Fasting-Mimicking Diet, Longevity, and Biological Aging with Dr. Valter Longo

Eating for longevity. A topic I’m very passionate about and one that has received incredible attention lately. How much protein should we eat to live longer? What about ketones, carbohydrates, and blood sugar spikes? Where does fasting fit in all of this? And what physical activity confers the most benefit for our healthspan? On this episode of New Frontiers, I pose all of these questions and more to one of the most brilliant minds in longevity science – Dr. Valter Longo. I’m so excited to have him as my guest once again – his grasp on the longevity literature is extraordinary, as is his immense contribution to this growing body of research. Dr. Longo and I discuss the fasting-mimicking diet, biological aging, macronutrient targets, the lifestyle pillars of centenarians, and much, much more. It was such a fun (and research-packed)conversation, just wait until you get your ears on it! As always, I would appreciate a thumbs up and a kind review wherever you listen to New Frontiers. – DrKF

Fasting-Mimicking Diet, Longevity, and Biological Aging with Dr. Valter Longo

What do epidemiology, clinical trials, centenarian studies and other research tell us about longevity? What do centenarians eat and how do they live? In this episode of New Frontiers, Dr. Valter Longo, leading longevity research scientist, director of the Longevity Institute at USC in Los Angeles and of the program on longevity in cancer at IFOM in Italy, shares an in-depth overview of the fasting-mimicking diet, macronutrients’ effect on biological aging, building life-long dietary changes and why we shouldn’t get too hung-up glucose monitoring devices. With an extensive research experience in the field, Dr. Longo highlights the most evidence-backed tools for extending healthspans.

In this episode of New Frontiers, learn about:

Dr. Kara Fitzgerald: Hi, everybody. Welcome to New Frontiers in Functional Medicine where we are interviewing the best minds in functional medicine. And today, of course, is no exception. I’m really excited to, once again, have Dr. Valter Longo joining me. We’ll link in the show notes my first conversation with him back in 2018, and it was just a terrific tour of the research he’s conducted and his background, his early inspiration, his mentors, et cetera.

So, we’ll park that in the show notes so you can access it. And then, we’re going to pick up where we left off then and talk about what he’s been up to, but let me just give you a little bit of his background before we do that. He is the director of the Longevity Institute at USC in Los Angeles and of the program on longevity in cancer at IFOM in Milan, Italy.

His study focuses on the fundamental mechanisms of aging in simple organisms and mice, and on how they can be translated to humans. Dr. Longo received the 2010 Nathan Shock Lecture Award from the National Institute on Aging and the 2013 Vincent Cristofalo Rising Star Award in Aging Research from the American Federation for Aging Research.

Dr. Longo, welcome to New Frontiers.

Dr. Valter Longo: Well, thank you. Thank you for having me.

Dr. Kara Fitzgerald: So, you’ve been a tour de force in science. I mean, you’ve just had publication after publication, really showing some extraordinarily impressive work on the fasting-mimicking diet. And I want to do two things. I just… You know, I think most of our listeners know, and probably have tried the fasting-mimicking diet, this is primarily a professional audience who’s listening to this podcast, but I’d like you to give an overview.

And then, I really, I just want to jump in and do a survey of what you’ve found over the years using FMD.

Dr. Valter Longo: Yes. So, the FMD was developed… Well, first of all, the periodic fasting, this idea of doing fasting for just a few days periodically was a response, it wasn’t really done by anybody else that I knew of. I mean, there are people that were doing this long, like two, three weeks long fasting like the Buchinger Clinic. But this, I wanted to test, I wanted to find a replacement for calorie restriction, right? So, is there something that we can do once in a while for a few days, and that would be long lasting.

So, that first started with water-only periodic fasting in mice and humans. And then, we realized that maybe like 12, 13 years ago in a first cancer trial at USC, that patients were not very happy about water-only fasting to treat cancer. And so, we went back to the National Cancer Institute, the National Institute on Aging, and they both funded us to help us develop the fasting-mimicking diet.

And so, the idea was to come up with something that would generate the same effects that the water-only fasting has on blood markers that we believe are central for the effects of fasting.

Dr. Kara Fitzgerald: I mean, so, you needed to create basically something that people would be able to adhere to, but was as effective. I mean, well, I guess my question is, I think water-only may not be as effective as fasting-mimicking. Is that true?

Dr. Valter Longo: Well, for sure, that is true if you think about safety, and standardization, et cetera. So, we have lots of things in the fast-mimicking diet that are there to prevent hypotension, hypoglycemia. And then, also, in some of the studies in mice, for example, we had one on inflammatory bowel disease in mice, indicating that it was the right idea to combine like the ingredients that you see in the centenarian diets in the FMD, because we saw the microbiota was built by the FMD in a way that water-only fasting could not do.

Probably because of the prebiotics contained in this plant-based diet, and in the plant-based fasting-mimicking diet, these prebiotics were helping to build lactobacillus, bifidobacteria and other beneficial microbes.

Dr. Kara Fitzgerald: Yeah. That makes a ton of sense to me that the information that you’re providing through the food could be designed in such a way to really yield extraordinary benefit.

I think one of the things I’ve observed recently, and I think that it’s a little bit of a springboard off of your work, and then, people have taken it a little bit further is that there’s some fairly extreme time-restricted eating structures that folks are following these days where less food is more, more hours in a fasting state is better. You know, one meal a day. A lot of people are doing maybe fasting a couple of days a week.

I want your thoughts on it. And I do want to underscore that we don’t want to forget that food is incredibly potent information. So, what do you think about these various time-restricted structures?

Dr. Valter Longo: I think that… I like to use the word of Greenspan, right? Irrational exuberance many years ago, right?

