Fasting and Biological Age With Dr. Valter Longo

How old are you? A better question might be: how old do you feel? While your birthday says one thing, your biological age—the health of your cells—might tell a very different story. And here’s the best part: unlike your chronological age, your biological age can go down.

But how? For years, fasting has been celebrated as a key to longevity. Yet the challenge of skipping meals is enough to make most of us shy away. What if you could trick your body into reaping the rewards of fasting—without starving yourself? 

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Transcript

Jonathan Wolf: Valter, thank you for joining me today. 

Dr. Valter Longo: Well, thanks for having me. Happy to be here. 

Jonathan Wolf: It’s a pleasure. And Tim, thank you as well. 

Prof. Tim Spector: Pleasure.

Jonathan Wolf: So we have a tradition here at ZOE where we always start with a quick-fire round of questions from our listeners. And we have very strict rules. You can say yes or no, or if you absolutely have to, you can give us a one-sentence answer.

It’s designed to be really hard for professors. Are you willing to give it a go? 

Dr. Valter Longo: Sure. 

Jonathan Wolf: All right, starting with you, Valter. Do we have more influence over aging than we realize? 

Dr. Valter Longo: Yes. 

Jonathan Wolf: Does having a longer eating window accelerate the aging process? 

Dr. Valter Longo: Not necessarily. 

Jonathan Wolf: Tim, could having a shorter eating window give you more energy?

Prof. Tim Spector: Yes, definitely. 

Jonathan Wolf: Valter, can we get the effects of fasting while still eating something? 

Dr. Valter Longo: Yes. 

Jonathan Wolf: And finally, you have a whole sentence. What’s the most surprising thing that you’ve learned about aging? 

Dr. Valter Longo: Probably that there is a way to turn on these reprogramming factors and rejuvenate the system without causing necessarily a lot of damage.

So that to me, it was a little surprising when Belmont and others came up with it. 

Jonathan Wolf: I’m definitely going to come back to that because you’ve raised more questions than answers for me at this point. So I’m very excited to get into it.

I was actually thinking just as we were getting ready for this podcast, that when I was younger, I never gave any thought to aging. I think like most young people, I just assumed I was going to stay young forever. Needless to say, I was wrong about that. And probably about many other things that I believed when I was 20. 

So now I’m in my late forties and I find myself thinking about aging a lot more often and sometimes worrying about that. So I’m eager to learn how I could stay healthy for many more years, and I’m excited to talk about it with the two of you. 

Valter, could you start at the beginning by helping us to understand what’s the difference between our actual age by, our number of birthdays and our biological age?

Dr. Valter Longo: Essentially, how functional are you? How able are you to reproduce, to run fast, et cetera, et cetera? In fact, some years ago, I introduced the concept of juventology, to contrast gerontology because it’s also the concept of how young you are versus are you aging or not. 

So I think that we’re missing this idea of youth span. I call it the youth span, right? So you’ve been told juventology and youth span. So the measure of how young you are. So if you’re 55, can you still run like a 35-year-old? Right?

So that I think is still somewhat missing in the field, you know, the measurement of youth. 

Jonathan Wolf: And Valter, if I’m 49 by the number of birthdays I’ve had and maybe let’s say that means I’m going to live for another 30 years.

If you figure out my biological age is 39, does that mean I’m literally going to live for an extra decade? Is that literally what biological age means?

Dr. Valter Longo: It means that your life expectancy is that. It’s going to be prolonged but doesn’t mean that you will live that much longer but so on average your life expectancy will be extended.

Jonathan Wolf: So it’s really like measuring like the actual state of my body being like an average person who’s thirty-nine rather than forty-nine 

Dr. Valter Longo: I don’t even know that we should use chronological age. I mean, assuming that the measurements are valid, but if that’s true, then you are 39, no matter what your chronological age says. 

Jonathan Wolf: And is it possible to have a biological age that is very different from your actual age? 

Dr. Valter Longo: Absolutely. So there was a study years ago, showing I think they were all chronologically 38 years old and some of them biologically were in their 20s and some of them were in their 40s and if not later. So yes, you can have a 20 years of difference between chronological age and biological age.

Prof. Tim Spector: You know, we did one of the big studies of biological age using the U.K. twins. And we’d measured about 3000 twins of different ages. And whilst there was a rough correlation between your birthday and your biological age within each age band, there was around a 20 to 25-year difference.

So you could end up with a 40-year-old having a biological age of 65. And a 65-year-old having a biological age of 40. 

Jonathan Wolf: And Tim, does that mean that if there was a 65-year-old with a biological age of 40, they’re actually likely to live a lot longer than that 40-year-old who had the biological age of 65?

Prof. Tim Spector: On the balance of probabilities, yes. I mean, at the moment it’s a rough prediction, but that’s what it’s showing, is that there’s big differences between individuals regardless of what your actual age is at that particular time. 

So this is why the whole field is, you know, we’re all living with different biological ages and most of us don’t know what they are. I think that’s the really quite fun thing about this. We’re obsessed with our birth date and being told that all 50-year-olds need to do this and 60-year-olds need to do this. 

