New Research Says Fasting Beats Cutting Calories – Leonie Heilbronn, Ph.D., with Dave Asprey : 781

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You're listening to Bulletproof Radio with Dave Asprey. Today we're going to talk with a major researcher on fasting, time, restricted eating and things like that, and even caloric restriction, which turns out it does work, although calories in, calories out doesn't seem to work in any of my life experiences or any of my research. But funny enough, in a fast with restricted calories, hey, maybe there's something going on there. We're going to dig deep on that. Her name is Leonie Heilbronn and she's an associate professor who leads the obesity and metabolism group at the Lifelong Health theme of South Australian health and Medical Research. That is a mouthful. But basically she's in Adelaide, Australia and studies this stuff, looking at how do we turn down chronic diseases like type 2 diabetes with nutrition. And she really looks at biological pathways, which makes me really want to do this interview because we get to talk about mitochondria and all sorts of signaling molecules. We shouldn't get too technical. I promise I'll explain everything if you're new to the world of biohacking along the way, if we use some weird analogies or whatever else. But you will learn something here and we're going to dig deep on fasting. Let's get into learning more about fasting from a world class expert. Leonie, welcome to the show.

Thank you, thanks for having me. Deb.

How did you get into fasting?

Right, so this started quite a while ago and it was back when I was a postdoc in the United States, in Louisiana actually, and we had read a paper about a mouse study where the mice were put on alternate day fasting. So that's fasting every other day for 24 hours. And these mice really had all of the same benefits of caloric restriction that we know about. So they had reduced glucose and insulin levels, so reducing their diabetes risk markers. And they, they had increased activation of a lot of the pathways as well that are involved with caloric restriction. So that was kind of the first time we'd noticed or realized that fasting perhaps was one of the ways that caloric restriction is, is all potentially working. And so we did a little study on, I think it was 16 people and they were all non overweight, so just normal, regular 20 to 25 to 55 year olds I believe. And we put them on alternate day fasting for three weeks. And some people did amazingly well, lost lots of weight and had great improvements in health. Overall, we saw great improvements in glucose and insulin levels and also reductions in cardiovascular risk markers in three weeks. And there were a few people that really hated it and didn't do so well, but they still were able to maintain the diet for the three week period. And yeah, that was kind of our first little foray into alternate day fasting.

Now you're talking about only having water for 24 hours every other day.

Yes. So that was water only fasting for 24 hours every other day. And we started the fast midnight to midnight as well with that first study. And so some people were actually fasting probably for almost 32 hours by the time they went to bed at night and got up in the morning after a fast day. So it was a long time.

And were these people working during that time? Were they doing their normal physical activities? It seems like most people would get kind of blown out by starting out fasting that way.

Yeah, no, everyone kept working. We had one woman on the study who was a kind of, she was a big runner and she also did a lot of soccer. And so she played two or three soccer games on a fasting day one time. So she was, she was hardcore. Most of us were like, I did the study. So it was a study literally with no money. And everyone was an employee at the Pennington, just about that, that did the study. So it was a kind, it was a pilot trial. We were mostly fit, young and healthy and everyone pretty much was active as well in that trial. So there was no, there were a couple people actually that were non exercisers. Maybe about 5 out of the 16 or 6 out of the 16 were non exercises and the rest were exercises. So it wasn't exclusion criteria when we did it.

What's interesting about that is that those are people who are already reasonably fit and had working metabolisms because they weren't overweight. And I've found that a lot of people, the 42% of people who are overweight or have meaningful weight to lose, they oftentimes get the hangry hypoglybitschy. You know, I, I can't do that and live my life when they start doing 24 hour water fasting. So I've been looking for ways to keep your brain working while getting into that, which has been a big, a big focus. But the goal would be that you ought to be able to just do that. And you said water only, but that was no coffee, no tea, no anything that one at all.

So the first study we did with nothing, nothing at all. So that was water only fasting. And that was three weeks in length. So the subsequent studies we've done, we've done them more in overweight people, not in young, fit, healthy people. So all of my other trials have been in overweight people and we have allowed coffee and tea and that kind of, we have allowed a limited amount of sugar free drinks as well during the fasting day really just to increase compliance. And the subsequent studies we've done have been three days a week of fasting and not doing alternate day just because it's a bit of a mess. I think people, a lot of people, when you're doing alternate day fasting, it's hard to plan your life because one day you're doing, you know, Monday, Wednesday, Friday and the next day it's Tuesday, Thursday, Saturday. So it's just, it's more difficult to figure out, to plan ahead. Whereas if you're doing Monday, Wednesday, Friday or your choice, it's just easier to know what's going on, when, when to go out, when to, when to stay home and that sort of thing.

It feels like getting compliance out of fasting. Look, if you're really obese, like 100 pounds overweight, like I was, or you have high risk of some disease, you're just going to disrupt your life to do it. And there's a lot of people like, oh, you know, I've got a little bit too much going on. But for that, making it a workable schedule seems like a major challenge with compliance. So that's been a big focus of this where you don't have to always stick to a strict schedule. So I love that you're like, just do three days because then you can line it up and your weekend's working. That extra day probably wasn't worth the trouble. Yeah, it's that. How much trouble is it? That's a big focus for everything because you know, we could do everything perfectly and then where we end up, yeah.

You got to be able to do it in the end of the day.

One of the other studies that I'm super excited to hear about, you're looking at 210 people with obesity comparing intermittent fasting and restricting calories. How far along is that study? Because I, I'm really hopeful to see the results, but can you share soon?