Dr. Kara Fitzgerald: Yeah.

Dr. Valter Longo: Lots of people are used to… You hear something good, like fasting, and then, people say, okay, must be everything about fasting is good. Let me just pick up whatever version I think is good. Right? And this is true for proteins, for anything that you can think of, right? The proteins are good. Oh, let me just have a ton of them.

Dr. Kara Fitzgerald: Right.

Dr. Valter Longo: Yeah. So, I think that, clearly, there are now meta-analyses that I use to teach to my students taking longevity courses, showing that if you skip your breakfast and fast for 16 hours a day, you’re going to have a shorter life most likely, right? Not a longer life, but a shorter life.

So, when you have meta-analysis… Now, they don’t talk about skipping dinner. Right? Or skipping lunch. Right? So we don’t know, of course, as you modify it, maybe now, you go from shorter life to longer life if you skip dinner. But until we have much more data, then I think we have to be careful, and say, what type of fasting, let’s say, daily fasting is not associated with problems at all? And 12 hours would be in that category. Right?

Dr. Kara Fitzgerald: Sure.

Dr. Valter Longo: So, I always say, I’ve never seen 12-hour time restricted eating to be problematic. I mean, if there is a paper, somebody, please, send it to me. But I’ve never seen it. So, yeah, so then, that’s a good one, right? And then, saying, no, don’t eat for 15 hours a day, eat for 12 hours a day. And that seems to be very, very solid, no side effects that we could tell and no association with shorter lifespan, more cardiovascular disease, et cetera, et cetera, more cancer as we’ve seen for the 16 hours, I mean, as we’ve seen for the breakfast skipping. But 16 hours is also associated with gallstones, increased gallstone operations in women with gallstones.

So another problem, right? Another issue that combined with the first one, now, you put it together and you think, okay, let me stick with 12 and not risk the… Now, I have problems and not solutions. Although, because people, of course, focus on the acute effects, right? So, acutely for a couple of months, you’re going to get a lot of benefits. If you fast for 10, 20 hours a day, of course, you’re going to, if you have insulin resistance, that’s most likely going to be improved, as well as other things. But that’s a problem, right? You cannot just look at acute effects. That’s at best one of the four or five pillars that people should use to get there.

And if anybody’s interested, since you’re talking to professionals, I just published a review Cell last month that goes through all of this together with Rozalyn Anderson who’s an expert in calorie restriction, and the person that ran the lifelong monkey calorie restriction studies. So, I think it’s a good read to see how do you get to this… You know, what are the solid nutritional interventions, and which ones are much weaker.

Dr. Kara Fitzgerald: Perfect. That’s great. Okay. So, folks, that’s on the show notes. You can just go over to the show notes and you’ll see where we’ve linked to the paper. Thank you. That’s actually really helpful. I mean, we could just underline that temporary aggressive structure, time restricted structures could be absolutely appropriate. But it is true, there’s some extraordinary kind of exuberance in this arena. And I appreciate your sort of tempered interpretation of it.

So fasting-mimicking diet, you’ve shown activation of stem cells, regeneration and rejuvenation in multiple organs and reduced risk for diabetes, cancer, Alzheimer’s, heart disease. It’s just, it’s pretty extraordinary. Go ahead. Yeah. Any comments on that, and where you’re heading next?

Dr. Valter Longo: Yeah. I think where we were always headed was the… You cut yourself and I don’t know if we talked about it last time we talked, but you cut yourself and within a couple weeks, that cut is almost perfectly repaired. Right? So that’s extraordinary, right?

Dr. Kara Fitzgerald: Yeah.

Dr. Valter Longo: Well, are we believing that, for the liver, for the lungs, for the gut, et cetera, et cetera, we don’t have that kind of potential? I think we do. And I think that fasting refeeding, if done correctly, can activate lots of this repair, replacement, regeneration systems. Yeah. So, I think it’s working in almost every division and every organ and system we looked at.

Now, we have lots of clinical trials running. Lots of clinical trials finished, right? So now, this year alone, I think we already had two collaborative papers published and we are going to have… And several now, you’re starting to see other groups. There was a paper, it was just published, fasting-mimicking diet against a plant-based normal calorie diet showing superior effects of the FMD in all kinds of metabolic markers.

So, I think, now, our own studies, but also, those of many, many labs, hospitals, and institutes around the world are going to hopefully move this into the toolkit of lots of doctors, so that it can be used against many diseases. Some of them will need, of course, much more data, but some of them, like now, we’re going to publish on diabetes, and we published already several papers that have to do with prediabetes, let’s say. So, that should be enough for the endocrinologist to begin to consider, to treat prediabetes, and potentially, diabetes.

Cancer, now, there are multiple trials, maybe six or seven trials that are concluded. They look very, very good, especially the one in Holland with 125 patients receiving chemotherapy. But absolutely, we need more trials, and we encourage everybody to contact me, and I help many, many hospitals build their trials and I’ll help others come up with new ones.

Dr. Kara Fitzgerald: It’s just terrific. I was talking to your team about maybe using the intervention that I studied, that you’ve been really supportive on in a fasting-mimicking structure. So, I don’t know if… I would love to work with you, and I will, again, on the show notes, folks, just kind of corral together some of these studies, the Holland study, and how to access Dr. Longo, if you would like to jump into doing some research.

I just want to say, I mean, this has to be just extraordinarily satisfying for you as scientist and just a human being, wanting to do something good in the world.

Dr. Valter Longo: Yeah. It’s funny because I just had an interview where a journalist was basically criticizing me because it was like, oh, now, you have professors, they start companies and they have things that are out there and lots of people are doing. Yeah, so it goes both way. Right? Some of it is very satisfying, and then, some of it is, you’re under attack continuously because in conflict of interest and this and that.