But within that, there’s this huge range. And this is what we see with centenarians who may have obviously different biological ages and may be fitter than people 30 years younger than them.

Dr. Valter Longo: Yeah. And of course, given that the sophistication of these biological aging methods is limited, right? So we’re going to find out that there are more limitations than we think, right? 

But initially, you get excited because you get a correlation and you say, well, people that have this epigenetic profile tend to die earlier or later, but then I think you realize that that’s not as sophisticated as you think it is.

So we’re probably going to modify. So maybe those 40 year old, their chronological 65 are not really 40, right? They may be 55, right? So I think that’s probably what we’re going to see.

To answer your question, I’m probably gonna say, maybe in between, maybe die at the same time.

Prof. Tim Spector: Because I’ve done three tests on my biological age test, three different ones.

One an epigenetic test, one a telomere test, and one using chemical metabolites, metabolomic test. And a fourth one, actually, I did something called GlycanAge, which is measuring these little sugars on your immune system. And the majority pointed to me having a lower biological age than my other one, but not all of them. They don’t all agree. So you can pick the one that suits you best.  

Jonathan Wolf: I think I would definitely pick the best one out of that. 

Dr. Valter Longo: But that’s exactly the way to do it, right? That’s the way to do it. Instead of getting the best one is use all four of them and then pick the average of the four because that’s probably much more likely to give you a good indication of your true biological age. 

Jonathan Wolf: And Valter, can I just walk into my doctor and say, I’d like to get a test for my biological age? And they will say, sure, Jonathan, and take some blood and then tell me what it is. 

Dr. Valter Longo: Most doctors will now, either they know of a company that does this, or they can find out. So most doctors, yeah, will be able to order you one

Jonathan Wolf:. And is there a specific test? What would be the test that you’re referring to when you say that?

Dr. Valter Longo: Different ones, right? So there is definitely the epigenetic one. That’s very common, both in Europe and the United States. So there are companies that do that and they’re just a kit, and they send you the kit and you send it back and they give you your biological age.

I really like the Morgan Levine, bio age, which is based on blood markers. And I like that because the blood markers that she selected are disease risk factors like A1C and blood pressure, et cetera. And so I like that because it’d be difficult to argue that somebody’s got lower A1C and lower blood pressure and lower inflammation, et cetera, et cetera would not be younger biologically, right? 

So that’s another one that any doctor can calculate it based on your blood markers. 

Prof. Tim Spector: There’s one called telomeres, which is sort of measuring the ends of your chromosomes. Which is being likened to the end of a shoelace that as you get older, it gets more and more frayed and tears off. The bit that’s remaining is called the telomere length. You can measure that, which was all very trendy about 10 years ago. It has some problems with it, as you get older, it may not work as well. 

And the final one is just doing these chemical metabolites, you measure maybe 50 or 100 of these metabolites that are related to age and you put them all together into a model and you can do them.

So there’s lots of different ways of measuring it. There isn’t really a gold standard as yet. And they all roughly agree with each other, but not a hundred percent. So that’s the problem. And some change with time more differently, don’t they? So that makes it slightly difficult to interpret.

Dr. Valter Longo: But those two will be less available, I mean most doctors will not be able to get you a telomere test, and certainly not a metabolomic test. But I would say most doctors will be able to fairly easily get you the other two.

Jonathan Wolf: So I’d love to go on having established that there is this difference between our biological age from just how many years since we’re born, understand more about how we age. Valter, I think yeast has helped you to make some breakthroughs here.

Dr. Valter Longo: Yeah, so I went from working with Roy Walford here at UCLA, with working on people and mice back to yeast, in the biochemistry department because I wanted real answers, right? 

So the genetics of aging was starting right back in the early 90s and so I decided that it was probably better to work with something very simple, so that we could identify the genes that control the aging process and we did.

My lab was the first one to identify the TOR S6 kinase pathway, in aging, in yeast. And this was in 2001. So rapamycin blocks this pathway, it’s called TOR S6 kinase. And so the rapamycin now, I would say it’s probably the one genetic pathway most recognized to affect longevity in all kinds of organisms, right?

Jonathan Wolf: So could you explain to me in simple words what that means?

Dr. Valter Longo:  Yeah. So it basically means that if you think about eating, and proteins, and amino acids. So proteins and amino acids do lots of things, but one of the things that they do is activate this pathway, this set of genes that have to do with cell growth and cell function.

And at the center of that is TOR, T-O-R, and then downstream of that is something called S6 kinase. So when you have certain amino acids, high levels of certain amino acids, and certain factors in the blood, this TOR is activated. And this is now recognized to accelerate aging in all kinds of organisms.

There was a famous paper following mine in the early 2000s, that then was done in mice in 2009, published in Nature, showing that using this drug called rapamycin, blocking TOR, extends the lifespan of mice in three different laboratories, one in Michigan, one in Texas, and one at Jackson Laboratories.