Soon, yeah. So the last patient finishes November 21st. So it, it's an 18 month trial. So we do a six month really active phase where we see them a lot and we help them out and that phase is over and then they have a 12 month follow up after that period where we really Let them go and say, we say try to continue doing this diet without our help and we bring them back 12 months later to see how they're going. So that phase does not finish until November 2021. So probably not till 2022 will we have the study out. So, so they take a long time, but I'm looking, I'm excited by the results.

So early results that are not, you know, statistically valid and all. Does one seem to work better than the other or you just have no clue yet?

We really don't have a clue yet. We have, you know, statisticians on this trial that blind everything and yeah, we, we don't, we don't have a handle on that at all unfortunately. We have done no, you know, no analysis on anything. So we have to wait till the end of the trial.

You're super blinded then. Well, kudos to you for doing, doing good science. And I'm sad because I pretty sure that what you're going to see, especially with a one year follow up like that, is the people who do calorie restriction gain all their weight back. Because all you have to do is watch the Biggest Loser and just go a year out from everyone who loses weight on that show and they're all fatter than they were in my own life, you know, I'd lose 20 pounds, gain 30, lose 30, gain 40, most likely because of ghrelin signaling. But then you do fasting or you do anything with ketones, it seems like it becomes a non issue. So I'm, I'm very excited to see those results.

I'm, I'm, I'm hopeful too, but I don't know. So there's only one real trial or maybe is there two now that, that have done this in large populations and they've shown that there wasn't any difference either between the calorie restriction and intermittent fasting groups at the, they've done 12 month follow up, not 18 month follow up.

Interesting.

They didn't see any difference between the chiral restriction intermittent fasting group. So I think that intermittent fasting really works for some individuals, but it doesn't, it doesn't perhaps work for all individuals. So there's, there's that, you know, we don't let them choose when they do these research studies. They get randomized into fasting or caloric restriction and they don't get to say, okay, I think that I'd suit fasting better or I'd suit calorie restriction better. And I think that, that some people, and I'm One of them. I, I prefer fasting and being able to eat what I like on the weekends sort of thing and then, you know, go hard during the week and. Yeah, so I think that some people really suit it and then some people get really grumpy during the fasting period and they just, from what I've seen, don't, don't habituate. So some people takes them a little while to get used to fasting and then some people just maybe never get used to it.

Do you track what people eat before they start a fast or how they end the fast, like what kind of food they're using?

Yeah, so we have done well, we are doing that now. So the, the last study that we did, we actually provided all the food to people so we wanted to really just control absolutely everything. We're trying to look at a lot of pathways. Yeah. So we, we gave them all of their food on the calorie restriction diet or we gave them all of their food on the intermittent fasting diet. Whereas this new study, it's, it's their choice. So we're, we're doing food diaries and tracking that sort of thing. So we'll have a better handle on that with the next trial.

My working hypothesis is that the people who don't acclimate to fasting are eating foods that cause cravings right before they start a fast. And when they tweak what they eat to avoid that, suddenly they can go through a fast. But if they eat the wrong stuff before the fast, they're just a train wreck. I know I'm like that. I can, I did a 72 hour fast a couple weeks ago just because it was kind of convenient. Like I've just, I've got it. I did six or seven shows and I'm just, I'm okay. But then, you know, if I was to eat something that was wrong for me, like a big old kale salad or something, I'm going to be ravenous and then it's going to be distracting and then, you know, I'm probably going to be less emotionally resilient than I normally would be.

Yeah. So yeah, I haven't studied that. But I don't disagree with you there. I think that that is potentially, potentially true. And, and yeah, it's, I, I don't actually know what the right food is to do that either. So it would be interesting to, to, to learn that, to see if there is something, something to that.

I will send you fast this way if you'd like to. It is not an academic book, but it has a lot of references. I'd be happy to, to do that, just to give you some ideas to think about the direction of it. But I. I find there's five big categories of foods that are triggers for some people and not others. And this is from working with very large numbers of people over the last 10 years on the bulletproof diet side of things, which is like, what are the triggers? But lectins are a major trigger for some people and different types of lectins for others. And they cause perturbations in ghrelin, insulin, and even overall anxiety. So if you get inflammation from a nightshade vegetable because of your genetics, you're going to have a craving. But the next person doesn't have those genetics, eats them and they're just fine. So it's really hard to tease out. You've got. Oxalic acid is another one that causes just environmental perturbations in people. You know, there's raw spinach and kale. Can be cravings. You've got phytates and things like that that come in whole grains for some people, a major issue. Other people, not that big of a deal. You can give one person beans or whole grains, and they're fine. The next person's like, I'm going to eat a horse. And so you get into these buckets, histamine will do it, too. Fermented tofu full of histamine. People are histamine intolerant, man. They're gonna need a cookie, right? And like, they cannot fast without turning into a jerk. But then teasing those out. And the final one is if you're eating things like mycotoxins or high omega 6 oils, both of those can cause, can cause cravings in people as well as things they're allergic to. So for me, it's been like, how do I get, you know, a million people to figure out what's doing it for them so they can eat everything else? And that's, that's been a challenge. But I do not publish studies the way you do. Although a few people have worked on studies using the bulletproof guidelines. But I, I imagine if you clustered for those things, especially the first three or four, you're probably like, that's funny. People eat pork, which is high in histamine, and those are the ones that have a hard time fasting. And the ones who aren't eating pork before their fast or processed lunch meats or whatever, they don't have a hard time. So I could predict those clusters, and I'd bet on it. But I could totally be wrong too. I, I bet you'd find another cluster I never even thought about.