So, yeah, it’s good and bad, but absolutely, I don’t mind. It’s part of what happens. I think we’re focused on… I always say, I think there’s going to be two worlds, right? In 5-10 years. It’s going to be a world that listens to really solid science and clinical data, epidemiological data, et cetera, et cetera. And then, maybe let’s say 500 million people, maybe a billion people, and then, there’s going to be the rest of the world that decides to do things the way they want to do them.

And I think as we’ve seen for this meta-analysis, the tremendous difference in life expectancy, it could reach the 15-20 years difference between those that the listen and those that don’t, right?

Dr. Kara Fitzgerald: Yeah.

Dr. Valter Longo: I’m focusing on those that are willing to listen. And I’m not just focusing on the idea of the moment, I think. But I really have a passion for, can I get you to 110 healthy? And if I don’t, I’m like, we got it wrong, more than, oh, I came up with the fasting-mimicking diet, so I’m going to keep pushing the fasting-mimicking diet. I want to say I like to be the first one that proves myself wrong. Right? So there’s a flaw with the fasting-mimicking diet, I want to find it. And if there’s something better, I want to find that, right?

And if somebody else finds it, then, I’m going to say, okay, well, this is even better than what we’ve done. And so, that’s what I’m going to recommend.

Dr. Kara Fitzgerald: Well, let me ask you, to that point, has there been anything? I mean, have you changed the macro or micronutrient ratios in the fasting-mimicking diet since you first launched it? Or do you have an eye towards changing it, you know, longer duration, shorter duration? I mean, what have you seen? What are you thinking about?

Dr. Valter Longo: Yeah. So, we are seeing, for example, there’s a lot of people that are allergic, intolerant, maybe develop, have autoimmunities. Yeah. So, we’re, now, working on non-inflammatory fasting-mimicking diet. We are working on… We have an FDA fasting-mimicking diet, which is a drug, and now, there’s an IND and we’re going to move forward with hormone therapy in breast cancer. And there’s a higher calorie supplemented in between one that we’re using for Alzheimer in a randomized trial in Italy.

We have a seven-day long autoimmunities version that has now been tested in several hospitals. Yeah. So, I think, obviously, we are keep-

Dr. Kara Fitzgerald: You’re tweaking it.

Dr. Valter Longo: Keep them in the laboratory and the clinical work guiding everything we do. And people don’t realize that every ingredient undergoes yearly scrutiny based on everything, and the feedback that we get from people, but also, the feedback that we get from the lab and from the clinical trials.

Dr. Kara Fitzgerald: All right. Right. What about any supplements? Are you thinking about concurrent supplementation with any vitamins or minerals?

Dr. Valter Longo: We… I mean, I always say that taking a multivitamin, multi-mineral maybe every three or four days is a good idea. The omegas are also very good idea, and everything else, I think, is still possibilities, but I think that each person should be looked at individually to see…

Dr. Kara Fitzgerald: Sure.

Dr. Valter Longo: … do they need something specifically or not. But I thought it’s things that everybody needs, yeah, probably not a bad idea. I don’t see many down the reason not to do a multivitamin, let’s say, every three or four days. And certainly, it’s not that easy to argue against omega 3, let’s say, fish oil. I mean, people could do that, but I think taking some fish oil maybe every other day or something like that, that probably is a good idea.

Dr. Kara Fitzgerald: All right. What else did I want to ask you in this arena? Biological age. So, I podcasted with Morgan Levine a little while ago, and she talked about… I think you guys have a study coming out. Maybe it’s in preprint. I don’t know if it’s in preprint or not, but you-

Dr. Valter Longo: It’s accepted. Yeah. Yeah.

Dr. Kara Fitzgerald: It’s accepted?

Dr. Valter Longo: It’s accepted but-

Dr. Kara Fitzgerald: Can you tell us about it?

Dr. Valter Longo: Two studies. Yeah. Yeah, I cannot, but I can-

Dr. Kara Fitzgerald: Hint around it.

Dr. Valter Longo: … tell what we studied. Right? So, we could tell. Yeah. So we studied, in two trials, for two trials, we obtained the blood, and using Morgan Levine’s biological age, bio age system, we determined biological age, and she uses blood markers. And I really like her method, because she looks at seven to 10 blood markers that are associated with changes in mortality based on the CDC databases.

So, yeah. So then, in both studies, we obtained the blood. Then, we look at these markers and we calculated the biological age. And so, I would say, within two or three months, hopefully, we’re going to publish both of the clinical studies including the effect of three or four cycles of the fasting-mimicking diet on biological age.

Dr. Kara Fitzgerald: And what’s the duration about for those?

Dr. Valter Longo: Well, yeah, three cycles once a month, right?

Dr. Kara Fitzgerald: Once a month.

Dr. Valter Longo: Or four cycles once a month. And one of the two studies was against the Mediterranean diet. So, what happens if you do Mediterranean diet for four months versus only, let’s say, five days a month of a fasting-mimicking diet and… Yeah. And-

Dr. Kara Fitzgerald: And what did you have them follow in between?

Dr. Valter Longo: Oh, whatever it is that they… No changes. Right? So, this is our MO, right? Of course, in the Cell review, I described the longevity diet, which is everyday, vegan, pescatarian and all of that. But for the FMD, we’re basically saying, we’re thinking of it as a medicine. Right? So instead of taking drugs, what if once a month… Well, in the trial once a month, I mean, we expect that, now, in a large trial that we’re going to run in southern Italy, we’re going to do every three months.

So, what if you did this every three months for five days, and it comes in a package, and you have everything in there, and you just take it as you take a medicine, a plant-based medicine, and then, you go back to whatever it is that you did before.

