's interesting because you said the diet was a high vegetable protein diet. And I was thinking the study from, I think it was Dr. Fontana's lab that showed that humans that undergo caloric restriction naturally gravitate towards eating more protein because it's more satiating. And so people that were eating a higher animal protein diet, even though they were caloric restricted so they were eating about 30% less normal food than they normally wouldn't.

would, their IGF1 levels were higher because the... Were normal, yeah. Yeah, they didn't go lower like they do in animal studies. Right, right. Until they restricted the proteins. Until they restricted the proteins. So they actually did the second study, Fontana and colleagues did the second studies, the follow-up in which they restricted the proteins and then the IGF-1.

Haven't seen that one. Okay. Yeah, I should definitely take a look at that. But for people that are listening and kind of wondering, we're talking about one of the major dietary regulars of the IGF-1 pathway, which... Maybe you can mention a little bit about the role of IGF1 in the aging process. Yeah, so proteins, in particular, sotamino acids, metionine, cystin, etc., they regulate IGF1 levels. And IGF1, in simple organisms, at least the orthologues of IGF1, as well as in mammals, seem to have an important role in aging.

It's not clear how much is IGF1 versus insulin versus growth hormone receptor-dependent signaling, which is independent of IGF-1. And insulin, most likely it is growth-a-ormone receptor. Grotormone and growth-a-mortemone receptor, the sort of master controllers, and IGF-1 seems to be one of the axis that regulates or accelerates aging in multiple. cell types. And from humans, there are some evidence with polymorphisms and various like growth hormone. Yeah, that's actually our work with not polymorphism, but mutations in the grotomoreceptor, something called E-180 mutation. And the people, well, we knew from

mice from the work of John Kavchik and Andre Barkey, the mice that have, their growth hormone receptor or growth hormone deficiency, live longer, about 40% longer. They also live much healthier. That's probably, you know, I think one of the most important observations that made in the aging field that, you can live 40% longer, and yet about health for the mice get to the end of life without any obvious pathological lesions, so they don't develop diseases. the controls, this is less than 10%. So,

and this, I'm pointing this out, well, it's a huge effect right there. I'm pointing this out because obviously people think that if we extend a lifespan of human lifespan, then it's going to come with a lot of more problems. And instead

in the mice, but also in our work in humans, where we've been following these people with Giotomor's receptor deficiency down in Ecuador. They're called a syndrome, they have a syndrome called La Ron syndrome. So they're very much the equivalent to the mice. And they don't have a very long lifespan.

They may live a few years more than their relatives. They don't have homozygote hormone receptor deficiency. But they're protected from cancer, they're protected from diabetes. And recent papers show that they seem to be protected from age-dependent, cognitive decline. And all of these are matched by the mouse work. So that makes you feel a lot more confident having the mouse data suggesting that this is a concerned effect of having low growth hormone. Of course, and then low IGF1, low insulin, and law tore and also I think low RAS, at least expression, activities a little bit harder to figure out in people.

Have you measured the IGF1 levels in these people with Laren syndrome? You've measured their IGF1 levels? Is that something that's achievable from doing the caloric protein restriction or the fasting, which we probably should probably start talking about? Yeah, we measure the IGF1. It's very low in this subject. Yeah, it's like 10% of the normal IGF1, circulating IGF1 levels. Oh, wow, okay.

Yeah. GF1, low insulin, and also we have, what we've done is we've taken the, this of course we can measure in their serum, right? But then we've taken this serum and we took human epithelial cells and we exposed the human epithelial cells either to control serum or to the serum in the lorone's, and then we looked at gene expression. And that showed that not only, the Tor was down-regulated, so it was, was, you know, and it was RAS, at least gene expression-wise, and a number of other genes that are associated with

accelerated aging. And cancer, wow. So maybe we can, I kind of took us off into the tangent here, but the fasting, you've done a lot of work on both doing a periodic fasting, water fasting, and also fasting-mimicking diet, which you can explain in a minute. But so I was kind of the, I found it kind of interesting, like the reason why you developed the fasting mimicking diet, at least I read in your recent book, the longevity diet, was, if I'm correct, because you were doing some studies on cancer patients.

And is that, is that correct? Yeah. So we, well, first of all, for a long time, I had been thinking about, how to get the benefits of color restriction without the problems of color restriction. And so that was something that I was looking for. And also, I, you know, back in the days in my graduate work, you know, we were starving yeast and bacteria and we had shown that this was very, very beneficial. So I was really, I wanted to look at the possibility that

prolonged fasting would be beneficial. And so then at a certain point when we discover that the proto-uncogenes, so the normal versions of the oncogenes that are so central in cancer, they are the genes that control cellular protection. And so from there came the idea that, and maybe we discussed it already in the first in the first interview. But there came the idea that if you start a system, the normal cells will become protected and the cancer cells will remain sensitive.

