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The Melanie Avalon Biohacking Podcast Episode #115 - Valter Longo, Ph.D.

Valter Longo, Ph.D., has thirty years of experience in the field of longevity and healthy nutrition. He is the Director of the Longevity Institute at the University of Southern California – Leonard Davis School of Gerontology, Los Angeles, and the Director of the Longevity and Cancer Program at the IFOM, The Italian Foundation for Cancer Research (FIRC) Institute of Molecular Oncology in Milan, Italy. He is the author of the best seller “The Longevity Diet” and the 2 Italian books “Alla tavola della longevità” (“At the Table of Longevity”), and “La longevità inizia da bambini” (“Longevity Begins in Childhood”). Professor Longo is also the scientific director of the Create Cures Foundation and the Valter Longo Foundation. In 2018, TIME Magazine named Professor Longo as one of the 50 most influential people in health care for his research on fasting-mimicking diets as a way to improve health and prevent disease.



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The Longevity Diet

10:00 - valter's Story

11:35 - why do we age?: Programmed aging

15:40 - do all species have an aging program?

16:30 - the longevity program: Offensive or defensive of aging?

17:15 - the relation to fertility

17:30 - the evolution of the longevity program

18:55 - "maintenance mode"

19:20 - what age do we enter each "mode"?

20:50 - the concentrated growth mode

21:45 - where is the information for again stored?

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26:20 - the research in calorie restriction and low protein for anti-aging

27:30 - the danger of Malnourishment and immunosuppressant

29:30 - bone fractures from lack of protein

30:05 - are the benefits additive, if you exclude for the downsides?

31:45 - mTor activation following a high protein meal

33:10 - transitioning off of a high protein diet

34:25 - plant protein vs animal protein

36:55 - high growth factors

37:40 - high protein vs energy toxicity

38:00 - milk based products

38:50 - the research in mice compared to humans

42:00 - the fasting mimicking diet

43:40 - biomarker response to the fasting mimicking diet

45:00 - Cholesterol and triglyceride markers

45:35 - fasting more than 12 hours

47:55 - breakfast eaters that also fast

48:40 - gallbladder study in fasting individuals

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54:20 - the 4 markers of longevity; the difference fasting vs fasting mimicking

57:50 - eating the proLon diet in a shortened window

58:10 - The proLon DIY

ProLon - Fasting Mimicking Diet

1:00:30 - STEM cells, is it a limited resource?

1:02:10 - fasting mimicking effect on autoimmune conditions

1:04:45 - the future of anti-aging and longevity: repair or replace?

1:06:30 - Embryogenesis


Melanie Avalon: Hi, friends, welcome back to the show. I am so incredibly excited about the conversation that I'm about to have. Listeners know that this topic is obviously very, very near and dear to my heart. I'm also the host of the Intermittent Fasting Podcast. Fasting is something I talk about and think about and research and do all the time. I am here right now with, honestly, a legend in the fasting sphere. I'm here with Dr. Valter Longo. Dr. Longo I went to USC, so fellow Trojan here, but he is the Director of the Longevity Institute at the University of Southern California, fight on. He's also the Director of the Longevity and Cancer Program at the IFOM in Italy. He's the author of the bestseller The Longevity Diet, which I read, actually I was going to say the day it came out, but I had a pre-copy of it. So, I read before it came out. But I also recently just re-read. He does so much in the fasting world, so much research, so much science. You also might know him as the developer of the fasting mimicking diet and ProLon, which I'm sure we will get into. I'm just so, so excited. I have so many questions. Dr. Longo, thank you so much for being here. 

Dr. Valter Longo: You're welcome. Thank you. 

Melanie Avalon: To start things off, most of my audience is probably very, very familiar with your work. I was wondering if you could tell a little bit about your personal story about what made you so interested in fasting and aging and longevity, and especially, like I love how you talk in the book about how in your background originally you were into music. It's a completely different train of thought, but how that actually relates to what you're doing today as well in your perspective of everything. A little bit of your story.  

Dr. Valter Longo: I was a music major, actually just performance major in Texas, University of North Texas, which is a great jazz program. But I'm pretty sure I wanted to study aging, because as soon as I was 19, as soon as I had an opportunity, actually they asked me to direct the marching band, and I refused. And so, they said, “Well, if you don't do this, you got to do something else.” I immediately said, “I want to study aging.” I went to the biochemistry department. I taught chemistry and biology, that's got to be the way to study aging. It was probably a good idea. I just thought what an incredible opportunity for science, to do science and to become a scientist. Even at that stage, I realized how aging was at the center of medicine diseases. I just felt it was such an incredible combination that I couldn't possibly think of anything else that would be so, so important to me, including the music. 

Melanie Avalon: One of the things you talk about in your book is how most of the medical system focuses on disease rather than the concept of aging. One of the things you say in the book, that is something that I've thought about a lot, is you talk about how people often ask, “Why do we age?” But if you step back and think about it, maybe the more appropriate question is, “Why wouldn't we age?” Then there's so many theories of aging. One of the dichotomies you set up that I'm also really fascinated by, is on the one hand, there are lot of theories about programmed aging. This idea that we wouldn't age, but we're programmed to age and so we have this program that causes us to age, but then you pause it that maybe instead, there are longevity programs, which I'm assuming if there are longevity programs that would insinuate that maybe we're naturally set up to age, but we have programs, so that we don't age. I was wondering if you could talk a little bit about the nuance or the difference there or what do you think is actually happening? Are there programs that are causing us to age? Or, are there programs that are keeping us from aging? 

