How a Fasting-Mimicking Diet Can Help You Live Longer

Transcript for the Video

Fasting-Mimicking Diet: Calorie Restriction and Longevity A Special Interview With Dr. Valter Longo

By Dr. Mercola

JM: Dr. Joseph Mercola VL: Dr. Valter Longo

JM: The foods you eat can have an enormous influence on how long you live and your likelihood and risk of contracting diseases. But what is the optimal ratio of foods that you should be eating? Hi, this is Dr. Mercola helping you take control of your health. Today I am joined by Dr. Valter Longo, who is a professor of gerontology and biological sciences at the University of Southern California. He’s also director of The Longevity Institute. Welcome and thank you for joining us today, Dr. Longo.

VL: Thank you.

JM: You have a long history. You’re a researcher. You’re a PhD, not` a medical doctor, but you’re doing extensive research on one of my areas of passion, which is optimizing mitochondrial metabolism with the use of dietary interventions. You have an interesting history too, and that you come through an area of calorie restriction. Perhaps you can describe your process of how you evolved and eventually focused on your current area of research.

VL: Yes. Actually, I was a student of Roy Walford many years ago. Roy was one of the pioneers of calorie restriction. He was a medical doctor. He was very interested in basically using diet to prevent and even treat diseases. That started back in the early ‘90s.

But then I went on to turn to a more molecular understanding of what connects each ingredient, what connects each amino acid, the sugars, the fats, the type of fats, to the pathways that we were studying, particularly the pro-aging pathways. Two of them we discovered. One called the PKA pathway, one called TOR-S6 kinase, both have now been shown to be central in the aging process, not just in simple organisms but possibly also in mammals.

JM: Is it true that your lab is one of the first ones or the first one that discovered the mTOR pathway, now called the mechanistic target of rapamycin?

VL: We didn’t discover the mTOR pathway. We discovered the role of the TOR pathway in aging and in the protection of the cells. Michael Hall actually discovered the TOR pathway a few years before us in yeast. It was at work in a simple organism called Saccharomyces cerevisiae.

JM: Okay. Good. Thanks for that clarification because we’ll talk about that a little bit later because that really plays an essential and profound role in really understanding how to optimize the diet.

But leading back to the calorie restrictions, I’ve interviewed Gary Taubes before and he’s not convinced. I’m not sure if you’ve met or know who he is, but he’s an investigative journalist in biological sciences. He’s not convinced, from his review, that there’s a lot of literature out there

that supports the use of calorie restriction for the extension of human lifespan. I’m wondering if you could provide us with your take on it.

VL: Yes. I would probably agree with him. When you look at calorie restriction, which means about a 30 percent restriction in calories below the normal level, and you do this all the time, even the monkey studies where they took about – at the University of Wisconsin and National Institute on Aging (NIA), they took monkeys and they restricted them like that for 25 to 30 years. The results are questionable.

The Wisconsin showed some effect on mortality and diseases, but in NIA, it didn’t. If you look at overall mortality, even the Wisconsin study showed that the monkeys that were calorie restricted for so long did not live that much longer because they had a lot less diabetes and cancer and cardiovascular diseases, but probably had higher levels of other problems. This is why we never really focused on calorie restriction, but tried to get the benefits of calorie restriction and at the same time not the negative effects. That’s where these periodic fasting- mimicking diets come from.

JM: Okay. Great. In addition to that, of course, there’s a practical challenge with the application of that because people are not going to be very compliant to calorie restricting. I think in one of your earlier interviews, you suggested that maybe 1 in 10,000 people could do that because it’s just not conducive of long-term compliance.

You mentioned this fasting-mimicking diet that provides many of the molecular benefits. Before we dive into that, let’s discuss some of the molecular benefits from calorie restrictions and the ones that you’re seeking to reproduce through this new type of approach that you’ve developed.

VL: Yes. I think there are multiple advantages or potential advantages. One of them, the biggest one actually, turns out to be the long-term effects on insulin-like growth factor 1 (IGF-1), one of the factors that regulate growth pathways, growth genes. This IGF-1 really pushes the cells, all kinds of cells – Not just IGF-1, but all the growth factors. But certainly, IGF-1 seems to be the major one that pushes the cells. But there is not much to grow or much room to grow. We have a lot of evidence that this turns into accelerated aging. That’s one of the effects of these dietary interventions.

The other one that we’ve seen is regeneration, rejuvenation, meaning that by killing a lot of cells and part of organs in systems, you get rid of a lot of dead cells, bad cells, damaged cells, and you turn those stem cells and they replace the old damaged cells with new ones. That’s what we think is another major effect. The third one is probably intracellular, meaning that the cell also undergoes somewhat of a cleanup during these dietary interventions.

JM: That would be autophagy or mitophagy.

VL: Autophagy, mitophagy, but maybe there are other processes that we still haven’t quite understood that have to do with repairing the system and giving the time to the system to repair itself.

JM: Would it be fair to say that this influence on IGF-1 is also similar to the growth hormone? Because the IGF-1 and growth hormone are seen to be closely related.

