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Intermittent Fasting: Fad or Metabolically Beneficial? with Dr. Michelle Woolhouse and Dr. Veronique Chachay

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Intermittent Fasting: Fad or Metabolically Beneficial? Dr Michelle Woolhouse & Dr Veronique Chachay

Dr. Michelle Woolhouse speaks with Dr. Veronique Chachay on the history and metabolic benefits of intermittent fasting, calorie restriction and time restricted eating and the challenges associated with studying these protocols. Veronique elaborates on the various forms of intermittent fasting and their role in both metabolism and weight management and how eating within a certain time of day may support the function of specific organs based on chrononutrition.

Intermittent fasting has been associated with a reduction in insulin growth factor 1 (IGF-1) production, suggesting a benefit for healthy ageing and a reduction in insulin resistance and the production of ketone bodies associated with the use of stored fats for energy and Michelle and Veronique cover these topics in addition to the potential for personalised nutrition and the adoption of intermittent fasting to suit a persons genotype. 

Covered in this episode

[00:29] Welcoming Dr. Veronique Chachay
[00:58] Defnining fasting
[05:54] The impacts of caloric restriction as a lifestyle
[08:55] Is calorie restriction for everyone?
[11:06] Time-restricted eating and chronobiology
[14:32] Different types of fasting
[16:44] The fasting-mimicking diet and influences on IGF-1 levels
[22:22] Ketone bodies and reduction of cellular inflammation
[27:54] Effects of intermittent fasting on cholesterol and triglyceride levels
[32:43] Personalised nutrition and genetics
[38:04] Fasting for weight loss and maintenance
[40:22] Fasting effects on immunity
[43:14] How fasting induces autophagy
[50:45] Thanking Veronique and closing remarks

Key takeaways 

  • Intermittent fasting, calorie restricted eating and time restricted eating have been associated with improvements in metabolic health, in particular with the modulation of IGF-1 production to support insulin sensitivity. 
  • Following a period of fasting, it is unlikely that someone will engage in bingeing to make up for calorie restriction. 
  • Time restricted eating supports the concept of chrononutrition, where we eat within a specific time period, ideally when the sun is up, to support the body’s circadian rhythm and natural digestive rhythm. 
  • Intermittent fasting is associated with an increate in ketone body production and the use of energy stored in adipose tissue and is a signalling molecule. 

Resources discussed in this episode

Dr. Veronique Chachay
Michael Mosley's 5:2 Fast Diet
Professor Valter Longo
Study: Intermittent and periodic fasting, longevity and disease (Longo, et al., 2021)


Michelle: Hi, and welcome to FX Medicine, where we bring you the latest in evidence-based, integrative, functional, and complementary medicine. I'm Dr. Michelle Woolhouse, and with us today is Dr. Veronique Chachay, researcher and lecturer of nutritional science at the University of Queensland. She's here to discuss the research around fasting, longevity, and optimal metabolic health. 

Welcome to FX Medicine, Veronique.

Veronique: Good morning, Michelle, how are you?

Michelle: I'm great. Thanks for being here. 

So, I want to start off our conversation today. It seems there are a lot of diet and lifestyle-based health trends these days that are hugely popular, things like the paleo diet, barefoot running, earthing. But one of the ones that I've found the most convincing and most intriguing from an evolutionary nutritional perspective, is that of short-term intermittent fasting. 

Veronique, can you start us off by talking through what you define as fasting? What do we mean when we say the word “fasting?”

Veronique: Yes, very good question because it's important when we talk about health benefits, expected or targeted, we need to put that in the framework of what pattern of fasting we're talking about. Because there is a thin line between fasting practices and then eating disorders issue as well, yeah?

So, fasting, as you mentioned in your introduction, is not new. It's probably something that the human physiology has practiced because of the way the food supply was having ups and downs throughout the year, for example. Where we go through periods of abundant food supply, and then periods where it was a little bit less and sometimes much, much less. So that forced patterns of abundance, or what we would call feasting, and fasting, that forced pattern has been there throughout all humankind, up until nowadays, where we have 100% of abundance all year round.

Now, also from a religious point of view, so as you know there is a number of practices as well there with different patterns, with different purposes. And often, I had an interest in looking at where did this all originate? It's also more from a mental training point of view, because it's about being able to control one's urge to overeat or to eat. 

