Could fasting extend your lifespan? | Dr. Valter Longo and Prof. Tim Spector

Summary

Podcast Summary: "Could Fasting Extend Your Lifespan?" | Dr. Valter Longo and Prof. Tim Spector

Release Date: January 23, 2025

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Introduction

In this enlightening episode of ZOE Science & Nutrition, host Jonathan Wolf delves into the intriguing topic of aging with two esteemed guests: Dr. Valter Longo, Director of the Longevity Institute at the University of Southern California and a pioneer in aging research, and Professor Tim Spector, a renowned epidemiologist and co-founder of ZOE. The discussion centers around the concept of biological age versus chronological age and explores how dietary practices, particularly fasting, can influence longevity and overall health.

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Understanding Biological Age vs. Chronological Age

Dr. Valter Longo introduces the fundamental distinction between chronological age—the number of years one has lived—and biological age, which reflects the health and functionality of an individual's cells.

“Biological age is determined by how functional you are, how able you are to reproduce, to run fast, et cetera” (04:57).

Key Points:

• Biological age can differ significantly from chronological age.
• Factors such as cell health impact biological age more profoundly than the passage of years.
• Lowering biological age can reduce the risk of chronic diseases like Alzheimer's, diabetes, and cancer.

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The Genetics of Aging

The conversation shifts to the genetic aspects of aging. Dr. Longo shares insights from his research, highlighting how specific genetic pathways influence longevity.

“If you have a lot of growth hormone, the receptor is activated and they're lacking this receptor. Right. So they're not able to…” (20:27).

Key Points:

• Genetic mutations can dramatically affect lifespan in organisms, as evidenced by studies in mice.
• In humans, genetics account for approximately 20% of aging influences, with the remaining 80% driven by environmental and lifestyle factors.
• Certain populations, such as those in Sardinia's "blue zones," exhibit remarkable longevity potentially due to favorable genetic variants combined with healthy lifestyles.

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Influence of Diet and Fasting on Aging

A major segment of the discussion revolves around how diet, particularly fasting, impacts the aging process. Dr. Longo emphasizes that fasting can revolutionize gene expression more effectively than many other interventions.

“Find me anything that will revolutionize gene expression more than fasting.” (26:57).

Key Points:

• Fasting induces significant physiological changes, shifting the body from using external energy sources to internal reserves like fat and ketone bodies.
• Autophagy, the process where cells recycle damaged components, is a crucial benefit of extended fasting, typically initiating after five days of water-only fasts.
• Intermittent fasting methods, such as time-restricted eating, offer varying benefits but must be approached cautiously to avoid adverse effects like increased mortality.

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Time-Restricted Eating and Its Effects

Professor Tim Spector elaborates on ZOE's large-scale study involving 140,000 participants who adopted a time-restricted eating window of 10 hours, fasting for 14 hours daily.

“A third of people found it really easy to do this and they actually carried on well past the three weeks…” (32:57).

Key Points:

• Time-restricted eating can lead to improved mood, increased energy, weight loss, and reduced waist circumference.
• Adherence varies, with one-third finding it easy, one-third struggling to start, and the remaining third discontinuing the practice.
• Sustainable, moderate fasting windows (e.g., 12-hour fasts) are recommended over more extreme fasting durations to maximize benefits while minimizing risks.

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Fasting Mimicking Diet: Concept and Benefits

Dr. Longo introduces the Fasting Mimicking Diet (FMD), a meticulously designed low-calorie, low-protein, low-sugar, high-fat, plant-based regimen that simulates the effects of prolonged fasting without complete food deprivation.

“It's a low calorie, low protein, low sugar, high fat, plant based diet that lasts between four days and seven days...” (36:20).

Key Points:

• FMD is intended to be undertaken periodically (e.g., five days every three months) to confer health benefits without the impracticality of continuous fasting.
• Clinical trials have demonstrated that FMD can lead to significant improvements in conditions like diabetes, reducing the need for medication in 70% of participants.
• Ongoing research aims to evaluate the long-term sustainability and efficacy of FMD in various populations and health conditions.

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Studies and Findings

The guests discuss various studies underpinning their claims. Notably, Dr. Longo mentions trials where FMD led to a reduction in biological age by approximately two and a half years after just three cycles.