So then, you know, we started testing this in cancer patients, but realized that they didn't want to fast. And then I think that gave us an opportunity and the motivation to look for a fasting, mimicking diet. So a diet that works as well as fasting, but allows patients to eat. And this was funded by the National Cancer Institute first and then by the National Institute and aging. And so it's of course exploring all these understanding, all the understanding of the connection between, let's say, amino acids and Thor and IGF1, sugars or certain sugars. and PCA, actually, we've shown that, as we had shown for yeast, we're now shown in mammalian

cells that glucose levels activate PCA. And so that's part of the, that's a lot of what went into the development of a diet that can nourish the patient and yet have effects on IGF1, GF1, ketone bodies and glucose that is equivalent to that of water-only fasting. So you basically looked at all these known genetic pathways from your work and others that, you know, so IGF-1, M-TOR, P-K-A, RAS. Yeah, RAS. Although RAS, may or may not be conserved the role of RAS,

we didn't really see it in mammalia cells yet. I mean, it's probably there, but we didn't see it, at least in the cells that we looked at so far. You know, it looks like IGF-1 and glucose can directly feed into P-K-A. and IGF1 can feed into PQAA. So we think that PQA is very central, maybe handling both the protein signaling and the sugar signaling. Interesting. Yeah, that's the interesting, what are your thoughts on, and I'm going on a tangent here,

I'm going to come back to it, but the, because you just mentioned this, the role of insulin in regulating IGF1, I guess, both. function and also levels. So there were some studies that I, and I'm not sure if this was Fontana or who, you know, did these studies, but they're saying that limiting the glucose intake was important for bioavailability of IGF1 through some of the insulin IGF1 binding proteins, like IGF1 binding protein 1, and also for regulating transcription of IGF1. Yeah.

So it's kind of... So it's all interconnected. obviously we don't know enough, you know, the association between, I mean, insulin and IGF-1 are very similar. They can interchangeably bind to the receptor, each other's receptor, with different affinity, of course. And so, yeah, how are they connected? I don't know, and I'm not sure that that is very well understood, but they're certainly connected. And there's certainly linked, both linked to croton-signalling. Yeah.

Yeah, I think there was another study, and this was in animals, and this is what really piqued my interest. I'll look up the reference and send it to you if you haven't seen it already, where I think the protein, limiting the protein intake, essential amino acids specifically, wasn't as key if the total kilocals were kept under a certain level. in terms of activating IGF1, so that there was this sort of energy threshold where if you had low enough energy specifically from like glucose, then your protein, your essential amino acids can go a little bit higher than they'd otherwise avoid.

Right, right. And this will be consistent with our work in yeast. In yeast, when you have, when you look at the aging rate, it's very clear that there is a network and it's not really a pathway. And the network is very much interconnected, you know, PQA and Tor and everything else, and PKKKNAs. And so actually in yeast, sugar seems to dominate. And the protein seemed to be second most important.

So if you remove sugar and you... increase the protein, consistency to what we were just saying, that's not so bad. But if you have both the sugars and the protein, then you see much more the protein-dependent sensitization. Yeah, it's extremely interesting. So I'll look up the reference, too, in case you haven't in it. And, of course, in the case of yeast, it's individual amino acids. There is no protein. Okay, so we went out back on a tangent, but this is why these discussions. discussions are so interesting. But so you were talking about the development of the fasting-mimicking diet and how you were looking at all these genetic pathways. And also you mentioned the ketone

bodies and what was the last thing for... Ketone bodies and glucose. And glucose, right. IGF1, NGFB1, glucose and ketones. And these are all things that regulate cancer growth as well. Yes. They can regulate cancer. They do regulate many cancers and in different ways. I mean, ketone bodies, you know, some will argue that hurt cancer cells. And but some cancers actually love to use both ketone bodies and sugar.

Yeah, there was a recent publication, I think. Yeah, so you can actually accelerate cancer growth with ketone bodies, but you can also hurt cancer cells with keton bodies. You know, this is why ketogenic diet, you know, I wouldn't get too, you know, confident about using ketogenic diet alone. against cancer cells because, of course, even fasting, a lot of cancer cells can adapt to the change environment. So, yeah, cancer is a very, it's so complicated when it comes to cancer, and it seems like

really, you really have to be careful when you're trying to treat the cancer. Yeah, and I think that there is a lot of, of course, the interest on the ketogenic diets and cancer treatment, and it's good. I think it can do, there are situations where the ketogenic diet can hurt the cancer growth. But, you know, as for fasting, we see that you need to have, in most cases, the powerful target intervention with the fasting. So, like, fasting and chemo, fasting and kinase inhibitors, you know, fasting and immunotherapy, for example. I will assume that the ketogenic diet alone is going to be a complementary intervention.

So now, for example, we're very interested in what happens if you do fasting ketogenic diet and cancer treatment together. That I think is very promising, particularly if you do it in the sense of... And we had patients that with very aggressive phenotypes that are... are doing this. So they do the periodic fasting making diet, then in between the ketogenic diet, and then they keep doing the radiotherapy, particularly like gliomas, radiotherapies and chemotherapy. And it seems to be working are certainly very promising. Wow. Is this an ongoing trial you were talking about? Or is it just...