Prof. Tim Spector: So a simple way to describe all of this, I think, is perhaps nutrient sensing in all the cells. So, this idea that all our cells have the ability to sense things like how much protein is around and perhaps glucose. 

These sensors are then key to how much the cells are going to grow or repair. And this is this new concept, regardless of the details of the actual mechanisms, the pathways, we all possess. 

For some reason, these cells are really tuned in to knowing what’s going on in terms of proteins and sugars and possibly also fats. And that regulates how our body repairs itself or grows or prevents aging.

And I think that’s what we’ve shown. Some of these drugs will either stimulate or block these systems. And that’s really what Valter has been discovering. 

Jonathan Wolf: And are you saying that if you have too many nutrients in your blood, that actually makes you age faster? 

Dr. Valter Longo: Yes, so, well, let’s say that it’s not really about too many nutrients, it’s about certain nutrients and so certain amino acids and certain carbohydrates.

In the case of yeast, if you had a lot of sugar and then you activated this second pathway called RAS and a lot of amino acids, TOR. So TOR and RAS together, if you block this pathway, then the yeast live five times longer. So if you block the sugar pathway and you block the amino acid pathway, then the yeast live five times longer.

If you did this and then you starved them, they live 10 times longer, right? So, that means there was other pathways, the additional pathways, other than the sugar and the amino acid, they were involved in accelerating the aging and the mortality of the yeast. 

Jonathan Wolf: Can I ask a really naive question?

I would have thought that having more nutrients would be better for living longer because I’d have all these things to feed me and repair me. Why is it that having more of this is actually bad?

Dr. Valter Longo: It probably has to do with reproduction, right? And, and the force of natural selection. 

Meaning that we’re here and every organism is here to reproduce and get out of the way essentially, right? So then if the nutrients are low enough that you can now have a normal course of reproduction, now you enter a maintenance mode. 

Evolution has basically come up with an alternative state where you can have a longer opportunity. So if you have not enough nutrients, then the offspring cannot survive, cannot be born and cannot survive.

And so, you wait until that opportunity comes around again, and that’s why yeast and bacteria and all kinds of organisms you can put in starvation condition, the standby. In fact, in yeast, it’s really remarkable because, of course, we extend the lifespan by tenfold, but there is something natural called spore state, and in the spore state, they live 100 times longer, right?

They’re in a what’s called a diapause, they’re just hibernating, if you will. So they’re sitting there and they’re waiting, waiting, waiting for years for the opportunity that food is going to come around and now you can grow, right? And you have your opportunity to reproduce, right?

So there’s a hundredfold difference between state one. So the normal state, you know, living in the fast lane and this, this spore state where you live very slowly, but for very long. 

Jonathan Wolf: I’m thinking about the analogy with my iPhone, you know, the power gets low and it goes into this like power saving mode and suddenly the battery goes for much, much longer, but it doesn’t allow me to watch TV, Netflix and get my email at the same time. 

Is that sort of an analogy here, that it’s sort of saying, well, the availability of these nutrients is lower and I’m setting my whole body to just like last much longer, but equally well, because I need to sustain myself until the point that I’m going to get these more nutrients or in my iPhone, plug it back into the power supply.

Dr. Valter Longo: Yes, absolutely. But now the science is basically now looking for, well, maybe you don’t have to be in hibernation. You could be in a very active state, but maybe not reproducing. And so most people don’t reproduce very many times in their lives, right? So why are we always in a pro-reproductive mode? 

Why don’t we get into maintenance mode, be very functional and very active? And then utilize this protection. And then, of course, exit from it only when we need to reproduce, right? So now you can exploit all this knowledge to age more slowly without having to hibernate. 

Jonathan Wolf: Does everybody therefore age at the same amount or does this depend so that I might age at a completely different rate than Tim because of the way that my biology is working?

Dr. Valter Longo: No, it depends. Fundamentally, everybody ages by the same processes, but then two people can age very differently.

So we’ve been following people in Ecuador. I mean, both mice, they have a growth hormone receptor mutation. So they lack the keyhole responding to the growth hormone, right? So if you have a lot of growth hormone, the receptor is activated and they’re lacking this receptor, right? 

So it’s like they didn’t have any growth hormone. And the mice live 40% longer and people, we don’t know if they live longer, but certainly they rarely get diseases, right? They seem to be as protected as the mice against diseases. 

But they’re basically saying a single mutation in a single gene can revolutionize not only the lifespan of the mouse, but the health span of the mouse. And so clearly two people can have different genes. 

So just these different genes can make a big difference and by the way, we suspect that in Sardinia and some of the other places in the world where there are these blue zones, even though this is not being talked about a lot, we suspect that a big component was genetics, right?

The group of people in Saulo, Villa Grande Strisaili, some of these little towns that have record longevity. They were born with the right genetic variance and so they were predisposed to live longer and then the lifestyle and the food, et cetera, made it even better. So that’s probably a good explanation for them.

Prof. Tim Spector: We looked at this in our twins, the genetics of aging. There is a genetic component to aging, but across the whole population, it’s actually less of an effect than, than for most common diseases. 