“Subjects that were asked to do the fasting, making diet monthly for three months, they showed a reduction almost identical in both trials of 2.5 years on average.” (41:27).

Key Points:

• FMD has shown promising results in reducing biological age markers and improving kidney function in preliminary studies.
• Long-term studies are underway to assess the durability of these benefits and potential long-term effects.
• The response to FMD varies among individuals, emphasizing the need for personalized dietary approaches.

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Practical Recommendations

Both experts offer actionable advice for listeners interested in leveraging fasting for health and longevity:

1. Time-Restricted Eating:

   • Adopt a balanced approach, such as a 12-hour eating window, to promote metabolic health without adverse effects.
   • Avoid extreme fasting durations (e.g., 16-20 hours daily) to prevent potential health risks.

2. Fasting Mimicking Diet (FMD):

   • Follow a clinically tested FMD protocol, typically involving 600-1,100 calories per day over five days.
   • Undertake FMD periodically (e.g., three times a year) to maximize health benefits while ensuring sustainability.

3. Holistic Lifestyle:

   • Complement fasting practices with a diet low in ultra-processed foods and rich in plant-based nutrients to reduce inflammation and support gut health.
   • Maintain muscle mass through exercise and engage in other healthy lifestyle practices to support overall longevity.

“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...” (49:41).

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Conclusion

The episode underscores the profound impact of dietary interventions, particularly fasting, on biological aging and overall health. Dr. Valter Longo and Prof. Tim Spector provide compelling evidence that strategic fasting practices, such as the Fasting Mimicking Diet and moderate time-restricted eating, can significantly enhance longevity and reduce disease risk. However, they also caution against extreme fasting regimens and emphasize the importance of a holistic approach to diet and lifestyle for sustainable health benefits.

Listeners are encouraged to consult with healthcare professionals before embarking on significant dietary changes and to consider personalized approaches to fasting and nutrition to optimize their health and longevity.

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Notable Quotes

• Dr. Valter Longo at [04:57]: “Biological age is determined by how functional you are, how able you are to reproduce, to run fast, et cetera.”

• Dr. Valter Longo at [26:57]: “Find me anything that will revolutionize gene expression more than fasting.”

• Professor Tim Spector at [32:57]: “A third of people found it really easy to do this and they actually carried on well past the three weeks…”

• Dr. Valter Longo at [36:20]: “It's a low calorie, low protein, low sugar, high fat, plant based diet that lasts between four days and seven days…”

• Dr. Valter Longo at [41:27]: “Subjects that were asked to do the fasting, making diet monthly for three months, they showed a reduction almost identical in both trials of 2.5 years on average.”

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For more personalized nutrition insights and to explore how you can optimize your biological age, visit ZOE.com and consider joining their tailored nutrition program.

Transcript

[Jonathan Wolf]

Welcome to Zoe Science and Nutrition where world leading scientists explain how their research.

[Tim Spector]

Can improve your health.

[Jonathan Wolf]

How old are you? Perhaps a better question is how old do you feel? Because you actually have two ages. One is the number of candles in your birthday cake, but the other is determined by the health of each individual cell in your body. This is your biological age. And while your birthday card might say 60, your biological age could be 45 or 75. When it comes to living a long and healthy life, it's your biological age that matters. Because as this number creeps up, so does your risk of getting chronic diseases like Alzheimer's, diabetes and cancer. The good news is, unlike the number written on your birthday card, your biological age can go down. Today's guest is Dr. Valter Longo, the director of the Longevity Institute at the University of Southern California. He's running one of the world's largest studies on aging, having created the term juventology or the study of youth. He was named by Time magazine as one of the 50 most influential people in healthcare. His groundbreaking studies have revealed how we can slow down, pause or even reverse the aging process. Folter is joined by Tim Spector, who runs the world's largest nutrition science study here at Zoe. Tim is one of the world's top 100 most cited scientists, a professor of epidemiology and my scientific co founder at Zoe. You'll leave this episode knowing how you could use fasting to take control of your biological age. And if you're looking to live a longer, healthier life, you should eat food that actually makes you feel good. Let me suggest you check out Zoe's personalized nutrition program. Because the food you eat isn't only making you tired, it's making you sick. Did you know that 60% of our calories now come from ultra processed foods? They're cheap, they're often loaded with sugar and saturated fats. They can last on your shelf for years. And they're engineered to keep you hooked. But every day there's more evidence that links ultra processed food with obesity, cancer, depression and many other diseases. We live with a food system that's rigged against us. Zoe's personalised nutrition program helps you break free. We point you towards the smartest food choices for you. And we'll make it easy too. Visit Zoe.com to get your at home test kit and personalised nutrition program today. Okay, let's get on with Today's episode with Dr. Valter Longo and Professor Tim Spector.

