What can fasting teach us about aging, and can the body receive some of its benefits without giving up food completely? Valter Longo, PhD, professor of gerontology and biological sciences, director of the Longevity Institute at the University of Southern California, and author of The Longevity Diet, joins The Future of Medicine for a wide-ranging conversation about nutrition, fasting-mimicking diets, protein, chronic disease, and the biology of longevity.
In this episode, Longo traces an unconventional path from aspiring rock guitarist to longevity scientist. He describes how the early death of his grandfather and the striking differences he observed between relatives living in Italy and Chicago helped shape his interest in why people age and develop disease.
Longo explains how experiments in yeast led his laboratory to study the effects of sugar, amino acids, and fasting on lifespan. He also discusses the development of the fasting-mimicking diet, a five-day, low-sugar, and low-protein eating plan designed to trigger some of the biological responses associated with fasting while still providing food.
The conversation also examines caloric restriction, time-restricted eating, breakfast skipping, and today’s enthusiasm for high-protein diets. Longo distinguishes between short-term changes in weight or metabolic markers and the much harder question of whether a dietary practice improves long-term health.
Together, Longo and host Euan Ashley explore what scientists are learning about nutrition and healthy aging, why extreme approaches can carry tradeoffs, and how carefully designed dietary interventions might one day become part of preventive medicine.
The Intro
“Ketogenic diet short-term is good, long-term it kills you early. The 16-hour fasting short-term is good. Long-term it kills you early. Very low carb diets. Short-term is good. Long-term it kills you.”
Dr. Valter Longo is a professor of gerontology and biological science and the director of the Longevity Institute at the University of Southern California. His research focuses on the fundamental mechanisms of aging, including the relationship between nutrition and longevity.
“Five days a month completely reversed everything — the cholesterol, the heart problem — and we didn't think it was going to be that much better.”
In this conversation, we talk about his early years touring in a rock band, the family history that informed his interest in aging.
“As a five-year-old, just seeing somebody dying in the room, his grandfather, thinking this has got to be the most important thing that I can do: figure out why people die.”
And how fasting mimicking diets can help people live longer, healthier lives.
Welcome to Stanford Department of Medicine's inside look at the future of medicine.
The Transcript
Dr. Euan Ashley: Well, Valter, welcome to Stanford.
Dr. Valter Longo: Oh, thanks for inviting me.
Dr. Ashley: Yeah, it's really great to have you here, and we've been really excited about your visit for As I was mentioning a few minutes ago in the warm-up here, we really love to dig into people's background, and you have a particularly interesting background, and the way it took you to where you are today, and the amazing work you're going to share with us at Grand Rounds. So let's go back to the past first of all — tell me about your life story, where you grew up, and in particular I'm kind of interested in your musical career, so make sure you tell us about that.
Dr. Longo: Yeah, so I grew up in Genova, Italy, but between Genova, which is in the northwest, and then Calabria, which is in the south, the southern tip of Italy. And then I moved when I was 16 to Chicago with some uncles and aunts, and I think watching my family in Chicago — having diabetes and cardiovascular disease, and they were all Italian, 100% Italian — and yet I didn't remember anybody in Italy in my family getting the same diseases. So that was an early motivation for me. I wasn't thinking too much about it because I was a musician, I was a guitar player, but I started thinking that's strange — multiple of them having advanced stage diabetes and lots of problems.
Dr. Ashley: So 16 years in Italy, then you moved to Chicago — tell us more about growing up in Italy there and what your aspirations were for the future. You mentioned you were a musician — was that your plan for life?
Dr. Longo: Yeah, I wanted to be a rock star, right? That's for sure. I told my parents when I was 12 I wanted to go to London. Of course they were laughing. But then a few years later they sent me to Chicago thinking I would come back in a month, and then of course I never went back. But Chicago was great, because I started taking lots of music lessons from lots of people, and there was somebody called Stuart Pierce who was doing bebop.
Dr. Ashley: I heard you were a jazz guitarist as well, right?
Dr. Longo: Yeah. Well, then I went to University of North Texas, which at the time was the leading jazz program in the US — believe it or not, in northern Texas. So I studied there, started with music, jazz performance.