Dr. Kara Fitzgerald: Wow. And have you studied… I’m sorry for not knowing this off the top of my head, toggling between longevity and FMD with any other kind of a control?

Dr. Valter Longo: Well, I mean, this trial that was just published, they did that, and it was… Let’s say, I think it was matched with a plant-based diet. So, the FMD cycles against a plant-based diet. And the one from Heidelberg University, they’re going to publish, it was, again, a fasting-mimicking diet against, I think, it was a Mediterranean diet done only for the five days a month.

Dr. Kara Fitzgerald: Okay.

Dr. Valter Longo: And this was for diabetic nephropathy. Yeah. So, there’s starting to be a number of studies that are comparing the FMD against controlled diet, in a healthy controlled diet. And I have to say though, I don’t know if you saw it, but we published, a few months ago, a paper in Nature Metabolism that was looking at mice connecting to what I said earlier about let them go back to whatever it is that they do.

So, we took mice. We gave them a high fat, high calorie diet, they became huge. And then, once a month, we gave them five days of the FMD, right? And then, back to the very bad Western diet. We thought we would get sort of an in-between effect. But in fact, it reversed basically all the things that we looked at. We looked at cholesterol, we looked at obesity, we looked at cardiac function, we looked at the glucose tolerance and just five days a month not-withstanding the terrible diet that they had in between was enough to bring them back.

Of course, they did not get the advantage of the fasting-mimicking diet as they will have when they’re on a normal diet. Now, the FMD makes you live longer than the control diet, but if you’re a mouse. But it was remarkable that the FMD cycles allowed everything, including longevity to be statistically not different from that of a control.

Dr. Kara Fitzgerald: That’s amazing. Yeah, that’s just really amazing. It seems like so much possibility. And if one could toggle between… Certainly as many people in our arena here in functional medicine are toggling between doing a periodic FMD, and then, another healthy diet, probably not dissimilar from your longevity diet. And so, I mean, it just seems like there’s a lot of possibility when you just stated your original mission to allow people to live to 110 healthy.

Dr. Valter Longo: Yeah. I think the reality is, if you look at smoking, right? So now, I mean, nobody in the world doesn’t believe that smoking kills you, yet, I don’t know what the new numbers are, but about half of the people that used to smoke are still smoking, right? So, we can have the attitude, oh, tough luck. You know, you should quit smoking, and if you’re going to get a problem, it’s your problem.

Or we could say, okay, we realized that some people are just going to have a bad diet, or a lot of people are just going to have a bad diet, we realized that, in the United States, 70% of people are overweight or obese, and in Europe, it’s about 50%. And we realized that we are going to push the longevity diet and Mediterranean diet and all kinds of other diets, but it’s going to be tough to convince maybe more than a quarter of the people.

I mean, I would say that’s an incredible scenario that we convince a quarter of the people to make lots of like adherence to… In Italy, for example, less than 10% of people do Mediterranean diet. Right? And Mediterranean diet is much more permissive than the longevity diet. That’s the reality. Right? And so, what do you do with everybody else? You just say nothing? Well, I think that that’s where the FMD comes in, and say, okay. And I don’t think… So, people from the company I founded, I always say, try to do it once a month. I think that people, lots of people will benefit if you do it three or four times a year.

So, now, it becomes very reasonable, right? So, it becomes very reasonable to say to somebody, okay, I don’t want to revolutionize your diet, but three or four times a year, can you do a cycle of five days of a FMD, it comes in a box, it’s very easy. And I see, maybe I’m delusional, but I see this being a 60, 70% of the people possibility, with some people maybe not getting too far and doing it twice, and say, oh, yeah, I got to do that again. But, yeah, certainly, moving in the right direction.

And also, I think what we see with the plant-based diet FMD, the people start gravitating towards the more plant-based nutrition, right, without us having to tell them to do that. This is something that we see over and over in the clinical trials. So, you do two or three cycles of the FMD, of the plant-based FMD, and then, lots of people say, you know what, I’m starting to eat less of this and less of that. And I didn’t become a pescatarian, but I’m certainly eating better than I used to do it.

Dr. Kara Fitzgerald: Do you… I mean, subjectively, I’m sure they’re clearly feeling better. There’s some sort of an underlying motivator to continue to follow some version of it. I mean, are you-

Dr. Valter Longo: Yeah, I think if you look at the animal studies, and I think these are also known for human studies, there’s something called food aversion, right? So, you eat a certain food, you feel bad, and now, you’re associating that food with feeling bad. And most likely, almost, for sure, there is also the opposite of that.

So, you’re starting to eat a certain set of foods in the FMD and you feel a lot better. And then, you have this connection with the food, you develop this connection, which you want to seek again more often, let’s say.

Dr. Kara Fitzgerald: Yeah.

Dr. Valter Longo: So yeah. I mean, that would be very interesting type of study to do. And I’m not sure that anybody has done these type of studies. But is it possible that there is an instinct to move towards a certain food after you’ve experienced feeling good with that particular food.

Dr. Kara Fitzgerald: I mean, we certainly see that in clinical practice anecdotally, when you prescribe a healthful diet and the patient is adherent to it long enough, they feel better, it becomes self-fulfilling. They want to stay on it. And then, they begin to juxtapose those times when they slip back onto their standard American diet with how good they felt on a healthy diet. It’s pretty extraordinary to witness that change.

And just beyond that is, since it’s often women who will come and seek functional medicine and adopt these programs, they can… And since in this country, they tend to be the shoppers and the cooks and so forth in the kitchen, there tends to be a family influence that can happen as well.

Dr. Valter Longo: Yeah.

Dr. Kara Fitzgerald: And…

Dr. Valter Longo: Yeah. The question is, then, do they do it because if you do it, because you know you have to lose weight or be healthier? That’s still tough.

