Dr. Valter Longo on Resetting Autoimmunity and Rejuvenating Systems with Prolonged Fasting & the FMD
Posted on July 9th 2018 (5 months)
This episode is a round 2 podcast. Click here to see the first episode recorded with Dr. Valter Longo.
Valter Longo, PhD, is a biochemist and professor of gerontology and biological sciences at the University of Southern California (USC). He directs the USC Longevity Institute as well as the Oncology and Longevity Program at the Institute of Molecular Oncology Foundation in Milan, Italy. His research centers on understanding the fundamental genetic and biochemical mechanisms of aging in yeast, mice, and humans. Dr. Longo seeks to identify shared molecular pathways in simple organisms and humans that can be modulated to protect against multiple stresses and treat or prevent age-related diseases such as cancer, Alzheimer’s disease, and others.
A path to longevity or at least reducing age-related disease."We knew from mice, from the work of John Kopchick and Andrzej Bartke, that mice that have either growth hormone receptor deficiency or growth hormone deficiency live about 40% longer. They also live much healthier." - Dr. Valter Longo Click To Tweet
Caloric restriction has long been the focus of promising aging research and research into the amelioration of age-related diseases. Early findings illuminated the role of calorie restriction in modulating adaptive cytoprotective mechanisms that enhance metabolic response and reduce oxidative damage and inflammation – factors related to increased longevity and decreased risk of age-related disease.
Research in animals has shown impressive results with studies in mice and rats showing chronic caloric restriction able to extend lifespan by up to 40%, showing the ability in some animal studies to virtually eliminate type 2 diabetes, and dramatically reduce cancer incidence. Similarly, increases in disease-free lifespan have also shown some promise in primate studies of caloric restriction as well.
Chronic caloric restriction, perhaps unsurprisingly, is not wholly without undesirable qualities such as slowed wound healing and altered immune function that can lead to increased susceptibility to infection according to some animal research. Not to mention being notoriously hard to practice with long-term human caloric restricters inadequately restricting protein and ultimately failing at reproducing some of the cellular signaling changes that seem to be important: namely, reductions in an important growth factor known as IGF-1.
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-only fasting. What sets this approach apart from that of chronic caloric restriction is that, rather than undergoing constant restriction, we can approach it as something that can be cycled periodically to achieve a persistence of effects, which the Longo lab's research indicates can last for at least several months after a 4 or 5-day cycle. These effects include the driving down of many biomarkers related to aging, including blood pressure, metabolic indices, and inflammatory markers.
Cycles of renewal that our environment has forgotten but our genes remember."These [renewal] programs, which may have been frequently activated under the normal conditions in which famine periods were commonly encountered, may remain dormant in individuals constantly exposed to food intake." - Dr. Valter Longo Click To Tweet
In this episode, Dr. Longo explains the origins of his fasting-mimicking diet and one of the most important things that differentiate it from the concept of caloric restriction: the refeed. His research has shown that mice on a version of his fasting-mimicking diet exhibit a shrinking of entire organs, such as the liver and kidneys, but this effect reverses without obvious pathological effects after the end of the cycle of fasting.
This characteristic cycle of targeted destruction and renewal that accompanies periodic fasting through the fasting-mimicking diet or FMD holds the greatest promise for diseases of autoimmunity, particularly multiple sclerosis. Dr. Longo’s work has shown that, in an animal model of multiple sclerosis called experimental autoimmune encephalomyelitis, the fasting-mimicking diet temporarily reduces the total white blood cells - lymphocytes, monocytes, and granulocytes -- by 40% to 50%. This shrinking of pathological markers activates stem cells, leading to the proliferation of oligodendrocyte precursors (myelin producing cells) and, ultimately, remyelination. Upon refeed, immune cells return naïve or at lower levels than controls -- in other words, with reduced autoimmunity.
It is the sophisticated nature of this process of breakdown and rapid rebuilding that suggests it might be a way 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. Our genes, however, shaped by the feasts and famine of the past, remember.
Exploiting the inability of cancer cells to adapt to extreme environments."We started testing in cancer patients but realized that they didn't want to fast. They gave us an opportunity and the motivation to look for a fasting-mimicking diet; a diet that works as well as fasting, but allows patients to eat." - Dr. Valter Longo Click To Tweet
Periodic fasting holds great promise as a complementary therapy for cancer because when coupled with chemotherapy, fasting induces differential stress resistance – a phenomenon in which healthy cells experience increased protection from stress, while cancer cells are simultaneously made more sensitive to it.
This quality of fasting may be particularly useful when used in conjunction with treatments that can have toxic side effects, helping to ameliorate side effects while potentially also enhancing the therapeutic impact.
This reduction in flexibility of cancer cells may be a consequence of accumulating mutations in growth signaling pathways (IGF-1 receptor and downstream proteins Ras and Akt are very common) which may cause a reduced ability for the cancer cells to switch to a "fasting-induced protected mode."
In this episode, we also discuss...
- 00:01:00 - The problems with using non-specific terms like “intermittent fasting” and a general exploration of what each of the terms that describe types of dietary restriction means, whether we’re talking about intermittent fasting, caloric restriction, time-restricted eating or periodic prolonged fasting. The latter of which is a special focus of Dr. Longo.
- 00:04:11 - What two seminal studies on chronic caloric restriction in primates from the 80s teach us about caloric restriction as a preventer of age-related disease, and how the effects of caloric restriction may actually be stronger when the diet that is being restricted is an unhealthy one – similar, in some ways, to the typical western diet.
- 00:07:34 - 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. Of particular importance is the protein or essential amino acid consumption.
- 00:08:06 - How the suppression of the IGF-1 pathway, typically a hallmark of prolonged fasting and caloric restriction studies and potentially needed for some of the benefits, may fail to be achieved in human caloric restricters that eat too much protein.
- 00:09:34 - How certain macronutrients influence the insulin/IGF-1/growth hormone axis interact to modulate aging in many cell types.
- 00:10:43 - How mice and humans who have growth hormone receptor deficiencies have low circulating IGF-1 – as little as 10% of normal levels – and have reduced risk of diseases like cancer, diabetes, and age-related cognitive decline, hinting at what future research might reveal about the beneficial effects of prolonged fasting and fasting-mimicking diets through the downstream effects of periodic deprival of growth-related factors.