VL: Yes. As far aging is concerned, they seem to be in the same axis, the growth hormone IGF-1 axis. For example, in mice, they have record longevity, are growth hormone receptor or growth hormone deficient. They are also IGF-1 deficient. That axis seems to be the most important.

Now, we followed for a number of years this group of people in Ecuador that are also growth hormone receptor deficient. They have the same or very similar mutation to the mice that have record longevity. A few years ago, we were shown that they seem to be pretty much protected from cancer and also from diabetes. We suspect that this protection is also extendable to more diseases. Although they may not be very much longer-lived than their relatives, they seem to be much healthier.

JM: Okay. Great. Now, one of the reasons I suspect that you’ve undergone or continued along your pathway is initially for longevity. The younger you are, the less important it seems to be, and as the older you get, of course it becomes more important.

Would you say it’s fair to summarize that if you optimized for longevity that you’re indirectly optimizing for actually preventing almost all chronic degenerative diseases and treating them, in many cases, if you optimize those pathways? They’re one and the same. If you’re optimizing for longevity, you’re optimizing for health essentially and prevention of disease.

VL: Yes. Prevention of diseases for sure. Treatment, I think it’s much more complicated. I think in that case, you have to exploit the understanding of normal cells and damaged cells, whether the cancer cells or neurons that are damaged, or whether they are autoimmune cells. That’s much trickier. I think that each requires a much different intervention, for example, for cancer with the combination of chemotherapy or other drugs and the timing. Treatment is much more complex to handle. I don’t think it can be handled simply by intervening on longevity.

JM: Right. But it does seem to form a foundational basis of which you can add other therapeutic modalities.

Can you describe what your fasting-mimicking diet is? It seems there are all these benefits that are being described to fasting. Initially, I wasn’t that strongly in favor of that because I thought there was some negative, like many people, some negative metabolic consequences, but it seems for most, it’s such a powerful intervention. But it’s not something you do the rest of your life, otherwise you’d be dead. Describe to us the evolution and what your fasting-mimicking diet consists of.

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VL: Yes. The hypothesis was when we first started, also considering the negative effects we were seeing from the calorie restriction, they say an immunity, maybe the response to wounds etc. We were thinking this cannot continue. As you just pointed out, we cannot be fasting all the time. You cannot even be calorie-restricted all the time. Is it possible that if you do it once in a

while, the body will have a memory of the metabolic switch and that will last a long time? That was what we tested first in simple organisms, then in mice. It worked very well.

If you take mice at middle age and you give them this periodic fasting. You put them twice a month for four days on a diet that is restricted in proteins, restricted in carbohydrates, but relatively high in fats. For just four days, it’s a low-calorie, low-protein, low-sugar diet essentially. Then you switch them back to the normal diet. It actually turns out that they eat normally, meaning that per month, they consume – they’re not restricted at all – they consume a normal amount of food, and yet they have half of the tumors. And even the tumors that develop, they develop later and a lot of them seem to be benign. They’re protected cognitively so they are much better at performing various cognitive tasks. They have reduced inflammation. They have a longer mean lifespan.

They don’t have a longer maximum lifespan and we suspect that that is because the very old mice did not like it at all to be fasting or to be on the fasting-mimicking diet. We think that now, for example, with their human fasting-mimicking diet, which we’ll talk about in a second, we basically say after 70, we don’t know yet.

It doesn’t mean that it may not be beneficial, but I think that we have to do more studies, and maybe we need to come up with a higher calorie version of the fasting-mimicking diet, which is now about 50 percent calorie restricted, so that we don’t have the good and the bad after 70. There’s no indication that before there are any problems. In fact in mice that were fairly old, they perform very well under fast-mimicking diet, but the very old ones did not.

JM: Okay. You have essentially two four-day periods in a month or a little less than 30 percent of the time in a month where they’re going to be calorie restricted, 50 percent less calories than they would normally take. It’s relatively low in protein and carbs and very high in high-quality fats. Is that a good summary of what you’re doing?

VL: That’s the mouse. The mouse study was designed like that. The human study is instead less frequent, five days a month, about the same idea, very low-sugar, relatively high complex carbohydrates, low-proteins, no animal products at all, and high levels of good fats.

JM: Okay. This is only five days once a month for the human version.

VL: Yes. In the clinical trial, we did three cycles of this once a month for five days. This was a randomized trial. Then we monitor people at the baseline, at the beginning before they started, during the diet, a week after the third cycle and then three months after the third cycle.

JM: Will this type of intervention be enough to put most people who’ve tried this into ketosis?

VL: Yes. Absolutely. They will temporarily be in ketosis. But this will only last about three days or so. It’s important not to push the patients to areas that we did not quite understand as much as we would like. I felt that the five days was an ideal time for compliance, but also for safety reasons.

JM: Most of these individuals who tried this are going to be in ketosis. Would this include the typical American who is overweight, maybe by 50 pounds or so, and has a long history of eating the standard American diet, which is high in refined sugars and processed foods? Or would they require a longer time? Because I know some people who seek to just do simple water fasting with no calories seem to have a struggle for a while to get into nutritional ketosis.

