podcasts

Kalea Wattles:
I love in your book, The Longevity Diet, you talk about the sustainability of a fasting-mimicking diet. It’s more well tolerated because there are carbohydrates included, and you talk about how most of the cultures of the world have some carbohydrate as part of their traditional food plan, and this continues to honor that pattern.

Valter Longo:
Yes, in selecting the content of the fasting-mimicking diet, we were worried about compliance. We knew that if eventually people did not like it, it would just go away. But we were also worried about safety, and unfortunately, all the people are not doing that. The question is, let’s say that you have a zero-carbohydrate diet and you go back and forth between high carb and zero carb, or very low carb. Well, what happens to the body? We don’t know. It could be that after you do this 1,000 times, you start having problems. This was why we wanted to have enough carbohydrate in there to still get this increase in ketone bodies, decrease in fasting glucose, but not risk this yo-yo between very low carb, very high carb, which the brain and every other system in the body may be affected by both negatively and positively. Yeah, it’s a combination of looking for compliance, efficacy, but also safety.

Kalea Wattles:
Sure. Just to summarize for those who might be listening, the plan is typically a five-day program. What I remember from your book is you recommend doing this twice yearly, is that correct?

Valter Longo:
Well, no. I recommend this twice yearly for somebody that is very, very healthy, so 10% of the US population. Then I think it’s up to the doctor, the dietician to look at a patient. For example, we’re about to finish a diabetes clinical trial in Holland, and that’s one cycle a month for 12 months. The idea on a diabetic, let’s say an obese person or overweight with diabetes, is to do it once a month. Then at the end of the year, after 12 cycles, you reassess, and you can ask the question, and the endocrinologist could say, “I’ll put you on once every two months and then maybe once every three months.” Getting to, let’s say, once every four months as the ultimate maintenance state so that the patient doesn’t go back to diabetes.

Kalea Wattles:
Yeah, thanks for clarifying. I think it’s fascinating, your research on how this food plan can really impact specific disease states. But in general, can you talk to us a little bit about a fasting-mimicking’s diet impact on aging in general, age-related diseases and longevity?