- 00:11:05 - How the growth hormone / IGF-1 axis got a big boost early on in scientific interest when it was revealed that mice that have either deficiency in growth hormone itself or the growth hormone receptor live up to 40% longer and how this is accomplished through what is essentially a delaying of the decrepitudes of old age.
- 00:13:42 - The clever experiment design where human epithelial cells were incubated either in serum taken from controls or the serum taken from growth hormone receptor-deficient Laron’s patients showed that the reduction in growth factors ultimately lead to the cells manifesting qualities of cancer resistance, like fewer DNA breaks but an increase in cell death, which is also an important protection against cancer known as apoptosis.
- 00:15:02 - The origins of what Dr. Longo calls the fasting-mimicking diet – a 5-day diet focused on recapitulating some of the benefits of prolonged fasting, like dramatic changes in metabolic biomarkers, but without some of the drawbacks like reduced compliance and other risks that can come with multiple days of grueling strict water fasting in large, heterogeneous populations.
- 00:15:42 - How periodic prolonged fasting or the fasting-mimicking diet may be able to render cancer cells more vulnerable while conferring stress resistance to healthy cells, a quality known as differential stress resistance. This can happen because of the way fasting interferes with what is known as oncogenic signaling. Also refer to 00:25:22.
- 00:21:41 - The mixed results associated with the use of the ketogenic diet in treatment of cancer and how some cancers seem to be hurt by the metabolic switch of utilizing ketone bodies, which creates oxidative stress from the use of mitochondria, while other cancers seem to be able to use ketones effectively as an energy source, potentially accelerating their growth.
- 00:22:54 - Some of the early but promising pre-trial clinical anecdata suggesting potential complementary roles for the ketogenic diet and the fasting-mimicking diet (FMD) used in conjunction with conventional treatments like chemotherapy or radiotherapy for certain cancers like gliomas.
- 00:28:05 - How oncologists might approach incorporating the fasting-mimicking diet, which is still seeking further clinical validation and approval, into their patients’ care (if they choose to).
- 00:30:44 - 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 health.
- 00:31:45 - How, in contrast to chronic caloric restriction, the fasting-mimicking diet seems to normalize biomarkers like blood pressure and fasting glucose rather than continuing to drive them down into ranges lower than might be considered healthy.
- 00:34:09 - The prospect of using emerging ways of measuring aging objectively, such as through DNA methylation profiles, to tell whether or not an intervention like fasting is having an effect on aging as a whole.
- 00:35:14 - How long the metabolic effects of the fasting-mimicking diet tend to stick around and how often Dr. Longo thinks the fasting-mimicking diet should be done for most people and what sort of factors influence that.
- 00:38:33 - The fasting-mimicking diet as a boon for the psychology of weight loss where, due to its cyclical nature, adherents can enjoy potential benefits like the reduction of harmful fat known as visceral fat while sparing subcutaneous fat and lean mass, without completely overhauling all other areas of their life the rest of the time.
- 00:40:09 - How the fasting-mimicking diet, due to the shortness of the interval, seems to avoid the deleterious and generally undesirable effect of slowing the metabolism down in the way so-called yo-yo diets seem to.
- 00:44:24 - How fasting, through the shrinking and then re-expansion of whole systems like the liver, kidneys, heart, and immune cells may represent a type of whole-system renewal that originated as a three billion-year-old self-repair mode that was only activated during periods of famine or inconsistent food availability, but might now be dormant in people living in a modern world of regular food intake.
- 00:45:39 - How Dr. Longo’s group has shown that, in animal models of multiple sclerosis and pharmacologically-induced type 1 diabetes, several cycles of the fasting-mimicking diet is able to reverse disease and restore healthful function. This mechanism also may generalize to erasing other diseases of autoimmunity through the destruction of autoimmune immune cells that are essentially reset through fresh differentiation from progenitors untainted by autoimmunity. A very exciting area of continued inquiry!
- 00:46:17 - How shorter fasts may fail to approach some of the effects of periodic fasting and the fasting-mimicking diet by failing to achieve adequate glycogen depletion and ketogenesis.
- 00:53:04 - How clinical trials demonstrated that the effects of IGF-1 are probably context dependent, exhibiting a sort of “Goldilocks principle,” in which too much IGF-1 promotes cancer, but too little (as in the case of chronic, long-term caloric restriction) negatively affects the immune system. But the refeeding that follows fasting mimicking creates an environment that may be just right: it switches on IGF-1, promoting the regeneration of healthy cells, even restoring full organ systems.
- 00:55:05 - The importance of adequate protein during the refeeding phase following prolonged fasting or the fasting-mimicking to promote proper growth signaling to restore systems that have been broken down.
- 00:56:01 - 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.
- 00:59:05 - A sneak peek at what’s covered in Dr. Longo’s new book, The Longevity Diet.
- Roy Walford
- Richard Weindruch
- Luigi Fontana
- John Kopchick
- Andrzej Bartke
- Morgan Levine
- Steve Horvath
Learn more about Dr. Valter Longo
- The Longevity Diet (his book)
- ProLonFMD 5 Day Meal Program
- Facebook Fan Page
- University of Southern California Faculty Page
- Growth-stunting gene may spare people from dementia
- Diet that mimics fasting may also reduce multiple sclerosis symptoms
- Fasting triggers stem cell regeneration of damaged, old immune system
- Diet that mimics fasting appears to slow aging
- Fasting-like diet turns the immune system against cancer
- Fasting during chemotherapy may offset some side effects of cancer-fighting drugs
- Scientifically designed fasting diet lowers risks for major diseases
- Fasting-mimicking diet may reverse diabetes
- Fasting improves efficacy of radiation therapy
- Fasting and less-toxic cancer drug could be alternative to chemotherapy
- He wants to sell you a $300 ‘fasting diet’ to prolong your life. It might not be as crazy as it sounds
Rhonda: Hello everyone, I'm sitting here with Dr. Valter Longo, for a round two podcast. I'm pretty excited to be back, it's been a couple of years since our last discussion, Valter.
In my mind, you are one of the leading experts in this realm of how diet and lifestyle all 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 describe...define and sort of describe some of the common denominators between various modalities of limiting food intake like caloric restriction, intermittent fasting, prolonged fasting.
Valter: Right. Yes. So, I think that we're at the point where we have to start...we have to stop using terms like intermittent fasting, because it covers almost everything, right? I mean, at least in the journalist mind, when they talk about intermittent fasting, it covers from two hours food...not eating, to one month. And of course they're 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 five-two, so having two days a week of 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-restricted 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.