We haven't started, I mean, we have trials on cancer, a number of trials on cancer. We don't have one on glioma yet, but I know that some groups in a result. they are, but they mostly have just done it with the ketogenic diet. But, you know, because it's so aggressive, and most people, you cannot tell a glioma patient or wait until the clinical trial is ready, right, because it's a very quick moving cancer. So in some cases, we just say, look, go to your oncologist and ask them if they're okay, letting you follow a fasting plus ketogenic diet plus 10. standard of care. So they're just adding ketogenic diet and fasting to the standard of care.

Yeah, okay. And that's, um, uh, so the, for the periodic fasting, is that also including the fasting mimicking diet, which they can talk to? Yeah. So, so the, yeah, the fasting making, I mean, not water only fasting, but we, FMD, ketogenic diet and standard of care. And, um, yeah, so. So I do remember that at least with, um, there's been a couple of studies that you were involved on with water fasting, you showed in, in a combination, with standard of care treatment, it seemed to be safe and also to some degree seem to sensitize some of the cancer cells to deaths and also maybe even protect some of the normal cells and some of these blood cells.

They weren't getting nutropenia or the myelotoxicity quite as significant as people that didn't do the fast. Do you have any... Now, I know you've published studies on the fasting-mimicking diet in animals and cancer in combination with standard of care. Is there any clinical trials that you're planning on doing with fasting mimicking diet and humans? Yeah. No, we're doing it, right?

So they're going a little bit slower than predicted, in part because we didn't see coming the food diversion. So patients, when you give them any food with something that is toxic, then develop a food diversion. So anything that you give them with the toxicity is now recognized as toxic also. And so now we're having to develop a number of new foods specifically to avoid the repetition. You cannot repeat anything twice, essentially. So if somebody has eight cycles of chemotherapy, we may have to give them eight different things, all respecting the formulation requirement. So, yeah, that surprises a little bit.

So we already, a couple hundred patients have already been involved in these multiple randomized clinical trials. And the good news is that there is no problems. We have seen any problems with the fasting in making diet and cancer treatment, but it's been slower than expected because of these, you know, A, because, of course, you cannot promise, you cannot go to a patient and say, oh, this is going to make you feel better. And if you give them a pill, it's much easier because there's no effort on the part of the patient.

With the fasting making diet, you know, if you knew it was going to be much better for you and somebody told you, I don't think it would be a problem because we see it with the, you know, a healthy subject. But if you don't know, you have cancer and then you have this food aversion altogether and makes it very tough for people. So we had about 40% thus for compliance. And so now we need to tweak it so we get to maybe 70%. Yeah, that sounds like a challenge.

But if there are oncologists right now that are interested in using the fasting, mimicking diet in combination with their standard of care treatment, that is something that they can do, correct? Well, yeah, the way we've been. putting it is that they can, if the patient cannot wait for the end of the clinical trials, and the oncologist agrees, you know, for whatever reason that they cannot wait, then they can certainly do it with the standard of care. So they do the standard of care and then the fasting making diet along with that.

Now, the FDA prohibits any product or any claim related to disease prevention or treatment for something that has not been FDA approved. So then, you know, I think an oncologist should be very careful in presenting it to the patient, so it has to be presented as something experimental that could be good for them or could be bad for them. And yeah, so that's a, of course, in mice, we have incredible results. We in many labs now have repeated this. So it works very, very well.

And so, you know, if somebody cannot wait, I think, then it's fair to go to oncologists and say, obviously, I'm running out of options. Shall we consider this one? Yeah. What does it take for how many, like, clinical trials, does it take for FDA to approve something? Is it? No, the FDA is a specific process.

So you have to enter, you have to file, it's an IND application, and it's a very expensive, a long process. It's not just trial. I got it. So it's, you know, it's three phases, phase one, two, three. And in the end, you probably have between 500 and 1,000 people, a thousand patients. and then they make a decision based on the data, whether it's approved or not.

The whole process usually cost about $50 million. Wow. So, you know, this is what makes it complicated, right? Because, yeah, it's not easy to justify this kind of investment on a diet. Yeah. So you do have evidence, and this is a recent publication, of yours that the fasting-emaking diet in healthy subjects can, it seems, affect biomarkers that are related to aging in a positive way.

Yes, aging and as well biomarkers for aging as well as risk factors for diseases, right? So this was a clinical trial, a randomized clinical trial with three cycles of the fasting, mimicking diet once a month for five days. for three months in a row. And then, of course, we looked at baseline, and there was a randomized crossover. So in each case, you'll have a group of controls, a group on a controlled diet,

and a group on the fasting making diet, and then the crossover. And, yeah, the results are remarkable. I mean, first of all, if you are a healthy person with, say, a healthy or a low blood pressure, nothing happens to you. And this is a really nice distinction with color restriction, for example.

earlier we were talking about, you know, are they all going to the same place? I don't think so. So, calorestition chronic, it keeps driving your markers down, right? So even if you started, I mean, if you look at biosphere two, and these were then confirmed by Fontana and others, if you look at biosphere two, even people that had at the beginning a low blood pressure, they kept dropping, and by the end of it, they had pressure like 85 over 55, right? And same thing for cholesterol, same thing for triglycerides, almost everything. It's really dropped to very low levels, fasting glucose.