Valter Longo:
Yeah, so we started, as everything we do, we start with animal models. We’ve shown that in mice, if you take them in middle age and you give them the fasting-mimicking diet twice a month, they live longer. They have about half of the tumors. The tumors are delayed, they have a lot less inflammation. So it has very powerful both regenerative effects and anti-inflammatory effects, and also it works on cognition. It’s making the mice much sharper, especially as they get older. That’s the mouse data. Then we did the first clinical trial in 2017, and that trial basically showed that the markers and risk factors for aging and age-related diseases were reduced. This went from IGF-1, C-reactive protein, cholesterol, blood pressure, triglycerides, fasting glucose, et cetera.Some of it was independent of the starting point, but most of these decreases happened in those that had the problem to begin with. So if somebody had a low fasting glucose and low cholesterol, we did not see a further drop. This is a very positive. Some people looked at it as a negative, said, “Oh, why didn’t you reduce glucose in everyone?” And our point was, you don’t need to reduce glucose in everyone. This is actually what happens with calorie restriction. This could be some of the problem of chronic calorie restriction, that you do reduce everything. You must start… if somebody starts with a fasting glucose of 80, which [is a] very healthy one, the calorie restriction might drive it down to 60, which may not be so healthy. Yeah, so then we did not see this after cycles of the fasting-mimicking diet, and these were done in a population that was 20 to 70, and there were three five-day cycles once a month for three months.We looked at the beginning, at the end of the three cycles. Then we looked at three months after the end of the three cycles. Interestingly, even three months after the end of the diet, we had about 60% of the significant effects still there, which tells you from that, say, two, three times a year for people that are healthy, that tells you that it lasts a while, but it doesn’t last forever. Eventually, the body and maybe whatever habits people have, within six months, you’ll be back to where you came from.Kalea Wattles:
It really sounds like doing intermittent times where you’re utilizing a fasting-mimicking diet helps the human organism remain resilient and maintain their homeostasis. That’s what it sounds like to me when I hear you speaking about the modulation of blood sugar and blood pressure and things utilizing an FMD.Valter Longo:
Yeah. I mean, we rely a lot on cells in mice for mechanisms. We’ve done models for type 2 diabetes, type 1 diabetes, inflammatory bowel disease, multiple sclerosis, et cetera, et cetera. What’s common among all of the things that we’ve done, including the work that we did on the brain, is the reduction of inflammation. It seems like the diet and the fasting is able to recognize damage, take it down. If it’s inflammation, it takes it down. If there are damaged cells, including cancer cells, it preferentially targets the autoimmune cells, the cancer cells. Then it stimulates in many different organs of the mouse, it stimulates stem cells. But these stem cells are standing by until you re-feed. Then the re-feeding moment is when the stem cells then go to work and they contribute to rebuilding at least parts of the system that has been shrunk, in essence, during the fasting-mimicking diet.It’s really this very remarkable shrinking and re-expansion mode that after the re-expansion ends up in a much more functional system. At least in the mice, it’s very clear. We can, let’s say, take a mouse, damage the pancreas to where it makes no insulin anymore—permanent, so it’s permanently type 1 diabetic, and it’s insulin resistant. Then both the insulin resistance and the pancreatic deficiency are reversed by the fasting-mimicking diet. It’s going in completely different directions. One to reverse insulin resistance, and then target the pancreas, turn on embryonic development–like programs. And then during the re-expansion, you see the beta cells that’s reprogrammed to regenerate, we don’t know yet, but certainly now they can generate new insulin-producing beta cells. Then the cells, once they’re re-established, they’re long-living, so you don’t need to keep doing it, so they’re essentially reversed. In mice, we’ve shown that you can reverse this damage to the pancreas and have now a functional pancreas that is no longer type 1 diabetes-like.Kalea Wattles:
I’ve heard you speak about the difference between biological age and chronological age, and now you’re mentioning organ function. Is that one of the ways that we’re measuring biological age?Valter Longo:
The biological age is that… we’ve been working with Morgan Levine, and also we’re working with Steve Horvath  now at UCLA. Morgan is at Yale. Morgan has been working on a blood biological clock. She looks at about 7-10 markers in the blood, and she looks at the enhanced CDC database, and she basically, based on real data, says, “If you look at a certain pattern of this 7-10 markers, they put you in a certain biological age and risk of dying in the following so many years.” That’s what we’ve been using, and pretty soon, we’re going to publish on the effect of the fasting-mimicking diet on biological age. What happens if you do three or four cycles of the fasting-mimicking diet—can you make a person younger? That’s an interesting possibility.And the other one is Steve Horvath, and he’s looking at the epigenetic clock. He’s looking at how the DNA is modified, and that’s also a very powerful one that generates more of a molecular clock that is correlated with the chance of dying and also the chance of potentially developing diseases. So we’re working with Steve now on that. We’re still at the setup stage.Kalea Wattles:
Great. As we’re thinking about biological age, we know that in regard to fasting and aging, like you talked about, many of your fundamental mechanisms have been studied in simple organisms, and then in mice, and then we translate this to humans. From your experience, can you give us some details on fasting and our diet quality in regard to immunosenescence?Valter Longo:
Yeah. Again, I have to go back to mice, and then I’ll tell you about humans. In mice, it’s very clear that if we take the mice and we give them the fasting-mimicking diet, during the fasting period, the hematopoietic stem cells start turning on. Then during the re-feeding period, and as we go back and forth, you see somewhat of a rejuvenation of the immune system, especially if you take relatively older mice. Then you keep doing this for four months or so. After eight cycles of the fasting-mimicking diet, you see this rejuvenating effect. You also see improved responses to the flu vaccine that we give the mice. Now we’re starting to see some evidence of that, for example, in humans. We see a decline, but not a severe decline, but about a 20% or so decline of the white blood cells during the fasting-mimicking diet. Then you see them going back to normal.Knowing what we know about the mice and the stem cell–based regeneration, we suspect that something similar is happening. We don’t know, because in humans, of course, it’s much, much more difficult to know what’s happening. You know that the white blood cells go down and they come back up. Now a multiple trial will show that, but does it involve the hematopoietic stem cells? Is there a replenishment of the good cells? Is there a destruction as we’ve seen for the mice in dysfunctional T-cells, et cetera, and a rebuilding of functional ones? We don’t know yet, but that’s certainly a possibility. Now we have several clinical trials that are addressing that.

Kalea Wattles:
Well, there’s never been a better time to understand how we can start rejuvenating the immune system as we’re supporting our aging population. Just to continue on that line of thinking, specific to the fasting-mimicking diet, what are some mechanisms or potential pathways involved with the diet’s effectiveness? You’ve mentioned stem cells, I would also love to hear a little bit about the impact on mitochondrial health. I see mostly fertility patients, and so I’m talking about mitochondrial health all of the time, and I’d love to know a little bit about how the FMD might support our mitochondria.