Dr. Ashley: And who were your major influences in jazz, or on guitar?
Dr. Longo: Well, I was listening to people like John Scofield and Pat Metheny, but I was really training to be a rock guitarist — I wanted to get the jazz background to be a better rock guitar player. That was the idea, to come to LA, and then being in a rock band eventually, which I did. But then, the second year of college, as a jazz performance major in Texas, they say, "You have to direct the marching band." And I say, "There is no way I'm directing the marching band." So that's when I switched to biochemistry.
Dr. Ashley: So this music college had a marching band? I didn't think music colleges had marching bands.
Dr. Longo: The marching band — you were required, as a music major, that was part of the curriculum.
Dr. Ashley: And then, just to jump back before you got there, in Chicago you were already playing publicly, right?
Dr. Longo: Yeah, I was already going to Rush Street, and I would go at night and just plug in with the blues musicians. As a teenager, it was great — I would take the train in the middle of the night, the "L," they call it in Chicago, which was not a good idea. But I would just take my guitar, and I never got robbed, believe it or not. But it was an experience.
Dr. Ashley: I'm a big jazz fan, and I actually — if I didn't play the saxophone, I would play the guitar. Jim Hall, Joe Pass, John Scofield, Mike Stern — and Bill Frisell, I love his sense of melody.
Dr. Longo: We have to jam at some point. That would be great, though I'm pretty rusty.
Dr. Ashley: Well, you went to music school — I had considered going to music school, actually. But you actually did, so I think that makes you a proper musician.
Dr. Longo: Yeah, and I have to say, when I switched from music to biochemistry, even though the biochemistry professor was like, "I don't think you're going to make it," I was like, this is so much easier. That school is really tough. So they almost wanted you out of the music school?They were trying hard — it's like *Whiplash*. Yeah, that was a great movie, by the way, well done.
Dr. Ashley: So then you switched your major to biochemistry, but you were still doing a minor in music?
Dr. Longo: Yeah, I was doing my music, and then I had a band all the way to my last year in the PhD at UCLA. We would leave Thursday night, go to San Francisco, Portland, Seattle, Spokane, then come back Monday morning.
Dr. Ashley: That's wild — was that a rock band, blues band, or jazz?
Dr. Longo: No, that was a rock band. This is the grunge era. So it was great, until professors at UCLA started coming to me and saying, "That's really nice that you're doing that, but..." So that was the end of it, during my PhD.
Dr. Ashley: They weren't so impressed with your music distraction?
Dr. Longo: I mean, I was thinking that was cool, but they were not so impressed with my music distraction, because it was taking up so much time — it wasn't like a minor hobby, I was touring with a band. We'd be playing all the major rock clubs, like the Whisky, the Roxy.
Dr. Ashley: The Whisky a Go Go — I'd heard of it before, because there's a gene that causes long QT syndrome, an inherited arrhythmia, called *human ether-a-go-go related gene*, and it's because when these flies were exposed to ether they would shake, apparently, like they'd dance in this Whisky a Go Go bar. Geneticists have a sense of humor, you know. Anyway, it's a potassium channel gene. So I'd happened to have heard of this place before — it was a pretty famous music venue.
Dr. Longo: Very famous — the Doors, and lots of all the top names in music history have been through there. But we were very small, of course.
Dr. Ashley: So what led you to go back — what led you to pursue a PhD, given that you now had your biochemistry degree, and science and music were both going — was the idea that science would continue in the PhD and music would continue through the band?
Dr. Longo: Actually, when I switched to biochemistry I wasn't interested in biochemistry — I was interested in aging. I don't know, for whatever reason, and I always speculate that when my grandfather died — I was five — and I was in the room when he died. As a five-year-old, I thought no problem, but just seeing somebody dying in the room, my grandfather, I think that stuck in my head for 13, however many years, and thinking this has got to be the most important thing that I can do — figure out why people die, right? So when I left music school, I was sure I had to study aging. It wasn't like, oh, let me look around for what else I can do. I thought, well, what better than chemistry and biology together to study aging.
Dr. Ashley: So even at that early moment, your choice of biochemistry was already dictated by a vision to study longevity. When was this in time?