The fasting amygine diet instead, it seems to, you know, if you have a blood glucose of 75, nothing changes. It doesn't drop it even more. If you had a fasting glucose of 106, almost in every case, it brings you back to normal. This is very interesting, right, and also very good for doctors. So now we have close to 3,000 doctors just in the US that are recommending the pro-lone fasting-making diet what was tested in the clinical trial. And this is a very important feature.

So the three cycles decreased in normal people, in people that had, I mean, I shouldn't say did nothing, did nothing that you can see in terms of markers because they already had good levels of these markers. But in people that had elevated cholesterol, it decreased cholesterol, the people that had elevated triglyceride, it decreased triglyceride, people that had elevated IGF1, probably people eating on a high protein diet, it dropped IGF1. And the highest people dropped dramatically, you know, came down about 60 points. And people that had high fasting glucose came down. People that had blood pressure that was elevated. Both systolic and diastolic had major effects.

people that has CRP, systemic inflammation, in almost every case, they move back to the normal range. So it's really powerful, I think, in resetting the system somehow that it's getting out of its functional ideal state. It resets it, and I think it really rejuvenates. now we're doing, we're trying to calculate based on, you know, publish profiles and also methylation profiles, is this rejuvenating you? And also A and B, after three cycles, what is your risk for diseases in the next 10 years

at baseline? And what is your risk after three cycles? And we suspect there's going to be a drastic change. Just, you know, if you think about it's three months, right? Right. It's just, uh, and this was a five-day fast each one week. Five days of, three cycles of a five-day fasting we're making diet. And then we measure it again.

And of course, all these things that I just say change, but what, you know, what if we go to, uh, to the databases and we plug in the numbers and we say, tell me, you tell me, what, I, what is the risk now compared? to be four, right? So we haven't finished that yet, but I think soon enough, I'll just say that it's very, the results look very promising. Great. I have a couple of questions.

So first, the, you measured these, these biomarkers at Baseline and then after the three cycles. Do you think if you were to have measured, you measured immediately after the third cycle? One week. One week, okay. So do you think... In three months. And we also measured again three months.

Oh, you did. And how were they? That was my question. So what were they like three months later? or do you have to keep doing it every? Yes. I mean, there were about 60% of the effects were still there. So you could tell that it was smaller,

about 60% of the changes were still significant. So, yeah, so this is why we say that, you know, on average people probably need to do it once every four months. And it's also important to point out that, you know, until millions of people do it, it should be on a need to do it basis, right? So, if you are an athlete, you have a great diet, you know, low protein, pescatarian, and you do all the right things, you exercise, et cetera. You probably only need to do it once or twice a year.

There's not very many people in the category, maybe like 5% of the population. And then as you move to a problem state, of course, then, you know, the minimal risk that is associated with doing a fasting and making diet, is a good risk to take because of course any drug that you take, any intervention that you do is going to have risks. And so now I think people, there's over 25,000 people that have done the fasting-making diet, the pro-long, the same diet that was tested clinically. We've had very few severe side-effect reports, right?

And even the ones that have severe side-effects, and even the ones that have severe side-effects effects, you know, they fully recovered and there was no evidence that it was the diet that they caused them, right? So it's very good news, right? And when you get to, this is what in the FDA terms will be considered a phase four. When you say, well, let's keep monitoring this once it's out in the market and see, you know, are there people that eventually show side effects that we didn't see in the FDA trials, right?

Of course, we didn't do FDA trials, but so we have done phase one, phase two, and I mean, skipped phase three, and now we're in phase four. Yeah, wow, that's really great. 25,000 people, that's a lot. So you were mentioning the frequency changes, changes, the frequency of doing this fasting mimicking diet may change according to someone's health status and how, what their lifestyle is, so someone that's obese or has high cholesterol, high triglycerides, high fasting blood glucose, all these markers that you mentioned, may want to do it more frequently.

Well, much more frequently, yeah. So somebody that has those problems, say obese and multiple markers for disease, a risk factor for disease, then once a month. And that's what the doctors have been doing. So they put them on once a month and then, you know, monitor the changes. If it works, then you can keep it going. It doesn't mean they're going to do it once a month for their entire life. the hope is that you slowly and in a and that's also very important this idea especially with obese

people we'll see how it works but um this idea that you can go back to your diet after five days right this is very mentally to people it's very important and say well I struggle for five days but then leave me alone for the next 25 um that that I think is both potentially at the mechanistic level but also the psychological level it could be a good way to go so I'll just see tell you, I have a friend of mine who was morbidly overweight. I mean, he was morbidly obese. He was, I think, at his highest weight was about 400 pounds and had tried all sorts of types of diets, you know, and never could really get anything to work and the compliance was low. But then he started doing these prolonged water fast. Now, he was doing, you know, five, seven days and he was doing

it frequently, like once a month. And he's lost 200 pounds. And I think for him, and he does exactly what you said. He likes food. He likes food and he likes to eat, you know, certain foods. That's amazing. But he's found something that works for him where he can, he just, you know, once a month, he does a five-day fast and then he goes back and he eats his- I want to talk to this guy. Yeah, I would absolutely like to put you in touch with him. He's actually applying to medical school now, but he's a very smart guy. He's a lawyer. And now he's going back to medical school because he's become very interested in obesity and all this, you know, stuff. So.