[Tim Spector]

Walter, thank you for joining me today.

[Dr. Valter Longo]

Well, thanks for having Me happy to be here.

[Tim Spector]

It's a pleasure. And Tim, thank you as well. Pleasure. So we have a tradition here at Zoe where we always start with a quick fire round of questions from our listeners and with 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.

[Tim Spector]

All right, starting with you, Volta, 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 temporary.

[Tim Spector]

Could having a shorter eating window give you more energy?

[Guest Speaker]

Yes, definitely.

[Jonathan Wolf]

Volta, can we get the effects of.

[Tim Spector]

Fasting while still eating something?

[Dr. Valter Longo]

Yes.

[Tim Spector]

And finally, you can have a whole sentence.

[Jonathan Wolf]

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, was a little surprising when Belmont and others came up with it.

[Tim Spector]

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 40s and I find myself thinking about aging a lot more often and sometimes sort of worrying about that. So I'm eager to learn, you know, how I could stay healthy for many more years. And I'm excited to talk about it with the two of you. Volta, could you start at the beginning about helping us to understand, like, what's the difference between our actual age by, you know, 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. Right. So I think that we're missing this idea of youth span. I call the youth span. Right. So juvenile 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. And so that's, I think, still somewhat missing in the field. You know the the measurement of youth.

[Jonathan Wolf]

When was the last time you listened to your gut? Zoe scientists are gut health experts. We have one of the world's largest microbiome databases and most scientifically advanced at home gut health tests. This lets us provide personalized nutrition insights and advice you can't get anywhere else. Listening to your gut starts with an at home test kit that helps you understand your body's responses to food and the good and bad microbes in your gut. Then Zoe's app helps you build life changing nutrition habits step by step. Become a Zoe member today and give your gut the love it deserves. The first step is easy. Go to Zoe.com and use the code podcast to get 10% off. As a Zoe member you'll get a comprehensive at home test kit and personalized nutrition program. So go to Zoe.com and get 10% off with code podcast. Now back to the show and volta.

[Tim Spector]

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 right, it's going to be prolonged, but it doesn't mean that you are, you will live that much longer. But so on average your life expectancy would be extended.

[Tim Spector]

So it's really like measuring the actual state of my body, being like an average person who's 39 rather than 49.

[Dr. Valter Longo]

Yeah, you are basically, I mean, I don't even know that we should use chronological age. Right, so you are, I mean, assuming that the measurements are valid. Right. But if that's true, then you are 39 no matter what your chronological age says.

[Tim Spector]

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

[Dr. Valter Longo]

Absolutely. Right. 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, if not later. So yes, you can have 20 years of difference between chronological age and biological age.

[Guest Speaker]

We did this, really one of the big studies of biological age using the UK twins and we had, we'd measured about 3,000 twins of different ages. And whilst there was a, a rough correlation between your birthday and your biological age within each 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.

[Dr. Valter Longo]

Wow.

[Guest Speaker]

And a 65 year old having a biological age of 40.

[Tim Spector]

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 60, 65 on the.

[Guest Speaker]

Balance of probabilities, yes. I mean at the moment it, it, you know, it's a rough prediction, but that's what it's showing is that there's big differences between individuals regardless of, of what your actual age is at that, 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, that's, 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, you know, centenarians who may have obviously different biological ages and, and may maybe fitter than people, you know, 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 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. Right. And so probably gonna modify. So maybe those 40 year old, their chronologically 65 are not really 40. Right. They may be 55. Right. So I think that's probably what we're gonna see. So to answer your question, they're probably gonna maybe, you know, and in between maybe die at the same time.