Dr. Longo: 18, 19 years of age. This is 1987.
Dr. Ashley: Late '80s, right? So the longevity movement that you've helped fuel, essentially, probably didn't gain huge momentum or real front-page news for another 10 or 20 years.
Dr. Longo: Maybe 20, right, because I always say that when I was at UCLA and they would ask us in biochemistry, "What are you working on?" We wouldn't say aging, right — being embarrassed. We'd say, "Oh, free radical biochemistry." People were making fun — I literally remember, I think it was at Washington University, and this must have been like 2002 or 2003, and they were still making fun of the aging field — somebody said, "Oh, there's this journal called *Aging*," and I'm like, "Hey, I'm a co-editor." And, "Oh, oops, sorry."
Dr. Ashley: Not anymore, no — it's really in a good spot now, which I think is a testament to the foundation that you and others built, and just a realization that we know so little about specifically cellular senescence and how important that could be. But since aging is something all of us inescapably experience, it seems like something we should all be interested in. So let's go back to your professor who said you got to do a bit less music and a bit more science — how did that work out? How did you balance that going forward in your PhD?
Dr. Longo: Well, I balanced that in the sense that I did both until I got to my postdoc — then I stopped, right, basically stopped. And I think they had a point, right — you just can't do both, at least at that stage. So that was a good idea. And then, with the end of the PhD also came the end of my music career. We had gotten a small contract from Interscope Records, but I think I would have needed a new band if I wanted to go anywhere. So it was a good time, but it was time to move on.
Dr. Ashley: Well, science is a team sport, and that's sometimes a bit like playing in a band — almost all science is collaborative in some way, and people are playing their individual roles. Tell us then, as you moved through your postdoc, how you started to really focus in on this area that would be your obsession for the next couple of decades.
Dr. Longo: Yeah, so the postdoc, of course, I was a student at UCLA of Roy Walford first, and Walford at the time was a superstar in aging — he was one of the pioneers of caloric restriction, a very simple intervention that had been established to be probably the most powerful anti-aging intervention ever. As medical students, that was all anyone taught us about aging, right — that's all we knew. So Walford had a lot to do with it. And Walford was the type of guy who would be on *Larry King Live* — Larry King had a big show where they interviewed famous people, and Walford would be one of the ones interviewed. So there was a very good time that I had with Walford, and then back to biochemistry. By the time I got to my postdoc, of course, I'd had a lot of exposure to some of the best people in the world working in aging — not just UCLA, but the Leonard Guarente lab at MIT was doing really, really good work, and Cynthia Kenyon up here in the Bay. There was a lot of exposure to conferences and the work by other, maybe six or seven, labs that were like a really relatively small community at that point. Everybody knew each other, and we'd go to Gordon conferences and it'd be like the same 10 people presenting.
Dr. Ashley: Was there a sense then, among that group, that you knew something others didn't — that it was just a matter of time before this broke into the big time — or was there a different sense at those conferences?
Dr. Longo: No, I think the sense was more that everybody was very passionate about it — and people were making fun of the field, so it wasn't exactly like, "Oh, now it's going to explode." We were wondering why nobody was interested. And by the way, I picked the worst field in that sense, and then the worst organism, and even the worst within that — I was working on starving yeast. People were making fun of yeast, and then yeast people were making fun of the people working on starving yeast. So I was in the absolute worst nightmare selection for a career, and everybody kept asking, "When are you going to stop working on this yeast? Why don't you start working on a real organism?"
Dr. Ashley: For context, because I'm sure some people listening don't have a good sense of this — today it seems obvious that you'd work on longevity and aging, among the most important things you could work on — give people a sense of why they were making fun of you, or thinking this isn't real science.
Dr. Longo: I'm told — and I don't know the details — that the same was true for neurobiology 60, 70 years ago: people said it's too complicated, why waste time learning about the brain. Or even deep learning and AI models more recently. I think if something is novel enough, it seems like a crazy field, a bunch of crazy people. Walford was a UCLA professor, a medical doctor, but people in biochemistry would say, "We don't know what they do over there," about pathology.