Yeah, well, I don't tend to look down at the micronutrient level to see what, what's going on there. So when we're, I mean, we're starting some studies, we're looking at macronutrient timing. So, you know, trying to put carbohydrates in the, in the morning when you are, I guess, most biologically ready to, to have carbohydrates. You know, you have a big insulin secretion in the morning. You're most insulin sensitive in the morning. So carbohydrates are probably the time when if you're going to have carbohydrates, you should probably have them in the morning. But we're studying that now. And also, you know, protein. So maybe there's some evidence of having it later in the day. It's not great evidence yet, but maybe, maybe that's the best time to have protein. So there's, there's that kind of timing of macronutrients and I think that's an emerging, emerging field right now where timing of things, you know, timing of medicines is really exciting field right now as well. So all of, all of the medications that people take is beginning to be an appreciation that maybe we're not looking at when they're taking the medications. And, and that could be, we might not be getting the optimal, best bang for buck. And the same thing with, with carbohydrates and protein. So yeah, I think that that is interesting. But I don't look at the micronutrients. We just kind of focus on the, the whole level. The whole level, I guess. Yeah.

The, the timing thing is something that you've definitely studied, you know, time restricted feeding. And I was interested. Your first study was midnight to midnight. But no one, at least no one healthy, eats at midnight on a regular basis. We'll put it that way. That's sort of the worst time.

Yeah, no, we didn't intend people start and stop eating then it was more like that they would just go to bed and then wake up in the morning. We actually had one patient in that study that did tell us he stayed up till midnight all the time and 8 at midnight and so, but everyone else was pretty much going to bed and waking up in the morning and having breakfast. So our time for our fasting studies, we've actually tried to do it in the morning. So 8am to 8am and in our second trial we're doing allowing an eating period of 8am till till lunchtime and then fasting for the rest of the day. So biologically that is probably the best time to be, you know, so you kind of kick starting your metabolism for the day and. But there is no studies really trying to test that hypothesis. There is one. Christa Baraday did a study where she was, she gave people fasting from breakfast. No, from lunch or from dinner or they had breakfast, tiny meals at breakfast, lunch and dinner as breaking the fast and they didn't see any difference between the three arms so didn't matter. But it was a really small study so it wasn't a lot of people in each arm. And so it really hasn't been tested. We're probably one of the few groups that have shown that fasting is better than calorie restriction for health. And perhaps it's because we put breakfast first. So we run at breakfast to breakfast rather than dinner to dinner, which is probably the easier thing to do. So it's probably easier to. Biologically you're more hungry in the evening than you are in the morning. But we've run it the other way around and we see that intermittent fasting in our hands beats caloric restriction in terms of health outcomes. But maybe it's because we've done the fasting from breakfast time.

It's a really interesting thing. The chronobiology like signaling pathways that I've looked at. It's pretty clear that if you wanted to do an ideal fasting window you'd eat sometime. I would say not too early in the morning but sometime after the sun comes up until about 2. However most people, it doesn't work from a livability perspective. So I'm like if you're really sick, do that. Otherwise having an early dinner as early as you can get away with 5, 5, 30 and eating between noon or two and that it works. But if you wanted it to work a little bit better and be harder to do you shift your eating earlier or if you have a hard time going to sleep at night. Protein before bed raises orexin, which is the same stuff that modafinil raises. So protein before bed in high doses can be stimulating. So I have found that generally moderate non sugar carbs in your last meal of the day tend to improve sleep for a variety of proposed reasons. But that people get more cravings if they have the carbs in the morning even though you're more insulin sensitive in the morning. And it's such a mishmash where I feel like if you're Doing any of these windows, you're still getting 80, 90% of the benefits. But there is an optimal window and you might be the person who is going to identify the perfect window first. From what I've seen, is there anyone ahead of you in the publication schedule that you're aware of?

We did a pilot trial, so we compared early time restricted feeding with delayed time restricted feeding. So we asked people to eat from 8 till 5, we got them to eat from 12 till 9 just because we kind of wanted to have a big gap. I wouldn't normally say 9 o' clock is a good cutoff. I would say probably a little earlier. But we're trying to.

It's way too late.

Yeah, we're trying to have a reasonable length eating window and, and doable eating window, but also have differences between the two arms. And when we did that, and you know this is a pilot trial, was a week long, it was in 16 patients. So there's lots of caveats, but we saw it didn't matter. So both of them improved glucose tolerance just as well as each other and there was no difference between the groups. So they're both better than baseline and they, they had, they were exactly the same improvement in glucose tolerance. So in our hands, in a very small trial, it, they were both effective.

When you say that there was no difference in health outcomes, how are you measuring health outcomes in the studies? Like what does that mean?

So a lot of mine are more focused around diabetes risk. So we do, we did a glucose tolerance test essentially so people. And we looked at the glucose and insulin responses to that. So they were both improved by around 20%. So quite big improvements when they did time restricted eating for just one week. So they had these big improvements in glucose tolerance. Now that's kind of the order of magnitude that you see when you do or it's bigger than what you see when you, when you give metformin. Right. So Metformin is a drug that people with diabetes take to help improve their glucose control. And we saw that time restricted eating had at least as good if improvement in that not in a diabetes population. They were just in an overweight population who had. They're all men with greater big waist circumference, so big tummies. So they're in the diabetes risk factor range, but they didn't have diabetes.