[Guest Speaker]

Cause 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 oh no, a fourth one actually I did something called glycan age, which these little sugars on your immune system. And you know, the majority pointed to me having a lower biological age than my other one. But not all of them. They don't all agree. You know, you can pick the one that suits you best if you, I.

[Tim Spector]

Was gonna say, I think I would definitely pick the best one out of that.

[Dr. Valter Longo]

I know, but that's exactly the way to do it. Right. That's the way to do it. Instead of getting the best one is no, use all four of them. And then pick the average of the four. Cause that's probably much more likely to give you a good indication of your true biological age.

[Tim Spector]

And Folter, 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 like, 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.

[Tim Spector]

And is there a specific test? What would be the tests 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 kid, you know, and they send you the kit and you send it back and they give you your biological age. I really like the Morgan Levine bioage, 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, I mean, 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 doesn't even need. Any doctor can calculate it based on your blood markers.

[Guest Speaker]

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. And the bit that's remaining is called the telomere length. And you can measure that, which was all very trendy about 10 years ago, 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, and there isn't really a gold standard as yet. And they all roughly agree with each other, but not 100%. 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 would be less available. I mean, most doctors will not be able to get your telomere test and certainly not a metabolomic test. But I would say most doctors would be able to fairly easily get you the other two. Right. Yeah.

[Tim Spector]

So I'd love to go on having established that there is this difference between, like, our biological age from just how many years since we were born, understand more about how we age. And Walter, 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, was working on people and mice back to yeast in the biochemistry department because I thought 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 we could identify the genes that control the aging process. And we did. Right. So we identified, in fact, my lab was the first one to identify the Taurus 6 kinase pathway in aging in yeast. And this was in 2001. So rapamycin blocks this pathway. It's called tau s cis kinase. And so rapamycin, now, I would say it's probably the one genetic pathway most recognized to affect longevity in all kinds of organisms. It basically means that if you think about eating and proteins and amino acids. Proteins and amino acids activate. They 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. 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, then was done in mice in 2009, published in Nature, showing that using this drug called rapamycin, blocking Tor extend the lifespan of mice in three different laboratories, One in Michigan, one in Texas, and one at Jackson laboratories.

[Guest Speaker]

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 I think 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, that's what we've shown. And these, some of these drugs will either stimulate or block these systems. And that's, that's really what Volta, you know, been discovering.

[Jonathan Wolf]

And are you saying that if you.

[Tim Spector]

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. And so 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 these pathways, then the yeast lived five times longer, right? 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 starve them, they live 10 times longer. So that means there was other pathways. There are additional pathways other than the sugar and the amino acid. They were involved in accelerating the aging and the mortality of the yeast.

[Tim Spector]

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 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 cannot have a normal course of reproduction, now you enter a maintenance mode, and evolution is 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 this is 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? But they're in 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. So there's a hundredfold difference between State one. So the normal state, you know, living in the fast lane and this, this sport state where you live very slowly but for very long.

[Tim Spector]

I'm thinking about 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, you know, watch Netflix and get my, you know, email at the same time. And is that sort of an analogy here, that it's sort of saying, well, the, 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, like, you know, 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 so 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.

[Tim Spector]

Is everybody therefore age sort of at this same amount, or does this depend so that, you know, I might age at a completely different rate than Tim because of the way that, you know, my biology is working?

[Dr. Valter Longo]

No, depends. Fundamentally everybody ages by the same processes. But then, yeah, two people can age very differently. Right. So we know that we've been following people in, 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 they're not able to. 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. And 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 is these blue zones. Even though this is not being talked about a lot, we suspect that a big component was genetics. Right. So the group of people in Cello or Villagrande estresale, some of these little towns that have record longevity, they were born with the right genetic variants, 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.