Dr. Ashley: I think the overarching paradigm was: if we want to help humanity, we should focus on disease. If someone shows up with a disease, that's something very concrete, something we can research, write a grant on — heart disease, atherosclerosis, cancer. Aging just seemed like a more amorphous concept — too complicated and too diffuse. What is it that you're going to get out of this?
Dr. Longo: And then, with the yeast — I made the mistake of saying I didn't want to do something called replicative lifespan, which is a unicellular eukaryote measure — everybody was measuring aging by how many times a mother cell generates daughter cells, and I said I don't want to do this, I want to study starving yeast instead — what I call chronological aging. And so it became an even bigger nightmare, because now nobody else was doing that — I was the only person on the planet studying it that way. It seemed like I was dead, right — I even started looking for something alternative to the PhD, maybe getting a job working in some biotech lab, because it just didn't look good at all.
Dr. Ashley: So then, track forward for us, because obviously this all changed over time.
Dr. Longo: Yeah, things changed within yeast — we started getting big papers because of the genetics. Once we started studying yeast chronologically, like every other organism, the techniques for yeast were remarkable. At UCLA, the microbiology and biochemistry departments were incredible — we had hundreds of mutants ready to go, so we had so much more power than any other organism. *C. elegans* had nothing, by comparison — we could do transposon mutagenesis, look for any gene we wanted, and bring the power of genomics to bear early with yeast.
Dr. Ashley: You could do a triple mutant in weeks, where with mice it would take years or decades.
Dr. Longo: Exactly right — if you wanted to do a triple mutant with mice, it would take years or decades. But with yeast, I could just go upstairs, grab a double mutant, then make my third mutation in a couple weeks, and I'd have a triple mutant.
Dr. Ashley: And there's been this sense — these competing ideas — that sure, humans are very far away from yeast, but on the other hand, so much of biology is shared that there's a lot of fundamental biology you can learn from yeast.
Dr. Longo: We forget that we've been co-evolving for three and a half billion years. Things split at some point, but we're still co-evolving, right — so there are fundamentals that are very central and controlling of everything, and that's still now the most important part of what we do.Would you rather biohack your way? We're in Silicon Valley, right, and here it's all about biohacking. But biohacking — I always say, you cut yourself, and within a couple weeks it's gone, perfect repair, right? That's three and a half billion years of evolution. So let's say you want to biohack your way to that — how many decades will it take you, if you stop all the natural processes, to biohack your way to almost-perfect repair like that? So that's why it was so important to identify already-evolved alternative aging modalities. In yeast, for example, you have three modalities: you can be in what's called post-diauxic phase, and you live about three, four days; you can be in stationary phase, you live three weeks; and then you can be in the spore state, you live two years — it's a hundredfold difference in lifespan between normal yeast and a spore, which is genetically the same yeast. I always thought, that's a trick that's already there. So I could biohack my way to the spore, or learn — can I get a spore that's high metabolism? So even with AI and all the AI in the world, three and a half billion years of evolution — you're not going to do it very quickly. You're going to do it, but how long is it going to take to get that sophistication? Very, very difficult.
Dr. Ashley: And I think much of the proof of the importance of what you say — that biology really is preserved, at least the important biology is preserved — is that your work has had significant impact also on humans, and some of the work you're best known for. So draw us a line between the work you're doing in yeast and where many people first perhaps think about the foundation that was built by caloric restriction, and specifically fasting, since obviously a lot of your work has been about the mimicking of fasting and the importance of fasting — something humans definitely understand because they do it every night. But also in today's world, where there's a lot of people skipping breakfast to fast for longer, or adopting the "5 plus 2" phenomenon you've spoken about, where they'll eat more normally for five days and fast for two — draw the line between your work in yeast and some of this work that many humans are thinking about or living day-to-day now.
Dr. Longo: Yeah, so in yeast we had two mutations that were very effective: one in the sugar pathway, RAS, and one in the amino acid pathway — protein kinase A signaling, to keep it simple. This was very clear from the mid-'90s. If you do a mutation in the amino acid pathway, the yeast live three times as long, and if you do it in the sugar pathway, they live twice as long. And if you do it in both pathways, they live five times as long. And if you do it in both pathways and you starve them, it's ten times. So that was very clear in my head from the very beginning — fasting can do things, but so can genes, and so can the regulation of genes. That's everything we do, based on that experiment. And I was lucky, because I had Walford, and Walford, when I joined the lab in 1992, was in Biosphere 2 — in the middle of the Arizona desert near Tucson — doing a human experiment on himself and seven other people.