And then calorie restriction is that...of course you can say some people use calorie restriction to define everything that is calorie restricted, but the people in the field talk about calorie restriction, when they hear calorie restriction, they think of chronic reduction of calories below the normal level. So, below the level that 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 let's say at least 2 days of fasting or longer, or 2 days of a fasting-mimicking diet or longer.
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. So 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. And this is what we and others, 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 calorie-restricted 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 on health.
Rhonda: 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?
Rhonda: And neither of them increased lifespan, but they increased healthspan?
Valter: No, no, no. The Wisconsin increased lifespan. Richard Weindruch was also a student of Roy Walford. 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, that was...there was a huge effect. If you look at the overall survival due to where all causes of mortality were taken into consideration, then the survival curves are very close to each other.
Rhonda: Would that be considered maximum lifespan? This one [inaudible 00:05:39]
Valter: No, this will be mean lifespan, mean and maximum, right?
Valter: So, 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 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-controlled diet. So the NIA had somewhat of an ideal diet, at least ideal monkey diet, and the Wisconsin didn't. The Wisconsin was a reasonably good model for the western diet.
Rhonda: 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?
Valter: Yes, probably genetic...
Rhonda: Do you know if 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...were IGF-1 lowered or mTOR?
Valter: Yeah, now I haven't looked at those papers 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% less sugars. So, yes, I will assume that both of them showed effects on the nutrient-signaling pathways and including TOR and IGF-1.
Rhonda: And I guess so 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 to, when you're fasting, to beta-oxidation, to...because that's...is that something that occurs during caloric restriction?
Valter: 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 chronically, when you're chronically restricted, it also depends how you restrict it.
So for example there are human studies where they show that because the people that are restricted were eating high protein, a high vegetable protein diet, and the IGF-1 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 bodies and fatty acids are concerned.
Rhonda: 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 would, their IGF-1 levels were higher because the...
Valter: Were normal, yeah...
Rhonda: Yeah, they were. And they didn't go lower like they do in animal studies.
Valter: Right, until they restricted the proteins.
Rhonda: Until they restricted the proteins.
Valter: So they actually did a second study, Fontana and colleagues did the second study, the follow-up in which they restricted the proteins, and then the IGF-1 went down.
Rhonda: I 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 regulators of the IGF-1 pathway which maybe you can mention a little bit about the role of IGF-1 in the aging process.
Valter: Yeah. So, proteins, and particularly certain amino acids, methionine, cysteine, etc., they regulate IGF-1 levels, and IGF-1 in simple organisms, at least the orthologs of IGF-1, as well as in mammals seem to have an important role in aging. It is not clear how much is IGF-1 versus insulin versus growth hormone receptor-dependent signaling, which is independent of IGF-1 and insulin, but most likely it is the growth hormone receptor. Growth hormone and growth hormone receptor, they are the sort of master controllers, and IGF-1 seems to be one of the axis that regulates or accelerates aging in multiple cell types.
Rhonda: And from humans there are some, there's some evidence with polymorphisms and various like growth hormone...?
Valter: Yeah, that's actually our work with not polymorphism but mutations in the growth hormone receptor, something called E180 mutation. And the people...Well, we knew from mice, from the work of John Kopchick and Andrzej Bartke, that mice that have either a 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 made in the aging field, that you could live 40% longer, and yet about half of the mice get to the end of life without any obvious pathological lesions, so they don't develop diseases. And that the control of disease is less than 10%.
So, and these...
Rhonda: It's pretty significant.
Valter: I'm pointing these out...Well, it's a huge effect right there. I'm pointing these out because obviously people think that if we extend the 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 growth hormone receptor deficiency down in Ecuador, and they're called, there's a syndrome there, a syndrome called Laron's 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 homozygous growth hormone receptor deficiency, but they're protected from cancer, they're protected from diabetes, and a recent paper showed 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 concern the fact of having low growth hormone, of course and then low IGF-1, low insulin, and low TOR, and also I think low Ras, at least expression activities a little bit harder to figure out in people.
Rhonda: Have you measured the IGF-1 levels in these people with Laron's syndrome? You've measured their IGF-1 levels, is that something that's achievable from doing the caloric-protein restriction or the fasting, which we should probably start talking about?
Valter: Yeah, we measure the IGF-1, it's very low in these subjects.
Rhonda: Very low. Okay.
Valter: Yeah, it's like 10% of the normal IGF-1, circulating IGF-1 levels. So there's extremely low IGF-1, 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 the serum and we took human epithelial cells, and we expose the human epithelial cells either to control serum, or to the serum in the Laron's, and then we looked at the gene expression. And that showed that not only the TOR was down-regulated, so was Ras, at least gene expression-wise, and a number of other genes that are associated with accelerated aging.
Rhonda: 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 periodic fasting, water fasting, and also a fasting-mimicking diet which you can explain in a minute.
So I was kind of...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 correct, the...
Valter: Yes. So we...Well, first of all for a long time I had been thinking about how to get the benefits of calorie restriction without the problems of calorie 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 beneficial. So I was really...I wanted to look at the possibility that prolonged fasting will be beneficial.
And so...then also the point when we discovered that the proto-oncogenes, so the normal versions of the oncogenes that are so central in cancer, they are the genes that control cellular protection. And so from that came the idea that...and maybe we discussed that already in the first interview. But that came the idea that if you starve a system, the normal cells would become protected, and the cancer cells will remain sensitive, so then we started testing this in cancer patients, but realized that they didn't want to fast.
And then I think they 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 on Aging.
And so it's of course exploring all these understanding, all the understanding of the connection between let's say amino acids and TOR and IGF-1, sugars or certain sugars, and PKA actually we'd shown that, as we had shown for yeast, we now shown in mammalian cells that glucose levels activate PKA, 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 IGF-1, IGFBP-1, ketone bodies, and glucose that is equivalent to that of water-only fasting.
Rhonda: So you basically looked at all these known genetic pathways from your work and others that...so IGF-1, mTOR, PKA, Ras?
Valter: Yeah, Ras. Although Ras may or may not be conserved. The role of Ras, we didn't really see it in mammalian 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 PKA, and IGF-1 can feed into PKA. So we think that PKA is very central, maybe handling both the protein signaling and the sugar signaling.