Why did you do all men? Only a third of fasting studies include women.

I think when they're pilot trials and this is where we're at with time restricted eating is that the big studies haven't really come out yet. There was one last year that was still in not a huge number of patients where they did time restricted eating versus control. That's the first big trial. So everyone else has been doing, you know, we have to get the funding so we have to run all these pilot trials in, in really small populations before we then get funded to actually run the big studies. And so we're at the stage now where I've got funding to run a time, big time restricted feeding trial. We're starting this year, but it takes, it takes a long time. So yeah, we tend to run behind a little bit just because it takes a long time to get the funding and a long time to do these studies.

And the big study that will be men and women.

This. Yep, we have.

Okay, good, good. Thanks for, thanks for doing that. So many studies are done on, you know, college undergrads 20 years ago where it was pretty much all, you know, young, reasonably healthy men for the most part. And it's, it's fine if it's an early trial because, you know, as long as we're, we're sorting it out for the big groups.

Yeah.

Another thing that you talk about in your research is one of my favorite compounds, nad. I've talked about this in my aging book and I've, I've done intravenous nad. Can you talk about what fasting or time restricted feeding does for NAD levels?

Yeah, so we have seen, and this is really just in mice at this point, but we've seen that fasting or time restricted eating in this case increased nampt, which is an enzyme that makes nad. And so the fasting increased the levels of NA and pt. And then we saw, and also an increase in NAD as a result. So in mice in the liver we saw a change. So there was a, there was a good effect of time restricted eating to boost those levels. And yeah, you can take things like nicotinamide and riboside and things like that that can boost those levels as well in the blood.

I've definitely had a few guests talking about nicotinamine riboside, nicotine mononucleotide, taking NAD orally and injecting it subcutaneously and with patches and intravenously. And I've done all the above and I'm not opposed to doing the other nicotine related thing. Actually nicotine, that was 1 milligram of nicotine as an anti aging metabolic enhancing substance, not tobacco. So it's, have you seen anyone looking at the effects of nicotine during time restricted eating?

No, I Had not even aware that that did that. So I hadn't, I hadn't, I hadn't looked into nicotine at all. Sorry.

Well, I mean, it's the same receptors in the brain that you were referring to, but a guy from Vanderbilt has been looking at nicotine and publishing papers since 1987 showing that it reverses Alzheimer's disease and it raises PGC1 Alpha, which is, you know, that exercise mimetic thing. So as an anti aging very low dose substance, it seems to have efficacy. But I'm sort of wondering if that's something.

And it's highly addictive. Right. So that's okay.

Oh no, it's not addictive at all. I'm just taking another one. It. Nicotine's addictive, but without smoking and all the smoking additives, it has a three day washout period similar to coffee.

Okay.

Where it's. But smoking with all the flavorings and especially vaping, it's way more addictive than straight nicotine. So I've started stop the psychological aspect.

As well as the.

Yeah, yeah. For three days you get, you get cranky if you're used to it. And I'm talking one to four milligrams a day. A cigarette has like 20. So very different. Yeah, but I've always wondered.

I haven't looked into this.

Okay, good deal. But when we talk about nicotinamide, I'm like, hey, that first part of that makes me, makes me happy.

Yeah.

You do have a study in overweight women though that you've done as well, right?

Yeah, tell me about that. So, yeah, this is the one where I was just mentioning before, where we fed them. This is the one where we fed them all of the food. So we had four groups of women. We had women who were randomized to intermittent fasting with caloric restriction. We had a caloric restriction group. So they were energy matched and provided all their foods. And then we had a group of intermittent fasting people that were not energy restricted, so no caloric restriction. And then we had the control group. So the intermittent fasting group fasted for three days per week from 8am so they had breakfast and then they fasted for 24 hours. And then the next day ate the intermittent fasting restricted people ate it about energy balance. And that is providing the same amount of calories as 70% restriction every day.

These are all women though, right? Just to be super. Okay, that's really unusual because not that many people have done women fasting studies, especially with the degree of comparing 70% of normal calories, 100% of normal calories.

Yeah.

Kind of summarize the results for listeners because this is really important science.

Well, we saw that intermittent fasting 70, so the caloric restriction, intermittent fasting, really, it outperformed caloric restriction in terms of weight loss and in terms of improving health. So it was unexpected. We did not, we thought that providing all the foods to everyone and we actually didn't want to get weight loss, we wanted to have exactly the same amount of weight loss in both the groups. So we could see, see whether intermittent fasting is beating caloric restriction without being different for body weight. And you know, the science never works out as you plan it. Exactly. But so we did see that the intermittent fasting group lost a little bit more weight than the chloric restriction group and they had better improvements in their health. So greater reductions in diabetes risk markers and greater reductions in cardiovascular risk markers than the calorie restriction group. So yeah, we, we proved that hypothesis. But we did get a little bit more weight loss than we wanted in one group. So that makes us, us not be able to say is it the weight loss or is it the fasting? Which is exactly what we wanted to do, which is better. So yeah, it was a little bit disappointing in the end. But the interesting thing for the women.

In the study, the women in the study, though, it wasn't disappointing at all because most people overweight are happy to lose some weight. So you did get a great outcome for the people in the trial, but the data hid from you. Okay, that's funny.