Dr. Ashley: Give us a one-minute sense of Biosphere 2 for people listening.
Dr. Longo: Biosphere 2 was eight people, and it was supposed to be like a moon station or Mars station — so there was an electrician and other different jobs, and Walford was the medical doctor inside Biosphere 2. They were locked inside for two years, that was the idea, and they were supposed to grow their own food. But within a couple months of entering they realized they weren't going to make it — some bacteria were degrading the cement, and oxygen levels dropped, and there were issues growing their own food. So Walford said, "Let's go on caloric restriction" — conveniently, the world-leading figure on caloric restriction saying, this is the way to save food, eat less. So they started the first human study on caloric restriction, and the results were dramatic — cholesterol level, blood pressure, glycemia, extraordinary. But then you looked at them and thought there's something wrong with this group of people, even though the markers are great — so thin, they looked thin but stressed out. So that exposure was very important for me, because I then said, I've got to combine the yeast and *C. elegans* and everything we're learning from all these organisms and mice, and make it feasible. And the caloric restriction data was starting to show good and bad — it would take decades until the real bad stuff came out, just like with the 16 hours of fasting now. We were starting to get an idea this wasn't just going to be all good — it was going to be good and bad. And then the monkey study that Richard Weindruch eventually did — he was in the same lab as I was, then went to University of Wisconsin and did a 30-year monkey study on caloric restriction — and it showed exactly that: you get a lot of benefits, and you get a lot of problems at the end. You don't live that much longer if you're chronically calorie restricted. I think the combination of that was really important then, to develop: okay, what if we intervene once in a while, for five days, and we don't fast people — we give them food, but food that mimics fasting? And I thought, everybody can do that — well, not everybody, but maybe 50% of people, say every three months, can do a five-day fasting-mimicking diet. And would we have the same side effects? No, because we had data from mice showing we didn't see lean mass loss, we didn't see the problems — we just saw the benefits of caloric restriction.
Dr. Ashley: So lay that out in a little more detail — what were those people experiencing, what would they eat daily, what was their diet like over a seven-day period?
Dr. Longo: Just five days, right — the FMD is five days, and it was designed based on the yeast work. We knew each ingredient that's blocking the fasting response — amino acids, sugars — that block the fasting response. So we eliminate everything, and you end up with a low-sugar, low-protein, high-fat, very healthy diet. And I had a good idea, back 20 years ago when I started working on it: let's make it like the longevity blue-zone-based food — Okinawa, Japan, Italy — let's take the common denominator, the healthiest food in the world, and use that to make the fasting-mimicking diet. I could have made it with lard instead of olive oil and nuts, and it still would have been fasting-mimicking, but I think we would have had a lower benefit.
Dr. Ashley: But also, thinking back to your own personal history, and the story you told at the beginning about moving to Chicago and seeing your Mediterranean relatives have disease — there's a whole sense, at least in current human history, of data and a feeling that a Mediterranean diet has hidden properties of benefit.
Dr. Longo: Yeah, although — one of the things I show is a study in mice from a few years ago, where we take mice and give them the worst nightmare diet, the Western high-fat, high-sugar, high-calorie diet, and they become huge. And then we take another set of mice and give them the same bad diet for 25 days a month or so, and then we give them five days of the FMD, identical to the ones that are always on the good diet.
Dr. Ashley: Oh, really?
Dr. Longo: Yeah, so at least for mice, there was no difference whether they had a good diet or bad diet — and I'm not advertising my book, *The Longevity Diet*, which talks about a very healthy, even better than Mediterranean, everyday diet — but at least that study showed, what if it doesn't really matter what you eat, right? I mean, it's remarkable, because we did the whole lifespan study — so you have the control diet and they live very long, and then you put them on the bad diet and it almost cuts the lifespan in half. It's remarkable, even in a mouse, how bad diet is at killing you early, giving you high cholesterol, high glycemia, all the problems people get. But then five days a month completely reversed everything — the cholesterol, the heart problem — and we thought it was going to be a little bit better, but it wasn't just a little bit.