Rhonda: 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 IGF-1, I guess both function and also level. So there were some studies that I...and I'm not sure if this was Fontana or who did these studies, but there are studies showing that limiting the glucose intake was important for bioavailability of IGF-1 through some of the insulin...IGF-1-binding proteins like IGF-1 binding protein 1, and also for regulating transcription of IGF-1. So, it's kind of...
Valter: 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, we...how are they connected? I don't know and I'm not sure that that is very well understood, but those are certainly connected and they're certainly linked, both linked to growth hormone signaling.
Rhonda: 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 IGF-1. So that there was like 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 go.
Valter: Right. And this will be consistent with our work in yeast. 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, PKA and TOR, and everything else and AMP kinase.
And so actually in yeast, the sugar seems to dominate, and the proteins seem to be second most important. So if you remove sugar and you increase the protein consistent to what we were just saying, that's not so, then it's not so bad. But if you have both the sugars and the protein, then you see much more the protein-dependent sensitization.
Rhonda: Yeah, it's extremely interesting. So, I'll look up the reference too in case you haven't seen it...
Valter: And of course in the case of yeast is individual amino acids, there's no protein.
Rhonda: So, we went out back on a tangent, but this is why these 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...
Valter: Ketone bodies and glucose.
Rhonda: And glucose, right.
Valter: IGF-1, IGFBP-1, glucose, and ketone bodies.
Rhonda: And these are all things that regulate cancer growth as well?
Valter: Yes, they can regulate cancer, they do regulate many cancers in different ways. I mean, ketone bodies, you know, some will argue that they hurt cancer cells, but some cancers actually love to use both ketone bodies and sugar.
Rhonda: Yeah, there was a recent publication I think.
Valter: So you can actually accelerate cancer growth with ketone bodies, but you can also hurt cancer cells with ketone bodies. This is why ketogenic diet, you know, I wouldn't get too confident about using ketogenic diet alone against cancer cells because of course even fasting, a lot of cancer cells can adapt to the changed environment. So...
Rhonda: Yeah, cancer is a very...it's so...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.
Valter: Yeah. And I think that there is a lot of, of course 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 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, fasting and immunotherapy for example.
So, 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, you know? That I think is very promising. Particularly if you do it in the sense of...And we have patients that, with very aggressive phenotypes that are doing this. So they do the periodic fasting-mimicking diet, then in between the ketogenic diet, and then they keep doing the radiotherapy, and particularly like gliomas, radiotherapies and chemotherapy. And this seems to be working, or certainly very promising what we're seeing.
Rhonda: Is this an ongoing trial you're talking about, or is it just...
Valter: 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 Arizona, they are...But then mostly they have just done it with a ketogenic diet. But because it's so aggressive, and most people...you cannot tell like glioma patient, 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 standard of care. So they're just adding ketogenic diet and fasting to the standard of care.
Rhonda: Yeah, okay. And that's, so the, for the periodic fasting, is that also including the fasting-mimicking diet which they can talk to…
Valter: Yeah. The fasting-mimicking diet, I mean, not water-only fasting, but FMD, ketogenic diet, and standard of care.
Rhonda: So I do remember that at least with...there's been a couple of studies that you were involved on with water fasting, you showed a combination with standard of care treatment, it seemed to be safe, and also to some degree you seemed to sensitize some of the cancer cells to death, and also maybe even protect some of the normal cells and some of these blood cells. They weren't getting neutropenia 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 on humans?
Valter: Yeah. No, we're doing it, right. So, we're going a little bit slower than predicted, in part because we didn't see coming the food aversion. So patients, when you give them any food with something that is toxic, they develop a food aversion. So, anything that you give them with a 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 for...So if somebody has eight cycles of chemotherapy, you know, we may have to give him eight different things, all respecting the formulation requirements. So, yeah, that surprised us little bit. But we already, couple hundred patients have already been involved in these multiple randomized clinical trials.
And then the good news is that there is no problems, we don't see any problems with the fasting-mimicking diet in 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 is no effort on the part of the patient.
With the fasting-mimicking diet, 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 a healthy subject. But if you don't know you have cancer, and then you have this food aversion, altogether, it makes it very tough for people.
So we had about a 40% thus far compliance, and so now we need to tweak it so we get to maybe 70%.
Rhonda: Yeah, it 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?
Valter: 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 a standard of care, and then the fasting-mimicking 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. So that said, of course in mice we have incredible results, we and many labs now have repeated this, so works very, very well.
And so, you know, if somebody cannot wait, I think then it's fair to go to an oncologist and say, "Obviously, I'm running out of options. Shall we consider this one?"
Rhonda: What does it take to for...how many like clinical trials does it take for FDA to approve something? Is it...
Valter: No, the FDA is a specific process. So you have to enter, you have to file, it's an IND application, and there is...it's a very expensive and long process, and it's not just trial. So, it's three phases, phase one, two, three, and in the end you probably have between 500 and 1,000 people, 1,000 patients, and then they make a decision based on the data, whether it's approved or not. The whole process usually costs about $50 million. And 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, you know?
Rhonda: So you do have evidence, and this is a recent publication of yours, that the fasting-mimicking diet in healthy subjects can, it seems, affect biomarkers that are related to aging in a positive way.
Valter: 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 it was a randomized crossover. So, in each case you'll have a group of controls, a group on a control diet and a group on the fasting-mimicking 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 calorie restriction for example, right? Earlier we were talking about, you know, are they all going to the same place? I don't think so.
So calorie restriction, chronic, it keeps driving your markers down. Right? So, even if you started...I mean, if you look at Biosphere 2, and these were then confirmed by Fontana and others, if you look at Biosphere 2, even people that had at the beginning a low blood pressure, they kept dropping, and by the end of it, they had pressure like 85/55.
And same thing for cholesterol, same thing for triglycerides, almost everything, usually drop to very low levels. Fasting glucose.
The fasting-mimicking diet itself, 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, and also very good for doctors. So now we have close to 3,000 doctors just in the U.S. that are recommending the prolonged fasting-mimicking diet, what was tested in the clinical trial, and this is a very important feature.
So, the three cycles decreased, in normal people did nothing, 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 the elevated triglycerides, it decreased triglycerides. People that had the elevated IGF-1, probably people eating on a high protein diet, it dropped IGF-1. And the highest people dropped dramatically, you know, it came down about 60 points.