Valter Longo:
Yes. We’re working on that, and so for sure it imposes a temporary ketone body and fatty acid–dependent metabolism, which is going to push the mitochondria probably to be more active or certainly to be in a different mode. How that then eventually alters mitochondrial number and quality, we don’t know yet. But because we see the mice living longer and we see the people being much healthier after the cycles of the fasting-mimicking diet, I would suspect that the mitochondria are going to be a part of it. Of course, the very interesting part is this possibility that I keep talking about of a system that is billions of years old and is there for the purpose of getting rid of anything that is damaged, regardless of whether it’s mitochondria, other organelles within the cell, or the cells itself.

I always talk about sleep, for example. What’s the purpose of sleep, or why do we sleep? Obviously, it’s not there by mistake. Now we don’t fully understand, but there’s definitely a purpose. Then what’s the purpose of fasting? Is it possible because it was so frequently done by humans and almost unavoidable, that fasting represented a moment where you do go through everything, including the mitochondria, and you pick the good and get rid of the bad? Now it sounds like science fiction, but is it? Because if you think about apoptosis, we all recognize that the body has a system in it to recognize bad cells and get rid of it.

So if it can recognize bad cells, are we to believe that after billions of years, it just figured out how to recognize a few bad cells, but it’s just completely unable to deal with bad mitochondria or any component of the cell that there may be dysfunction? That’s what we’re looking at, is a multicellular and cell system and intracellular systems that may be in need of a checkpoint and in need of a filter. Maybe the fasting-mimicking diets represent that filtering moment where these programs are activated to pick the good and get rid of the bad.

Kalea Wattles:
I love that you brought up sleep, because that’s the perfect lead in to my next question. Our annual conference in 2020 really focused on circadian medicine. And it got us thinking about how does circadian rhythm or a patient’s chronotype potentially play into the effectiveness or the benefit of a fasting-mimicking diet? Is there any connection between our eating pattern and our circadian balance in this way?

Valter Longo:
Well, I mean, of course, the circadian clock is very much interconnected with the feeding pattern. There is a connection, and probably there’s going to be genes that work in the circadian clock that also play a major role in the fasting-dependent effects. We haven’t looked at it. I know that Satchin Panda is looking a lot at that and how it relates to intermittent fasting. But yeah, I will say that the circadian genes are probably going to be part of the fasting-mimicking program. But to what extent and how important are they, I think in the case of what we’re talking about, we’re pushing the system to a very different level than what you may get in say 12, 14 hours of fasting.

It takes a couple of days for the human body to reprogram into a fasting mode. To start producing high levels of ketone bodies, for the brain to start functioning partially on beta hydroxybutyrate, et cetera. I think there’s also some things that are very, very distinct. This opportunity, for example, if you take an extreme. They say that a person can survive about two months without food. What would happen if somebody had a major damage somewhere in the body and you kept that person for say, a month and a half without food? I mean, I’m not proposing that we do that, but I’m saying, theoretically, is it possible that that organ shrinks so much that then you have an opportunity to regenerate the entire organ? I’m just trying to distinguish it from the circadian clock.

We’re talking about things that are very, very different. Each have value, but yeah, this is what we’re looking at. Is it possible to go back to embryonic development? Or an embryonic development–like modality that is able to regenerate part of your pancreas, part of your liver, your lungs, or even all of it eventually? I mean, we’re still in the early phases, but could it be that we find ways to completely change your lungs in 20 years? But yeah, that’s the possibility of this or where we are. That’s what we’re beginning to look at, multi-system regeneration.

Kalea Wattles:
Hearing you talk is reminding me, the other day I looked up, working on a project, the definition of the word restoration. It was basically bringing something back into the state in which it belongs. That’s what it sounds like we’re doing, to me. This is really a restorative process, a really intentional restoration of the human organism.

Valter Longo:
Yeah, it could be restorative. It could also be rejuvenating in the sense that you could take a car and you restore it. Now, when you restore it, it’s still an old car. It just looks good and it runs great. But you can say, “Okay, now I change every piece of it.” It’s a brand new car. Yeah, that’s a different type of restoration. Now you just have a brand new young car and that young car can now go for 200,000 miles versus something that you restore, but it’s still got an old engine. It’s still got some wear and tear or lots of wear and tear. Even though it’s restored, it’s going to eventually break down again. So it’s very, very different. But yeah, understanding that we’re still in the early, early phases of being able to… we’re probably now reaching the restoration phase. Now we have to look at, is it possible that you can now make a brand new car? That’s the hard part.