And what we saw really was they were doing great on the fasting days. So our ladies in that study, you know, it was an eight week trial. It wasn't long, long term. And in this case, I think more than 50% were very happy to do it. I think intermittent fasting was very new when we ran that trial too. So it really only just come out. Michael Mosley's book had what came out during the trial and so it was all over the media and they were excited to be a part of, of this study. And so I think that maybe that had something to do with it, I don't, I don't know. But they, they were very adherent and they had trouble eating on their eating days enough. All the food we gave them, so they weren't actually that hungry. They had their fasting day, they did great on it. They were really compliant. And then they got to their eating day and they didn't eat all the food we gave them. So that's why they lost that little bit more weight, I think than, than the calorie restriction group. I don't think it was magic. I don't think that they had, you know, super metabolisms or anything like that. But, but maybe there were some appetite changes that makes them not be so hungry and potentially it's ketones, potentially it's ghrelin. We don't, we don't know that, that they are, you know, even they're not that hungry the next day. They can't, they can't overeat. They don't want to overeat.

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No, we're not certain at this point. And yeah, it could definitely be the ketones coming up. And I mean, we know that from all of the LCD diets that are out there and how that works, we don't know. But the LCD diets, they really bring up the ketone levels. The liquid calorie diets and your paleo type diets bring up ketones and they are, in humans anyway, suppressing hunger. And how, how that works really has not. Because it doesn't seem to work so well in mice and so they can't test the mechanisms quite so well as they can do in a mouse model.

Have you ever looked at ketone levels directly during any of these?

Yes. So we always measure ketone levels with the women, with the women's study. Yeah. So they're, they're definitely up. And they're up. Maybe. It depends. I mean, the longer you fast, the more they go up. So when we did the first study with alternate day fasting way back in 2005, and they actually fasted for almost 32 hours, you know, their ketone levels were sevenfold higher. Ketones start to come up at around 16 hours after you start to fast and they keep going up from there. So the longer you fast, the higher your ketone levels go. But it's interesting, there's a lot of variation in that. So when we look at our ladies and they're, you know, they're telling us they're fasting and some, some of the, some of the ladies have big increases in ketones with the 24 hour fast. And some of them only go up by that small amount. Maybe they got 0.1 and some of them got 0.4, 0.5. And so you see there's a big, there's a big variation in individual changes in ketones. And this is when we were providing their foods to them. So it wasn't what they were eating the day before. The other thing we were seeing was that during the week. So when we get them to fast on Monday, Wednesday and Friday, by Friday, their ketone levels are kind of higher than they were on Monday. So that third fast in the week and they had. And I guess they reset a little bit on the weekend by having that two days of eating. So on that Saturday, Sunday, so they'll kind of back down again on that Monday. So. So I think doing that third day of fasting per week, I think that it kind of additive.

Along the way, I found some research. I've put in a couple of my books and I don't remember where it was done, but they were finding a level of 0.38 in the blood for ketones was affecting CCK and 0.48 was affecting ghrelin. So you could raise CCK at 0.38. So I've always said, look, do whatever it takes to get your ketones to 0.5. And if fasting alone does it, if not, MCT oil works just fine. But once you hit 0.5, you just stop thinking about food and then fasting just, it just doesn't matter. So I'm.

Are you doing this by urinary ketones or are you doing this? Like, was that. That was a study.

This was a study. I don't remember. It was pro with that level with a point, a second decimal point almost has to be a blood ketone, not a urinary ketone, because you can't get. Can't get good stuff. The idea there that for people who don't get a ketone bump, you're just at 0.1. It takes more willpower. And so I'm like, how do I take what little we know, which is way more than we used to, and turn it into actionable stuff so people don't get hangry during the day? Because that was Always my issue when I was really heavy and I've heard it from so many people and we're both kind of getting these little illuminating facts that are out there and then saying, oh, which ones matter? So what is your favorite or what is the most interesting of all of the metabolites or compounds that you're seeing of affected by fasting? Like what. Which one intrigues you the most?

I mean, I mean, I think they all interact at a lot of times too. I don't know that I want to hang everything on a ketone I have, you know, so we've tried to so with, with our human studies. So you'll try and look at things that predict the change. So you'll say, okay, let's look at the change in the ketones and look at if they correlate with the change in the weight loss. Or let's look at the change in fatty acids and. Or the change in amino acids and say, do they relate to those things? And you know, we haven't seen anything to me that's going to put me in one direction. But you know, again, I'm going to hang my hat on the new study coming up, I think, because it's big and we should be able to answer more of these questions. So I'm hoping that that will do it. But yeah, I haven't been able to hang a hat on something at this point, unfortunately for you, Dave, or I'd be publishing a lot better paper, I think a lot better.

Oh, you definitely aren't certain yet, but let's say that you had to hang your hat somewhere right now. And if you were going to, you were going to guess. This is always the hardest thing for true scientists to answer because, like. But I don't know for sure, but you're going to place a bet. Like, I'm going to give you a million dollars and you got to bet on something. Where would you put it?

I don't want.

It's okay to be wrong. You just lose the bet.

Yeah, yeah, yeah. No, you're right. I one thing do you know, because I haven't really measured it yet. I'm gonna, I'm gonna go back to the nad. I'm gonna go back.

Oh, you are interesting.