VL: Yes. We wanted to, first of all, reduce the burden to the very lowest point. This is why on Day One, for example, the human diet has got about 1,100 calories. This, I think, helped tremendously, compared to let’s say water only fasting, for compliance and also for safety. Water only fasting at least should only be done in clinics. I mean people do it outside of the clinic, but it doesn’t mean it’s a good idea.

In the five days, I think it was also important to keep the sense to patients, especially the ones who are obese like you just pointed out. You only have to do this for five days, and then you go back to what it is that for you is so important. This is, I think, really key because the adjust gradually allows the patient to move into this idea of spontaneously maybe even decide “I don’t need that much sugar anymore because I was five days without it. Now, yes, I still want it but maybe I can reduce it a little bit.” We’re seeing that a lot. It’s a slow process. But in addition to the long-lasting effects, are also some of the behavioral changes that may occur when you can at least do this for five days.

JM: Sure. Also, if they shifted more towards burning fat as their primary fuel, then they’re going to have the ability to reduce their cravings quite dramatically because they are burning fat and they are not craving the sugar as much. When you can’t burn fat, you have to have something for fuel. Your body requires and demands it. If most people are using carbohydrates to supply that fuel, then they’re going to feel miserable. But when they make that shift, it’s going to be a little easier. I think that helps the whole process.

I’m particularly intrigued because I really am fond of what you’re doing and I think that makes a lot of sense. Why don’t you just describe what metabolically goes on during this fast? I think we alluded to it earlier with respect to the autophagy, mitophagy, rebuilding, repair, and improvement of IGF-1 hormones and the magic that truly occurs. That’s sort of a negative. It’s like exercise. It’s good for you overall, but initially it actually damages the muscle tissue. Similarly, when you’re fasting, you’re actually, in some ways, damaging yourself. But the magic, I believe, occurs in this refeeding phase when you’re actually rebuilding the cells. Can you describe that process?

VL: Yes. The process, I think, is really comprehensive, meaning almost everything changes. What I tell patients is, “Work with the doctor. Be careful because this really changes your body in a way that almost nothing has. Nothing that I can think of.”

For example, the IGF-1 goes way down, the glucose will go way down, the ketone bodies are greatly elevated. The reason is, as you pointed out, that the body starts burning fat. It turns out that instead of burning all fats, it burns primarily the visceral fats. This is a really important point. We really did not see much of a significant difference in the subcutaneous fat. We saw a

significant difference in the abdominal fat, indicating that this is coming mostly from one source. Maybe this is the reservoir where the body goes first when the glucose is not coming in.

I think that the clearance of the damaged cells is also very, very important. Now, we’ve shown this in a mouse and human preliminary multiple sclerosis trial, in which we were able to show that each cycle of the fasting-mimicking diet is able to kill some of the autoimmune cells and then turn on the stem cell and regenerate cells that are no longer autoimmune.

Now the human trial is still preliminary, but certainly it was very promising. Especially when you consider, like in the mouse, we saw a temporary reduction, which is counterintuitive, but temporary reduction of the white blood cells in the patients. Over 70 percent of the patient had over 20 percent reduction in the white blood cell number. That told us that it is working in people like it’s working in mice.

The system tries to save and maybe some redistribution but also we believe killing off white blood cells, turning on the hematopoietic stem cells. Then when you refeed, and only if you refeed, the stem cells are now giving rise to young and functional white blood cells. We now, at least in the mice, have evidence that this happens everywhere, but also human clinical trial supports the notion that this is also happening everywhere in the human body.

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JM: Yeah. A particularly fascinating aspect is that it also seems to improve stem cell production. Of course we need those to continue to be healthy. In fact, many people actually undergo stem cell transplantation for a variety of reasons. But it would seem to be far safer, less expensive, and perhaps even more effective if you can do it naturally with dietary modulation like you described.

VL: Yes. I think the big advantage is the coordination, right? When you inject somebody with stem cells, stem cells don’t have a program that goes along with them. Stem cells without an order to do specific things – I think that with fasting, when the level of white blood cells shrinks and it goes to a lower level that is a clear program that is turned down during the refeeding, rebuilding, telling the system to rebuild everything that is missing. I think the advantage is not just having the stem cell, but having the stem cell know exactly what to do.

Now we have a number of papers that are going to come out on this. We’re starting to see a lot of similarities with the embryonic or the developing cells and developing organisms. This may be one of the very few interventions that bring organs and systems back to – well, of course not completely – back to that level. It certainly exploits what they always knew how to build an organ, to partially regenerate it.

JM: Sure. If we can now dive into some of the details and the specifics, I’m wondering if there is a difference in the macronutrient calorie distribution between the fasting phase or the calorie reduced phase and the refeeding or refueling phase. Are they still about the same percentages of nutrients? High percentage of high-quality fats, low in proteins and net carbs, or is that different in the different phases?