Dr. Valter Longo: That's a great question. Back in the days of Darwin, Wallace, and lots of others, they all had thought that aging was likely to be programmed. Meaning that if we try to stay be selfish and live as long as possible, we will probably hurt the species. But eventually, they forget about that and this went out of fashion maybe over 100 years ago. It was replaced by all kinds of other theories, evolutionary theories which do not involve a programmed to age. Most evolutionary biologists will say, “We're not programmed to age.” And then, we came around, I think, I forget how many years ago, almost 20 years ago, and we published a paper in yeast, in our unicellular eukaryotic, we’ve been demonstrating that they were programmed to die as an organism. But then, of course, one thing is a simple organism like that unicellular, one thing is human beings. We propose that aging can be programmed, but that doesn't mean that every organism is programmed to die, which is very different from program longevity, which is the name I gave to my own theory of aging.  

I basically thought, well, who cares about aging. I always say, I'm in the school of gerontology, but I always very much dislike gerontology, the study of aging. I'm much more interested in the study of youth. The study of health. So, then the question is, how do you maintain a youthful state for however long? How do humans stay young for 40 years? What is the program the term is that? I thought, that's got to be the way to look at aging, not so much what are all the details of how things go wrong, but what is this beautiful program that keeps everything almost perfect for so many years? In a mouse, that's a program that goes about one and a half years, the mouse lives two and a half years, and this very sophisticated youth programs last one and a half. In people, we live for 80 years, and they say that their program lasts about 40 years. But can we make it 60 or 70 years? I think we can, but it's not easy. I think that's hopefully the answer to your question. 

Melanie Avalon: You said not all species have these programmed aging, are there exceptions?  

Dr. Valter Longo: We only demonstrated for one. Darwin and company will be very jealous of the technology we now have, because they had that idea a long, long time ago, 150 years ago or so, but they didn't have the tools to test it. I think then the theoretical people came around and say, “This is all wrong,” but this is now just tested and demonstrated, I think most, people argue you with that, for one simple organism. And it doesn't mean that a mouse, or a monkey or a person are programmed to age, but maybe. This opened up the possibility that not only there is a longevity program, there is also that problem. 

Melanie Avalon: Do you think most animals or species have the aging program? 

Dr. Valter Longo: It's hard to know. I think it's possible, but it's very difficult to know. Even more difficult to demonstrate. It took us 10 years to demonstrate in yeast. We talked a lot about it, how would you demonstrate this in people, and it's even hard to come up with the experimental power to demonstrate, so we couldn't figure out what will constitute the demonstration. Maybe that's one of the reasons why we never got into it. 

Melanie Avalon: It's pretty cool, though, vindicating Darwin, and all these people from so long ago. The longevity program, is it an offensive or is it a defensive? Is it actively creating youth? Or is it just defending from aging? 

Dr. Valter Longo: Offensive, by far. It's force of natural selection, is why it's called the force of natural selection, so on the attack. You have a force that whose purpose is to keep everything almost perfect. Why is that because the offspring has to be almost perfect. Until it is, the whole process is futile. Until everything is almost perfect, it's better not to do it at all. This is why if you do not have enough calories, the system doesn't allow you to reproduce. Basically, makes the decision that you don't have enough to carry out the almost perfection. So, I stopped you from doing it in the first place. 

Melanie Avalon: Does the longevity program always relate to fertility? 

Dr. Valter Longo: Yeah, to evolution, and therefore to the ability of propagating the germline, the DNA. Yes. 

Melanie Avalon: If humans reaching a point where we don't necessarily have children, do you think that longevity program would eventually figure that out and adapt accordingly? It seems it kind of isn't aware that we don't always have children now. Why is it still in place, if a person doesn't have a child?  

Dr. Valter Longo: Well, because this is millions and millions of years. It takes millions of years to develop this, and it will take millions of years to go away. The system came up in response to a need, of course, to protect the germline, protect the DNA and make sure it keeps on going and it keeps on expanding. Now of course, we don't reproduce that much. Or if we do, we only do that for a couple times in our lives. So then while we and others are working on is, can you exploit this fact? Why are we always stuck in this reproductive mode growth and reproductive mode, when we never use it? We're not growing, we're not reproducing 99.99% of the time. So, why are we always in that mode? Like you say, that mode belongs to ancient history. Now we're saying, well, why don't you switch to our what's called a maintenance mode, standby. And only when you need to reproduce, get back into this reproductive mode, and reproduce? Then we see in lots of organisms that when you go to the maintenance mode, you age much more slowly, so that's what we and a few others have been proposing. Let's stay in this alternative mode, most of the time, until it's necessary to get into the accelerated aging mode. 

Melanie Avalon: Those different modes, like the growth in the maintenance mode, for a typical human, what years did those modes start at? 

Dr. Valter Longo: Well, those modes will start at, let's say, maybe 13 or 14. It's a difficult question, but let's say you're 13 or 14, when you become reproductive, from that moment on, you're both growing and reproductive. In a sense, we're always stuck in that mode. From that age on, it never goes away. Why? Because historically, nobody cared about us. Evolution, let's say, not nobody, but evolution doesn't care about. Evolution cares about the DNA. Then evolution basically selected based on, I'll keep you stuck in the growth and reproductive model, so you can have as many children as possible, and then get out of the way, or possibly take care of your grandchildren. So, there's some hypotheses about that. But yeah, so now, of course, if you don't do that anymore, could you let's say, at age 18 or 19, once you're fully grown or 20, could you now go and be in a maintenance mode until, let's say, 32, you decide to reproduce, you get back in that just enough to reproduce, and then go back to the maintenance mode. 