Dr. Kara Fitzgerald: Yeah. That’s right.

Dr. Valter Longo: If you do it because it makes you feel good, then, that’s much easier, right?

Dr. Kara Fitzgerald: Yes.

Dr. Valter Longo: And you are doing it, because, hey, I like this more now. I like it more when I eat this versus that. So, I used to eat steak every day, and now, I tasted the soup with lentils. You know what, that soup made me feel good. So now, maybe I like it more than the steak every day.

So, if that happens, then, it’s a for life change, right? If it’s a calculation, then, it’s less about, one to two years, and then, you’re going to go back to whatever it is you came from.

Dr. Kara Fitzgerald: Yeah. That’s right.

Dr. Valter Longo: I think that’s a difference. Right? It has to be much more instinct-driven than calculated. And then, it has a chance of staying with you for a long time.

Dr. Kara Fitzgerald: Absolutely. Yeah. No doubt about it. Okay. So, another thing that’s happened that I’ve observed is your research started to just really, again, influence us profoundly. I mean, those of us practicing medicine and just regular people and how we’re prescribing protein, and fervently, in our clinic here, we all started measuring IGF-1 and pulling back on protein. And we have really fairly modest protein requirements in the methylation diet that we have published on.

But I’m seeing that there has been some challenge to this idea of continual low protein. And I know you say, obviously, when you get older, to bump protein up to maintain muscle mass. But I was just reading recently about higher, significantly higher protein intake in a metabolically-healthy individual and sort of pulsing this protein to purposely stimulate mTOR and IGF production to lay down muscle.

So, I think much greater protein requirements and branched-chain aminos which are from animal sources primarily. So, in healthy individuals, sort of pulsatile ingestion of higher amounts of protein as associated with health, and potentially, longevity. I want to hear your thoughts on that.

Dr. Valter Longo: Well, longevity, I like to see it. Right? I always say if you study people… I just saw documentary the other day and it had the heroin from back in, I don’t know, 120 years ago. Right? They used to sell heroin. I was really surprised, and I forgot what the claim was. You could think of cocaine or heroin, and you could say, well, if you study people on cocaine, you probably see a lot of benefits. Right? But, of course, nobody would recommend that people go on drugs for the rest of their lives. Right?

I think that this is why, in the Cell review, we spend a lot of time explaining, right, so you have to have multiple pillars and you have to say, well, okay, you have pulsatile protein intake high, right? So, when you increase, that could very well be the worst thing you can do for cancer, for example.

Dr. Kara Fitzgerald: Sure.

Dr. Valter Longo: So, you have a system that is standing by, a pre-cancerous cell, all of a sudden, you have tons of protein. IGF-1 is going to go sky high, mTOR is going to go sky high, that looks, that’s exactly how we try to promote cancer in the lab. Right? Especially if you have a carcinogen of some kind, it could be the sun, right? It could be… So now, you’re combining a carcinogen, maybe something you ate with this high protein, and now, you have the recipe for cancer.

Also, because IGF-1 is an anti-apoptotic agent, so you have anti-apoptotic pro-growth, so, you may have a problem. But hey, maybe not, right? Maybe there’s a reason why that doesn’t happen. Okay, fine. Then, you got 30 years of studies ahead of you to disprove these 30 years that we just finished very, very clearly showing a low but sufficient protein diet, mostly vegan, et cetera, et cetera, et cetera is associated with, if you start 20, 13 years of increased life expectancy, and we’ve shown in our study with Morgan Levine, by the way, if you have a high-protein diet, a 75% increase in the risk overall mortality, and a 400% increase in the risk of cancer mortality. Right?

So these are huge numbers. Yeah. And I think they’re supported by the Harvard study, they’re supported by the Simpson and our study mice, they’re supported by the studies over and over and over showing methionine restriction, protein restriction, extend lifespan. They’re supported by the Laron studies where protein response pathways, when these genes are inactivated, the mice live longer, the people never develop cancer, diabetes, et cetera, et cetera. So, yeah. So, just overwhelming evidence against it.

Of course, you cannot confuse low protein with malnourishment. That is two very different things. Right?

Dr. Kara Fitzgerald: Right.

Dr. Valter Longo: So, if you have low protein and we’ve shown, for example, in the trial that we published with women with breast cancer last year, where we gave them a muscle training exercise, we give them the right amount of protein and the fasting-mimicking diet, and they’re actually…

Actually, we give them a little bit too much protein in between fasting-mimicking diet cycle. But the point of the study was that if you have the right type of exercise and in the right amount of protein, you can certainly keep a good muscle mass. Because we gave too much, they actually started increasing muscle mass, which was really bizarre.

But I lost that fight, that one time with the physicians, because they were convinced, the one, in overfeeding proteins to the women in the clinical trial, and there was no need to do it. But sure enough, that resulted in an increased muscle mass, which was not needed.

Dr. Kara Fitzgerald: Well, let me just ask you this though. There was a 2014 study out of, I think, UCLA, looking at NHANES data and those in the highest quartile for muscle mass, these were middle-aged men and women had lived the longest. So, there is something to having the-

Dr. Valter Longo: So, I mean… Yeah, I mean, that, you could be looking at frailty, right? So, the muscle mass could be a… And we see this, for example, in the same study I just mentioned, after 65, those that have low protein, they did the worst for overall mortality, for cancer mortality, et cetera, et cetera. So, clearly, you need to be strong, let’s say, right?

Dr. Kara Fitzgerald: Yeah.

Dr. Valter Longo: You cannot be frail.

Dr. Kara Fitzgerald: Yeah.