Kalea Wattles:
Well, that sounds even better, to make a whole new car. I think that’s even more desirable. Thinking about just how we use a fasting-mimicking diet and how clinicians talk about the benefits of an FMD with patients, can you give us a sound bite, if you will, about how we should talk about or answer the question: how does the fasting-mimicking diet fool the body chemically into thinking it’s fasting? How can we talk to patients about that in a way that makes sense for the public?

Valter Longo:
Well, first of all, I think it falls in a very respectful way. When I designed the fasting-mimicking diet, I didn’t design it to biohack. I designed, yes, to take advantage of technology but also be respectful of what happens during fasting, what’s generated in the body. For example, glycerol is something that is generated in the body, and sure enough, glycerol is part of the fasting-mimicking diet. Certain fats are generated during the fasting by the body. Those fats are in the fasting-mimicking diet. So I was very respectful of what fasting has always been and what fasting generates in the blood stream. Then it was also, it was worried about, say, is your blood pressure going to drop too much? Is your glucose going to drop too much? Or is the glucose or the blood pressure of 1% of the patients going to drop too much?

To us, that’s not acceptable. That’s what the fasting-mimicking diet is trying to do. It’s trying to biohack, but in a very respectful manner. Also, respectful if you look at it, and that was a very, very good idea that I had, which was, let me combine the longevity diet and the fasting-mimicking diet. What does it mean? I went around the world, whether it was Okinawa or Southern Italy or Loma Linda, to look at the foods that were a common denominator between all the people that live a long, long life, or all the zones that had record longevity. As I was coming up with the ingredients for the fasting-mimicking diet, I also wanted to match that. I wanted to match the science, the tradition, but also the longevity ingredients. Then you have essentially a vegan diet that has got all ingredients that are associated with long life or extended life. That was a very good idea.

If you look at our paper from a couple of years ago, in inflammatory bowel disease, mostly mice, it looks like because of the content that I just described, the FMD was more beneficial than water-only fasting, which can only do certain things to reduce inflammation, but it was not as effective in causing colon and intestinal regeneration. So the prebiotics, the plant-based ingredients that were in the diet, together with the fasting properties, I think generated a much more potent effect.

Kalea Wattles:
That’s a great lead in to something I’ve been thinking about. We’ve seen this rise, I would say, in the maybe alternative medicine community of the carnivore diet. I was just so interested as I was listening to your longevity diet, and it’s healthy fats and legumes and fish a few times per week. It seems somewhat at odds with a strictly carnivore diet. I just would love to get your thoughts on if there’s a place for a more carnivorous plan with any conditions, or if we should steer clear for the most part.

Valter Longo:
I mean, I think we’re going in the opposite direction for obvious reason. CO₂ production of the animals and lots of reasons that where I think it’s going to be more and more difficult to consume as much meat as we’re doing now. And then the science is also pointing in the opposite direction of now vegan. Keep in mind, vegans have lots of problems. A new paper should come out looking at fractures: two and a half times more fractures in the vegans, but the pescatarians, on which my longevity diet is based, did not have that. I think that a certain type of vegetarians and certain type of pescatarians seem to be doing by far the best. Now, let’s also keep in mind not what the diet is, but what the diet will be by the time the public consumes it.

If you say carnivore diet, is it possible there is a specific, grass fed, perfect carnivore diet that is going to make people live long? Absolutely. Is it likely that a significant portion of the people out there are going to consume it? Very unlikely. People have a hard time doing very basic things. I always say, people have a hard time. They drink four coffees a day, go to three coffees. Yeah, then I think we need to have recommendations that are much more, so solid that if you say to somebody, “Eat a vegan diet plus fish twice a week,” I mean, it’s a pretty simple recommendation. It’s inexpensive, and most people can do it. If you start saying, “Have a carnivore diet,” you’ve got to start with a lot of explanation and a lot of rules and regulations. And by the way, you don’t know if it’s true. Because the pescatarian diet has lots of data now, including the data from centenarians.

I’ve never seen a long-lived population around the world have a carnivore diet. It’s already a bad start. In my book, I talk about five pillars of longevity, and one of them is epidemiological data. Epidemiological data does not support a carnivore diet. Then if you look at the centenarians, they don’t eat a carnivore diet. Neither the Okinawans, nor the people in Loma Linda, nor people in Southern Italy, if you look at clinical studies, and most clinical studies will have something negative to say. I mean, again, of course, somebody can argue, “Oh, if you ate this and that and that,” yes possible. But we don’t know. Once we collect 30 or 40 years of data equivalent to what we have from this pescatarian diet, including, let’s say, the Mediterranean diet, which is an in-between, only then can you say, “Okay, let’s forget about the Mediterranean diet and the Okinawa diet and the longevity diet, and let’s adopt something that is much more risky,” because meat is so much associated.