And the people that had the high fasting glucose, came down. People with blood pressure that was elevated, both the systolic and diastolic, had major effects. The people that had CRP, systemic inflammation, in almost every case they moved back to the normal range.
So it's really powerful I think in resetting the system somehow, that it's getting out of the...its functional ideal state, it resets it, and I think it really rejuvenates. Now we're doing...we're trying to calculate based on published 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, it's three months, right? Is just...
Rhonda: And this was a five-day fast each? It was one week...
Valter: Yeah, five days of...three cycles of a five-day fasting-mimicking diet, and then we measured again, and of course all these things that I just say change. But what if we go to the databases and we plug in the numbers, and we say, tell me, you tell me, what is the risk now compared to before? So we haven't finished that yet, but I think soon enough. And I'll just say there's very...the results look very promising.
Rhonda: I have a couple of questions. So first the...you measure these biomarkers at baseline and then after the three cycles. Do you think if you were to have measured...you measured them immediately after the third cycle, or...?
Valter: One week.
Rhonda: One week? Okay. So, do you think...
Valter: And three months. And we also measured again three months
Rhonda: Oh you did? And how were they...that was my question. So, what were they like three months later? Do you have to keep doing it every, you know, month?
Valter: Yes. I mean, there were, about 60% of the effects were still there. So you could tell that they were smaller, but 60% of the changes were still significant. So, yes. So this is why we say that 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, pescetarian, and you do all the right things, you exercise, etc., you probably only need to do it once or twice a year. It's not very many people in that 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-mimicking 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-mimicking diet, the prolon, the same diet that was tested clinically.
We've had very few severe side effect reports, right? And even the ones that had severe side effects, they fully recovered and there was no evidence that it was the diet that caused them, right? So, it's very good news, right?
Then when you get to, this is what in the FDA terms would 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 and phase two, and skipped phase three, and now we're in phase four.
Rhonda: Wow, that's really great. Twenty-five thousand people, that's a lot. So you were mentioning the frequency 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 like...
Valter: Well much more frequently, yeah. So, somebody that has those problems, say obese, multiple markers for disease, or risk factor for disease, then once a month, yeah. And that's what the doctors have been doing. So they put them on once a month, and then 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 that's also very important, this idea, especially with obese people, we'll see how it works, but this idea that you can go back to your diet after five days, right? This is very mentally, to people is very important. Say, "Well, struggle for 5 days, but then leave me alone for the next 25." That I think is both potentially at the mechanistic level, but also the psychological level it could be a good way to go.
Rhonda: So I'll just 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 fasts. 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 certain foods, 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...
Valter: I want to talk to this guy.
Rhonda: 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 stuff.
Valter: So we're running our trial in Holland on diabetes patients, many of which are going to be obese, and yeah. So, that's our hope, that hey, 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 these 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, you know? Doing it this way. So if you take somebody and you put him like say two months on a very low calorie diet, and you make him exercise, that seems to be a problem. Why? Because of course they can't keep doing that. And then when you eventually go back to a normal diet, your metabolism is now slow.
But doing it like this for these five days, particularly in the fasting-mimicking diet, seem to be not doing that. So the body doesn't quite ever switch to a slower 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 have a long-term plan to lose weight.
Rhonda: For me I would almost think that you'd have the opposite effect that these yo-yo diets that people are claiming lower your metabolism, I would think because you're spending five days in more of a fasting state, or a fasting-mimicking state, that you are becoming more metabolically flexible because you're switching to being able to oxidize fatty acids and then...so you're being able to kind of switch between carbohydrate, you know, using glucose as the main source of energy and using fatty acids...
Valter: Not only switch, but what we suspect is happening...in mice we've shown that per month, if you take mice and you put it on a fasting-mimicking diet, they of course have less calories during the five days, 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 over-eat everything they under-ate during the four days, right?
Valter: So they eat exactly the same, but they lose a lot of weight. So we suspect that what's happening is that fat-burning mode keeps them going. So they never quite...I mean, they probably get back to a relatively normal metabolism, but not quite the same. So 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...
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 calorie restriction, you lose fat, water, and muscle. Right? And almost every diet is the same way. And in this case it's really 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...it doesn't touch subcutaneous fat for some reason, and only goes to the main depot, the visceral fat. So that's great news.
But the muscle is also decreased. But then, when you refeed, 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 their normal muscle mass.
So now you have a specific effect on visceral fat, no effect on subcutaneous fat, and no or very little effect on even absolute lean body mass. In fact the relative lean body mass goes up. Right?
Rhonda: Yeah, because in your study the lean body mass...
Valter: Relative goes up. Absolute, either in one arm wasn't affected, in one arm was just slightly decreased. So, good news because it's probably one of the very few methods to maintain normal lean body mass while losing fat.
Rhonda: 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 refeeding phase the re-growing, 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-mimicking diet in animals, where they lose a significant amount of their different organs, right? And I think that you...maybe you want to talk about this, the...what...
Valter: Yes. So in mice for example, if you look at the weight of most organs, and this of course was known for calorie restriction long term. But with fasting, and fasting-mimicking diet, this happens much more rapidly. So the organs will be smaller, and at the end of the days of fasting-mimicking diet, and then you refeed and of course they go back to the normal level, right? So there is really, there is 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 certainly of course we are also very interested in, is there 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 went back to normal. So yeah, so we suspect that there are these fasting-dependent, depletion of both intracellular components, you know, autophagy, and cellular components, and then we've shown the stem cell to be activated, and then the stem cell during the refeeding 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 do it 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 takes 30 hours to complete the food digestion, from the time you eat to the time that all the calories have been taken up, it takes probably over a day.
So that's a very important distinction between the prolonged fasting and everything else, including calorie restriction, which does not have the refeeding moment, right?
So, if the rebuilding happens during refeeding and you never have it, then of course you're missing out the reconstruction part, which is as important as the destruction part.
Rhonda: You brought up so many different interesting points that I kind of want to touch on. So first the threshold between, you know, like you're mentioning the threshold between when you're actually getting rid of intracellular compartments through autophagy, clearing away protein aggregates, pieces of DNA and things like that, but also, and 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 sclerosis and the other was the, I think type 1 diabetes.
Valter: Yeah, ours was not, that one particularly wasn't, was not autoimmune. We're doing the autoimmune. There's type 1 induced by, pharmacological induced.