VL: Yeah. It’s different. Basically, what we did to us was also important again thinking about how applicable this is. We just told people, “Go back to whatever it is that you eat normally.” Patients just returned to their normal diet. Now, we did give them a transition, one day of transition diet that is relatively light, low-protein, minimal animal products. One day to make sure that it’s not too much of a switch from very low to very high in between diets in less than one day. Then on Day 7 or so, patients go back to their normal diet.

JM: Okay.

VL: Refeeding is using a normal diet.

JM: Okay. The challenge with that, as I’m sure you and everyone watching this understands, is that the normal diet for most people is atrocious. That would be a kind description. I mean they are just consuming fuels that are almost beyond reprehensible and never designed for optimizing longevity.

I’m wondering, with your passion in longevity and your understanding of molecular biology and studying this for decades, if you could design an optimized program, not just put people on what they’re going to be compliant with, which is probably going to be a lousy choice. If you have any thoughts and recommendations on optimizing it for those who would be complying to whatever the ideal might be.

VL: Yeah. I wrote a book on this. Pretty soon it’s going to come to the U.S. By the way, all of the profits go to research. I hope you go buy it. It’s called, at least in the Italian version, it’s called the Longevity Diet. I have to see what the American title would be. I used basically all of the decades that I spent working on aging, not just to describe the fasting-mimicking diet, but also describe the everyday diet based on the centenarian studies, the phenological data, clinical data, mouse data, etc. Putting all that together, then I can map this mostly plant- and fish-based diet. A pescetarian diet that is low in protein and high in nourishment, a lot of legumes and some fish, low sugar, high complex carbohydrates, and high good fats.

It has a lot of similarities with the fasting-mimicking diet, but of course, in a way to allow people to maintain a normal weight, and also maintain high nourishment. We see this all the time in cancer patients, but not just in cancer patients that people often go from one problem to another, from an atrocious diet, like you described, to a deficient diet. The deficient diet, whether it’s B- 12 deficient or is protein deficient, could be as bad as the atrocious diet just by shutting down the ability of the immune system to fight infections or to fight cancer cells. I think if you go too far on each side, you could be in trouble.

JM: I definitely want to explore that. But just before we do that, I’m curious as to the approximate macronutrient ratios that you came up with in your book for the pescetarian version. What were the protein levels, carbs, and fat?

VL: It’s about 55, 35, 10. Fifty-five complex carbohydrates, 35 fats, and 10 protein in percentages.

JM: Sure. Relatively —
VL: Trying to keep the protein above 0.7, 0.75 grams per kilogram of body weight per day, or

0.35 grams per pound of body weight per day.

JM: Which would come out to about a gram per kilogram of lean body mass, which might be a more accurate way to assess it because there’s a wide range of people’s lean body mass. It’s actually what you want to base it on. It sounds like it’s about a gram per kilogram. That, I would assume, underlines your previous focus and work with the mTOR pathway and the appreciation. Maybe you can discuss a little bit about that now because we don’t hardly ever have a change to interview an expert in that pathway since – well, at least initially, many people weren’t studying. There are more researchers now.

But with your specific focus on longevity, I’m wondering if you could talk about the influence of protein on longevity and health, because it’s my impression that most of us are eating far too much protein.

VL: Yes. Absolutely. We published a paper on that a few years ago, showing increased mortality in Americans, particularly cancer mortality in Americans who had the high-protein diet. This makes sense.

One of the reasons why it makes sense is that proteins, in particular, short amino acids, leucine, methionine, they are central regulators of these growth factors, particularly IGF-1, that we just mentioned earlier and that they have a pro-aging and also pro-damage effect. The higher level of protein, the higher level these amino acids, the higher activity of TOR-S6 kinase pathway. As a consequence now, we have very clear evidence in many organisms that this TOR accelerates aging and also accelerates mortality, meaning that all kinds of organisms will die earlier and develop many more diseases when they have this path reactivated.

The other pathway, which is much less known, which also was first described in my lab, is the sugar PKA pathway or Ras/PKA pathway. Now there is starting to be evidence from our lab and others that this may also be conserved. Meaning that in addition to the protein pathway, there is also sugar pathway. That is as bad or almost as bad. I think we’re probably going to hear a lot more about that. We’ve been saying that for 20 years now, but I think finally we’re starting to see this conservation of facts in multiple organisms, and starting to see the data from mice and also some of our own data from human samples. I think that, awfully soon enough, it would be more accepted as another key pro-aging pathway.

JM: I’m sorry. Could you expand a bit about the PKA pathway, because I don’t recall hearing that before and what that acronym stands for?

VL: Protein kinase A. Protein kinase A in yeast, they are known for decades that responds to sugar. The more sugar there is available, the more this pathway, this gene gets activated. This gene then in turn can inactivate certain transcription factors – in yeast, they’re called Msn2, Msn4 – that are very important for protection of the cell, but also for the reprogramming of the cell into a more what we call a maintenance state.

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For the longest time, it was just a yeast story. Now we’re starting to see evidence from mice, both with PKA and also RAS in yeast acts upstream of it. We’re starting to see evidence that this may represent another set of genes that went active, make the organism age more quickly and also develop more diseases.