Dr. Ashley: And you've shown this in mice and in humans?
Dr. Longo: Well, in humans, we finished the trial — we have a 500-person trial, finished in southern Italy. I can't talk about the results yet, but the trial has three arms: one is nothing, obese and overweight people with one risk factor — high blood pressure, high cholesterol — everybody's got a problem, not a big problem. Then one group does an FMD every three months — a lot of the earlier trials we did were every month, and now we think most people can do it every three months, five days each time — they just get a box, like medicine, a very standardized box. And the third arm is the "longevity diet" — we throw everything at them: 12-hour time-restricted eating, mostly vegan, pescatarian, everything you can think of, plus the FMD. So we'll see — that's coming.
Dr. Ashley: You heard it here first. One of the things that's obviously less common, especially at the moment with the FMD, is that it's low protein, and a lot of health influencers and even doctors are recommending higher-protein diets. What do you make of this trend toward more protein?
Dr. Longo: We like to look at multiple pillars, right — a lot of people look at epidemiology and that's it, and we think epidemiology is extremely important, probably the number one pillar in our view. But then, what about centenarians, what about clinical trials, what about mice and rats? If you put it all together, you come up with low-but-sufficient protein — low but sufficient, you cannot be malnourished, like we said about caloric restriction. At a certain point the level becomes too low. And soon enough we have several papers that are now accepted, or close to it, making the case that "protein" as a number is irrelevant — it should be amino acids, it should be amino acid profile, because from a legume to fish, the essential amino acid content could be a three- or four-fold difference. So if you're talking about a gram of protein, it could be one gram or four grams, depending on how it matches the essential amino acid profile.
Dr. Ashley: So your strategy is to provide the essential amino acids and not much more?
Dr. Longo: I think it's looking that way — it's like medicine, right, how powerful a few amino acids are. A few of the essential amino acids can completely change the frailty or the lifespan of a mouse, at least, and of rats. Now, if you go to humans, is all that lost, like it might be in yeast and worms and flies and mice and rats and probably monkeys? Probably not. So my argument would be that we need to know your frailty level, and then match the amino acids so that it's sufficient for what you're trying to achieve.
Dr. Ashley: Because clearly there are a lot of people trying to build muscle, either for cosmetic reasons, strength reasons, or anti-frailty reasons, and there's some reasonable evidence — though none of it as strong as maybe the health influencers suggest — that increasing protein in your diet, up to a certain level, improves muscle bulk gains in response to resistance training.
Dr. Longo: Right, but these are short-term effects, right? There's a lot of things you can do short-term — ketogenic diet is one. Short-term is good, long-term it kills you early. The 16-hour fasting — short-term is good, long-term it kills you early. Very low-carb diets — short-term is good, long-term it kills you early.
Dr. Ashley: But do we actually have evidence that the 16-hour fast itself kills you early, or is that from meta-analysis on breakfast skipping?
Dr. Longo: We have a lot of evidence for that — 16 hours, with breakfast skipping. The new data is indicating it doesn't even matter if it's breakfast skipping or not, but long fasting — which is what most people doing 16 hours are actually doing — is associated with increased overall mortality, increased cardiovascular mortality, and not a small increase — a doubling of cardiovascular mortality in people who skip breakfast. This is meta-analysis, not just one study, so it's very clear. So breakfast skippers consistently do very poorly, and my colleagues argue it's because people who skip breakfast have bad lifestyles overall. But my argument is: if it was so good for you — and it is good, you get a lot of benefits — why wouldn't you at least see them come back to normal? It could be weight loss, insulin resistance, maybe better sleep in some cases — so if they have bad habits, and now they're doing something very healthy, why don't we see them at least going back to normal — no good, no bad? Instead we see negative, over and over. This tells you it's not a good place to start. Now, if you go to 12 hours of time-restricted eating, you see no problems — and of course 12 hours, which most people don't really do anymore, since you could say 12 hours is just eating normally. Well, it used to be, but it's not anymore. So I think 12 hours gets you there more slowly, but there's no association with increased mortality.