Yeah, I think that that is a pathway that's really super interesting that is activating a lot of things. But the other thing that we're doing in this study is, is looking at autophagy. So autophagy, autophagy, as you mentioned before, and I guess it's kind of Hard to explain, but it's kind of like this cellular self eating process. So when you're fasting or when you restrict amino acids, you activate or you inhibit MTOR and you activate autophagy. And autophagy goes around and it chews up all of the broken bits in your cells and it makes energy out of them. Now, we know that autophagy is activated in mice when they fast, but we really don't know what's happening and whether 20 hours or 24 hours or however many hours are necessary to activate autophagy in humans. And the other thing you need to look at is not just the markers of autophagy, but how it is changing when you challenge it. And so we're taking blood samples from our patients and we're challenging them with chloroquine, which inhibits autophagy. So we're looking at their ability to kind of quickly shut off autophagy or to activate autophagy in the flip side. And so we're looking on fasting days and on eating days and in calorie restriction and in fasting. And so I'm kind of really excited about those results as well. And so we've again, we've actually finished collecting the bloods for that, for that sub study of this trial and they're going to be run hopefully this year. But yeah, so all the bloods are collected and they've all been treated with their chloroquine. And we're going to be excited to see whether we're changing autophagy also in our humans when we do fasting versus calorie restriction.

Oh, I can't wait to see the results of that study. Have you ever personally used metformin or rapamycin or any of the other, you know, advanced senolytic autophagy kind of things during a fast or do you sort of leave that for the mice?

Yeah, no, I haven't. I couldn't tell you what they're, what they're like. I have a friend that does metformin periodically and he likes it, but I haven't, I haven't tried that. Nope.

I first went on metformin for about three years when the first trials came out in 2003 that said it was a caloric restriction mimetic. And I met the team from Biomarker Fibers Pharmaceuticals who had published that first research. And I just, I didn't feel that good on it. And I now there's some evidence that it inhibits, I think, cytochrome two or something, some kind of Mitochondrial inhibition.

It's a mild mitochondrial poison.

Yeah. And that doesn't mean it doesn't make you stronger. But probably taking it every day isn't good and taking it when you exercise isn't really that good. And taking it during a fast might be good. But I'm hopeful that over the next few years we get more info about the proper timing of metformin and these other things like rapamycin, the anti aging.

Did you lose weight substance.

On metformin? I had already lost a lot of the weight that I wanted to lose. And let's see, this was back in 2003. So I was probably about. Yeah, I think I was mostly I would have been doing my vegan diet phase then, which was a very bad move. So I probably lost weight from malnutrition and excessive all sorts of toxins. That was not a good outcome, even though I was a very careful vegan with lots of blenders and whatever. So it was probably confounded that way. But I've gone on and off it since then and I've never felt great on it. And so maybe it just doesn't agree with me. But I'm happy to take it once a week. But I decided it wasn't a regular thing.

There's a definite. So they see responders and non responders with metformin in diabetes all the time. So there's people that just really don't to respond respond. And I guess it's genetics. They don't really have a way to pick them except for if it's not working quickly, they might as well try something else. And so there is a definite degree of responders in individuals with metformin that.

Could be it as well. And there's probably some genetic things, some microbiome thing and who the heck knows? You published something in the Journal of Clinical Endocrinology and Metabolism just last year in 2020, talking about impaired lipid metabolism that you could reverse with caloric restriction. But you looked at if versus cr strangely it looks like a 24 hour fast impaired insulin sensitivity. Can you talk about what you found there?

Yeah, so definitely we are seeing that and I'm not surprised really. So fasting always impairs insulin sensitivity. I actually thought 24 hours would be. Wouldn't be enough to do it. This is again in women we tested this. So 24 hours of fasting is enough to impair insulin sensitivity. So you need to. So when you're not eating you need to spare glucose. And so one of the things that happens when you fast Is you raise. So you have lots of lipolysis, lots of fat burning going on and you raise your lipid levels up. You know, you drop your insulin levels. You have the, yeah, the non esterified fatty acids levels come up in your blood and there are lots of, lots of things going on. But you will induce insulin resistance in muscle. It was transient, so it was gone by the next day when they fed. So we saw this transient switch in insulin sensitivity. Insulin resistance, insulin sensitivity, insulin resistance. And so I'm not terribly surprised. The test that we do for that also is looking at maximal insulin sensitivity. So you're kind of looking at the, it's not a physiological test. We shove somebody full of insulin and you're really looking at really high levels. And so, and we're testing how they're, how sensitive they are to that insulin, to that maximal insulin dose, how their muscles are insulin sensitive. So it's not something your body actually normally sees. So we're retesting that using a meal tolerance test in this study again. So we're going to do a meal tolerance test test on a fasting day and I want to see whether we're changing how the body is handling glucose in response to refeeding, essentially on that.

To a normal refeeding, not the frappuccino with 200 grams of sugar refeeding.

Right, right. Well, we're still doing a milkshake, so it's still a little bit abnormal. But yeah, so we're doing. It's quite a challenge still, I think. So we kind of are maxing the stuff system a little bit. Maybe we shouldn't have gone. So if we'd done a, if we'd done a solid meal as people normally would eat, we might see something different again. But we, we chose to do a milkshake just because it's kind of easy to standardize in the lab.

There was a recent big media blitz about, oh, the worst thing you could do for breakfast. And it had to do with drinking coffee before breakfast or after breakfast. But their definition of breakfast was a straight sugar, like a glucose tolerance test. Like, well, it was really coffee before a glucose tolerance test or coffee after a glucose tolerance test. Which one was better for you? But that was not a breakfast any human would eat, even at, you know, a donut shop. So I was, I was surprised. But it did look like coffee certainly was having, you know, a negative effect right before a huge amount of sugar. Any ideas on how important coffee is during a fast? I know you allow it and I know it doubles ketone production, but kind of. What, what's your, what are your thoughts on that?