JM: Okay. Sounds like they’re related to sirtuins, which we know are connected to longevity. VL: Yes. We don’t know how, but it’s likely that sirtuins – I mean we know that they’re

connected to some of these genes. It’s not clear what the relationship is yet.

JM: Okay. One of the factors that really intrigued me with your work was this focus on cycling. As we’ve mentioned earlier, there are many benefits from fasting or calorie restriction, but there’s no way you want to do that indefinitely. It’s going to be, I think, counterproductive. I’m wondering similarly if there’s this goldilocks window of protein. We’ve just finished describing the downside of excess protein. But even if you had optimal protein or you’ve minimized the activation of the TOR pathway with sort of the optimal – 1 gram per kilogram of lean body mass of protein intake.

The goldilocks window I’m referring to is this balance that we have between losing lean muscle mass as we age, or sarcopenia, and sort of keeping the optimized activation level of TOR. Do you think there’s a benefit to going to high levels of protein, maybe 1.5, 2 grams per kilogram for a short period, maybe a day when you’re doing strength training exercises, then go into this cycling method. It’s sort of a similar cycling that you’re doing with the fasting-mimicking diet.

VL: Yes. I think so. There are a number of groups that are now looking at the relationship between protein and muscle protein synthesis. I think that they’ve clearly shown, for example, that 30 grams of salt proteins are needed in one single meal, associated with strength training, in order for the muscle protein synthesis to occur. I will say that there is an optimal level.

We have also, in the paper that I’ve mentioned earlier, we showed that there were before 65 and after 65 groups, meaning that people that were 65 or younger, benefited from the very low protein, but people who were 65 and older did not benefit. We suspect that that is because in the 70-, 80-year-olds, that extreme low level of protein intake may not be as beneficial.

Now, the correct study has never been done, meaning that there has never been a study where you take 1,000 healthy 80-year-olds and you give them exactly a low level of protein and you see how they do compared to the ones that eat 1.5 to 2 grams per kilogram a day. I suspect that they will still do better. Because usually when these studies are done you do a survey among the people that report having low protein are people that are sick, people that are frail, people that are malnourished. You bunch them all together. You might have 10 percent are super healthy, but 90 percent have problems.

It’s amazing that even before 65, that group performs better or much better than the well- nourished group. Anyway, most likely, the lower layering life higher protein intake is better, but

a very high protein intake is probably still detrimental. There was no evidence in our study that the people that had the high protein intake, even at older ages, did better. It was sufficient to do the moderate protein intake even in older ages.

JM: That’s good. I know the studies haven’t been done, but I’m wondering, from your understanding, the molecular biology of it, if it still makes sense to do this after you’re older, 65 or 70, to do this pulsing version, especially integrated with weight, strength training, and exercise program. Not to have high protein or higher protein every day, but to have higher levels every day.

I was not familiar with the 30 grams per meal intake on those days that you’re doing the strength training. Maybe two to three days a week, maybe four days a week. Would that make more sense and then go back to the lower versions? I mean this pulsing seems to be key to biological health.

VL: Yeah. I don’t remember the exact number. But they were talking about leucine as being the key activator for TOR, and TOR being an important trigger for the building process. They basically published that once you push TOR and you start the process, 30 grams are all you need. It doesn’t matter whether you have three times as much. Now if you do that twice, you might get that building twice, occurring twice. If you do it in the morning and do it at night, then of course that makes a difference. This is what the studies really clearly showed.

Answering your question, the pulses are key because that’s all that matters. You just have to have enough protein, TOR activation, the building process occurs and then that’s long lasting. If you just did that once a day, it would probably be sufficient to keep good muscle mass. They haven’t done long-term studies on this, so we don’t know the best way. But certainly, the short- term studies indicate that you don’t need a very high protein, but you do need sufficient protein and you need the training to optimize the muscle building.

JM: Those of us who aren’t researchers don’t really have access to measure the TOR pathway like you do. I have no idea. Once you activate it with the 30 grams of optimized branched-chain amino acids, how long does that pathway stay activated for? Is it an hour, two hours, 12, 24? I have no idea.

VL: I don’t know if anybody has done that in humans, so we don’t know. But we do know that that activation, once you have enough of the amino acids, that activation is sufficient to carry on the long-term protein synthesis in the muscle. It may not matter how long it stays on. It may just matter that the process is activated and maybe the satellite cells in the muscle are going to work to generate new muscle and bring in the amino acids to do the building. I think for people out

there, I don’t know that it’s necessary to know how long TOR is on, but maybe the amount of the amino acids is sufficient to get the muscle effect.

JM: Okay. Thank you for that explanation. Now you also have sought to use this intervention, this fasting-mimicking diet, in the treatment of cancers in the university that you work with. From watching the previous interview that you did, it sounded like it was an arduous process in that it took five or six years before they even got to the point where they were willing to adopt it until you radically modified it. Why don’t you comment on that attempt and where you are now with it?