[Guest Speaker]

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 the most common diseases. So we think that the contribution at a population level is only about 20% heritability of that effect. But as Walter said, there might be certain families or certain areas where they have a concentration of 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 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. Right. What does it mean? It means a mouse lives for two years versus 80 because of the genes. Right. So genes can make a mouse. And that's what I was saying earlier. You know, just a mutation in the in1 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 other things that happen to you. Right. And so genetics are less important. But if you manipulate genes, you know, there's limitless potential. Right. So as we know, you know, say if you. A rat lives more than a mouse. So there is genetic difference between a rat and a mouse are minimal, but that's enough in a monkey, the difference between us and monkey genetically is very small. But those 1% or whatever is responsible for almost a tripling of lifespan. Right. 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, you know, probably lifestyle choices.

[Tim Spector]

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 like, you know, sister mouse, when none of that happened. Yeah, 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.

[Jonathan Wolf]

Care, and they referred to you as.

[Tim Spector]

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, particularly, they have a lot of control over their. Over their food.

[Jonathan Wolf]

Could you start by taking us through.

[Tim Spector]

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 than those five days. Right. 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. Right. 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. And ketone bodies are this. 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 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 acid 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. 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 thinking 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.

[Tim Spector]

So Voltaire, 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. And 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. And 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 that everybody, people fast for three hours and they think out of jizan. But, but it does, it probably takes about five days to get there.

[Tim Spector]

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 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, 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, let's say water only fasting for 3, 4, 5 days before they see this. At least some of the cells. Now 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.

[Tim Spector]

So if you're not willing to fast yourself for five days, is there any positive impact on your body from 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]

Yes. 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 is called time restricted eating. Something that Satchin Panda and others have worked a lot on in time restricted 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 there's studies of all studies indicating that this is why I was always against it. And now there is 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, is the one that, you know, I never met a doctor or anybody that argue with it. And yet most people eat in America, and I'm assuming in the UK for about 14 to 15 hours a day. Right. So that means they fast for only, let's say nine hours or so. 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 color, whatever. But that seems to be very, very good.

[Tim Spector]

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 sort of stay healthy for more years?

[Dr. Valter Longo]

I mean, the mouse studies will indicate. Yes, and I think there are, 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 doesn't mean that they're going to make your life longer. If in fact there is, you know, this association with, you know, increased mortality is correct. Right.

[Tim Spector]

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, you know, like say GLP1. So lots of things are beneficial short term, but then, you know, medicine is not really set up to think about long term effects. Right. So yeah, so, and 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]

The show you're listening to right now that's providing you the latest evidence based health and nutrition information from the world's top scientists. While making it takes a lot of time, we think it's well worth it, all in the name of improving your health. All we ask in return is send a link to this podcast to someone you think would benefit and if you haven't already, click follow this podcast wherever you're listening right now. Okay, let's get back to the show.

[Tim Spector]

Tim, I'd love to bring you in here both because I know this is something that you studied 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 you know, what we found there. But also more broadly.

[Guest Speaker]

Yes. So we did what we call the Zoe Big if study, which was time restricted eating, not actual fasting. But 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's, that's still safe. We can disagree on some of the epidemiology, but I think, you know, whereas more extreme fasting, I do worry as well about, about that. So we were asking people to do fairly 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 for alone for six months. And 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, 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, they get into it and I think they will get benefits. Some people do find it rather hard to, to go long periods without eating. And that just showing this, you know, as we know at Zoe, all about personalization that, you know, there are these differences between people that make it harder or easier. So yeah, I'm all for this not too strict time restricted eating, but it not necessarily for everybody. We didn't try the 12 hours. So it could have been that most people, it would be even easier to do the 12 hour.

[Dr. Valter Longo]

But what was that? Did you actually ask them what they actually did? Yes, you told them to go 10 hours, but did they do? Because in the studies of Sachin Panda it tells them 10 hours, but then it's about 11. Right. So this gets closer to 12. So do you know what they actually was that they did?

[Guest Speaker]

Yes, we did. And a third did it quite sort of religiously. And there was this middle group that actually went back, you know, and probably managed 12 hours most of the time. But they didn't seem to get quite the same benefits. But I think, yeah, but 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, people are more likely to adhere to it long term and get benefits than really going for some superhuman effort.

[Tim Spector]

Now 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? And so starting a long time ago, I knew, well, we first did a trial, I think it was 2010, on cancer patients. And 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'll be much more, 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.

[Tim Spector]

And Voltaire, you asked them to fast how much before?

[Dr. Valter Longo]

For three days.