Melanie Avalon: Rather than having a blend of growth and maintenance, having a concentrated growth mode, when you're reproducing? 

Dr. Valter Longo: Yeah, the idea back in the days was, of course, to have 20 children, 25 children. Maybe half of them will die and the other half will not die right away, maybe half of that would die eventually before age 20, so you needed 25 to hopefully have 2 or 3, they make it 50 or 60. 

Melanie Avalon: From this concept of fertility, in a way, a pre-puberty child compared to somebody in menopause, are both in a state of not fertility, yet the child, the body knows that it hasn't had a child yet. With the menopause, it's like the body knows that it had a child. Where's that information stored because for the baby, they're not aging, because they haven't had the child yet. With on the flip side, the menopause, even though they're not fertile, their body knows they've had a child, so they're aging. Does that make sense? Where's this information? 

Dr. Valter Longo: Well, of course, in the child, the idea is that the human organism is very complex, and needs a long, long time to build that complexity and sophistication, and that perfection. Then with the menopause, the argument could be in line, and this is an argument and speculation could be in line with programmed ageing. It is possible that at a certain point, evolution put a stop at women's ability to reproduce because of some of the arguments you can make about older people taking up the resources. That's one possibility. The other possibility is, maybe the older woman is now able to take care of all these children better if she stops right then, because she doesn't know how to stop, there is a biological stop to it. That will also make sense. 

When you're 50, if you could continue to reproduce, in the old days, instead of having 25 children, you will have 45 and there is a danger that you're not going to be able to take care of them, there's also danger that as you're getting older yourself, you're going to have damage offspring. And so now, there is another reason to maybe put a hold to it, but it's speculation. It's not a field that is very developed. It's extremely interesting one, but I've never seen any official explanations for menopause.  

Melanie Avalon: This is so, so fascinating. Practically and realistically, extending our lifespan, what have you found in your research with yeast and rats and humans as far as fasting and calorie restriction and low protein intake? Are these all stimulating the same genetic changes? Or, are they different pathways? 

Dr. Valter Longo: They're all stimulating the same evolutionary strategy. Proteins and fasting removes everything. If you're fasting the system is forced into this maintenance mode, because there's just not enough-- nothing to grow on and nothing to reproduce with. But then proteins are at the very center of that a big growth and reproduction. If you have proteins, you're not going to be able to have a child, so that it makes sense that the removal of these ingredients will cause the system to force the system into this alternative, slower aging mode. And that's exactly what we observe. The problem that for 100 years was ignored by many, many people, including my boss, Roy Walford, back in the days at UCLA, was that this can also if you don't really, really, really know what you're doing come with malnourishment and lots of problems. 

The wishful thinking for the longest time was that the severe restriction was all good. Now we know it's about health good and health bad. I always say, most things that are old, the health good and health bad. If you are severely restricted, yes, you turn this alternative mode and you age more slowly, etc. But then you also become malnourished and you may be immunosuppressed. So, immune system might start malfunctioning, you lose muscle mass, you lose bone density. Just to give you an example, paper came out showing vegans have two-and-a-half-fold increase in hip fractures. Just by being vegan, not even no restrictions and just probably a pretty good diet generally. Now it doesn't mean that every vegan is malnourished, but certainly two and a half times more factors, it's just remarkable.  

The other side of the metal is malnourishment. With the fasting, and particularly periodic fasting, the question has been, can you just intervene, let's say once every three months for five days? And could that reprogram the system into a maintenance mode without making you lose the muscle, the bone, and without forcing you to do something extreme and very unpleasant for so long. I guess I spent 30 years now since the Walford years in 1992 investigating how to do that and I think we feel we're pretty close to that. 

Melanie Avalon: Going more into that, that three-day program. Just practicing mentioning the vegans for example. So, is that from the low protein intake, the bone fractures? 

Dr. Valter Longo: It's probably mostly from the low proteins, it could also be from the general low calorie. It's low calorie, low protein, but then also the restriction. No milk, no cheese. The pescatarian, for example, they did not have that problem. In most cases, they were even better. There was a trend for better than the carnivals, but for the vegans, you saw-- so lots of restrictions, and on top of that protein restriction. Why? It will take about half a kilogram about one pound of legumes per day to have enough protein for most people. 

Melanie Avalon: If there weren't those issues, do you know if the effects for the aging perspective are additive, assuming you don't die from malnourishment? If you combine low protein and fasting or combine calorie restriction and low protein, do they add on to each other? Or, is it pick one, like low calorie or low protein? 

Dr. Valter Longo: They may add on to each other, but they may add on to the problems as well. If it is a very low calorie, low protein, you're never going to get diabetes, let's say, you rarely, rarely get diabetes, you're probably going to be very protected from cardiovascular disease, you're going to protective from cancer, at least there's all the data to just including lifelong data for monkeys. But you might be very vulnerable to viral infections, and it doesn't even have a bacterial infection. It doesn't even have to be all viruses, all bacteria, it could even be protected against some, but if all of a sudden, you're only protected against health for the type of bacteria and the type of viruses that puts you in very high danger eventually to be in trouble because of an infection. They could be additive, but it could be additive in the good and in the bad. 

Melanie Avalon: That makes sense. I'm so fascinated by it, because the diet that I pretty much follow in my daily life, is I do intermittent fasting, one meal a day in the evening, but it's extremely high protein, actually. I'm always wondering if since I'm doing the fasting, is that creating all the benefits while still getting all the benefits of high protein? Do you know how long mTOR remains elevated from a high protein meal? Can it be mitigated by a daily fast? Or, do you really need to fast longer? 