VL: Yes. The initial diet was fasting, water only fasting. We felt that people wants me to explain what the potential was. They would do it. But patients didn’t want to do it. Oncologists didn’t want to do it. It took us forever to even collect data from 18 patients. We just recently published on that.

Then we went to the National Cancer Institute and they funded a grant to develop what we call “fasting-mimicking diet.” That’s where the fasting-mimicking diet comes from, from our cancer studies actually. We eventually adopted it to normal people. We developed this diet.

The idea was a diet that has the same effect on IGF-1, IGFBP1, glucose and ketone bodies as water only fasting does. We had to match the efficacy. It was important to Dan Klein that this has a reasonable chance to be as good as water only fasting in the a) protection of patients against cancer, and b) desensitization of cancer cells to chemotherapy. Sorry, protection of patients, not against cancer – well, against cancer, but more so against chemotherapy, and then making it worse for the cancer cells once the patient receives chemotherapy.

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This we’ve shown very, very clearly in mice. Now we have data in multiple clinical trials supporting this. I have more studies coming out in the next year or two. Hopefully, soon enough, this would be standard of care.

JM: With the publication of your studies, do you believe that there is an increase in adoption of these fasting-mimicking diets by oncologists to at least use this as an adjunct to their current treatment program?

VL: Yes. Both in oncology and other doctors, I think there are about 600 doctors in the U.S. alone that recommend fasting-mimicking diets developed in my lab. In cancer, of course, it’s a little bit trickier because oncologists are waiting for the more conclusive clinical trials. We understand that. I think soon enough – well, we’ve already seen a big difference.

There are a lot of oncologists that are already saying “My patients can now wait. I will allow them to go on a fasting-mimicking diet or a fasting.” Some of them are resistant. Some of them are very favorable. Some of them even encourage it. But I think it’s going to be much, much higher used once the larger clinical trials are completed.

JM: Great. Another researcher has been doing this for a while using these types of diets to treat cancers, Dr. Thomas Seyfried, who I’ve interviewed. He’s a professor of Biology at Boston College. I’m wondering if you could describe the differences between his approach and yours. My guess is that he’s doing a more chronic long term, although he has some interventions of periodic fasting and water fasting. But I think it seems like you have more cycling in your process.

VL: Yes. Actually completely different. As far as I know, his diet is a ketogenic diet. Very high fat, normal calorie, I think relatively high protein diet.

JM: No, no. It’s not high protein.
VL: But it’s relatively high, right? So —

JM: No. It’s still about a gram per kilogram. Maybe 10 percent are calories, 8 percent of calories, somewhere in that range.

VL: Okay. One gram per kilogram. But it is said there that there is a good amount of calories because it’s normal caloric. A good amount of calories come in from proteins, which we of course have shown, for example, in our mouse studies to be able to completely reverse the protection of normal cells.

If you have the fasting-mimicking diet or fasting, and then you give mice a normal level of protein, they can reverse a lot of the protective effect. That’s why we take it to a much lower level than that. Of course, there is this chronic, meaning you give it to the patient for a long time and we just give it to the patients for five days. As far as I know, their major use has been for myeloma patients, right?

JM: A very difficult cancer to treat. Notorious for being resistant to conventional treatments.

VL: Now, the question for the ketogenic diet. For example, we used it for multiple sclerosis in the mouse model. Even though it was chronic in the mouse model, at least for multiple sclerosis, it didn’t work very well. It worked a little bit, but not very well. One of the reasons for that may be that once you maintain the normal level of calories coming in, the body figures out how to get back by gluconeogenesis, etc. a relatively high level glucose. I’m not sure how it affects for example growth factors.

Those are things that we’d love to look into, especially because we know that growth factors and glucose levels are very important to health. Low levels of this are very important for the effects that we see in both the normal cells and on the cancer cells.

JM: I sort of stumbled onto a process that I call “Feast-Famine Cycling,” which is somewhat similar to what you’re doing. I personally engaged in long term, you know by six months or so, of chronic ketogenic nutritional ketosis. I started noticing some adverse side effects. I think it’s probably related to the mechanism of the action of insulin, which many people aren’t aware of.

The way insulin works is not by driving glucose into the cells, that’s what’s conventionally taught, but it really works by stopping the liver’s ability to produce glucose. If you have very low levels of insulin, you’re not going to be able to suppress hepatic gluconeogenesis. Your blood sugar, paradoxically, even though you’re not having any carbohydrates, it will rise pretty dramatically because your body wants that high level of sugar.

Interestingly, when you have relatively high glucose level and you have really low insulin levels, if you eat sugar, your blood sugar drops, which is absolutely counterintuitive. But it’s related to the mechanism of insulin. That’s when it became really clear to me once I understood that you really have to do the cycling, because you really do want to keep your glucose level low. If you do too much of the glucose restriction and protein restriction, it’ll be counterproductive. This cycling is absolutely imperative. I think that is the key to optimizing the whole molecular pathways that are involved in chronic disease and longevity.