Anyway, so, because of that, there's been these observations. So, in certain populations where the fasting is a regular religious practice, there seem to be less chronic disease, for example. Or maybe at the end of the… so you would recall there was this study, the Geosphere study where people were under a big bubble, a glass bubble, where they lived for 18 months just looking at self-sustainability, so growing their own food, etc.
Now, out of that, they had issues in the sustainability aspect of it. So, they were actually deprived of food or of the normal supply that one would need. And so, at the end of it, they had lost a fair bit of weight, but also had a number... And we're not talking people who necessarily needed to lose weight, right? So, it was not for the purpose of weight loss. 

But there were metabolic benefits of this period of time. And so, that was really the start of saying, “Okay, what's happening during fasting here?” I mean, is it just a matter of losing weight? And then of course, as we know, losing weight induces so many metabolic benefits by itself, right?

Michelle: Yeah, that's right.

Veronique: And so, I guess the most popular would have been obviously the 5:2 diet that Dr Michael Mosley has investigated by his own purpose with a documentary, I think it was 2012, I think, it came out. Where he went to actually interview different scientists who research in the field of calorie restriction, which means putting animals on a restriction of a certain amount of energy compared to what they would need, and then see what happens, and also looking at the clinical aspect. 

So, what came out of that is that there is a definite benefit of reducing, basically putting the body under mild stress. So a calorie restriction is perceived as a stress. And then as a result, so, same principle of the Hormesis theory where we put a little bit of stress and that induces, or activates all the genes that are about resilience, about defence, about detoxification, and so on.

So, the calorie restriction on optimal nutrition, the "CRONies," so that's a movement that exists worldwide, where people willingly, I mean by choice, not just through a period of 3 weeks or anything, but as a lifestyle, reduce anything between 25% to 40% of their estimated energy requirement, based on weight, physical activity, basically anthropometrics that we use to estimate energy requirement. And they do that as a lifestyle.

Michelle: Do they do that all the time or they do that intermittently, or do they do that in certain parts?

Veronique: Yes. No, no, so that is on a permanent basis. So the...

Michelle: Oh, right.

Veronique: ...calorie restriction on... But the key thing here is calorie restriction on optimal nutrition. So they don't...

Michelle: They don't have tiramisu for dessert?

Veronique: You couldn’t just have chocolate bars through the day. It's about having optimal nutrition in terms of micronutrients. And so, they do that. So the aim here is to increase what we would call health span, and potentially as well lifespan because that's what's been observed in the mice models of calorie restriction, right?

Michelle: Right.

Veronique: Okay, but that is coming with benefits, but we don't have really those evidence in terms of the lifespan of a human being because we don't have the studies and we can't conduct those studies. However, there is some studies reporting on biological age-similar people, but those who calorie restrict as a lifestyle versus those who just eat normally. And so, comparing individuals at 45, 55, 75, and looking at the actual physiological age, and showing that there appears to be definitely health benefits of calorie restriction in that sense, because...

Michelle: So what are they looking for when they're looking for that benefit? Are they looking at metabolic factors, are they looking at...?

Veronique: Yes, so metabolic factors such as, so the typical kind of disease that would develop over time when we have an abundant diet of all sorts, with gradually more sedentary lifestyle is things like nonalcoholic fatty liver disease, for example. Which actually is called, I just realised now it's called MAFLD, metabolic.

Michelle: Yeah, that's right.

Veronique: It's interesting. Metabolic fatty liver disease. So, for example, in that same line of thought, the body composition, so composition of fat mass versus lean body mass. Things like balance, you know the test on one-foot balance...

Michelle: Yeah.

Veronique: ...closed eyes, and so on. Reflex response, like speed of reflex.

So this kind of general what we attribute to normal ageing, so normal ageing affects those functions. And so comparing that with calorie restriction practitioners, there seem to be a maintenance of more youthful metabolic markers of that sense. 

Now, with this though, the big discussion is, is it suitable for everybody? Is it a sustainable way of living? So, yes, in certain environment it's doable, but in others, it's not so practical to do that. 

And then, is it suitable for everybody? So, there is evidence that it's very, again, that thin line to go towards eating disorder behaviours, you know? That has brought a big concern, shall we say. And so, this is how then, looking at the benefit of those restriction but doing it in an intermittent way started to come up as a potential. 

And also, I must say I think the intermittent fasting research has been also motivated by the observation of the shift workers who do intermittent, but in the other way around. Because if they work at night time the food supply is not maybe the same, so they tend then to go also for other types of macronutrient distribution and types of food which then associates or brings association with metabolic dysregulation later on. But that observation of that shift work which completely puts everything upside down was another source of information saying that perhaps the calorie restriction, as in an intermittent way, could be useful. 