We can, I mean, we allow it for, to make people happy, I guess. You know, we know that if you, if you don't get coffee when you normally have coffee, you have a headache. So, you know, it's, it's like a, it's just like nicotine, it's like a drug. And you will, you will have a caffeine withdrawal during your fasting day, which is already, you know, hard. So to, to not allow coffee during that, that day is, is going to have a negative effect on people who normally drink coffee. But it also gives them something to, to fill their belly and do while other people are eating so they can have a cup of tea or a coffee. And that's why we do it rather than, than trying to activate or double any pathways or anything like that. So it's more of a site, we do it for a psychological aspect and to help people stick to otherwise fasting.

I have found that black coffee absolutely helps with fasting at adherence because of the social aspects you just talked about. And then there's the, the caffeine doubling ketone production. So the people who are at 0.1 might get to 0.2 if they have, you know, a couple small cups of coffee. Which for the low ketone responders is maybe enough to, to feel the difference. And I, I just, I know betting.

Against whether they were coffee drinkers or not, the ones that didn't change actually.

It would be, I would want to know. Yeah, I, I, I just, I've always found betting against coffee in general is a bad idea. When I opened my coffee shop in Santa Monica, the Bulletproof Cafe across the street, there was a place called Gunpowder Tea. And it was kind of funny because we had bulletproof and gunpowder, but they had a big sign up front that said no coffee here. And I'm like, it can't be good for business because they're all going to come over to my side of the street and the other store did close. So.

Does she sell tea as well?

Yeah, we have bulletproof tea. You know, we'll, we'll make you a matcha with butter and MCT oil and stuff in it.

Okay.

And, and also without butter if you want it that way.

But it was never tried coffee with butter.

I'm sorry, You've got to give it a shot. It'll, you'll try it and literally it's actually really big in Australia. Bulletproof has always been big there. But then you'll try it and all of a sudden you'll want to run a trial on it because of what it does cognitively. It's like the anti hangry thing for doing fasting. There's certainly no amino acids in there, especially if you make it with ghee versus butter. So it's not going to activate, it's not going to break autophagy by amino acid metabolism, that's for sure. And it doesn't raise insulin in third party studies. So there's that. But there's stuff we don't know because there haven't been enough clinical trials saying what does it do for instance to the microbiome specifically and what impact would that have on firmicutes versus bacteriodes which are, are independent factors. And there's all kinds of neat stuff to learn. So give me time, I'll do some more research because at this point so many people have lost a ton of weight. I know the hunger effects, but the why is something I'm still circling around. You also looked at in a study, I think you touched on it earlier, but I wanted to review it with listeners you talked about. This is from the Obesity Journal. You looked at time restricted feeding early versus time restricted feeding, feeding delayed, which we talked about earlier. And then just overall whether they did it or, or didn't. Um, but it was interesting because you were looking at continuous glucose monitoring, something that I, I do as well with the Levels Health device. And what did you guys find around just overall time restricted fasting? Regardless what, what was the, what was the positive outcomes when you didn't pay attention to the time of day?

So with the continuous glucose monitors, so the, so they were down. So we had reductions in. So that's, we've done another study since we haven't published it yet, we're about to. And the, so with that study we saw overnight glucose levels were down definitely, but they were up a bit during the day so that we didn't see any overall change in 24 hour glucose. But really we saw a swing back to circadian pattern. So if we looked at the continuous glucose monitors at baseline, they were kind of, you know, just all over the place here. Whereas if you did time restricted eating, you really bought a 24 hour cycle back into glucose so that you had low glucose levels at night and higher glucose levels of the day. And that's probably what we're supposed to have in our next study, which we'll hopefully have out soon. We did see that 24 hour glucose, meaning glucose was, was, was it down? I Think it was significantly down only by about 0.2 millimole. Can't translate that into milligrams per deciliter anymore. Is it 4 or 5? 4 or 5.

I think you multiply by 17 or something.

Something. Yeah. 18. Yeah. So, yeah, so it was, it was down. And we also glycated haemoglobin was down in our next study as well. So the diabetes risk markers are improving with time. Time restricted eating for sure.

At this point I am really comfortable telling people, look, don't eat after about 5:30 and if you do that you're probably gonna live longer. Would you say that that's likely true?

Yeah, I think that 5:30 is tough for some people and so maybe we might need to be a little more lenient and say 6:30? Yeah, 6:30. Because you know, by the time you get home from work sometimes it's just tough. So if you put too great a time pressure on people, what I'm worried about is they go, oh, I have to eat by this time. I better stop at McDonald's on the way home and grab my dinner. And I'm pretty sure that if you did that sort of thing, you will be undoing some of the good things of time restricted eating. So, you know, I like time restricted eating because, you know, it's really hard to change everything about your life to change everything that you're eating. To change, you know, to, to, to say, okay, I, I don't want to eat this, I don't want to eat this. I have to change to be this diet quality. And that's really hard for people to maintain for a really long period of time. We've shown lots of that. Lots of times when you have people who, who start, who get diabetes and start going to see dietitians, they have this immediate great response in changing a lot of their diets qualities and changing everything they're eating. But they slip back over, over time. And so, you know, I think that time restricting is great because you don't really have to change everything that you're eating and you're still going to have some, some really good effects. But I think if you started to have bad behaviors because of time pressure, then, then you're not going to see the improvement that, that okay, we'd hope.