VL: Yeah. I think you hit it right in the head. Meaning that if you understand the mechanisms, like you just described, this is really important. This is essential. You have to understand exactly what goes on. Because if you don’t, you’re going to get surprises. I think maybe you were surprised after six months that you’re starting to see problems. I’ve also seen some of that, for example, in the alternate day fasting.

There are some papers showing benefits, but there are some papers showing detrimental effects. It’s just up and down, up and down. They may not be doing this all the time. It may be not such a good idea. I don’t know. I’m not saying I’m not against it. I’m just saying that you need studies and you need mechanisms. Until those are available, I warn people to be very careful because it could give you surprises.

JM: In another philosophy that I resonated with that you have is basically that a little bit of knowledge is dangerous. By that I’m referring to the use of drugs, specifically metformin and rapamycin, which we know have beneficial effects and may be useful agents in certain disease states, but to be used prophylactically by those who are seeking to extend their lifespan may not be a wise idea. But you see a lot of people recommending and endorsing these strategies and I just cringe when I hear it. But I was just overjoyed to hear your perspective on this, which was “Don’t do it.”

VL: Yeah. I think that whether it’s metformin or rapamycin, we discovered that TOR pathway and aging, so we would have loved to say “Take rapamycin every day, which is a TOR inhibitor.” But I always thought from the very beginning, we actually had the first data on rapamycin in 1997. We never even published it. The reason why is that we felt that if it’s so essential to the cell, how can it be that you block something to essential and it just does good and no bad at all, right? I couldn’t believe it.

Then 2009 came and other studies came and still no negative. Then you started seeing all the negative studies: hyperglycemia, cataract accumulation, testicular degeneration, etc. After the good news came the bad news. I think that’s what people underestimated. When you have a sophisticated blockade but very unsophisticated effect, which is completely block an enzyme, that’s most likely going to have bad effects sooner or later.

JM: Yeah. I think part of those side effects that were described were related to the chronic uninterrupted use of those in relatively high doses completely suppress it. Maybe, just like what we’re talking about cycling, that the smaller doses done intermittently might have some benefits. But certainly, it seems to be far wiser, safer, less expensive and far less side effects is to do it with your food.

VL: I think so. Also because there is a long, long history of use by large clinics, the Buchinger Clinic in Germany, the TrueNorth Clinic in the United States, these clinics see [inaudible 50:04] year. They do much more severe restriction for much longer times.

[—–50:00—–]

The safety record, at least according to them, is extremely good. That was really reassuring for us. I mean we felt that we had to the clinical trials, but it certainly was good to know that thousands and thousands of people that do much more severe intervention every year and they’re fine.

JM: I’m wondering as the director of the Longevity Institute, if you’re still actively involved in longevity research, specifically as it relates to dietary strategies.

VL: Yes. Absolutely. I say 50 percent of my lab works on longevity. In fact, all these series of papers that we continue to publish dealing with regeneration are really focused on rejuvenation. Can you make the brain younger? I think that that’s really going to be a big research effort in the future for us and for many other people. I think, again, the ability to awaken systems that have been dormant for a long time and then know exactly what to do is very much underestimated and underutilized.

I think we need to really exploit these billions of years of evolution that generated these programs that are so good in making a perfect liver or a perfect heart. Of course we’re only beginning to understand that, but if we were able to fully understand how you regenerate or how you generate a heart to begin with, and can you redo it in an adult? We don’t know that. But certainly this fasting-mimicking diet suggests that at least some of that can occur with every cycle. Definitely longevity is our key interest.

JM: Yes. My guess is that some of our viewers may be a little bit distressed when you say billions of years of evolution on that, but that’s not certainly human evolution, but many of these pathways that you’re studying are in very primitive organisms that have been around for that long. Maybe you can touch on that before we go to the next question.

VL: Yes. My work started with bacteria many years ago. You starve bacteria and they live longer. After that, I starved yeast, also unicellular organism, what we use to make bread. A microorganism, and they live a lot longer. It was very obvious that this is something that started billions of years ago, the ability of any organism once it’s starved to stop and go into a protection mode that may be also somewhat regenerating and rejuvenating.

JM: Terrific. I have two questions for you with respect to aging. As an aging and longevity researcher, if you could provide your best recommendation for what to do now on that and would just essentially be just reading your book on the longevity diet that hopefully would be published in the United States soon. Answer that question. I have a follow-up question for that.

VL: Yeah. Before the book comes out, I have a Facebook, Prof. Valter Longo page that people can go to get updates. In the pescetarian diet, that I’ve already described, the key is low protein but sufficient two phases of life. When you get older, keep a normal weight and be highly nourished even if you have to add to your diet more ingredients that might not have been part of your diet before.

For example, I started talking in the book about some cheeses that all the centenarian population around the world, like goat cheese. You may not have wanted to use frequently when you were younger, but you can use when you’re older. Or maybe some yogurt, or maybe some eggs. Some of these things I exclude before 65 to 70, but then I say, “They’re really very rich in nutrition.” A lot of centenarians do it, so it might be a good idea.