Yeah, so we're running now a trial. in Holland on diabetes patients, many of which are going to be obese. And yeah, so that's our hope that, A, you know, people always ask, you know, there's famous papers that have shown what they call the yo-yo diets, right? They've shown that this can actually lower your metabolism. If you have this prolonged starvation period, it can lower your metabolism and then you tend to gain weight. but in mice and in humans, we're seeing really the opposite,

doing it this way. So if you take somebody and you put them, like, say, two months and a very low calorie diet and you make them exercise, that seems to be a problem. Why? Because, of course, they can keep doing that. And then when you eventually go back to a normal diet, their metabolism is now slow.

But doing it like this for these five days, particularly in the fasting-making diet, seem to be not doing that. So the body doesn't quite ever switch to a slower metabolism. metabolism because it's so short. So I think we'll see, but I think it may very well represent a very good way to psychologically and also physiologically get the people to help them, you know, have a long-term plan to lose weight.

For me, I would almost think that it would have the opposite effect that these yo-yo diets that people are claiming lower your metabolism. I would think because you're your, you're... spending five days and more of a fasting-mimicking state, that you're becoming more metabolically flexible because you're switching to being able to oxidize fatty acids, you know, and then so you're being able to kind of switch between carbohydrate, you know, using glucose as a main source of energy and using fatty acids. Yeah, not only a switch, but what we suspect is happening.

In mice, we show that per month, if you take mice and you put on a fasting-making diet, they, of course, have less calorie during the four days in the case of mice. But then their metabolism seems to be speed up to the point that per month they eat the same calories. So they overeat everything they under ate during the four days, right? So they eat exactly the same, but they lose a lot of weight, right? So we suspect that what's happening is that fat-burning mold keeps ongoing. It keeps going.

So they never quite, I mean, they probably, you know, get back to a relatively normal metabolism, but not quite the same. So they keep burning, they keep burning fat a little bit to the point. I mean, we're investigating this now at the molecular level, but that's where we suspect that, you know. And of course, people, we saw the abdominal fat loss and we saw the weight loss. And so we suspect that the same is happening. Another interesting thing, which makes a lot of sense. We didn't think about it too much at the beginning, but the muscle is, so almost every diet, including color restriction, you lose fat, water, and muscle, right?

And almost every diet is the same way. And in this case, it's very interesting because you now temporarily lose muscle, and, of course, you lose abdominal fat, because after a few days, this becomes your reservoir. I mean, all the, all the, it doesn't touch subcutaneous fat for some reason. It only goes to the main depot, the visceral fat. So that's great news. But the muscle is also decreased. But then when you feed, the muscle is rebuilt.

I mean, we have evidence for regeneration in mice. We don't know yet in humans. But certainly, the people go back to the normal muscle mass. So now you have a specific effect on visceral fat, no effect on my, on subcutaneous fat and no or very little effect and even absolute lean body mass. In fact, the relative lean body mass goes up. That's, yeah, because in your study,

the lean body mass. Relative goes up. Absolute, either in one arm wasn't affected, in one arm was just slightly decreased. So good news because that's probably one of the very few methods to maintain normal lean body mass while losing fat. And that's very important to a lot of people. I mean, you don't want to lose muscle mass.

Muscle mass is also very important for longevity. And that's actually a question I was going to ask you because I wasn't sure what the mechanism was, but the shrinking of the organs and then sort of in the refeating phase, the regrowing, is kind of something I wanted to talk to you about as well, this rejuvenation process. Because you've obviously shown this now in several different studies, both with fasting and fasting-may-beating diet in animals. where they lose, you know, a significant amount of their different organs, right? And I think that you, maybe you want to talk about this?

Yeah, so in mice, for example, if you look at the weight of most organs, and this, of course, was known for caloric restriction long term. But with fasting and fasting-making diet, this happens much more rapidly. So the organs will be smaller. And, you know, at the end of the days of fasting-mimicking diet, and then you feed it, and of course they go back to the normal level, right? So there is really this shrinking and re-expanding effect. Now, we don't know how much of it is cells becoming smaller versus cells being killed,

but clearly there is killing of cells. And something, of course, we are also very interested in is their preferential killing of the damaged cells. And we've started to show that in our multiple sclerosis mouse model. And also the human study, there was evidence that the white blood cell level temporarily was reduced during the, at the end of the fasting cycles and then, you know, went back to normal. So, yeah, so we suspect that there are this fasting-dependent depletion of both intracellular components, you know, autophagy and cellular components.

And then, you know, we shown the stem cell to be activated, and then the stem cell. during the refeating part. And that's another very important point is that differentiates it to most of other interventions, right? All of a sudden, even the intermittent fasting, because you don't have enough time if you do like even one day, it barely even gets you into the ketogenic mode, right?