So we think that the contribution at a population level is only about 20% heritability of that effect. But as Valter said, there might be certain families or certain areas where they have a concentration of these, these genes. 

But across the board, 80% of aging, I think, is probably more environmental apart from these special families. Which was a bit of a shock at the time because we thought actually, genes would be the answer to most of, most of aging and longevity issues, but it turns out not to be true. 

Dr. Valter Longo: Yeah, but now keep in mind, this is let’s say between twins, but genes are really controlling, completely controlling generally the lifespan. 

What does it mean? It means a mouse lives for 80 because of the genes, right? That’s what I was saying earlier just a mutation in that one gene can make that mouse live 40% longer. 

Now in the general population, most of what determines whether a twin lives longer or shorter is lifestyle and all the things that happened to you. And so genetics are less important. But if you manipulate genes, there’s limitless potential. 

So as we know, let’s say a rat lives more than a mouse. So the genetic differences between a rat and a mouse are minimal, but that’s enough. In a monkey, the difference between us and a monkey genetically is very small. But those 1% or whatever, is responsible for almost a tripling of lifespan between humans.

If you just look at the population, most of the reasons why people live longer do not have to do with genes, but with probably lifestyle choices.

Jonathan Wolf: They change one gene in the mouse, they then reduce the number of calories each day, and it lived twice as long as it’s sister mouse where none of that happened. That is remarkable. 

Can I move us on? Because I think we’ve understood now that aging can be very different between people. And I think everyone listening to this wants to be in the group where their biological age is much lower than their chronological age. And I know this is really your big area of focus with your research on aging and longevity. And I understand my team tells me that. 

You got a spot on Time Magazine’s list of the 50 most influential people in health care, and they referred to you as the fasting evangelist, which I love. So I’d love to talk about fasting and how it can connect to this aging process because obviously nobody listening is going to be able to change their genes at home, but clearly they have a lot of control over their food.

Could you start by taking us through what happens to someone’s body during a fast and why that can be linked to what happens in terms of the aging in their body? 

Dr. Valter Longo: I always challenge everyone with the question, find me anything that will revolutionize gene expression more than fasting. And I still haven’t got anybody to even come up with something that they think could challenge it. 

Meaning if you fast a person for let’s say five days, it’d be hard to find something else that causes more changes in the body. Of course, if you go longer, even more changes, but I say anything you can do in five days.

So everything happens during fasting for obvious reasons. So you now can no longer rely on energy coming from the outside. You need to rely on energy come from inside and so the body slowly gets into a modality where it starts burning fat and relying on fatty acids and ketone bodies. You heard of ketogenesis and so ketogenesis refers to making these ketone bodies that are byproducts of fat breakdown, essentially, breakdown and then reprocessing. 

So for example, the brain after three or four days of fasting starts functioning both on glucose and on ketone bodies, and the heart can function using fatty acids and other organs. I use fatty acids, which is basically fat breaking down, fats that are broken down.

Then there’s something else that’s called glycerol that is released and glycerol and amino acids coming from muscle and other systems. They can be used for gluconeogenesis. So now the body can make its own glucose because of course there is no carbohydrates coming from the outside, right? 

So these are just some of the examples of the things that happen in a human body in the fast.

Now, a lot of people use words like autophagy and think that’s going to happen very quickly. So autophagy is this process where cells begin to eat themselves, right? Eat their own components. So they shrink and they start eating themselves. 

Jonathan Wolf: So Volter, that’s a good thing if your cells are eating themselves, it doesn’t sound like a good thing. 

Dr. Valter Longo: It is a good thing, right? So, these bacteria do it and yeast do it and all organisms do it. So it’s an opportunity to get rid of a lot of normal components, but junk, real junk that accumulated in the cell. So in that sense it’s an opportunity to clean up. So it’s a good thing. 

Our group that we collaborate with has done a clinical trial showing that the markers of autophagy don’t seem to be measurable until about day five, end of day five in the human blood. 

But that’s one of the things, people fast for three hours and they think autophagy is on, but it probably takes about five days to get there. 

Jonathan Wolf: So just to play back, you’re saying that if you got into a state where your cells are actually sort of eating themselves, they’re getting rid of sort of damage, that could be good, but you’d actually have to starve yourself for five days before that would happen.

Dr. Valter Longo: Yes, of course, and I think we’re going to talk about it. 

So we’ve been working for many, many years and how you don’t have to starve yourself to get some of these effects. And that’s where fasting-mimicking diets and other things come in. But yes, normally a person will have to do, say, water only fasting for three, four, five days before they see this, at least some of the cells.

We don’t know what other cells do, but let’s say the blood cells, they seem to be going into this autophagy process by day five. 

Jonathan Wolf: So if you’re not willing to fast yourself for five days, is there any positive impact on your body from fasting more rapidly? Because you were talking about how it transforms your body in five days.

Most people listening are probably not going to fast for five days, but obviously there’s a lot of interest in intermittent fasting or all these other sort of things. Is there any impact on your body from shorter periods of fasting? 