The other thing I talk about is 12 hours on, 12 hours off on food, meaning that you can do eight to 16. You only eat for eight hours a day and then you fast for 16. But I think it’s too extreme. There are some data, some studies suggesting increased gallstone incidents. Twelve and 12 is probably a very good compromise. I always liked to say “Let’s get the benefits, but let’s not risk the negative.” Twelve and 12 is really a good thing to do, especially if you tend to gain weight.

I also introduced the concept of two major meals a day for people that tend to gain weight or are overweight, and three meals a day instead for the people that don’t have the problem or tend to lose weight. That’s also very important, that the abdominal fat is regulated and just the overall weight stays healthy, both not being underweight or overweight. Those are the major recommendations and the high nourishment.

I also, for example, give simple advices like, “take a multivitamin every three days.” Why every three days? Because probably every day, you will eventually find out that that’s not good for you. Some studies suggest that. But every three days, it probably eliminates most of malnourishment. At the same time, the chance that it does you damage is extremely low, considering how many studies have been done on them and showing usually neutral effects.

JM: Do you think there’s any concern about using intermittent fasting long term or should that also be cycled up?

VL: Intermittent fasting usually refers to every other day fasting?

JM: Oh. I’m sorry. That’s a good question. Let me be more precise with my question. By intermittent fasting, I’m referring to the 12 to six or eight-hour window of restricting your calorie ingestion. That’s my term. Can you do that long term or should you cycle that up, too?

VL: No. The 12 and 12 is what people have always done, right? It’s called time-restricted feeding. But if you look at centenarians, whether it’s Loma Linda or Okinawa or the Southern

Italians, people that are most successful almost unanimously contain their feeding period within 12 hours, 8 am, 8 pm. I think that the chance that that is going to cause problems is extremely low.

If you go to eight hours, it’s different. Now you start to say 8 am to 4 pm, well it could not have any effects, or maybe it is a contributor to this weight loss a lot of older people will have, which usually is associated with frailty. I don’t think it’s such a good idea. Again, after 65 to 70, people tend to lose weight. I think it’s better to increase the food intake, making sure that a healthy weight is maintained. Some of these things are way underestimated, the importance of them.

JM: Okay, good. The next question to that with respect to the meals, I’ve come to believe from a molecular perspective (I’m studying the mitochondria) that it may be unwise to have your largest meal certainly before you go to bed, but even later in the day.

Ideally, the best timing for your largest meal of the day or the greatest amount of calories would be before your biggest activity. For most people, that’s going to be either in the morning or at noon. When people eat a large dinner, sometimes socially there’s not really a practical alternative. They come home to their family. They’re going to eat at 6 or 7 o’clock at night and they just watch TV and go to bed. I’m not sure that that’s the wisest strategy for optimizing longevity.

VL: Yes. It probably is not. In the book, I talk about staying about four hours away, having about four hours from your last meal to your sleep time, as long as it doesn’t bother you. If you keep it four hours away and you don’t have reflux or other problems, I think it’s fine. I did not see any evidence for that being a problem or any evidence that it shortens your life. But for most people, this could be a problem. I think you’re right. A larger lunch. This is very typical among centenarians, to have a large lunch and very small and early dinner.

JM: Okay. Great. I’m wondering, again, as 50 percent of your research is on longevity, if you’re involved in network with all the other researchers who are doing this. What do you see as the most promising intervention that you could suggest that lies on the horizon that might be able to be utilized in the near future?

[—–1:00:00—–]

VL: I think time-restricted feeding, so that this restricting the time of feeding in the workplace by Satchin Panda and others, I think is the most promising. Of course, metformin would be very nice, once A. Barcelo and others that are studying it come up with large thousands of people studies. That would be very interesting especially because at least a percentage of the people are not going to be able to do either time-restricted feeding or periodic fasting, or fasting-mimicking diet. I think for them, maybe metformin, if it turns out not to have side effects after you do it for 20 years, maybe that’s a good option. But we’d love to wait and see.

JM: Alright. I think I finished my questions. I’m wondering if you have anything you’d like to emphasize or some topic to review that I haven’t already asked you about?

VL: No. I think the main thing is to work with established products, but also doctors and nutritionists and dietitians to make sure that the power of these diets is not underestimated. I think a lot of people think that they can do it at home. They can just cook it up. We’ve seen, both in Italy and the United States, a lot of people ending up in the doctor’s office with a lot of problems because of that.

JM: Okay. Good. We’ll definitely keep posted on your new book. Any idea when it’s going to be out in 2017 in the United States?

VL: I hope by the end of the summer. Again, if people go to the Professor Valter Longo Facebook site, I’ll give them an update on our papers, when we publish things, and also when the book is going to come out.

JM: Perfect. The best way to keep in touch with what your research is doing is your Facebook page, Professor Walter Longo.

VL: Valter Longo, with a V.

JM: Valter. V. Not with a W, with a V. Alright. Thank you for all your research. I greatly appreciate the time and opportunity to capture a portion of what you’ve been learning for the past few decades. It’s always a privilege to connect with people who, like you, are so committed to uncovering some of the details of what it takes to be optimally healthy.

VL: My pleasure. Thank you very much. [END]