So now you've got the...there's, again, lots of different wording that you said, from the popular press and so on, different wording for it. But you could call that periodic fasting, within a seven-day window where you've got either two consecutive or distributed days of fasting. And it doesn't mean that it needs to be zero intake. It can be just like a certain percentage or maybe 0% to 25% of usual intake.

Michelle: Michael Mosley's advice is to have 500 calories for women and 600 for men, so that's around probably 20% to...?

Veronique: That would be 25%. Yeah, 25%. Then there is what we will call the time-restricted eating or TRE, or time-restricted feeding. And so, this would be within a 24-hour cycle where we've got a feeding window, anything between 8 to 10 hours perhaps, or depending. You can do it more or less strict. And then the rest is fasting, as in proper fully fasting then.

Michelle: So you're fasting for 14 to 16 hours, is that around...?

Veronique: That's it. Yeah. So some people would push it even further, but that is again why does one do that, and what's behind them?

Michelle: Yeah, is their benefits?

Veronique: But that would be about the 8 to 10. So, this time-restricted feeding brings in that chronobiology aspect of it, that it is better to feed during the day or during the waking hours like even daylight signalling because of all these internal regulation through the clock genes, about the chronobiology dictating when things happen. So when is there upregulating of genes? When there is downregulation of genes expression. And so, to feed at the time when we are more likely to express the genes, for example, to produce  enzymes in digestion, for example, then it obviously makes sense to have that during the day as opposed to the middle of the night.

Michelle: That's so fascinating, that chronobiology, I love that term. Having that circadian kind of regulation. That makes so much sense to do that.

Veronique: And the translation of that is then to go into Chrono nutrition, they call it even now. That's a very popular term. But I mean...

Michelle: I know that when I studied Vietnamese medicine, so it's like Chinese medicine but from Vietnam, they would often talk about various different organs of the day, having their ideal time with the gut and the liver almost been switched on overnight around that kind of midnight to 3 a.m. So this idea of Chrono-nutrition or chronobiology is obviously the ancients or the traditional practitioners have known about this for a long time.

Veronique: Yes, which is really interesting. And I think this is why... I share the interest in that field as well with you. From a dietitian's point of view to study all the different nutrition or diet therapies around the world from different backgrounds, to then understand why do they say that we should have a very light meal at nighttime, or eating during the day, and so on. All these things. And there is not necessarily a biochemical explanation, because the knowledge was not on that level at that time.

Michelle: That's right.

Veronique: But there was some intuitive knowledge, definitely. And fasting comes into that. Even animals like to fast when they're not feeling well or when... 

So there is this element where why should we have a feeding regimen that is dictated by cultural habits, or by the timing of the day? "Oh, it's 12:00. I need to eat." No, it's not that. It should be, "I'm hungry, I need to eat," and that's it. 

Anyway, so then we're talking about also, so we had time-restricted eating which is the time period thing. Then we had the periodic fasting which could be those two days over a seven-day. Two days either consecutively or alternating. You could have the alternate-day fasting, so ADF is a short for that. So we're talking one day on, one day off, one day on, but two all the time. And that is more commonly done just by reducing the calorie intake on the fasting days.

Michelle: So is that down to sort of that 500-600, or are they doing more like the 800 fasting?

Veronique: From the literature it's from the 0% up to 25% of calorie intake, sort of thing. And then there would be those long-term fasting which is when people go...well, that would be under medical supervision where there is a much longer window of fasting.

Michelle: So they might go for like five days or seven or...

Veronique: Yes.

Michelle: ...even longer than that?

Veronique: There is little evidence on that.

Michelle: Right. So we're including all of the nutrients and we're sort of taking away the calories but making sure that the nutrients and micronutrients are all catered for.

Veronique: Yeah. That's why I say under the long-term fasting, it would need to be under medical... It's hard to talk about it in terms of evidence, because I can send you literature and even documentaries which talk about those, we call them the health sanitarium, I think in Germany, and in Russia, where they practice the long fasting. 

So this is just water fasting, purely water fasting. So we're talking up to three, four weeks, but under medical supervision. And they're getting vitamin supply as well and mineral supply. And that is to address things like arthritic conditions, even diabetes, and so on. That would be more... I put it under therapy.

Michelle: That would be more disease-focused.

Veronique: Yeah, and therapy, definitely. Then we need to mention also in the intention of making all these more palatable, if I can say, more something that people are likely to take on as a health habit for, again, long term... 