Dr. Valter Longo: Yeah, so there’s lots of different types of fasting and each can have problems and solutions.

Now, the one that I like after doing this for a long time, is one that’s called time-restricted eating. Something that Sachin Panda and others have worked a lot on. The entirety of the eating, like with all things, people started abusing it and started doing 16 hours of fasting per day or 18 hours or 20 hours.

And so I was against that and I’m still against that because those 16 hours and even 14 hours or longer are associated with lots of side effects, lots of problems in the long run, right? And one of them is gallstone problems. 

But the worst one is the association of breakfast keeping with increased cardiovascular mortality, increased overall mortality, right? So there’s meta analysis and that means studies of all studies, indicating that. This is why I was always against it. And now there’s a group that is suggesting that even if you skip dinner, this could be problematic. 

So I think instead the 12-hour time-restricted eating is the one that I never met a doctor or anybody that argue with it.

And yet most people eat in America and I’m assuming in the U.K. for about 14 to 15 hours a day, right? So that means they fast for only, let’s say nine hours or so.

So I think that going back to 12 hours of fasting and 12 hours of feeding, which most people say, well, it’s normal. It’s a normal eating pattern, fine, call it whatever, but that seems to be very good.

Jonathan Wolf: It’s come up on various podcasts about various benefits you might get, but does this actually affect the aging processes that you were talking about that could make us stay healthy for more years? 

Dr. Valter Longo: The mouse studies will indicate yes. I think we’re starting to see some studies indicating reduced biological age, but I don’t know if anybody’s ever tested the say 11, 12 hours of eating.

Most studies have looked at longer ones, right? So longer interventions, of course, are going to have more benefits and might even reduce biological age more dramatically short term. But it doesn’t mean that they’re going to make your life longer if in fact there is this association with increased mortality is correct.

Jonathan Wolf: You’re saying for people who are fasting for more than 12 hours a day, you’re talking 14, 16, 18 hours of fasting, you’re worried that although you might see short-term benefits, you’re actually concerned that in the long term you might actually die sooner rather than actually be healthier. 

Dr. Valter Longo: Yes. And I think this is the concern with lots of drugs and lots of interventions like say GLP-1.

So lots of things are beneficial short term, but then medicine is not really set up to think about long-term effects, right? I think fasting, because it is so powerful, is in the same category, but the 12 hours, I’ve never seen any negative studies, epidemiological or otherwise.

So I would say that that’s a very good recommendation. It seems to be working for aging. It seems to be working for metabolic issues, not as well as the 16 hours, but well. And so I think that’s a good, safe option to the 16 hours.

Jonathan Wolf: Tim, I’d love to bring you in here because I know this is something that you study quite a lot and also because ZOE conducted a study on I think about 150,000 people didn’t it, on intermittent fasting.

So I’m really curious about your view and what we found there but also more broadly. 

Prof. Tim Spector: Yes, so we did what we call the ZOE Big If study, which was time-restricted eating, not actual fasting. So it was just trying to see what it was when you went to the general population rather than specific volunteers in a lab, which are not generalizable. How easy would it be for people to do?

So we had 140,000 people from our ZOE database that signed up for this program. And we said, okay, we want you to do three weeks where you’re eating in a 10-hour window and you’re fasting for 14 hours, which I still think is reasonable. 

I think somewhere between 12 and 14 hours, I believe the evidence shows that that’s still safe. We can disagree on some of the epidemiology, but I think where is it more extreme fasting, I do worry as well about that. 

So we were asking people to do a modest change. And what was really interesting is that a third of people found it really easy to do this, and they actually carried on well past the three weeks. They went on a lot of them for six months.

Those people got real benefits in mood and energy. They lost weight and waist circumference improved and they actually had less hunger by doing that. So they really liked it. A third of people never found it too much and they didn’t actually get started and a third started and sort of gave up. 

There are certain people that it probably really suits and they feel very comfortable, it feels natural to them and they get into it and I think they will get benefits. Some people do find it rather hard to go long periods without eating.

Just showing this, as we know at ZOE, it’s all about personalization that there are these differences between people that make it harder or easier.

So, yeah, I’m all for this not too strict a time restriction eating, but it is not necessarily for everybody. We didn’t try the 12 hours, so it could have been for most people, even easier to do the 12 hour. 

Dr. Valter Longo: Did you actually ask them what they actually did? 

Prof. Tim Spector: Yes. 

Dr. Valter Longo: You told them to go 10 hours, but did they do it? Because in the studies of Sachin Panda, it tells them 10 hours, but then it’s about 11, right? So it gets closer to 12. So do you know what they actually was that they did?

Prof. Tim Spector:  Yes, we did. And a third did it quite sort of religiously. And there was this middle group that actually went back and probably managed 12 hours most of the time, but they didn’t seem to get quite the same benefits.

But I think, realistically what’s more important is that people sustain this for long periods of time. Therefore, I agree the general principle that having more modest goals is people will be more likely to adhere to it long term and get benefits than then really going for some superhuman effort.

