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

27:52So, Volta, that's a good thing if your cells are eating themselves? It doesn't sound like a good thing. 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 accumulates in the cell. So in that sense, it's an opportunity to clean up. And so it's a good thing. A 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 autophagy is on, but it probably takes about five days to get there.

28:36So 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 actually have to starve yourself for five days before that would happen. Yes, of course. And I think we're going to talk about it. So we've been working for many, many years on 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 say water only fasting for three, four, five days before they see this, at least some of the cells.

29:11Now, 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. 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? Yes. So there's lots of different types of fasting, and each can have problems and solutions.

29:52The one that I like after doing this for a long time is one is called timer-sit-eating, something that Sachin Panda and others have worked a lot on. In time with 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 Goldstone problems. But the worst one is the association of breakfast skipping with increased cardiovascular mortality, increased overall mortality, right?

30:32So there's meta-analysis and this mean 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 hours time recited eating is the one that, I never met a doctor or anybody that argued 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 I think that going back to 12 hours of fasting and 12 hours of feeding, which most people say, well, that's normal.

31:14That's a normal eating pattern. Fine. Call it whatever. But that seems to be very, very good. 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? I mean, the mouse studies will indicate yes, and I think we're starting to see some studies indicating reduced biological age, but I don't know if anybody's ever tested, 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.

31:55But it 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? 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? Yes, and I think this is the concern with lots of drugs and lots of interventions, you know, like say GLP-1. 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?

32:38So, yeah. 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 to the 16 hours tim i'd love to bring you in here both 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 you know what we found there but also more broadly yes so we did what we called the zoe big if study um 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 you know volunteers in a lab which are not generalizable how easy would it be for people to do so we had 140 000 people uh 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.

34:02I think somewhere between 12 and 14 hours, I believe the evidence shows 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 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 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 uh 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 even easier to do the 12 hour.

35:33But what was that? Did you actually ask him what they actually did? Yes. You told them to go 10 hours, but did they do it? Because in the studies of Sachin Panda, he 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? 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 is is more people more likely to adhere to it long term and get benefits than than really going for some superhuman effort 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.

36:38Could you explain what it is and why you think it's still beneficial for longevity? 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 were much more resistant.

37:20But the cancer cells were much more sensitive, right? So we brought this to the patients at USC Norris Cancer Center nearby here. And, Volta, you asked them to fast how much before? For three days. So they actually eat no food or anything for three days. And now this is 2010. Now everybody talks about fasting. And 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 diets.

37:53So it was first funded by the NCI and then by the NIA. And, yeah, 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 got to a point where we were looking for four markers, IGF-1, IGF-PP-1, 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.

38:32But then we combined that with the idea of periodic fasting. 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, you know, what are only fasting first? And then, of course, then we say, well, even better, what if we did a periodic fasting mimicking diet? And yeah, so then we've done lots of trials, I think 35 trials already, looking at this periodic fasting, mimicking diet.

39:16And 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-making diet cycle.

40:03So they did monthly. So these diabetics were doing fasting-making diet once a month for 12 months. By the end of it, they saw... How many days per month? 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 improved so much. 70 % of them reduced drug use. They improved 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 it 12, maybe not even 12, but let's say 12.

40:39And 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. And so now we're formally testing that in southern Italy in a 500-patient trial, three arm, and one is a 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 a 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 won't change or they'll go back to whatever it is that they used to do.

41:19But maybe if the doctor was on board once every three months, you know, 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. it. 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? Yeah. So we did that in two trials. And in both trials, two and a half years of biological age reduction after three cycles.

41:58So this is using what I was Wow, 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. 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, what's your reaction to that? 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. 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.

42:50And so it has a pragmatic element to it, which I think is really exciting. So I think the test will be, you know, these long term studies to say, well, at three or five years, you know, have have things really changed permanently? Or is this a temporary? Will the body reset itself? I guess is always, you know, this is what we're always fighting in medicine is 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. As part of several trials, we did a three-month follow-up and about 40 % of the effects are gone after three months, right?

43:34So 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 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. The latest one was on kidney. We're showing that the fasting mimicking diet, usually it was mice and people, and now this one was rat and people.

44:16And 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, 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 normal state. So we have pictures in something called special transcriptomics. So it looks at the profile of a gene expression and the different cell types. And you see that the toxin completely disrupts this, right?

44:59And then you start the fasting-making diet, and everything goes back in the right place, right? You see these developmental genes being turned down, and 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.

45:39And we can talk about it. 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? No. Normally, you will have damage and permanent damage or certainly long-term damage. And now we did it in the first randomized crossover, small trial pilot, 13 patients, 7 and 6. 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-making diet, they were showing long-term benefits in proteinuria and other markers of kidney disease.

46:24Now, small, but now because we have larger trials in other type of diseases, I think it's certainly very promising. 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. 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. Most of these studies are not even done by us, right?

47:03They're done by universities. So Heidelberg did one study on diabetes. is University of Leiden, 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, right? University of Rome did the 13-patient kidney disease 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, you know, a week ago and said, we're done.

47:40And let me show you the results. 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? Yeah, so there is a protocol, a 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 1 ,100 calories, depending whether it's used for cancer or diabetes or people that don't have any problems.

48:2361100 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? So their version is 1 ,100 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, you know, high fat, low sugar, low protein. 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 think about?

49:05No. 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 inflam ageing which is this this concept that our immune system is just triggered all the time accelerates aging i think is 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%.

49:56Currently 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, 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?

50:41Thank you both. We've definitely hit time. I've really enjoyed that. It's 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. 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 sort of 15 healthy years in other ways.

51:17So I think that's very exciting that you have that control and that the science is really saying that. Walter, 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 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.

51:46So 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 isn't an achievable thing for almost anybody. Had a bit of a discussion about the duration.

52:21I 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 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? Yeah, you'd be worried. Yeah, concerned, definitely. So some discussion about, I think, general alignment, you know, Tim maybe is saying a bit more flex about the time 12 to 14, but both agreeing that going to very short periods of time, in your opinion, is not going to make you live longer, and it's probably actually the reverse.

52:56Is that? In the opinion of epidemiology. 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 of rest of probably four months, right?

53:35That'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. 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.

54:11And 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 the benefits. Not just hard work. We don't know what the negatives could be long term. 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. That's okay. Wait until we have more data and long-term data and we'll see. Brilliant. And then 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.

54:51and 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. Thank you. Thank you. It's a pleasure. 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.

55:25If 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.

56:05Will 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 slash podcast, where as a podcast listener, you'll get 10 % off. As always, I'm your host, Jonathan Wolfe. Zoe Science and Nutrition is produced by Julie Pinero, Sam Durham, and Richard Willem. The Zoe Science and Nutrition podcast is not medical advice. And if you have any medical concerns, please consult your doctor. See you next time.

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