So we're talking about the health span, extending that duration of life where we are healthy. There is all these different protocols that come that have flourished in. And some of them are more or less, well, founded but I need to cite the calorie, sorry, it's called the fasting-mimicking diet from the research group from Valter Longo in UCLA

So Valter Longo is one of the...so he's researching in the field of gerontology, which is understanding the ageing process, and how can we address that early on so it doesn't get to the geriatric state. And so, he started a long time ago with animals and even looking at the benefit of fasting in conjunction of cancer therapy. But that is another topic we can talk about it, definitely. So talking about this as being an adjuvant during chemotherapy, but it's a different field. 

But, anyway. So, he researched that a lot. And then he also looked at more the metabolic markers such as insulin growth factor 1, so IGF-1, and what are the IGF-1 levels, how they are associated with health or disease. And noticing that with fasting, we are able to lower those IGF-1 levels. Now, again, I need to put this into... It's all cautionary here because IGF-1 levels, they're very important at certain time of life, and they're perhaps not as important later on in life, is the system because it's a growth factor, right?

Michelle: That's right.

Veronique: So when we are young we want it, plenty, in growing.

Michelle: Yes. Because it works hand in hand with growth hormone, yeah?

Veronique: Exactly, yeah.

Michelle: Yes. So it's great when we're growing, but we don't want so much when we grow older because we're not growing so much, so it's going to grow things that we don't want to grow.

Veronique: Exactly, exactly.

Michelle: Like something like cancer.

Veronique: Exactly. But at the same time, in preparation of today, I was reading a review about, just actually from that group, recent, I think published this year. Looking at what are the optimal level of IGF-1. And it seems it's a bit like one of those J curves.

Michelle: Yeah. That's right.

Veronique: And so, too little is not good as well. Even for older people it's not good to have too little. But nevertheless...

Michelle: So you want to be in that sweet spot.

Veronique: Yeah, it's about modulating that dose. And so, dietary factors are involved in IGF-1 production. For example, we know that high insulin or elevated insulin levels in the blood will drive the production of IGF-1 in the liver. So, why do we have high insulin? Well, we would get raised insulin when we consume a lot of carbohydrate or excessive sugar all the time. I mean, insulin is super important, so we don't want to bag insulin. But it's about becoming maybe insulin-resistant with ageing. So that means we have a little bit of more elevated insulin.

Michelle: And the statistics on insulin resistance is enormous. I mean, we've got huge percentages of the world population now showing levels of insulin resistance. So, this is a really common issue where fasting may become like, I guess, a way to approach that might suit people.

Veronique: To modulate that, yes.

Michelle: That's right.

Veronique: Because by modulating, so restoring normal insulin function, then we don't have the signalling to produce more IGF-1, so that's one of the thing. And also, according to this group, it's the branched-chain amino acid. 

So we've got 20 amino acids that we use from our diet. Some are essential, some are non-essential. Non-essential, meaning that the body can make them itself. But the essential have to come from the diet and some of them are those branched-chain amino acids. So they're three in particular, and they seem to promote as well, more or less indirectly, the IGF-1 production. So with this in mind, this group has developed a protocol called the fasting-mimicking diet. So it's a propriety program with all sorts of little powders…

Michelle: Secret ingredients.

Veronique: ...and vitamins and all this kind of thing, yeah. But it's an interesting one. So it's a 5-day program where you drop the energy intake from, so I'm talking calories here, from a normal 2500, 3000 for men, or 2000 to 2500 for women. You're dropping to, not excessively, 2000, but there is a definite breakdown of macronutrients, so protein, carbohydrates, and fats. So that's for one day. And then for 5 days, it drops even further to 900. So it's not excessive. But it's, again, breaking down the macronutrients in a specific way. 

And the aim here is to promote the...so I don't know if you want to talk about this now. But it's one of the mediator of all the fasting benefits, or one of them I should say, is the ketone body beta-hydroxybutyrate. So as we are switching from...if we start fasting today, what are we going to do? We're going to first use whatever carbohydrate store we have in the body, and that is in the form of glycogen. So liver glycogen will be broken down so it becomes sugar, again, glucose, which is then released into the bloodstream. And that still sort of becomes the first source of energy for cells.

Now, why do we use glucose? Because it's a lot more quickly utilised in turning to fuel that cells can actually use, right? And then in the muscle, the muscle glycogen, so that doesn't contribute to blood glucose. It's used locally for muscle. Now, once this is depleted, there is no more stores, then gradually, I mean, not just suddenly, but gradually, progressively, the body starts to break down fat stores a lot more. And so here, when we break down our fat stores, what we end up having is not just a twinkling...that's not the word. A little flow. We don't get just a little flow of...