[Tim Spector]

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

[Dr. Valter Longo]

Yeah. And now 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, IGF1, IGFPP1, glucose and ketone bodies. There were 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%, Italians 50%. So we thought maybe there is a periodic way to intervene, right? You can do 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 the periodic fasting mimicking diet then we've done lots of trials Now, I think 35 trials already looking at this periodic fasting mimicking diet. And so this is a low calorie, low protein, low sugar, high fat, plant based diet that lasts between four days and seven days, depending on what we're trying to treat. Then you know, the patient gets a box. And that's a medicine, right? Or that's potential medicine, let's say. And so we tested it now for lots and lots of different things. I think the most advanced ones is diabetes. Now very clearly we're seeing regression diabetes, regression diabetes, remission. And the beauty I think is with that, lifestyle changes. Right? So we ask. And the universal laden trial with 100 patients actually looked at lifestyle and saw no difference other than a little bit increase in exercise towards the end of the 12 fasting migraine diet cycle. So they did monthly. So these diabetics with doing fasting migraine diet once a month for 12 months. By the end of it they saw.

[Guest Speaker]

How many days per month?

[Dr. Valter Longo]

Five days.

[Guest Speaker]

Five days per month.

[Dr. Valter Longo]

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 them reduce drug use. They improve so much. Then we basically think, and we've seen this, we have clinics for my foundations and so that we can switch them to 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 might 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. And so now we're formally testing that in southern Italy in a 500 patient trial. Three ARM and one is control fasting, making diet once every three months and then fasting, making diet every three months, plus what I call the longevity diet. And so we'll see. We're now at patient 400, so we've got 100 patients left. But, yeah, 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 these five days. And once you're done with the five days, you're done for three months.

[Tim Spector]

And volta, because you talked about diabetes here, but before we were talking about longevity. Do you believe that this sort of fasting, mimicking diet, this five days sort of 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.

[Tim Spector]

Let me just play that 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, making diet monthly for three months, they showed a reduction almost identical in both trials of 2.5 years on average.

[Tim Spector]

Tim, what's your reaction to that?

[Guest Speaker]

It's very exciting that you might be able to trick the body into this, into this state. And I think the question is whether this is sustained over time because you might get a temporary change in your. These markers of biological age. But I do think 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. And 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, at three or five years, have things really changed permanently or is this a temporary Will the body reset itself? I guess is always. 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. And now in the Italian trial, we are doing a second follow up trial. So the patients finish 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. The latest one was on kidney. We're showing that the fasting mimicking diet we did usually was mice and people, and now this one was rat in people. And so we use a kidney toxin and we damage the kidney, and then we start the cycles of the fasting making diet. And you see the kidney basically turning on these developmental genes, including Yamanaka factors, these reprogramming factors. So these factors that 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 normal state. So we have pictures in something called special transcriptomics. So it looks the profile of a gene expression and the different cell types, and you see that the toxin completely disrupts this. Right. And then you start the fasting making diet and everything goes back in the right place. Right. You see these developmental genes being turned on and then, then everything returns to normal, as if the body has always had the ability to start from zero. Right. And so I always say if you cut yourself, after a couple of weeks, this cut, this wound is repaired. Right. Is it possible to deliver the pancreas and lots of the human organs now have the same ability to truly reset. They have 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.

[Tim Spector]

So the kidney was damaged when you then just applied this diet and nothing else? No other drugs? Actually sort of 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 in the first, in a randomized crossover small trial pilot, 13 patients, 7 and 6, and we saw a patient with kidney damage, kidney disease. We saw long term effects 12 months. After 12 months they were still just by doing three cycles of fasting making 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]

Do you know someone who wants to feel and look younger? Why not share the very latest scientific information on how intermittent fasting could make a difference? You could help them take a step towards a healthier version of themselves. I'm sure they'll thank you.

[Tim Spector]

So you're looking, 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]

Most of these studies are not even done by us. Right. They're 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 I'm 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 University of Rome. 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, you know, usually we get a call from like from Stanford. Now, three, four years later, I cannot tell you the results, but certainly I got a call a week ago, say we're done and let me show you the results.