Jonathan Wolf: I know you’ve developed something called the fasted-mimicking diet And so I’d be interested to understand what that is because I think this ties into this question around how can you do something that’s sustainable and something which is trying to get these aging benefits? 

Could you explain what it is and why you think it’s still beneficial for longevity?

Dr. Valter Longo: Yes. So I mentioned my second favorite fasting intervention, which is time restricted eating. But my favorite of course is what we developed in my lab, which is looking at fasting more like a medicine and when do you need to fast? 

So starting a long time ago, I knew, well, we first did a trial, I think it was 2010, on cancer patients. We were testing the hypothesis that, coming from mice, that if you treated mice with chemotherapy and you fasted them before you treated with chemo, they were much more resistant but the cancer cells were much more sensitive, right? 

So we brought this to the patients in USC Norris Cancer Center nearby here.

Jonathan Wolf: And Valter, you asked them to fast how much before? 

Dr. Valter Longo: For three days. 

Jonathan Wolf: So they had to eat no food or anything for three days. 

Dr. Valter Longo: Yeah, this is 2010. Now everybody talks about fasting. In 2010, it was not like it is right now. So they were worried, and the oncologists were worried, everybody was worried, and so it took forever to finish their trial.

So then we went to the NCI, National Cancer Institute, and National Institute on Aging, and they funded research for fasting-mimicking diet, right? So it was first funded by the NCI and then by the NIA. And the idea was very straightforward. 

We knew the sort of relationship between food ingredients and these pathways, TOR and RAS and all of that. And so we just played with that knowledge. We utilized that knowledge to then get to a point where we were looking for four markers, , IGF 1, IGF PP1, glucose, and ketone bodies. 

They’re fasting response markers, meaning that we wanted to match the effect of the fasting-mimicking diet and water-only fasting on this fasting response, right? So once we achieved that, then that was it, that was fasting mimicking diet. 

But then we combined that with the idea of periodic fasting. Let’s say we think that if most people were willing to do daily changes, we would not have Americans, 75% overweight and obese, British, 60%, and Italians, 50%.

So, we thought maybe there is a periodic way to intervene, right? You can do the fasting once every month, two months, three months. And water-only fasting first. 

And then of course, then we say, well, even better, what if we did a periodic fasting-mimicking diet? So then we’ve done lots of trials, I think 35 trials already, looking at this periodic fasting-mimicking diet.

So this is a low calorie, low protein, low sugar, high fat. A plant-based diet that lasts between four days and seven days, depending on what we’re trying to treat. Then, the patient gets a box and that’s a medicine, right? Or that’s potential medicine, let’s say.

So we tested it now for lots and lots of different things. I think the most advanced one is diabetes. Now, very clearly we’re seeing regression, diabetes regression, diabetes remission. And the beauty I think is without lifestyle changes, right? 

So we asked, in the University of Leiden trial with a hundred patients actually looked at lifestyle and saw no difference other than a little bit increase in exercise towards the end of the 12 fasting-mimicking diet cycle.

So these diabetics doing fasting-mimicking making that once a month for 12 months, by the end of it, they saw…

Prof. Tim Spector: How many days per month? 

Dr. Valter Longo: Five days, five days per month, five days a month. And then they were allowed to go back to whatever it is that they do. 

But now the beauty is that they improve so much, 70% of reduced drug use. They improve so much. Then we basically think and we’ve seen this, we have clinics, my foundations and so that we can switch into three or four times a year. 

That’s it, right? So year one, you do a 12, maybe not even 12, but let’s say 12 and then year two, you may be able to go down to four to six cycles and year three. We’re hoping you’re down maybe to three cycles and that’s it. So you do it once every four months. 

Now we’re formally testing that in southern Italy. In a 500-patient trial, three arms, one is a control fasting-mimicking diet once every three months, and then a fasting-mimicking diet every three months plus what I call the longevity diet.

So we’ll see. We’re now at patient 400. And so we’ve got 100 patients left. But the idea is, yes, we can try to get people to change everything they do, but they’re probably either one change or they’ll go back to whatever it is that they used to do. But maybe if the doctor was on board, once every three months.

If you have a problem, you can consider doing this five days and once you’re done with the five days, you’re done for three months.

Jonathan Wolf: Volter, because you talked about diabetes here, but before we were talking about longevity. Do you believe that this fasting-mimicking diet is five days every few months can improve the biological age, make you younger on the inside that we were talking about at the beginning of the podcast? 

Dr. Valter Longo: Yeah. So we did that in two trials and in both trials, two and a half years of biological age reduction after three cycles. So this is using what I was telling you earlier. 

Jonathan Wolf: Wow, let me just play that [back]. You’re saying that you did it three times, and your measured biological age improved by two and a half years.

Dr. Valter Longo: Yeah. So subjects that were asked to do the fasting-mimicking diet monthly for three months, they showed a reduction in, almost identical in both trials of 2.5 years on average. 