Dr. Valter Longo: It's certainly been mitigated. I would say there's really no reason to have a high protein diet. There is no reason for muscle building, there is no reason for anything else that I've ever seen, so the data, even in children that have very high protein diet is almost undetectable effects on growth, compared to those that have normal protein diet. Probably best to go to a normal protein diet, then the rest of it is that you decide to do. But I think that there is really, I don't remember, because even the studies on muscle building, they show about 30 grams of proteins of good quality proteins, maximize muscle growth in that particular training session. Let's say that you went to 60 grams a day, that's about as much as muscle as you could possibly grow. So, yeah, and that's still a pretty reasonable, reasonably low protein diet. So, yeah, I would not know of one benefit of being on a very high protein diet. 

Melanie Avalon: I like it for the extremely high satiety. I basically eat a lot, but I think it might end up being naturally calorie restricted just from the satiety factor. I want to be low protein and spirit, and when I try it, I just get starving. I don't know if that's like, maybe I need time for my nitrogen balance turnover to adapt to it, but I'm haunted by this protein question. 

Dr. Valter Longo: The recommendation I give is to, of course, you do need an adaptation period. The recommendation I give is to eat lots of good fats and lots of vegetables. They actually have the same effect. It might take you a couple of months to convert. But let's say that you rotate among the vegetables that you like and don't hurt you, or don't bother you. Eventually if you have a big dish that contains, let's say, olive oil, and broccoli, and spinach, and whatever it is that you like, that eventually will fill you up. Both at the level of the intestine and the stomach, and at the level of the brain, for the great majority of people. It is possible the genetics do affect people in different ways. You might have some genes that make you particularly dependent on animal protein to say. So, that's a possibility. 

Melanie Avalon: Have you done studies on high plant protein versus high animal protein, or on the flip side, low plant protein versus low animal protein and how that affects things? 

Dr. Valter Longo: We've done that, and we've done it along, and we've done it with Ed Giovannucci of Harvard. In both cases, if you look at overall mortality, those that had high proteins from animals, they live shorter, and there was quite a difference. The low protein people had 75% reduced risk of mortality, compared to the high protein group. But if it was high from plant, then that effect went away. When it came to cancer, that was no longer the case. It went from four-fold increased risk to three-fold increased risk for those that had the highest protein intake. Ed Giovannucci showed the same thing. Showed the lots of negative effects of a high protein diet only if it is animal based. 

Melanie Avalon: Are those people eating like a maintenance diet, calorie wise? 

Dr. Valter Longo: No. Your case and the case, so many people, of course, yeah. If you're doing certain changes, they may be that they help against the high protein, but it may be that if they do not. So, you're gambling basically. It's a big gamble. This is why in the book, I talk about five pillars, and the idea is, let's say that you do 18 hours of fasting a day, and then you have lots of animal proteins, could the 18 hours of fasting a day, get rid of all the problems of the proteins? Yes. But did anybody ever do that study? No. So, it's like going to Las Vegas. 

Melanie Avalon: I want the study done. Have there been studies done on not fasting, but calorie restricted high protein diets? 

Dr. Valter Longo: Yes. But they're usually the studies lasted about a year or so. And who knows what's going to happen. But the people that had the high protein, they were coloristic, that high protein, the IGF-1 was not significantly lower, until they went to a low protein diet. Calorie restricted high protein was not different from the regular animal containing diet on growth factors. 

Melanie Avalon: Growth factors aside, did they experience the proposed negative effects of high growth factors? Or, did they not? 

Dr. Valter Longo: No, this is calorie restriction. So, they were eating, say 1800 calories a day, and this is mostly males. It was working. They were doing very well. But they did not get the benefit of this IGF-1, which is the very center of longevity studies in many, many different organisms. Then the question is, would they get for example after 20, 30 years, would they get the benefits on cancer? Would they get the benefits on diabetes? Etc., maybe yes, maybe not. But they were doing the changes, lots of changes were very positive in spite of the IGF-1 being normal. 

Melanie Avalon: The IGF-1 and the issues from it, is it possible there's difference between it being from protein versus from just energy toxicity? Like too much energy in the system? 

Dr. Valter Longo: IGF-1 is known to be affected by lots of things, including energy, calories is known to be affected by milk-based products, and by protein. In fact, we are about to publish a meta-analysis on that, looking at all the things that are in the diet that affect IGF-1. So, yeah, there's different things that are affected. But in the human studies, only protein-- so if you took calorie restricted people, normally they ate lots of proteins like you, and they do not have a lower IGF-1. If they then kept the same identical calorie-restricted diet, but they went to low protein, now you saw a big drop in IGF-1.  

Melanie Avalon: Okay, gotcha. In your research, I'm assuming, you do a lot of research in yeast and mice and humans. When you're doing research and mice, I've had this question for so long, how does it compare a mouse to human as far as the timing? A typical fast in a mouse, like a 24 hour fast, does that correlate to a 24 hour fast and a human? Or is that more like days in a human?  

Dr. Valter Longo: Well, it depends on the mouse. Mice, let's say in a couple days, they will get the benefits of-- and there is all kinds of fasting, but let's say we're talking about the longer fasting. Most mice in a couple of days will get the maximum benefits of fasting, sometimes it takes three days, and for people is about twice as much. It doesn't mean that it's equivalent, but it means that you see a lot of positives and we don't see any negatives. It is possible that to say 20 days of fasting are equivalent to or if not 20, let's say 10 days of fasting are equivalent to two in mice. But we can't do that because it's too difficult and it would potentially have safety issues.  