And of course, if you didn't eat for one day, you wouldn't want to break down too many of the components that's probably having all the glycogen and having all the digestion. It takes 30 hours to complete the food digestion, right? And from the time you eat to the time all the calories have been taken up, it takes probably over a day. So, yeah, so that's a very important distinction between the prolonged fasting and everything else.

including car restriction, which does not have the refeeding moment, right? So if the rebuilding happens during refeeing and you never have it, then, of course, you're missing out the reconstruction part, which is as important as the destruction part. You brought up so many different interesting points that I kind of want to touch on. So first, the threshold between, like you're mentioning, the threshold between when you're actually getting rid of, of intracellular compartments through autophagy, clearing away protein aggregates, pieces of DNA

and things like that, but also damaged mitochondria, but also the clearing away of complete cells and particularly damaged cells, which is very interesting to me because, as you mentioned, you've shown this now, and there's two different animal models for autoimmune disease. One was multiple scrosis, and the other was the, I think, type 1 diabetes. Yeah, ours was an auto, that one particularly was not autoimmune. We're doing the autoimmune, with type 1 induced by pharmacologically induced. Ah, okay. So it has potential for...

Yeah, but I can tell you, we've now confirmed all the autoimmune diseases. So I think it's going to be applicable to many autoimmune diseases. That's... So this is what's so cool because, I mean, the, you know, the potential for this type of, you know, fasting to cause cells that are preferentially damaged to be cleared away by apoptosis, which makes sense. I mean, I spent six years studying apoptosis. I know a lot about it, and, you know, cells that are damaged preferentially die.

I can tell you from doing multiple experiments. Even during development, right? Yeah, during development as well. That's the way that the good and the bad are... Right. It's also how cancer cells are primed to die as well, because cancer cells are damaged. They are mutated and completely damaged, and that may be also why they're very sensitive to stress. Yeah, and also, I mean, something that is...

it's a speculation, but we're starting to think more and more, at least I'm starting to think more and more, is that, you know, I always say if you cut yourself, it doesn't matter where you cut yourself, or if you hurt your head, the system repairs it, right? Or repairs almost anything. And so, you know, what about the inside?

You know, is it possible that we never develop a way to fix damage organs and various systems? So we're starting to think that maybe fasting represented that opportunity to fix the inside, right? And maybe, and just maybe, because everybody had to do it by force, they were forced to do it because there was no food at some point of your month, almost unavoidably, you probably were with no food. And so because it was almost unavoidable, it was probably something. that, you know, I always also think about sleep, right? And in sleep, you feel so tired that you have to sleep. Because obviously people would have gone to sleep just on their own, right?

But in the case of fasting, because it was imposed by the environment, I suspect that maybe we never develop something that forces you to fast. And so now that we eat all the time, we just completely lost this auto repair mode, right? And this could be remarkable because imagine if we had this ability, if you have damaged liver, that fixes it, if you have damaged immune cells that are autoimmune, that clears it. And so you never develop a defense against autoimmunity because fasting always took care of it. Now, all of a sudden, you get rid of fasting and all these things start building up,

whether it's insulin resistance or liver damage. fatty liver, et cetera, et cetera, right? So this could be really, and people always are surprised when we say, you know, we're publishing all these different diseases. But if that's true, then it makes sense, right? Right. Because, for example, in multiple sclerosis, you see on one side, it kills the immune cells, it then it turns on the stem cells, then turns on the oligodendrocytes,

progenitor, and replace. I mean, it's very, it's like, how does it know how to do all of this? And it does it all in such a sophisticated manner. But if it was an evolved process, that would make a lot of sense. The thing that's so interesting is how the stem cells, you know, the clearing away of these damaged cells through apoptosis, activating these stem cells, which then have to repopulate whatever organ or tissue we're talking about, how they actually can make normal like cell. You're talking about, in the case at least for autoimmunity, you know, or type 1 diabetes or multiple sclerosis,

how they make their immune cells normal. You know, that is so... Yeah, but that makes sense, right? Because if you turn out a stem cell, you imagine now that you're not going to turn on a damaged stem cell. There's got to be a selection process to pick... True. So the stem cell is now, of course, going to give rise to normal blood cells, right?

They wouldn't have any way to make an autoimmune cell. So, I mean, Yeah, so because that happens, I think, in the differentiated cell at the colonel. So you expand already the differentiated cell. So even, I think, theoretically, that makes perfect sense that once you turn on the stem cell, the endopiative stem cell, you will make a healthy, now you can always turn that healthy cells into immune cell. But at least initially, you will make a healthy one.

And that's exactly what we see happening. So the refeating phase is really important for, I, our, recall in our last discussion, you mentioned the refeating phase was really important for the stem cell proliferation. So after you activate them, you want them to proliferate and continue to grow. And you had mentioned, if I remember correctly, that IGF1 played a major role in that proliferation because it is, after all, a growth signal, you know. Yeah. So there is no doubt. We haven't spent too much time on it, but it's pretty obvious and that, you know, you'll need growth factors to do that.