Dr. Valter Longo: And so, it makes sense that if you look at a bunch of people, and the ones that have muscle are probably well nourished and those… Hopefully, they have a pretty good diet, but it may make sense that they beat those that might be malnourished, and they may be frail, et cetera, et cetera. But that doesn’t mean that they’re going to be the ones, the high protein is going to make you live longer, because clearly, we see over and over, the vegans and the pescatarian and the vegetarian, and this is like many, many studies, right? They are the ones that are living the longest.

And if you look at the Okinawans and if you look at the people from the longevity zones of Loma Linda, et cetera, et cetera, I mean, you’re not going to see bodybuilders there. You’re going to see, if anything, the opposite. You’re going to see a lot of frail people. They may be protein malnourished, which is not what we want. So, we want to obtain the longevity effect, but we want to avoid that 70, 75 year old, and after, frailty that you even see in the record longevity people.

Dr. Kara Fitzgerald: And what about in this country where legumes can actually spike blood sugar. I mean, I’m with you on the impressive diets of those regions where there’s a high percentage of centenarians, but again, the standard American who’s not very metabolically flexible doesn’t do well with some of what these blue zoner diets are comprised of.

Dr. Valter Longo: Yeah. But these are what I call health pillar approaches. Right? A spike in sugar is irrelevant if you’re insulin sensitive and healthy.

Dr. Kara Fitzgerald: Interesting.

Dr. Valter Longo: So, you need to get in this, I call it winter mode, right? So, everybody in the United States or most people are in this summer mode where we are accumulating fat, because it used to be, 10,000 years ago, if you don’t accumulate fat when there’s a lot of food in the summer, you have the fruits and the nuts and the honey or whatever, you’re going to die in the winter. Right? So, yeah, if you’re stuck in the modality, of course, the spike… And I’m not even sure that that’s clear that the spike… I covered papers in my class where there’s some large studies showing high glycemic food is not associated with weight gain. So even, that is tricky.

But let’s say that it was negative, right? So, yeah, it’s going to be negative if you’re otherwise insulin-resistant. And I like to see papers showing that. So yeah, the legumes, the last thing you have to worry about is the sugar spike, because the legume by having a low protein content and certain amino acid are low should help you lose weight. And also, as we’ve shown very clearly now, should help downregulate the growth hormone IGF-1 axis, and is associated with insulin sensitization, in spite of obesity, right?

So, both in the mice and the humans with growth hormone IGF-1 deficit… So, if you inactivate the protein signaling pathway, in spite of obesity, you remain insulin-sensitive.

Dr. Kara Fitzgerald: Right. Listen, I want to just say what you said again. The spike in sugar is irrelevant if you’re insulin-sensitive. So, you’re clearly

Dr. Valter Longo: In fact, it might be good for you. It might be building. It might help you.

Dr. Kara Fitzgerald: Right.

Dr. Valter Longo: Now, we know that sugar, as we shown decades ago in yeast can help drive TOR, right? So now, you need a certain amount of leucine to build muscle to drive TOR, and it may be… And this is what we are actually, in collaboration with Cabo, some of the data was suggesting that the higher sugar may be helping you actually in muscle building. Just to give you an example. We don’t know…

Dr. Kara Fitzgerald: Yeah.

Dr. Valter Longo: I’m not saying as statement…

Dr. Kara Fitzgerald: Interesting.

Dr. Valter Longo: … that it’s a fact, what I’m saying it’s a possibility, the spike in cholesterol could help you. Of course, the spike can hurt you if, somehow, it’s contributing to-

Dr. Kara Fitzgerald: Well, I mean, it makes sense. I mean, I’m just thinking as a… I used to compete as a cyclist, and I still like to ride, and there’s no doubt about it that I do better when I’ve got a spike in my sugar, that I’m releasing some glycogen. I mean, it would make sense that we would be designed evolutionarily to maybe have a little sugar with whatever animal meat we might be gnawing on back in the day, and those together would influence what we do.

Dr. Valter Longo: Yeah. And I mean, sweets, forget legumes, right? Multiply by 10, if you look every centenarian around the world that I’ve met, they had regular sweets, maybe not a lot, but probably every day. Right?

Dr. Kara Fitzgerald: Right, right.

Dr. Valter Longo: So, it’s not uncommon to eat chocolate every day. And when I brought… I followed Emma Morano who got to 117, and when she was 116, I brought her a cake and she put it aside. And I thought, nah, I made a mistake. Who brings a cake to 116 year old? And then, one minute later, her niece calls me from the balcony, she’s like, she’s eating the cake. And that cake was gone in a matter of like 10 minute, the whole cake.

Dr. Kara Fitzgerald: That’s so funny.

Dr. Valter Longo: So, yeah. Imagine now, that, against the legumes, right? So…

Dr. Kara Fitzgerald: Sure. Sure, sure. Well, let me ask you this then. Because, you know, I think your research has been very influential, and I think it’s caused a lot of shifts in our world. Continuous glucose monitors are a big thing right now. And people will set a very tight range, like I’m going to keep my sugar within 70 to a hundred, regardless of what I’m eating, and one has to control what they’re ingesting pretty tightly to never spike above a hundred.

I mean, there’s been a lot of attention around spikes as being detrimental, and again, you’re saying, no, that’s not true.

Dr. Valter Longo: I’m saying unless you have A1C not an ideal range, throw out the continuous glucose monitor and live your life.

Dr. Kara Fitzgerald: That’s great.

Dr. Valter Longo: Because if anything’s going to shorten your life… Yeah. I agree. Once you start getting the A1C, you’re starting to get 5.3, 5.4, yeah, okay. Now, what’s going on? Why are you getting that?

Dr. Kara Fitzgerald: Sure.