Melanie Avalon: When you say like two or three days in a mouse, that's two or three completely fasted days or with an eating window? 

Dr. Valter Longo: Completely fasted days. That's one type of fasting. Then you can do let's say alternate day fasting. And there most people have done the same, I'm not sure that's necessarily a good idea, but that's what people have done. They take the mouse and they fasted every other day, or they take a person and they fasted. Fasting, we don't do that, we don't do either-- We do only 12-hour time restricted eating and then we do the periodic fasting. I do recommend for people overweight to keep probably lunch or dinner and eat breakfast, if they in the period where they're gaining weight. 

Melanie Avalon: When I'm reading fastest studies, like you mentioned alternate day fasting, or if there were studies doing a 16:8 approach in mice, I'm always just wondering if I should take that at face value for translating to humans or if it has more implications, if it's more stressful on the mouse? 

Dr. Valter Longo: Yeah, no, you shouldn't any mouse data at face value. I think the mouse data is just there to guide us to epidemiological, clinical studies, studies of centenarians. Those are the pillars that I described in my book. The mouse should be like, “Hmm, that's how it worked.” Okay, so then let me go to human clinical trials, etc., immunology, and see what's the human version of that, but often time people, and it happens to us also for cancer, the CML study, and we fasted, say, the mice for two days, and those two days in for the cancer treatment, which is, of course, very dangerous. 

Melanie Avalon: For your fasting mimicking diet, how do you set it up in the mice? 

Dr. Valter Longo: Well, we give them the fasting mimicking diet, so we give it to them for either now where we have the humanized version is either four or five days. We do it the same way. After a while, I think we get a sense for, I will translate things because we look at market, so we look at IGF-1, glucose, ketone bodies. When we do human clinical trials, we look at how long does it take for IGF-1 and glucose, and now leptin to decrease. Are we satisfied with that level decrease? If we are, that's okay. In mice, we get much more deeper or larger effects much earlier. So, you can get 70% decrease in IGF-1. In people, you might get 30% or 25%. We have to do things in mice and keep in mind, that's a mouse and then translate it. And there's not always a mathematical formula in different diseases and different trials, we do different things for people, sometimes you go seven days, then you go for days, and then you go five days, even in human. 

Melanie Avalon: I was reading a research paper last night that was comparing the days and a mouse to humans, and how it changed based on the developmental stage of the mouse. It was really complicated. I was like, “Oh, my goodness.” With the fasting mimicking diet, do people respond pretty similarly with their different biomarkers? Or, is there a lot of variants and how people respond just with growth factors and glucose and all of their blood markers? 

Dr. Valter Longo: Some people will respond very different than others. But on average, they say the majority, and sometimes the great majority of people respond similar. Even between different trials. We now done at least four trials, where we looked at maybe five or six trials, actually, we look at IGF-1, etc. In every trial, we see a significant change in the IGF-1 and leptin and insulin etc. But most people, I want to say on average, people are responding. Then if you do what's called a scatterplot, and you look at our each individual responder, you might even have a couple of individuals I want to say 100, that move in the opposite direction. You see a very clear everybody goes down, and then you see maybe a couple that will stay the same or even go up. So, yeah, those are the exceptions. But overall, in many of the markers, we see similar changes for the great majority of the people. 

Melanie Avalon: What do you see in the cholesterol and triglycerides, and so people are probably losing weight, does that go up transiently during the fasting mimicking diet? 

Dr. Valter Longo: Yes. It seems to go up transiently a little bit and then eventually, after three cycles, we see a significant decrease, particularly in the total cholesterol. It's not a big effect, it's not we see with other markers, let’s say glucose, or even blood pressure. But, yeah, we see, I think even in the newer trials, we see a small, but consistent decrease in total cholesterol. 

Melanie Avalon: You talked about how you set it up with not fasting more than 12 hours. What's the reasoning for that? Or, what concerns you about that? 

Dr. Valter Longo: Well, what concerns me about the say 16 hours are a few things. One is all the data on breakfast skipping. There's a number of studies including our own, which we never published, looking at what happens to people who skip breakfast, and most people do 16 hours, not all of them, but most of them who will skip breakfast. The breakfast skippers tend to live shorter and have more diseases the ones they have breakfast. And, of course, you could say, well, maybe the breakfast skippers have bad habits and other problems, but I always say I'm very surprised that if the 16 hours was so beneficial long term that that wouldn't counterbalance the problems. Why don't they at least live normal? 

When you see a negative association like that, you have to wonder maybe there are problems with the heart, maybe there are problem with some other systems that is continuous, say higher level of ketone bodies, this continuous fasting may be affecting. The other one, is the gallstones. The people that fast for 16, 18 hours a day have about twice as much the chance of ending up losing their gallbladder, compared to those that fast forward 10, 11 hours a day. Combined these two things have to make you consider the long fasting is something that people should just do for a relatively short period. If you do it for a couple months, because you're trying to go from A to B, I think it's probably a good idea. But if somebody says, “I don't want to live like this,” I will say probably not a good idea. I will go with the 12 hours, 13 the most. Reason for that is that that does not involve breakfast skipping, it does not get in the danger zone for gallstones. And I always say I've never seen a single negative study about it 12 hours on, 12 hours off or so, that's pretty good. 

Melanie Avalon: Have there been studies on breakfast eaters who fast longer? Just eating in the morning? 