Rhonda: Okay. So it has potential for...
Valter: Yeah, but I can tell you, we've now confirmed it with all the autoimmune diseases. So I think it's going to be applicable to many autoimmune diseases.
Rhonda: So this is what's so cool because, I mean, the, you know, the potential for this type of 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 and cells that are damaged preferentially die, I can tell you from doing multiple, multiple experiments.
Valter: Even during development, right? In development. I mean, that's the way that the good and the bad are...
Rhonda: 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.
Valter: Yeah, and also, I mean, something that is a speculation but we're starting to think more and more, or 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 what about the inside? You know, is it possible that we never developed a way to fix damaged organs and various systems? So we're starting to think that maybe fasting represents 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 wouldn't 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 developed something that forces you to fast. And so now that we eat all the time, which 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 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, etc., etc., right?
So, this could be really...and people always are surprised when we say, you know, we're publishing on all these different diseases, but if that's true, then that make sense, right?
Valter: Because for example, in multiple sclerosis, you see on one side it kills the immune cells. It then turns on the stem cells, then turns on the oligodendrocytes, progenitor, and replace...I mean, it's very...it's like, how the hell 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.
Rhonda: 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 life cell. You're talking about in the case at least for autoimmunity or type 1 diabetes or multiple sclerosis, how they make their immune cells normal, that is so...
Valter: Yeah, but that makes sense, right? Because if you turn on a stem cell, you imagine now that the...you're not going to turn on a damaged stem cell, there's got to be a selection process to pick the...So the stem cell is now of course going to give rise to normal white 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, the clonal, 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 hematopoietic stem cell, you will make a healthy...Now, you can always turn the healthy cells into autoimmune cell, but at least initially you will make a healthy one, and that's exactly what we see happening.
Rhonda: So the refeeding phase is really important for, I recall in our last discussion you mentioned the refeeding 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 IGF-1 played a major role in that proliferation because it is after all a growth signal, you know?
Valter: Yes, so there's no doubt. We haven't spent too much time on it but it's pretty obvious 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 IGF-1, in cancer, that failed, right? And we thought, well maybe they failed because the IGF-1 was also needed for example for the immune system to be built or rebuilt, and, in those trials, right? So then the generation of healthy cells is as important as the low IGF-1...generation of healthy cells is IGF-1-dependent, is probably as important as the killing of damaged cells that is low IGF-1-dependent, and the turning on of stem cells, which is also low IGF-1-dependent. So...
Rhonda: Oh, it's low? I thought it was higher, the...turning on the stem cell...not turning on, the proliferation of them is high IGF-1, correct?
Valter: Yeah, no, but the turning on, the initial one is low. So low now is the signal to self-renew, you know?
Valter: So now you have a population, a small population of stem cells that are just active and standing by. Then probably when IGF-1 goes back up, now they are the ones that are pushed by IGF-1 to proliferate and to differentiate, probably also to differentiate. Proliferate and differentiate. Because now you want to rapidly make...
Rhonda: Make new cells.
Valter: ...a lot of white blood cell for example or whatever it is.
Rhonda: So that's my question about, my question to you then is for the refeeding 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 IGF-1 activated during that specific time window? Is that something that you...
Valter: Yeah, there is no doubt that when you refeed, you have to have sufficient protein to rebuild. And if you 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 IGF-1. 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 IGF-1. Insulin and IGF-1.
Rhonda: 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?
Valter: 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?
Rhonda: Well, I mean, I'm talking about, you know, maybe both. If there's...I don't know if there are other longevity markers that people can do now that are clinically available?
Valter: I mean, yeah, I think there are things that you can measure, that may predict your...
Rhonda: Okay, let's do longevity, let's do, yeah, biological age, let's say.
Valter: Yeah, biological age I will certainly...you know, this is what are markers, certainly IGF-1, insulin, glucose, inflammation, systemic inflammation, so CRP, 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 fatty liver. These are more pathological or pathology-oriented, but certainly they can be major determinants of, or certainly can influence cellular functions like insulin resistance. And so those are some of the things that I would, I want to see in the ideal range. Of course blood pressure is another one.
Then Morgan Levine, she's now at Yale, she has, 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...some of the ones that are overlapping were the ones that I said, but there are other ones that are not, that I didn't list. So, people can look up her papers. And also of course, you know, the methylation profile, that seems to be predictive of...I mean, nobody does it now I think to the public...
Rhonda: That's Steve Horvath's work you're talking about?
Valter: Yes, but I'm assuming that soon enough it is going to be available.
Rhonda: Is it? Oh cool. Please let me know when it is, because I'm very interested.
Valter: I saw there are commercials now about telomere measurement at home, right?
Valter: So now I'm assuming that soon enough people are...at least a doctor will have the ability to assess methylation patterns.
Rhonda: Cool. So you have a new book out, called "The Longevity Diet," which is the longevity diet...
Valter: Yeah, "The Longevity Diet," and it's divided into two sections, the first half is all about everyday diet, and in this everyday diet I talk about five pillars of longevity. I basically say 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 system being cars and planes. And I always thought that it's very, a very good way to remove, I mean, together with the other four pillars, to remove all the uncertainties and say, well how do systems that we build age? To just get a fundamental understanding of the environment and how the environment affects the complex systems.
So the first health is that. And centenarian groups, the ones that have record longevity from around the world who 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 that 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 used 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-mimicking diet, and you know, on normal people, some of the things we discussed, and then a chapter on diabetes type 1 and type 2, there is a chapter on autoimmunities, there's a chapter on Alzheimer's and neurodegeneration, and a chapter on cancer. 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, basically it says, well, here's what you could do every day, but then you can introduce the periodic fasting-mimicking diet. Of course you're going to need your endocrinologist to make the decision whether this is clinical trial type of intervention or they can actually do it. That is very tricky, so probably best, 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.
Rhonda: That's very cool, I think that's, the fasting-mimicking 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 not only, you know, causing these diseases, but also in the treatment and how some of them respond to treatment.
Valter: And again, is not just metabolism. Really, we're looking at the ability in evolved self-repair 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 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 damaged system, this is much more than metabolic intervention, this really deals with three billion years of learning how to fix a liver. 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 undergo autophagy, mitophagy, etc., etc., and now 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.
Rhonda: Right, reset. That's a great way of explaining it. The reset is probably what I'm most excited about, is that they're clearing away the damaged cells and then rejuvenating or fixing things.