Jonathan Wolf: Tim, what’s your reaction to that?

Prof. Tim Spector: It’s very exciting that you might be able to trick the body into this state.

And I think the question is whether this is sustained over time, because you might get a temporary change in these markers of biological age.

What I like about it is that it’s accepting that people aren’t going to do long fasts, for long periods of time outside a laboratory. So it has a pragmatic element to it, which I think is really exciting.

So I think the test will be these long-term studies to say, well, three or five years, have things really changed permanently or will the body reset itself?

I guess this is what we’re always fighting in medicine is the body’s ability to recalibrate and realize it’s being fooled. And the question is, it seems to work short term. The question is, is this going to work long term, but it’s very exciting. 

Dr. Valter Longo: As part of several trials, we did a three-month follow up and about 40% of the effects are gone. After three months, right? So yeah, it makes sense that you will have to keep up every three months.

Now in the Italian trial, we are doing a second follow-up trial. So the patients finished the first six months of treatment and now we’re starting a one-year follow-up after they’re done with the six months, right? 

So then we’re trying to see in those that had benefits after the six months, can we keep them for another year and how much of the changes do we keep?

So we just published one of the many papers where the latest one was on kidney. We’re showing that the fasting-mimicking diet, usually was mice and people, and now this one was rat and people. So in the rat, so we use toxin, kidney toxin. And we damage the kidney, and then we start the cycles of the fasting-mimicking diet.

And you see the kidney basically turning on these developmental genes, right, including Yamanaka factors, these reprogramming factors. So these factors have the ability to turn any cell into a sort of young pluripotent stem cell. 

So you see that the kidney is basically being reprogrammed to go back to a young pluripotent normal state.

So we have pictures in something called special transcriptomics that looks the profile of a gene expression and the different cell types. And you see that the toxin completely disrupts this right? 

Then you start the fasting making diet and everything goes back to the right place, right? You see these developmental genes being turned on and then everything returns to normal as if the body has always had the ability to start from zero, right?

So I always say if you cut yourself after a couple weeks, this cut, this wound is repaired, right? Is it possible to deliver the pancreas and lots of the human organs now the same ability to truly reset? 

They had the information, right? And this is why I was saying earlier about the Yamanaka factors, and I’m really impressed with the work by Belmont and others, in forcefully turning on these Yamanaka factors, and we can talk about it. 

Jonathan Wolf: So, the kidney was damaged, when you then just applied this diet, so nothing else, no other drugs, actually a whole set of repair mechanisms got switched on in this rat that basically healed this problem, and I think you’re saying that that would not normally have happened?

Dr. Valter Longo: No. No, normally you will have damage and permanent damage or certainly long term damage. And now we did it in the first in a randomized crossover, a small trial pilot, 13 patients, seven and six. And we saw a patient with kidney damage, a kidney disease. We saw long-term effects, 12 months. After 12 months, they were still, just by doing three cycles of fasting-mimicking diet, they were showing long-term benefits in proteinuria and other markers of kidney disease. 

Now, small, but now because we have larger trials in other type of diseases, I think it’s certainly very promising. 

Jonathan Wolf: So you’re now doing a set of studies in human beings for this diet, to see whether or not you can deliver the same sort of benefits you’ve been seeing in these animals.

Dr. Valter Longo: Yeah, most of these studies are not even done by us, right? They are done by universities. So Heidelberg did one study on diabetes, University of Leiden did the other one. Stanford is now doing a study on Crohn’s disease, another one on colitis, University of Miami. So I think we’re just helping everybody.

We did it in mice. We did the work in mice and rats. And then the one that I just mentioned is the University of Rome, right? University of Rome did the 13 patient kidney disease, a clinical trial, right? So we’re basically telling the story and then we help them develop the trial. 

And then usually we get a call from Stanford now, three, four years later, I cannot tell you the results, but certainly, I got a call a week ago, that said we’re done and let me show you the results.

Jonathan Wolf: So I think we’ve heard how this fasting mimicking diet works and the science that would link that to hopefully longevity and more healthy years. 

So if someone wants to try this themselves, your recommendation is that they don’t do it on their own, but they follow a very specific protocol. Could you just give me a high-level understanding of what that is? 

Dr. Valter Longo: Yeah, so there is a protocol, a clinically tested protocol and a clinically tested fasting-mimicking diet. So people should do the clinically tested fasting mimicking diet. 

Basically it’s usually between 600 and 1100 calories, depending whether it’s used for cancer or diabetes or people that don’t have any problems. 600-1100 calories per day, and it’s a low sugar, low protein, low calorie, and high fat.

The version for people that don’t have diseases, right, that version is 1100 calories on day one, and then it goes down to about 770 to 800 calories on day two, three, four, five. And again, plant-based, high fat, low sugar, low protein. 

Jonathan Wolf: So we’ll put a link in the show notes for anyone who wants to understand how to get that.

Tim, I think we’ve heard a lot about the anti-aging through fasting. Is it all about fasting if we’re thinking about anti-aging or are there other things that you would, you would think about?