Dr. Valter Longo: Breakfast eater, they fast-- Well, no, that would be nice to happen. What happens to people who skip dinner? Yeah, so we don't know. Yeah, it is possible, but we go back to the gambling. Even if there was a study, it took 20 years of breakfast skipping studies come up with the negative, and meaning that every single study was negative. It is even somebody publish something was good or bad, we wouldn't really know until 20 years go by and we have enough data to say, “Okay, now we're getting a pretty good idea what's going on, breakfast skipping is not good for you.” 

Melanie Avalon: I've been really curious about the gallbladder thing. I was trying to find studies about it. I found one that was really perplexing. It was saying that at 12 hours, there was an increased risk of gallstones. But at 16 hours, there wasn't and then it went down. Do you think it's possible, it could be a transitory thing, like with cholesterol rising during a fast? 

Dr. Valter Longo: Studies that I've seen and I've looked at three or four different ones, is a 16, 18 hours is the maximum risk. And then if you go for three or four days, then it goes down. Then it goes back down, because this cholesterol aggregates, eventually with the long fast disappear. For sure one study, with women looked at 16, 18 hours, and that's where they saw the peak risk. [unintelligible 00:38:28] who you're referring to, so if you want to send it to me, I'll look through it. But I've seen several all in agreement with this long fasting, daily fasting. And if you look at even medical clinics, in most of the cases, they'll say, people that fast regularly, they put it as a risk factor for gallstone. 

Melanie Avalon: I'll send it to you. I'd love to get your thoughts on it. It makes me really wonder about people who are doing like a daily 24 hour fast. If there's that possible potential of a risk because of the increased risk or because they're fasting just a little bit longer, is it mitigating the risk? 

Dr. Valter Longo: This is turning people into guinea pigs. This is why in the book, I talk about five pillars. I think that making it to 110 healthy is an extremely difficult task, as it is, probably best to take very little chances. In evolutionary biology, we have a saying that is, most mutations are deleterious. What does that mean? That means that most changes you do to DNA are actually problematic, but rarely a mutation is making things better. The same is true for any change that anybody can do, not based on any real deep data. The most of these changes are going to be detrimental. Well, why is that?  

Well, because after billions of years of evolution and certainly then tens and thousands of years of evolution of humans, we do things for a certain reason. Why do we eat three times a day? Why most people eat and fast for 12 hours? Why most people sleep at night? Are all of these just happened to be like that, and they're probably not needed? Or are they in fact, the result of evolution and over selection, even the last 4000 or 5000 years, is likely that whatever medical doctors or scientists we had started making observations. Well, people that do this don't do so well. Eventually we do what we do, in most cases, not all cases. Some things maybe just bad idea, then we need to eliminate, but this is why you want to usually we go to the centenarians, for example, and we say, well, what's common between Loma Linda, California, Okinawa, Japan, Seoul or Sardinia, and some of the other very lonely areas of the world? And then we say, okay, that's probably a pretty good strategy, because it allows all these people to not only live long, but to reach record longevity. Everything else is a really sort of dangerous gamble. 

Melanie Avalon: That's really interesting. I had not heard that before about most changes being negative, or more likely to be negative. Wow, that's really interesting. You talk about how when you were creating the fasting mimicking diet that the four blood markers that you found, either-- I don't know, was it fasting? It was the low IGF-1, the blood glucose, the high ketones and the high growth factor inhibitor. I was wondering with those markers, is there really any difference between being in the fasted state creating that compared to doing the fasting mimicking diet creating that or is it pretty much the same? Is there anything else different with having the complete absence of food? 

Dr. Valter Longo: Yeah. The big difference is that what I think is really fundamental, which is biohacking is perfectly fine. But we have to be respectful of where we come from and what we've been doing and what we know works. When I came up with the fasting mimicking diet, it was also the idea of be respectful of all these nutrients and these ingredients they made so many people live so long, and be so healthy, and they were vegan ingredients. I went in and looked for the things that independent of the fasting made people healthier and better. It was a very good idea.  

For example, a couple years ago, we published on the inflammatory bowel disease, we showed that that water only fasting actually made the gut leakier, and the fasting mimicking diet was much stronger in the regenerative process, and also in causing changes in the microbiota, lactobacillus bifida bacteria that protecting microbiome. Even though I didn't necessarily expect this, I'm happy that I picked this, I was respectful of what hundreds of years of research are shown to be positive in all these ingredients, all these vegetable ingredients, and the prebiotics that they contain, because it turned out they, yes, they are positive, and yes, they fed the good bacteria, which then protected the gut from leaking, and also stimulated regeneration and stimulated all kinds of protective effects. So, yeah, that's just one benefit.  

Of course, the other benefit is eating. One thing that is underestimated by most people is how difficult it is for people to go. I always say it's very difficult for people go from four coffees a day, three coffees a day. So, I think it's very important that for most people to give them alternatives, and where they can maintain these habits of eating, and the ritual of eating, while at the same time gaining the benefits of fasting. And then of course, the safety concerns. Water only fasting could cause hypertension, hyperglycemia, low salt level leading to hypertension, in extremely low glucose levels, carbohydrates level that or absence of carbohydrate levels in the food that can lead to hyperglycemia. These are just some of the many reasons why the fasting mimicking diet is there, anything is there to stay, and not the least is that the physician eventually is going to want to see something that is [unintelligible 00:44:50] clinically in a very consistent way. And they're only going to accept that and not improvise the intervention. 