But I do, I quickly want to just mention, because I do recall now one of your studies that you, at least in the clinical studies with the fasting-mimicking 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 are trying to...you know, increasing them, but are you looking...is that something now you're moving forward with, and are there clinical studies to look at?
Valter: Yeah. Now, yeah, we're looking at that. I mean, of course we never took biopsies. I always feel bad about taking people's biopsies because it's very painful usually to take their skin. So we had blood and it's not so easy to measure stem, circulating stem cells. I mean, now, techniques are getting better, and so I think hopefully 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 University of Verona in Italy, I think as part of that, we have biopsies, muscle biopsy. And so that should give us a better idea about at least some tissue, associated stem cells, satellite cells for example.
Rhonda: I'm so excited. I'll definitely be following your research.
Thank you so much Valter for the discussion and your, talking about your book, "The Longevity Diet." I look forward to talking to you some more.
Valter: Yeah, yeah. Thank you for all the very good questions.
AMP Kinase (AMPK)
An enzyme that plays a role in cellular energy homeostasis. The net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, skeletal muscle fatty acid oxidation, and glucose uptake; inhibition of cholesterol synthesis, lipogenesis, triglyceride synthesis, adipocyte lipolysis, and lipogenesis; and modulation of insulin secretion by pancreatic beta-cells.
An intracellular degradation system involved in the disassembly and recycling of unnecessary or dysfunctional cellular components. When involved in cell death, this process is known as **autophagic dell death**. Prolonged fasting is a robust initiator of autophagy, and is thought to help protect against cancer and even aging by reducing the burden of abnormal cells. **However, the relationship between autophagy and cancer is complex**: autophagy may prevent the survival of pre-malignant cells, but can also be hijacked as a malignant adaptation by cancer, providing it a useful means to scavenge resources needed for further growth.
A bidirectional cell signaling pathway that may regulate cell function, metabolism, or other aspects of physiology. Most signaling pathways are unidirectional. However, an axis may involve two or more signaling proteins and their secreting organs or cells in a type of feedback loop. For example, the growth hormone/IGF axis, also known as the **Hypothalamic–pituitary–somatotropic axis**, is a highly regulated pathway involving IGF-1 (produced by the liver), growth hormone (produced by the pituitary), and growth hormone-releasing hormone (produced by the hypothalamus).
The process by which fatty acid molecules are broken down. Beta-oxidation occurs in the mitochondria and produces acetyl-CoA, FADH2, NADH, and H+. Under conditions where glucose is limited, beta-oxidation is an important preceding step for producing the acetyl-CoA needed for **ketogenesis**.
C-reactive Protein (CRP)
A ring-shaped protein found in blood plasma. CRP levels rise in response to inflammation and infection, or following a heart attack, surgery, or trauma. CRP is one of several proteins often referred to as acute phase reactants. It binds to the phosphocholine expressed on the surface of dead or dying cells and some bacteria, activating the complement system and promoting phagocytosis by macrophages, which clears necrotic and apoptotic cells and bacteria. The high-sensitivity CRP test (hsCRP) measures low levels of CRP in the blood to identify low levels of inflammation that are associated with risk of developing cardiovascular disease.
A type of growth hormone receptor mutation commonly found among people of Spanish and Jewish descent that results in Laron syndrome, a genetic disorder characterized by unusually short stature. Scientific evidence suggests that people with Laron syndrome have lower risk of developing cancer or type 2 diabetes.
A molecule composed of carboxylic acid with a long hydrocarbon chain that is either saturated or unsaturated. Fatty acids are important components of cell membranes and are key sources of fuel because they yield large quantities of ATP when metabolized. Most cells can use either glucose or fatty acids for this purpose.
A glioma is a type of tumor that form in the brain in a type of neuron called glial cells. Roughly one-third of all brain tumors are gliomas. Malignant gliomas are highly aggressive, and survival rates for patients poor: approximately 10% for 3-year survival, according to one analysis for the 2009-2010 period. A protein associated with human cytomegalovirus (HCMV), a widespread beta-herpes virus, is expressed in >90% of gliomas.  Logan, J., et al. "Has the survival of patients with glioblastoma changed over the years?." British journal of cancer 114 (2016): e20.  Barami, Kaveh. "Oncomodulatory mechanisms of human cytomegalovirus in gliomas." Journal of Clinical Neuroscience 17.7 (2010): 819-823.
A highly branched chain of glucose molecules that serves as a reserve energy form in mammals. Glycogen is stored primarily in the liver and muscles, with smaller amounts stored in the kidneys, brain, and white blood cells. The amount stored is influenced by factors such as physical training, basal metabolic rate (BMR), and eating habits.
A series of enzyme-dependent reactions that breaks down glucose. Glycolysis converts glucose into pyruvate, releasing energy and producing ATP and NADH. In humans, glycolysis occurs in the cytosol and does not require oxygen.
The production of red bloods cells, white blood cells, and platelets from hematopoietic stem cells, which occurs in the bone marrow. Also called hematogenesis, or hematopoiesis.
Hematopoietic stem cells (HSCs)
An immature cell that can develop into all types of blood cells, including white blood cells, red blood cells, and platelets. Hematopoietic stem cells are found in the peripheral blood and the bone marrow and give rise to both the **myeloid** and **lymphoid** lineages of blood cells. The process by which blood cells are produced is known as **hematopoiesis**. Myeloid cells include monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, and megakaryocytes to platelets. Lymphoid cells include T cells, B cells, and natural killer cells.
Insulin is a peptide hormone secreted by the beta cells of the pancreatic islets cells and maintains normal blood glucose levels by facilitating the uptake of glucose into cells, regulating carbohydrate, lipid and protein metabolism and promoting cell division and growth. Insulin resistance, characteristic of type 2 diabetes, is a condition in which normal insulin levels do not produce a biological response and lead to high blood glucose levels.
Insulin-like growth factor 1 (IGF-1)
One of the most potent natural activators of the AKT signaling pathway, stimulator of cell growth and proliferation, potent inhibitor of programmed cell death, primary mediator of the effects of growth hormone, and has been implicated in contributing to aging and enhancing the growth of cancer after it has been initiated. Similar in molecular structure to insulin, IGF-1 plays a role during childhood for growth and continues later in life to have anabolic, as well as neurotrophic effects. Protein intake increases IGF-1 levels in humans, independent of total caloric consumption.