To see you make so much sense. You're basically saying if you continue eating whatever you eat now and you add time restriction, you're going to improve. But if you add time restriction and lower your food quality, you might not improve, which totally makes sense. And and it's that where do you get compliance versus where do you get great data? And that's always been the challenge unless you're doing time restricted feeding, you know, in a prison system or something. And we're already. So go ahead. I would say we're already so mean to people in prison anyway and we feed them the worst food and treat them really poorly. I, I don't believe it's nice to experiment on them. So.

No. Well, we have an argument here that perhaps our prisoners are treated better than our nursing home folks. So, you know, the nursing home budgets are half the prison budgets and so in terms of what they're providing those people. So we've, we've got a big fight on our hands here I think in Australia trying to improve diet quality nursing home residents, which is super important as well. So. Yes, but yeah, the, I think that if you improved your diet quality or at least stopped eating all the things that you used to eat and drink with time restricted eating, you know, you will improve diet quality a little bit anyway. So hopefully you, you know, usually the things that people eat at 8, 9 o' clock at night are alcohol and ice cream and chips and you know, that kind of poor quality food. I think so. So they are probably cutting that out with time restriction. We don't find that people tend to move it, Some people do to move it from 9pm till 9am but you know, we did that for our trial that I was just talking about earlier that hasn't come out yet. But we all we did was move an ice cream from 9pm to 11am so we fed them during the trial and you know, they, they still improved glucose control just from having that, moving that food around.

Oh, that's so cool. So it's when you eat as much as what you eat, what do you do now that you have all of the benefit of all this research? So do you have breakfast? Do you have dinner? What's your average practice when you're doing things the way you want to do them?

Right. So I've just come back from three weeks of holidays where I've done absolutely nothing and I do need to reset, I think. So I'm going, I haven't started yet, but I will. And when I do it, I will do. When I decide I needed to lose 5 kilos or something like that, I will do like a three day a week period. I don't do what I tell my patients to do and I tend to have a big kind of bowl of vegetables in the evening as my 500 calories, ish thing. And so I, I would get a whole bunch of broccoli and cauliflower and brussels sprouts and root vegetables, not potatoes, and roast them in the oven and have them for my dinner on a fasting day. So I feel somewhat full when I do that. The other thing that I do quite regularly is to have breakfast and dinner and don't eat during the day.

Okay, cool. And that works, that works for me. And also when you say three days a week, you're talking every other day, you're not doing three contiguous, right?

No. So I don't tend to do three. Yeah, three days together. I tend to do every other day. And also I don't do time restricted eating. I mean, I try, I have, I haven't really tried to do it. Actually, I should, I haven't, I have never really tried to go, let's eat between 10 and 6 and yeah, I haven't done it. I'm more of a, if I'm gonna fast, I want to go hard, lose weight and go a bit longer. So what we see with our time restricted diets is we see improvements in health, but we don't see a big change in body weight generally. So you lose two or three kilos, but some people do better. That's true, some people do better, but most people don't lose much weight. But that's the exciting thing with time restricted eating, I think, because you improve health even though you don't lose much weight.

This is more of a meta question for you. So I've talked with Satchin Panda and he tends to go out and just try everything on himself, Right. And he's like, oh, I told my mom to do time restricted eating and her, you know, her diabetes went away. Like, who would have, who would have thought an earlier dinner would do that? But so many of the people I've interviewed who are academic researchers have never tried the substances or the techniques or just don't do the ones that they're studying the most. Why do you think that is?

I don't know. I think that. So, you know, I, I exercise a lot. I do a lot of high intensity exercise training. Never studied high intensity exercise exercise training, but I do high intensity interval training.

Interesting.

And I do do fasting as a, as a way to stop to, to claw back Christmas and, and parties in the new year.

Okay.

Yeah, so I, I do that, but I just haven't done time restriction eating yet. So.

Okay. You're not alone there, by the way. Like, like, no, no judgment. Or anything. It's, it's just, it's. It's an interesting. It's an interesting. I think it's a mindset thing about, like wanting to know with a hundred percent certainty before you do it. And I thought you might have a thought about it. I've asked Craig Venter.

Yeah, it's absolutely why I did fasting. So I've done that plenty, plenty of times.

But that's your favorite. So that's what you do. Because it works.

Yeah, yeah. And I actually have also done a lot of four days a week, so a thousand calories, five days a week, and then eating what I want on the weekend, too. So I've never studied that one, never tested that one, but that's another one.

It's kind of the fasting, mimicking diet perspective. Right?

Yeah.

Okay. Awesome. Well, so you have tested a bunch of the stuff, but not all the stuff that I hear you there. Well, Leonie, thank you for sharing all this time and precious knowledge. And also thanks for doing the hard work to get the knowledge in the first place. I genuinely appreciate your work in the world and you're shedding light on something that we didn't know about. And I think every year from here on out, for the next 10 or so years, we're going to just keep going. Oh, wow. Who would have thought that, you know, this food at this time is ideal. So thanks for being one of the pioneers.

Great. Thank you so much.

If you guys want to know more, there isn't a particular URL for you to go to. You can go to researchers Adelaide Edu AU Profile leonihalbron. So that's something that'll be in the show notes for you, but basically you're going to see a list of academic papers because we are talking with someone who actually spends her time getting knowledge, not necessarily going out and being an Instagram celebrity. So we're learning directly from the scientists. And just one more time, thank you for being on the show.

Great. Thanks for having me, Dave. It was fun.

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