I mean, we published a paper five years ago looking at… people that had an animal based, high-protein diet, which will be almost everybody on a carnivore diet, had fourfold increase in risk of cancer in the 65 and younger population. Yeah, fourfold increased risk. I mean, this is a very big number, and people at the beginning thought it was a mistake, but it was not a mistake. This comes from the CDC database. Yeah, so then all these things have to be kept in mind, and I’m not talking about ideology at all. I will say if the carnivore diet had evidence and then it was just a matter of saying, “Oh, but the environment and all of that,” I think I would have to qualify that. But I’m just talking about strict, pure science.

The carnivore people need about 30 years of work before they can be as convincing, provided that everything works out as good as with the pescatarian diet, et cetera. Then they also have to show compliance. Is it possible that this particular diet could be something that most people could do? We already know that the pescatarian diet is something that people can do, because we have people in many places of the world that have done it, and they made it to 100 doing that. I’m saying it’s a very tall wall to overcome by the carnivore people.

Kalea Wattles:
Yeah. Well, thank you for that explanation. That was super helpful and interesting for me to hear. I love that you returned to this compliance piece, because something I want to ask you about is, are there components of the fasting-mimicking diet that can be personalized for individual patients based on their preferences or unique needs? What parts can we tweak as clinicians?

Valter Longo:
I think that what we’re trying to do is we’re trying to involve the FDA now and try to transform, especially for physicians, the fasting-mimicking diet into true medicine that [is] FDA approved. I will say, change very little or nothing unless the patient needs to. For example, some patients, there’s no way that they can go without coffee. In that case, we say, before you quit, you can have one coffee a day. Somebody may be allergic to olives or they cannot eat them. Then you can keep them out. The physician can do some adjustments based on what the patient absolutely cannot do, because this is, of course, five days of nutrition. It’s not like taking a pill that most people can do.

Kalea Wattles:
Perfect. Well, we’ll stick with the program for now. As we’re coming to the end of our episode, I want to touch on research a little bit. You shared so many takeaways from your research over the years, and we know that you’ve really looked at the beneficial impact on cancer, depression, cardiovascular disease, metabolic syndrome. Are you able to share a preview of any ongoing research projects that you have or hypotheses that are on the horizon?

Valter Longo:
Yes. For sure I would say cancer, that 2020 has been a very good year for the clinical cancer trials, including the 125-patient trial in Leiden, in Holland, showing very positive results for breast cancer chemotherapy including the fasting-mimicking diet. Then I will say we’re getting very, very confident about the cardiometabolic, or certainly the metabolic effects of the fasting-mimicking diet. Now we are in trial number three, and there are several more. So we’re starting to see over and over and over almost identical results. Then we’re starting to say, “This has got potential for FDA approval.” I really believe, I’m very confident that if you’re looking at diabetes, pre-diabetes metabolic syndrome and also prevention of cardiovascular disease, this is the way to go. I mean, this should be in the toolkit of every physician. Understanding that, yes, we need the FDA to approve it. But we’re set and now doing that and approaching the FDA.

Now there’s also issues because the FDA basically says, “Oh, if it’s nutrition, it may not necessarily be something that you need to have approved by the FDA.” But, I mean, the argument is that this is a true medicine. It comes in a box and should be given independently of what somebody eats. In fact, I say, the worse the diet that somebody has, the more they need this once every month or two or three months. That’s going to be the argument. We’ll see what the FDA will have to say about that. But either way, I think they’ll either allow it as a medical food or as an FDA drug.

Kalea Wattles:
Wonderful. Well, as I’ve implemented a fasting-mimicking diet with my own patients, I really deeply appreciate how easy it is to actually implement and how straightforward the process can be. So I wanted to thank you so much for your time today and sharing these insights about the fasting-mimicking diet. It’s been just a pleasure to talk to you, and we’re very excited to see you later this year at our Annual International Conference. Thanks for being with us.

Valter Longo:
My pleasure, thank you.

Kalea Wattles:
To join the conversation on this topic, visit IFM’s pages on Facebook and Instagram. For more information about functional medicine, visit ifm.org.

---

IFM’s Intermittent Fasting: Therapeutic Mechanisms & Clinical Applications course provides an evidence-based overview of several of the fasting methods listed above and outlines potential contraindications and points of personalization for each patient’s unique health needs and goals.