Dr. Ashley: So the difference between 12 hours and 16 hours is a doubling in cardiovascular mortality?
Dr. Longo: Nobody's really tested 12 hours specifically, because it's never been directly compared — most of the data is on breakfast skipping, and that's very negative. There's newer data saying it's fasting of 14, 15, 16 hours that's bad, but I've never seen anything negative at 12 hours — there's a Chinese group I think using enhanced data that looked at over 14 hours of fasting versus less than 12 hours. All the data is showing that breakfast skipping is negative, and now nobody has carefully compared the two, but certainly if you do 12 hours, a lot of Sachin Panda's data indicates you get benefits — maybe not as big or as quick as at 16 hours. So that's why we're saying it's much easier, much safer, probably less likely to cause side effects like muscle loss — so that's probably a much better way to go.
Dr. Ashley: Do you think these studies are overall large enough — I mean, you described a randomized trial you're doing, which is obviously our gold standard — do you think most of the data in the field is large enough to draw these conclusions confidently?
Dr. Longo: I don't think you can draw conclusions confidently, but I think you can say: there's 30 years of research, epidemiological study after epidemiological study coming up with big numbers of increased risk — there's consistently increased risk in breakfast skippers. That doesn't give you confidence to say "I know for sure," but it gives me confidence to say I'm not starting with that — let's start with something that doesn't have that association. Maybe it is fine, and some people I talk to — a physician, last night — say, "I do 16 hours, and maybe you're going to live forever doing your 16 hours, but maybe not — take a chance." That's really a statistical issue, and that's all it is.
Dr. Ashley: But then, going back to what you said a few minutes ago — you have data that would support that you could have a very unhealthy diet for 25 days, and as long as you have five days of the fasting-mimicking diet, you can reverse your blood markers?
Dr. Longo: Yeah, but I wouldn't — this is why we say to everybody, do it all, right — have the healthy diet, and maybe 20 years from now we'll know for sure, once 20 trials have been done and we keep getting the same result.
Dr. Ashley: And those markers — are they things like cholesterol and blood sugar, or much more extensive, inflammatory markers as well?
Dr. Longo: We have inflammatory markers, yeah, and we have lifespan — in mice we look at cholesterol, fasting glucose, lots of different things, and in humans we have like a hundred different markers, epigenetic clocks, telomere length, name it. But the most important of all is lifespan — the five days are bringing the lifespan back to statistically normal, but a little bit shorter than the good diet. So bad diet plus FMD is statistically the same, but if you look at the curves, they're dying a little bit earlier compared to the good diet.
Dr. Ashley: And if you take the same markers at week two, in the middle of the poor-diet period, I assume those markers are off, in the negative?
Dr. Longo: We take them in the middle of the bad diet — a lot of markers are not off, actually. Ketone bodies, for example, during the bad diet, are still elevated, which means the fat cells seem to continue in a "good diet" mode even though they're on the bad diet. We did RNA-seq, and the fat cells are very active — a lot of mitochondrial biogenesis markers.
Dr. Ashley: So there's even a forward effect from the five days into the next period of bad diet that seems to be protective in the moment?
Dr. Longo: I think it's a modality — they switch to something else and stay in it, which makes sense if you think about evolution: periods where you're exposed to lots of food, and periods where you're exposed to no food at all, like grizzly bears and emperor penguins of the South Pole. Emperor penguins do two months with no food, so beforehand they have to accumulate fat, and once they're sitting on the egg for two months, they can't eat — so they switch to burning the fat, no matter what, and even if they eat something, that modality probably doesn't change. So it looks like the FMD is that switch — once it switches, the body starts using the fat that's been stored, and it keeps going. This is why the ketone bodies, even days later, are still high — a major increase — because everybody else is putting away fat, and you're using fat.
Dr. Ashley: Interesting, really interesting. Well, Valter, thank you so much for coming to Stanford — we're really excited to see your data and have you present at Grand Rounds, and thank you so much for joining us here on the future of medicine.
Dr. Longo: Thanks a lot.