So this also makes us think about, for example, the clinical trial, the multiple clinical trials that were done on IGF1 in cancer that failed, right? And we thought, well, maybe they failed because the IGF1 was also needed, for example, for the immune system to be built or rebuilt in those trials, right? So, yeah, so then the generation. of healthy cells is as important as the low IGF1. So the generation of healthy cells that is IGF1 dependent. It's probably as important as the killing of damaged cells that is low IGF1 dependent.

And the turning on of stem cells, which is also low IGF1 dependent. Oh, it's low, I thought it was higher. The turning on the stem cell, not turning on, the proliferation of them is high, high IDF1. Yeah, no, but the turning in the turning. And the initial one is law. So law now is the signal to self-renew, you know. So now you have a population of, a small population of stem cells that are just active and standing by. Then probably when IGF1 goes back up, now they are the ones that are pushed by IGF1 to proliferate and to differentiate, probably also to differentiate, proliferate and differentiate.

Because now you want to rapidly make a lot of, you know, whiteblast cells, for example. or whatever it is, yeah. So that's my question to you then is for the refeating phase. Then you may, is that, do you think then, for example, having some protein would be a little more important because you want protein being essential amino acids, because you want a little more IGF1 activated during that specific time window? Is that something that you... Yeah, there is no doubt that when you feed, you have to have sufficient protein to rebuild.

And if you don't, I mean, you really don't. I mean, you really don't have the bricks to rebuild whatever system you partially broke down. So, yeah, protein and also protein are going to drive the IGF1. So the whole system, of course, is set up to the sugar and the protein is set up to give the signals to rebuild, which is probably through IGF1, insulin and IGF1. Excellent. So just since we're running close to out of time here, what are your top five biomarkers that you think are indicative of something that people can, that are indicative of healthy aging

that people can maybe go to their clinic and measure? Yeah, so if you, I went to the clinic. I mean, if you're talking to the masses, And you're talking about health or you're talking about pure longevity? Well, I mean, I'm talking about, you know, maybe both. I don't know if there are there longevity markers that people can do now that are clinically available? Yeah, I think there are things that you can measure that may predict your biological. Okay, so let's do longevity.

Let's see what, yeah, biological age, let's say. Yeah, yeah. Yeah, biological age, I would certainly, you know, this is what our markers, you know, certainly IGF1, insulin, glucose, inflammation, systemic inflammation. So CRP, and most doctors can measure that. You could also, if you wanted to add, I mean, triglyceride. And then you could add things such as, for example, you know, fatty liver. These are more pathological or pathology oriented, but certainly they can be major determinants

or certainly can influence cellular functions like insulin resistance. And so those are some of the things that I want to see in the idea of range. Of course, blood pressure is another one. And then Morgan Levine, she's now at Yale. she has a she and others have a set of

markers that are taken from large population and they seem to be predictive of biological age and I don't know some of the ones that are overlapping with the ones I say it but there are other ones that are not that I didn't list so

people can look up her papers and also So, of course, the methylation profile that seems to be predictive of, I mean, nobody does it now, I think, to the public. Is Steve Forbeth's work? Are you talking about? Yes, yeah. But I'm assuming that soon enough it is going to be available.

Is it? Oh, cool. Please let me know when it is, because I'm very interested. I saw there are commercials now about telomere measurement at home, right? So yeah. Yeah. Yeah. that soon enough people are, at least the doctor will have the ability to assess methylation patterns.

Yeah, cool. So you have a new book out called The Longevity Diet, which is the Longevity Diet? Yeah, the longevity diet, and it's divided into two sections. The first health is all about everyday diet. And in this everyday diet, I talk about five pillars of longevity. I basically say, you know, let's base the decision on diet, on epidemiological studies, centenarian studies, basic research focus on longevity, clinical studies and studies of complex systems, and complex systems being cars and planes.

And I always thought that it's a very good way to remove, I mean, together with the other four pillars, to remove all the uncertainties and say, well, I'll do. do systems that we build age, to just get a fundamental understanding of, you know, how the environment and how the environment affects the complex systems. And, yeah, so the first half is that. And the centenarium groups, the ones that are, have record longevity from around the world were really important. You know, for example, I always say to people,

the ketogenic diet. Well, let's look at groups that have record longevity. They use the ketogenic diet. None of them, right? So that's very important to say for the safety component. Once you make a decision about what the science tells you, it's always good to look around the world and say, how commonly use is this diet.

And if the answer is it's not used at all, you're really taking a chance on this diet. And the other half of the book is about the fasting-making diet and normal people, some of the things we discussed. And then, you know, a chapter on diabetes, type 1 and type 2. There is a chapter on autoimmunities. There is a chapter on Alzheimer's and neurodegeneration and a chapter on cancer on cancer. Yeah, so it goes through all the major, and a chapter on cardiovascular disease. all the major diseases and tries to, you know, mostly based on data out there and combine

it with what we learn to try to provide people with complementary intervention. So for example, if you look at diabetes, it basically says, well, here's what you could do every day, but then you can introduce the periodic fasting making diet. Of course, you're going to need your endocrinologist to make the decision. whether this is a clinical trial type of intervention or they can actually do it. Diabetes is very tricky, so it probably be best to keep it within a clinical trial. But, you know, some endocrinologists may be experienced enough to follow their own patients and allow them to do it.