[Tim Spector]

Yeah, so I think we've heard how this fasting mimicking diet works and the science that sort of would link that to hopefully, you know, 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]

Yes. So there is a protocol, clinically tested protocol, and a Clinically tested fasting making diet. So people should do the clinically tested fasting making diet. And basically it's usually between 600 and 1100 calories depending whether it's used for cancer or diabetes or or people that don't have any problems. 6001100 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 you know the plant based high fat, low sugar, low protein.

[Tim Spector]

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 there are other things that you would think about?

[Guest Speaker]

No. Well, this is super interesting and definitely has a place. But just fasting if you've got a terrible diet is 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 and inflammaging which is this concept that our immune system is just triggered all the time accelerates aging I think is getting increasingly recognized in the field. So that people ought to be thinking about that who are interested in aging is cutting out ultra processed foods right back to levels below 10%. Currently in the US 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 you know, 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.

[Tim Spector]

Thank you both. We've definitely hit time. I've really enjoyed it. It's very interesting. I think I may have only understood half of it but tends to explain it all to me afterwards. I'm going to try and do a quick summary. 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 know, you could have the body of a 35 year old or a 65 year old. And that is based upon, you know, 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 sort of 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 Volta, you then taught 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 like change one gene and calorie, restrict them and they could live twice as long. So it's this ability to really transform how long, you know, animals and fungi and these sorts of things live. And that 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, well, it has to, because otherwise your body would die. So it makes this really big shift. And I think we talked about two things. We talked about time restricted eating. And you said actually you really do believe that sort of limiting your eating to 12 hours of eating, 12 hours of not eating could really help you stay younger. So that is like, you know, very even. I can do that. Right. Like that is 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 4, 14 hours fasting per day without negative impact. I think you both agreed that going to like very short windows of time when you eat, like, you know, six hours or maybe even eight hours is probably not healthy. Is that Tim, am I saying that fairly?

[Guest Speaker]

Yeah, you should be. Yeah. Concerned, definitely.

[Tim Spector]

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

[Dr. Valter Longo]

Probably actually the reverse in the opinion of epidemiology.

[Tim Spector]

Perfect. And then we talked about this fast mimicking diet that you've been building based upon all your research, which I understand is sort of this idea that you eat this special meal which is both, you know, it's reduced, it's a lot of it's very much reduced calories compared to normal. But it's not absolutely fasting. It's carefully designed to have sort of the nutrients in it that sort of 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, you do that again for five days, you've done a lot the.

[Dr. Valter Longo]

Rest of probably four months. Right. 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.

[Tim Spector]

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, you know, 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 like, clearly it's still hard work to do that. So you want to do that sort of as infrequently as possible to get.

[Dr. Valter Longo]

The benefits, 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 of 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.

[Tim Spector]

Brilliant. And then I think we wrapped up, Tim, with you saying that from your perspective, you know, fasting alone is not enough, that we need to think about the diet that we have all the rest of the time and that in particular if you're eating like this, you know, high levels of ultra processed food and then think that sort of just fasting is going to fix it all, you know, 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. Thank you.

[Tim Spector]

It's a pleasure.

[Jonathan Wolf]

Now if you listen to the show regularly, you already believe that changing how you eat can transform your health. But you can only do so much with general advice from a weekly podcast. If you want to feel much better now and be on the path to live many more healthy years, you need something more. And that's why more than 100,000 members trust Zoe each day to help them make the smartest food choices. Combining our world leading science with your Zoe test results, Zoe is your daily companion to better health for life. So how does it work? Zoe membership starts with at home testing to understand your unique body. Then Zoe's app is your health coach, using weekly check ins and daily guidance to help you shift your food choices to steadily improve your health. I rely on Zoe's advice every day and truly it has transformed how I feel. Will you give Zoe a try? The first step is easy. Take our free quiz to find out what Zoe membership could do for you, Simply go to Zoe.com podcast where as a podcast listener, you'll get 10% off. As always, I'm your host, Jonathan Wolf. Zoe Science and Nutrition is produced by Julie Pinero, Sam Durham and Richard Willin. The Zoe Science and Nutrition Podcast is not medical advice and if you have any medical concerns, please consult your doctor.

[Tim Spector]

See you next time. Sa.