Dr. Valter Longo: Probably, I will do FMD, I will do the fasting-mimicking diet. Then, you’re going to go right back to where you came from. I would intervene with the everyday diet, and that’ll go away. But if it doesn’t go away and it’s unexplained, yes, absolutely. For people that have that problem, then, they continuous glucose monitor, it’s good. And you can see, start seeing, well, which foods are affecting you in your blood glucose and why. Right?

Dr. Kara Fitzgerald: Yeah.

Dr. Valter Longo: So, yeah, that may be… But for everybody else, I think, yeah, it’s really… If anything, it could be problematic in the long run to be worried about, in the absence of an A1C elevation…worrying about what spikes and what doesn’t spike, I mean, stick with the pillars. Meaning, including the food of centenarians from around the world, right?

Dr. Kara Fitzgerald: Yeah.

Dr. Valter Longo: So, this is, if you stick with things that people have consumed for a hundred years and they reach record longevity in many different areas of the world, you’re good. Now, it might not work for you, and so, that’s one of the things that I say. So, if you’re gluten-intolerant, or if you have celiac disease, or if you have intolerance to tomatoes or to nuts, that’s a different story. Now, you got to avoid that. But I think that all this technology and trying to monitor everything is just going to get people to be stressed out about all of this and not enjoy the foods like legumes.

I mean, if you look at the Fadnes study, the Norwegian study that just came out, the number one food for life expectancy extension was legumes.

Dr. Kara Fitzgerald: Yeah. Okay.

Dr. Valter Longo: And this was China, Europe, and the United States, considered millions of people meta-analysis. This is not a study, one study. This is looking at all studies and looking at databases in three different continents.

Dr. Kara Fitzgerald: What’s a good A1C, in your opinion, or what you’ve seen in your research?

Dr. Valter Longo: Well, different people obviously, probably below five is good. But some people could be… And also, it probably depends in different ages. You know, it could be the 80 year old and A1C that is higher may not be such a bad thing. Right. So, we know that weight maybe around 25 BMI if you’re 85 years old may be a good thing.

Dr. Kara Fitzgerald: Right. Yeah. That’s right.

Dr. Valter Longo: So, as long as you’re generally healthy and you’re not diabetic, et cetera, et cetera. Yeah. So I think that probably age-dependent and people-dependent, but in general, if you can stay below five is probably good. Yeah.

Dr. Kara Fitzgerald: And what about BMI for younger individuals?

Dr. Valter Longo: Well, BMI, I always look at this data where, I think for males, keeping your fat, first of all, because BMI could be telling you a lot and nothing.

Dr. Kara Fitzgerald: Right. Yes.

Dr. Valter Longo: Let’s say you keep your fat below, let’s say 20% if you’re a male and maybe not too much higher if you’re a female… Then, the BMI 22 to 23 seems to be ideal for mortality for males, and it’s a little bit lower for females. The ideal one. Now, it doesn’t mean that you cannot be BMI 19 if you’re a woman and be very healthy, but I’m saying, in general, if you take a million people in the, say, 20-21 range seems to be ideal for females and 22 to 23.5 seems to be idea for males for overall mortality.

Dr. Kara Fitzgerald: So, getting into ketosis, I mean, obviously, on the fasting-mimicking, one would be… I mean, is it worth it to measure ketones? I feel like I know what your answer’s going to be there based on what we just talked about. But…

Dr. Valter Longo: Yeah, absolutely not. Keep your ketones low most of the time, but I think it’s very important to have moments of high ketones in the fasting, in a natural way, and those seemed to be very beneficial. Now, is it possible that if you have high ketones all the time, this could be beneficial? Certainly Eric Verdin and others have shown in mice that this could extend the lifespan, but these are very extreme diets. Right? So, how many people are willing to do that? And then, what could be the bad side of the ketones? We don’t know.

Yeah. So, I think that if we had three or four lives, I would say, well, give it a shot. You know, try something different in your next life. Having one life, I would say, probably want to stick with that common denominator of epidemiology, clinical studies, centenarian study, basic research, and most of this, or if not, all of it, suggest high carbohydrate diet and fats, but mostly, from plant-based sources and low to moderate protein intake mostly from plant-based sources.

This seems to be pretty consistent over and over and over, and people shouldn’t confuse the high carbohydrate with high calorie, right, from carbohydrate. Yeah. So, it’s high carbohydrate having the… Being able to maintain that BMI, let’s say, between 21 and 23 and a half, and be able to maintain the [body] fat below 22% or so. Yeah. So, those are probably the ideal diets.

Now, the Lancet study meta-analysis from a few years ago on lifespan showed that if you had a 20% carbohydrate diet which should probably be associated with high ketones, you had a 60%-increased risk of mortality, overall mortality. And the best was when you had carbohydrate in the 50, 60% range. Yeah. So, those seemed to be the type of diet that matches long, long lives, and not associated, that I could tell, with any side effects. So you don’t need to be frail with this diet, that you don’t need to be, have low muscle mass.

So, there is no reason to… I mean, to me, there’s no reason to go to the ketones until we have much more data proving, or certainly, getting close to it, that there are no side effects and it’s all positive and it’s very consistent, like we said, for all these that I’m talking about.

Dr. Kara Fitzgerald: Yeah. Right, right, right. Last time we podcasted, you said something sort of compelling about people ingesting the exogenous ketones who are on a very high carbohydrate diet and sort of the biochemical cacophony of that information.

Dr. Valter Longo: Yeah. Then… Yeah. Yeah. I think, yeah, I always say like, imagine if you’re hybrid car was trying to run both in gasoline and electricity at the same time, but it was not programmed to do that. Right? So, what would happen? Well, I don’t know, but it may break down eventually. Right? So if you just rewire it, so, it’s like, I want to get more power out of it. And so, I’m going to rewire, so, it’s feeding from both engines. Well, that could be a problem.