Yeah, it's very cool. I think that's the fasting-imicking diet being used as a metabolic treatment for various diseases that you just mentioned, obviously many of them need to be under the care of a physician is a very promising field because, you know, as we're learning now, metabolism plays a major role in, you know, not only, you know, causing these diseases, but also in the treatment and how, you know, some of them respond to treatment. Yeah, and again, it's not just metabolism. Really, we're looking at the ability in evolved, self-free.

prepare mode, right? So, I mean, almost every disease, let's say that you have high cholesterol. What do we do? We block cholesterol synthesis, right? But is that sophisticated? Not very sophisticated, right? And all, you know, say the great majority of the drugs are like that. You know, if you have an autoimmune disorder, you have something that blocks a cytokine or,

you know, a receptor, very unsophisticated, right? So if there is, and I'm not sure. that there is, but it looks like there is. If there is a self-repair mode that goes after almost every damage system, this is much more than metabolic intervention. This really deals with three billion years of learning how to fix a liver. I mean, of course, starting with bacteria, but the process of autophagy started back then in bacteria. Now you're using it to, let's say, a muscle cell that is insulin resistant. Now you might push it to undergoes. autophagy, mitophagy, et cetera, et cetera, and now you just maybe that resistant cell is no longer

resistant, right? So that's the power of this, I think, much more than the metabolic, you know, pushing the cell into a different metabolic state. I think it's pushing it into a different metabolic state while it's doing this reset. Right, reset. That's a great way of explaining it. The reset's probably what I'm most excited about, is that they're clearing away. the damage cells and then rejuvenating or fixing, you know, fixing things.

But I do quickly want to just mention, because I do recall now one of your studies that you, at least in the clinical studies with a fasting mammaking diet, I think you were trying to look whether or not there was some stem cell activation and there was sort of a trend. You had seen mesenchymal stem cells, a trend, you know, increase in them. But are you looking, is that something now you're moving forward with in other clinical studies to look at. Yeah. Now, yeah, we're looking at that.

I mean, of course, we never took biopsis. I always feel bad about taking people's biopsis because it's very painful, usually to take the skin. So we had blood, and it's not so easy to measure circulating stem cells. I mean, now techniques are getting better. Right. And so I think, awfully now we can have a better look at the circulating one. But, yeah, we're definitely going to look at, I think in the trial that we're now doing

athletes, we're doing a trial with athletes. in the University of Verona and Italy, I think as part of that we have biopsis, muscle biopsy. And so that we should give us a better idea about at least some tissue associated stem cells, satellite cells, for example. I'm so excited and I'll definitely be following your research. Thank you so much, Walter, for the discussion and you're talking about your book, The Longevity diet. I look forward to talking to you some more.

Yeah, yeah, thank you for all the very good questions. that's a wrap thank you so much for taking some of the time out of your day to listen to what we discuss and similarly a huge thanks to dr valger longo for his participation in this conversation and even more so for the profound work he's produced that has arguably shifted the entire landscape of the field of aging today we talked quite a bit about a few genes that are relevant to aging and longevity the IGF1 receptor and the growth hormone receptor are some in ultimately many genes that can have some influence on longevity there are also polymorphisms in Fox O3, Sur T1, T53, AKT1, IL6, and many more. And if you've used any of the popular

consumer genetic testing services like 23 and me, you can find out a little bit more about them. The good news is, is that while at least part of aging is genetic, a whole lot of it, as you may learn in this interview, is environmentally influenceable. That doesn't make the genetics part any less interesting, however. To learn more about that, head over to foundmyfitness.com forward slash genetics. That's found my fitness.com forward slash genetics, G-E-N-E-T-I-C-S. You'll find these polymorphisms in a report called the longevity report found at the bottom of the page. So make sure to check that out. Hey you, yeah, you. You know who you are. That crazy deep biology person probably rocking the earbuds and enjoying that sweet, sweet podcast pros, wanting to know everything there is to know about

the growth hormone IGF-1 access and its downstream growth-siggling pals. You're the reason we put these episodes together. This podcast exists because people like you exist. You rel-red, unique snowflake you, because to everyone else, none of this matters. Therefore, if this stuff really hits the spot for you, you should absolutely consider becoming a monthly supporter of the show. To learn how you can help me keep it going through a pay what you can pledge or the equivalent to a monthly coffee date, head over to found myfitness.com forward slash crowd sponsor. That's found my fitness.com forward slash C-R-O-W-D-S-P-O-N-S-O-R, crowd sponsor. Finally, this podcast is not meant to be medical advice, but instead a scientific discussion.

Please keep that in mind and follow good common sense and consult with the physician where relevant, especially for the management of any kind of honest-to-god medical condition. Thank you so much for listening, and I'll catch you next time.