A physiological condition in which cells fail to respond to the normal functions of the hormone insulin. The body produces insulin, but the cells in the body become resistant to insulin and are unable to use it as effectively, leading to high blood sugar. Beta cells in the pancreas subsequently increase their production of insulin, further contributing to a high blood insulin level.
A diet that causes the body to oxidize fat to produce ketones for energy. A ketogenic diet is low in carbohydrates and high in proteins and fats. For many years, the ketogenic diet has been used in the clinical setting to reduce seizures in children. It is currently being investigated for the treatment of traumatic brain injury, Alzheimer's disease, weight loss, and cancer.
Molecules (often simply called “ketones”) produced by the liver during the breakdown of fatty acids. Ketone production occurs during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, or prolonged intense exercise. There are three types of ketone bodies: acetoacetate, beta-hydroxybutyrate, and acetone. Ketone bodies are readily used as energy by a diverse array of cell types, including neurons.
A type of dwarfism in which the body cannot use growth hormone due to mutations in the growth hormone receptor gene, one of which is known as an **E180 mutation**. People with Laron syndrome are typically very short in stature (males – about 4.5 feet; females – about 4 feet) and may have poor muscle strength and endurance. Scientific evidence suggests that people with Laron syndrome may have substantially reduced risk of developing cancer or type 2 diabetes, an effect that scientists would like to recapitulate, possibly through strategies to reduce IGF-1 signaling.
Also called white blood cells (WBCs). Involved in protecting the body against both infectious disease and foreign invaders. Leukocytes are distinguished from other blood cells by the fact that they retain their nuclei. They can be subdivided by lineage: myeloid or lymphoid. These cells make up approximately 1% of the total blood volume in a healthy adult. A cycle of **prolonged fasting** has been shown in animal research to reduce the number of white blood cells by nearly one third, a phenomenon which is then fully reversed after refeeding.  Cheng, Chia-Wei, et al. "Prolonged fasting reduces IGF-1/PKA to promote hematopoeietic-stem-cell-based regeneration and reverse immunosupression." _Cell Stem Cell_ 14.6 (2014): 810-823.
Macroautophagy vs. Microautophagy
**Macroautophagy** is used primarily to eradicate damaged cell organelles or unused and/or damaged proteins. This involves the formation of a double membrane known as an autophagosome around the organelle marked for destruction before delivering it to a lysosome. **Microautophagy**, on the other hand, involves direct engulfment of cytoplasmic material by the lysosome via a process of invagination, meaning the inward folding of the lysosomal membrane.
Mechanistic target of rapamycin (mTOR)
A genetic pathway that senses amino acid concentrations and regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. It integrates other pathways including insulin, growth factors (such as IGF-1), and amino acids. mTOR plays a key role in mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain. It is dysregulated in many human diseases, such as diabetes, obesity, depression, and certain cancers. mTOR has two subunits, mTORC1 and mTORC2. Also referred to as “mammalian” target of rapamycin. **Rapamycin**, the drug for which this pathway is named (and the anti-aging properties of which are subject to much study), was discovered in the 1970s and is used as an immunosuppressant in organ donor recipients.
Scientific evidence suggests that restricting methionine can mimic the effects of dietary restriction and extend lifespan in many organisms. Methionine is a type of amino acid present in many foods, especially eggs, meat, and some nuts and grains. Methionine restriction reduces IGF-1 signaling, which may play a contributing role in methionine’s ability to mimic the effects of calorie restriction. Evidence from animal models suggest, however, that methionine restriction has effects that are distinct from caloric restriction: Methionine‐restricted rats exhibit a dramatic increase (84%) in blood glutathione levels, a result not observed in caloric restriction .  Miller, Richard A., et al. "Methionine‐deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF‐I and insulin levels, and increases hepatocyte MIF levels and stress resistance." Aging cell 4.3 (2005): 119-125.
A type of glial cell that is involved in the production of myelin, providing support and insulation to axons in the central nervous system. A single oligodendrocyte can extend its processes to 50 axons, wrapping approximately 1 micrometer of myelin sheath around each axon.
A gene that has the potential to cause cancer. A proto-oncogene is a normal gene that regulates cell growth and proliferation but if it acquires a mutation that keeps it active all the time it can become an oncogene that allows cancer cells to survive when they otherwise would have died.
A gene in two or more species that has evolved from a common ancestor during a speciation event. Orthologous genes encode proteins with the same function in different species.
Phase 4 Clinical Trial
The postmarketing surveillance stage. A clinical trial conducted to identify and evaluate the long-term effects of new drugs and treatments over a lengthy period for a greater number of patients. Phase IV research takes place after the FDA approves the marketing of a treatment.
Protein kinase A (PKA)
A family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). Protein kinase A has several functions in the cell which vary with cell type, including regulation of glycogen, sugar, and lipid metabolism. Kinases, in general, modify the activity of other proteins by chemically adding phosphate groups to them in a process known as **phosphorylation**.
Randomized Controlled Trials
A study in which people are allocated at random (by chance alone) to receive one of several clinical interventions. One of these interventions is the standard of comparison or control. The control may be a standard practice, a placebo ("sugar pill"), or no intervention at all.
Ras is a family of related proteins called GTPases that function as molecular switches regulating pathways responsible for cell growth, proliferation, differentiation, and survival. _Mutations in the Ras family of proto-oncogenes are very common and are found in 20% to 30% of all human tumors._
Single Nucleotide Gene Polymorphism (SNP)
A change in one nucleotide DNA sequence in a gene that may or may not alter the function of the gene. SNPs can affect phenotype such as hair and eye color, but they can also affect our disease risk, the way we absorb and metabolize micronutrients, macronutrients, and much more.
An excess of visceral fat is known as **central obesity** or **abdominal obesity**. Visceral fat, in contrast to subcutaneous fat, plays a special role involved in the interrelationship between obesity and systemic inflammation through its secretion of **adipokines**, which are cytokines (including inflammatory cytokines) that are secreted by adipose tissue. The accumulation of visceral fat is linked to type 2 diabetes, insulin resistance, inflammatory diseases, certain types of cancer, cardiovascular disease and other obesity-related diseases.  Fontana, Luigi, et al. "Visceral fat adipokine secretion is associated with systemic inflammation in obese humans." Diabetes 56.4 (2007): 1010-1013
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