Melanie Avalon: When listeners, if they do ProLon or do the fasting mimicking diet, I got a lot of questions asking because a lot of my listeners do practice intermittent fasting or do like a one meal a day pattern. Can they eat the fasting mimicking diet, the ProLon in a shortened window? Or does it need to be throughout the day? 

Dr. Valter Longo: It can either in the shorter window, but I don't recommend that it goes less than 12 hours.  

Melanie Avalon: Okay. I know this might be a loaded question, but how do you feel about doing DIY versions? I know there's a lot of people out there trying to do DIY versions of it. 

Dr. Valter Longo: Obviously, I'm not in this to make money, I donate everything to charity, I don't take consulting from the company. To me, it makes no difference. I think that people should stick with what's clinically tested, and not trying to improvise. We've seen so many people get in trouble. Some people end up in the emergency room. It's hard to explain to anyone how complicated some of these things are. Especially when it gets into cancer, into diabetes, into interaction with drugs, on and on and on. Even an expert, we seen medical doctors get in trouble for improvising. I think even for an expert, it would be extremely difficult to have it all figured out, and be able to do their own thing. So, I will say, we're really looking at minimal investments and there's certainly that, I hope, at some point, this is just free for people. As part of insurance companies, reimbursement, etc. Until then most people have to do this maybe three times a year. So, it's really a minimal investment that most people can afford. I will say, I would strongly, strongly recommend to do that. I don't mean to try to advertise the company, but really based on do what's extensively tested, not just for efficacy, but also for safety hundreds of thousands of people. 

Melanie Avalon: I'll put a link in the show notes to ProLon. I would love, love, love for listeners to try it and report back and tell me their findings doing it. I know, especially for a lot of my listeners, I think a lot of them are into really high-quality food anyway. It might actually be cheaper doing ProLon for five days compared to the food that they might be purchasing originally. Some random, just rapid-fire fasting questions that I still have. Do you know with stem cells, because you talk a lot about stem cells in your book and how the fasting mimicking diet and other things affects themselves? Do we have a limited number of stem cells? Can you deplete your stem cells if you do too many of these practices? Or, is that not a concern? 

Dr. Valter Longo: Well, no, it is a concern. We didn't see these in mice [unintelligible 00:48:00]. We started middle age, and we went all the way to very old age. We did not see this. But we did see at a certain age, the mice were not doing so well anymore, let's say the equivalent of a nine-year-old. It is possible that some depletion of stem cells was involved there. We don't recommend the fasting mimicking diet to say after the age of 70 in most cases. In general, I don't recommend more than three times a year unless somebody has to do it. So, yeah, those are all things that should protect people from even the possibility of running out of stem cells. In fact, probably the opposite. As you promote the stem cell dependent-- I mean, we know this very well for mice, for humans we're still at the beginning of the studies. But let's say for mice, when you expand the stem cell population, now you have much more of these pluripotent stem cell which very clearly-- not pluripotent but long-term acting stem cells, [unintelligible 00:49:05] very clearly for the blood system. Once they expand their what's called self-renewing stem cells into the kind of stem cells that can eventually maybe prevent depletion of stem cells and not--  

Melanie Avalon: That's exciting. Do you see with the fasting mimicking diet, people that have immune conditions, autoimmune conditions, does it speed up the process of eradicating immune, autoimmune problematic cells? What's the normal half-life of an immune cell that's targeting something it shouldn't be targeting? Can a fasting mimicking diet eradicate that? 

Dr. Valter Longo: Yeah. We publish a number of papers on that. We did that for multiple sclerosis, which is autoimmune. We did that for inflammatory bowel disease, and now we're doing other autoimmune disorders. So, yeah, very clearly in the multiple sclerosis and IBD, mouse studies, we have shown that the fasting mimicking diet could lower and, in some cases, eliminate the autoimmune population. In the multiple sclerosis, we also had a clinical trial, a small clinical trial, but a clinical trial showing already effects that are stronger than continuous ketogenic diet. This was a continuous ketogenic diet against just one single, one week long fasting mimicking diet, and the FMD worked better in improving the quality of life of the patients.  

Now we have multiple trials, at least five or six around the world on autoimmunities and we just have to wait and see. But certainly, at least in mice, we're starting to get the picture that fasting and the fasting mimicking diet, which is respectful of where fasting comes from, are activating a very sophisticated set of programs that go after anything that is damaged, because otherwise, it will be very difficult to justify. Why does it work with so many different things? Then it will make sense that any organism will have the ability to get rid of damaged components, and then turn on regenerative programs and replace the damaged components with new ones. How do we know if this works? If you get yourself in the skin, within a couple of weeks is back to almost perfect status. We already know. Is it possible that no matter where you cut yourself that fixed, but if there's a problem with your liver, or there's a problem with autoimmunity in the gut, or autoimmunity in the spinal cord, that cannot be repaired, extremely unlikely. Probably the body has the ability to repair many, many different things. But we moved away from fasting further and further, and eventually we maybe get rid of something that is the most powerful thing that you can do to achieve that. 

Melanie Avalon: That is really, really incredible. Speaking of repairing, so the future of longevity and anti-aging, is it repair or is it replacing? 

Dr. Valter Longo: The future, in my very biased opinion, is in activating embryonic developmental programs. As we be showing with the fasting mimicking diet. The future is, I always say you think a 40-year-old or a 45-year-old men and women, and they can make a perfect child, a perfect baby. So, that tells you that no matter how old, the cells that come from these individuals are, they know how to make something perfect. And so that's the future. It's very clear that that's the way to go.  