Dr. Kara Fitzgerald: Right. Yeah. I mean, again, it isn’t how, certainly we didn’t evolve using both of those tools simultaneously, at least, not in high, high, high amounts. So, the exercise prescription, I mean, what’s ideal?

Dr. Valter Longo: Yeah. Again, I stick with the meta-analysis, 150 minutes a week seems to be close to ideal. You go 300 and not much changes as far as mortality is concerned. It’s doable for most people. Yeah. And then, on top of that, add about at least an hour a day of walking. That seems to be very, very common among centenarians. Even though there’s not much science behind it, but I think it’s a good idea.

Dr. Kara Fitzgerald: Resistance training, high intensity interval training, getting your heart rate up, et cetera, what do you think?

Dr. Valter Longo: Yeah. Yeah. I think about 10%, the data suggests about 10% of the exercise should be strenuous, or should be pushing yourself more or a lot more, depending on the age. Again, these are recommendations. One thing if you’re 20 or 30, one thing if you’re 80. Right? So, I wouldn’t tell an 80-year old to do 10% of, do 15 minutes of strenuous exercise. So, yeah, adjust it for age-dependent and health-dependent factors. I think that some of it should be pushing yourself more.

And weight training, of course, yeah, you have to keep all the muscle challenged. Probably learning how to do all kinds of different resistance training is important maybe with an expert that they can point you in the right direction.

Dr. Kara Fitzgerald: Is there too much exercise?

Dr. Valter Longo: I talked about it in my first book, and I said, it’s not easy, because when you look at the data for too much exercise, you don’t see too much of it.

Dr. Kara Fitzgerald: Yeah.

Dr. Valter Longo: But you certainly hear the stories, we had NFL players coming to see us with all kinds of problems. And so, you would think, right, that if somebody overdid it, eventually, I think that the system or different parts can get worn out. So, yeah, I think so. But the data is not very clear on it.

Dr. Kara Fitzgerald: Right.

Dr. Valter Longo: But maybe not too many people are working on excess exercising.

Dr. Kara Fitzgerald: Well, you know, so, when we were looking at it, there is some evidence of a pro-aging effect with some professional athletes. I think one of the study we cited was a small, looking at Polish weightlifters. It was like a pretty…

Dr. Valter Longo: Yeah. Yeah.

Dr. Kara Fitzgerald: … rareified group. But the other piece that, like, if you want to find a population that’s low in secretory IgA, one of our main immunoglobulin to fight off infection in saliva or in a nasal swab, look at an athlete post-season, they’re always low. And that seems to be when they are at risk for upper respiratory infections and stuff like that. So…

Dr. Valter Longo: Yeah. Interesting. Because one of the first cases of almost lethal COVID in Italy was a marathon runner, somebody that had been pushing himself to the limit. Right?

Dr. Kara Fitzgerald: Yeah.

Dr. Valter Longo: I don’t remember if he died, or was very close to dying, but it was interesting because this was the early, early days of COVID and the whole nation talked about it. And it was strange. Right?

Dr. Kara Fitzgerald: Yeah.

Dr. Valter Longo: Why would this young person, athlete be one of the first one that ends up in the ICU?

Dr. Kara Fitzgerald: Yeah.

Dr. Valter Longo: So…

Dr. Kara Fitzgerald: Makes sense.

Dr. Valter Longo: … it may be relating to the same thing you’re saying.

Dr. Kara Fitzgerald: Yeah. Secretory IgA, just a drop in it, it’s like, if you want a population of mercury toxicity, you look at dentists. And if you want to see a bunch of people with low secretory IgA, you look at an athlete post-season, at least for a little while, I think. That’s been published on.

Well, anyway, Dr. Longo, it was just, really, a treat to get to talk to you and hear about all the things that you’re up to, and your command of the literature in your field is really nice. I know everybody’s going to appreciate it. We’ll corral together as many of those citations as we can, you guys. Just go over to the show notes to grab them, and just congratulations on doing such, such, such good work for all of us.

Dr. Valter Longo: Yeah. Thank you. And you’re doing great work, so congratulations to you.

Dr. Kara Fitzgerald: Thank you. All right. To be continued.

As always, thank you for listening to New Frontiers in Functional Medicine, where our sponsors help bring the very best minds in functional medicine, and today is no exception. Not everyone can be a sponsor on my platform, and I so appreciate the good work, relentless research, and generous support from my friends at Biotics, TA Sciences, and Integrative Therapeutics. These are brands I know and trust in my own clinic and can confidently recommend to you. Visit them at BioticsResearch.com, TASciences.com, and IntregrativePro.com, and please, tell them you learned about them on New Frontiers.

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Valter Longo is the director of the Longevity Institute at USC in Los Angeles, and of the Program on Longevity and Cancer at IFOM (Molecular Oncology FIRC Institute) in Milan. His studies focus on the fundamental mechanisms of aging in simple organisms and mice and on how they can be translated to humans. Dr. Longo received the 2010 Nathan Shock Lecture Award from the National Institute on Aging (NIA/NIH) and the 2013 Vincent Cristofalo “Rising Star” Award in Aging Research from the American Federation for Aging Research (AFAR).

ValterLongo.com

Dr. Valter Longo on New Frontiers (2018)

Nutrition, longevity and disease: From molecular mechanisms to interventions

Fasting-mimicking diet prevents high-fat diet effect on cardiometabolic risk and lifespan

Estimating impact of food choices on life expectancy: A modeling study

Dr. Valter Longo TEDx Talk

Younger You

DrKF Study

DrKF FxMed Resources

DrKF FxMed Clinic: Patient consults with DrKF physicians