Prof. Tim Spector: No. This is super interesting and definitely has a place but just fasting if you’ve got a terrible diet, it’s probably not going to work. 

So, I think the other message is that your daily food you’re eating when you’re not fasting is also really important because we know that particularly ultra-processed foods are going to be pro-inflammatory. 

Inflam-aging, which is this concept that our immune system is triggered all the time, accelerates aging. I think is getting increasingly recognized in the field. 

So people ought to be thinking about that who are interested in aging, is cutting ou, ultra-processed foods right back to levels below 10%. Currently in the U.S. they’re above 60%. 

So major reductions in that ultra-processed food, which affects your gut microbes, which affects your immune system, really important. As well as eating more plants and looking after your gut microbes, because your gut microbiome is really linked to your immune system, which has really important effects on dampening down this inflammation and helping the aging process.

So I think, like all these things, a holistic approach is important. So diet, maintenance of muscle mass, exercise, whatever. So don’t forget the bigger picture as well. If you are going to go for time restricted eating or these fasting mechanisms. 

Jonathan Wolf: Thank you both. We’ve definitely hit time. I’ve really enjoyed that. Very interesting. I think I may have only understood half of it, but Tim’s going to explain it all to me afterwards. 

I’m going to try and do a quick summary and correct me if I get any of this wrong. I think the first thing we took away is that biological age is absolutely not chronological age. So you might have 49 birthdays, but actually your body, you could have the body of a 35-year-old or a 65 year-old, and that is based upon the lifestyle that you’re going through. So that’s really meaningful. 

And you said that if my biological age was 35, I genuinely could be living another 15 healthy years in other ways. So I think that’s very exciting that you have that control and the science is really saying that. 

Valter, you then talked to us a lot of the different science you’ve been doing and the thing that really stuck with me is this idea that you were sort of doing these mice experiments and you’re saying you could change one gene and calorie restrict them and they could live twice as long.

So it’s this ability to really transform how long animals and fungi and these sorts of things live. In your research, there was nothing that can have as big an impact of fasting in just a few days on people. So there is this thing that fasting has this sort of profound change in our biology and you were describing it has to because otherwise your body would die so it makes this really big shift. 

I think we talked about two things, we talked about time-restricted eating. And you said actually you really do believe that limiting your eating to 12 hours of eating, 12 hours of not eating could really help you stay younger. So that is, even I can do that, right? That isn’t an achievable thing for almost anybody.

Had a bit of a discussion about the duration. I think Tim said he felt very comfortable you could go to 14 hours fasting per day, without negative impact.

I think you both agreed that going to very short windows of time when you eat,  six hours or maybe even eight hours is probably not healthy. Tim am I saying that fairly? 

Prof. Tim Spector: Yeah. You’d be concerned. Definitely. 

Jonathan Wolf: So some discussion, but I think general alignment, Tim, maybe saying a bit more flex about the time 12 to 14, but both agreeing that going to very short periods of time and your opinion is not going to make you live longer.

Dr. Valter Longo: In the opinion of epidemiology. 

Jonathan Wolf: Perfect. And then we talked about this fasting- mimicking diet that you’ve been building based upon all your research, which I understand is this idea that you eat this special meal which is reduced, it’s very much reduced calories compared to normal, but it’s not absolutely fasting.

It’s carefully designed to have the nutrients in it that trigger a similar response as if you were fasting but without actually having to starve yourself completely. 

That you do that for five days, then you have the rest of the month off, do that again for five days.

 Dr. Valter Longo: The rest is probably four months. That’s what we think realistically, three times a year, if not less, and do it only when you need to do it. It’s not about doing it as frequently as possible so you can live forever. It’s about don’t take any chances, do it as little as possible. But do it when you need to do it. 

Jonathan Wolf: And you have done some studies, I think the one that I remember now is the one where you did sort of three cycles monthly and you said those individuals on that study actually their biological age improved by two and a half years.

So in human beings, you did that study, it’s short term and you’re now looking at the long term follow up, but you’ve seen real responses to that. And I think what you’re saying, if I understand is, clearly, it’s still hard work to do that. So you want to do that sort of as infrequently as possible to get the benefits.

Dr. Valter Longo: Not just hard work. We don’t know what the negatives could be long term, right? This is why we want to say, if you need to do it because whether it’s weight or diabetes or lots of other things that we’ve seen being useful for, then you need to do it. 

But if not, then let’s wait, you know, that’s okay. Wait until we have more data and long term data. And we’ll see.

Jonathan Wolf: I think we wrapped up Tim with you saying that from your perspective, fasting alone is not enough that we need to think about the diet that we have all the rest of the time. That in particular, if you’re eating high levels of ultra-processed food, and then think that just fasting is going to fix it all, you’re skeptical about that. You need to think about the whole thing. 

Thank you both very much. I very much enjoyed it. And I hope we can come back again in the future as more of these studies are completed and understand better about what we can do. 

Dr. Valter Longo: Thank you. 

Jonathan Wolf: It’s a pleasure.