Now, the more we are respectful of the history of that, and the more we're going to get there, the better we're going to get there without doing lots of damage to lots of people. That’s, I think, certainly fasting and fasting mimicking diets are one way to do it and maybe there is other ways to do it. But I think that's the way to go. If you have a damaged pancreas, as we shown, you do the fast mimicking diet and now is embryonic like developmental program it turns on, you start seeing Nanog and F4 and all these genes that are really only there when the mouse is first born. Within weeks, they start rebuilding the cells of the pancreas that will no longer work. And they know exactly what to do. It's really, really remarkable how it works. This is why you cannot think that it's a program in a very sophisticated one. And we're just giving them the goal, but we don't know what we're doing, and the system already know where it's [unintelligible 00:53:49]. 

Melanie Avalon: With embryogenesis, since it's creating something new, it sounds like it's kind of a hybrid of repairing and replacing for aging and a human, if you're activating that and the pancreas or other, or is it just repairing with these factors that are typically only used in an embryo? 

Dr. Valter Longo: It's not necessary repairing because in the process of fasting, you're shrinking, the system is shrinking. All this is doing is to probably say, and I always use the analogy of the woodburning train. It's probably saying, if I'm a train that burns wood, and I'm running out of wood, I'm going to go back into train and pick the oldest wood that I can find. The chairs that are ruined, and I'm not going to pick the good wood. I will put the bad one and then I'm going to burn that. In the process I'm going to become lighter, I consume less energy, I make it to the next train station. And then once I make it to the next train station, I can rebuild whatever parts of the train I took off. So, yeah, and this shrinking is getting rid of things by self-eating process. There's nothing to repair necessarily, in the re-expansion, in the stem cells and other cellular components are used as a guideline to rebuild. Why? Because every cell already has the genetic material and knows how to do that. Then you're just using the genetic information and the local information. Pancreas, I can see that things are not working very well. Somehow, I'm guided to make new pancreatic cells that make insulin, for example.  

Melanie Avalon: Wow, that's fascinating. Do you think immortality is an option or even aging backwards? 

Dr. Valter Longo: Yeah, it will be for sure. Immortality is a tough one, but aging backwards, yes. Immortality is a tough one. And then it gets into all kinds of ethical issues. It's a tough question to answer, but in this now what we're focusing on. I think if we could live 120, 130 very healthy, that will be a big, big achievement. Not only that, but could we live to 80 very healthy, very young? Can we be young until 70 or 80 and healthy until 130, and then die right after that, that will be sort of like an ideal situation for everyone. 

Melanie Avalon: Yes. This is amazing. Well, the last question that I ask every single guest on this show, and it's actually something that you end The Longevity Diet book with. It's just because I realized more and more each day, how important mindset is surrounding everything. What is something that you're grateful for? 

Dr. Valter Longo: I'm grateful for having parents that got to a very old age. [laughs] I think I have the genes. I have good genes. 

Melanie Avalon: Genes are the number one factor in longevity? 

Dr. Valter Longo: If you look at these a lot of these longevity zones from around the world, when we started looking into it, it turns out that nutrition is very important and exercise of being active is very important. Most of the time, we also see what appears to be a very strong genetic component. Recently, I went down to my parents’ area of the world, and there's a guy named Rocco Longo that lives about two miles away from my parents’ house in a little village. Rocco was 100 years old and still driving. Usually when, when 100-year-old tells you, “I'm driving,” you say, “Yeah, right.” And this guy, he's going to the grocery store every day with his car, he is in perfect condition. So, I thought I just hope I'm related to this guy, because he's looking good. 

Melanie Avalon: Oh, I have to ask, is he a wine drinker? How do you feel about wine? 

Dr. Valter Longo: Yeah, there's nothing wrong with wine. I have to say three to five drinks a week are mostly associated with neutral to positive effects. People that need to watch out or those that have risk factors in the family for certain cancers, including let’s say breast cancer. Although the effect of alcohol on breast cancer is not a big one, but yeah, there are a few cancers for which alcohol is a risk factor. So, if you have high level of that cancer in the family, probably not a good idea even to drink less than five. But otherwise, for most people, there is nothing wrong with drinking three to five drinks a week. I will say if you haven't drunk before and you don't have the need to drink, there's no need to start. It's not something that we recommend as a way to live longer is, is probably-- if you look at all the meta-analysis and all the studies of studies of longevity is fairly neutral. There is no good or bad effects. So, I will say, if you like to drink up to five drinks a week is fine. And if you don't, don't start. 

Melanie Avalon: Well, that works for me. Well, thank you so much. Dr. Longo. This has been absolutely amazing. I follow your work so intensely and I'm just so grateful for everything that you're doing. For listeners, I'll put links to everything in the show notes. There will be a full transcript. I definitely recommend doing the ProLon and letting me know how it goes and sharing it in the Facebook group and all of that. Is there any other links, how can people best follow your work? 

Dr. Valter Longo: My work USC, University of Southern California and also the foundation. We now have a clinic, Create Cures Foundation. I think it's createcures.org. Please, if you're interested, it's a nonprofit foundation trying to help people that are in trouble, but also trying to help everybody else. And, yeah, so createcures.org, and of course the books and all the profits from the book from my part, it goes to the foundation. 

Melanie Avalon: Awesome. Well, thank you so much. This has been so wonderful. I so appreciate your time, especially with the time change for listeners, Dr. Longo is in Italy right now. This has been absolutely amazing and hopefully we can talk again in the future. 

Dr. Valter Longo: Sounds good. Thanks a lot. 

Melanie Avalon: Thanks. Bye. 

Dr. Valter Longo: Bye. 

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