Michelle: A trickle.

Veronique: ...gradual energy. Yeah, that's it. Not gradual. But when we break down fatty acids, it's a huge, it's like the hose is turned on really, really large. And so, it's like we have the molecules to produce energy in much larger quantity, and so much larger than what we actually need. And so, there is a way to deal with this large amount of molecules, and that is to convert them to what we call ketone bodies. So some of it will be used to produce that energy that the cell use. Some of it will be diverted to ketone bodies. So it's basically having an intermediate sort of packaging of this extra molecule.

Now these ketone bodies, so there's three of them. The one that circulates, really, that can be measured is beta-hydroxybutyrate or BHP. And this beta-hydroxybutyrate is then taken to other tissues. So that conversion happens in the liver, right? So then it's taken to all sorts of tissues, so to muscle, to the heart, to the brain. And at these tissues or at these location, the cells are able to use the ketone bodies to then produce that fuel that they need. So, in other words, it's actually a new fuel. 

And what is now being studied, so for the last five, six years, it's really, really apparent this beta-hydroxybutyrate, not only it is a fuel, but it is also what we call a signalling molecule. Something that is going to induce or activate pathways within a cell, that make the cell being able to detoxify better, to regenerate, to dampen inflammatory pathways. And so there is a definite molecular benefit for that.

Michelle: Yeah. It's really interesting to see that we've got this ancient kind of practice that has got some spiritual aspects and some very significant biological kind of aspects that we're now finding, I guess, the mechanism to explain that we've got these chemicals that we can make inside ourselves that actually activate pathways to help us detoxify, regenerate...

Veronique: That's right.

Michelle: ...and de-inflame a cell. When we look at the chronic disease crisis that we're in, let alone a viral crisis of a pandemic, but we've got another crisis which has been going on for 40 or 50 years is chronic disease issue. And we now know that it's due to subclinical inflammation.

Veronique: That's it.

Michelle: We've now got a way to understand that by doing something like a intermittent fasting, or periodic fasting, or this fasting-mimicking diet, that we may have a way in which to ameliorate this sub-acute chronic inflammation that is creating chaos really, across the world really. It's not just across western world.

Veronique: Yes, across the world, absolutely.

Michelle: It's across the world with westernised and highly processed diets, which is just fascinating.

Veronique: Absolutely. It's like an inborn mechanism in a way, it's part of the... And it's somehow, without crossing the line here, it's almost giving some credit to those more traditional ways of looking at healing that says fasting can make you feel better, fasting can heal yourself. Obviously, it's a big statement, but there may be some truth just because of that mechanism, for example.

Michelle: I think there's a lot of wisdom to be learnt from traditional societies. We can talk about my views, I guess, of their ability to kind of tune in and be present, and to really understand nuances so much more than we can in this fast-paced world as well.

Veronique: Yes. Yes.

Michelle: The other mechanism that I always think is really interesting is the role that I've read about intermittent fasting or time-restricted eating on really simple things like cholesterol and triglycerides. So do we have enough clinical evidence to say, we've all had in our clinics patients that we've tried, I guess, the Mediterranean diet, and their cholesterol still remains high, or the triglycerides still remain high. Or they aren't able, I'm thinking of one patient in particular, who we just couldn't get those triglycerides down. She was a Mediterranean woman so she was on a Mediterranean diet. Anyway, but when we started introducing fasting as an option for her, she did lose a significant amount of weight, and her cholesterol did return to a much better health.

Veronique: Level. Yeah.

Michelle: So have we got some research to show that this particular impact on time-restricted eating or periodic fasting, for example?

Veronique: You're talking about cholesterol, so if anything, I was reading a paper that is just about to get published, at the moment. And so that was in an older population, so we're talking about like 55, and over, shall we say, but the majority being over 65. And so, in this particular case, what they were looking is the extended fast. So the extended nightly fast, we're going to call it, so less than 10 hours, or 10 to 12, or more than 12 hours. 
And in this particular case, they found that it was not beneficial for their population because their HDL, so the high-density lipoprotein cholesterol, the one that we would...

Michelle: The good cholesterol.

Veronique: ...associate with good cholesterol, yes, so that was actually being lower in those people. And then the potassium was much higher and the chloride was lower, I think, from memory. 

Now, when I see a study like this, especially as a dietitian, I'm like, “What are the confounding factors?” And again, we need to remember that these studies, and any studies that are working under the gold standards of our evidence, so how we rate evidence is, obviously the highest level of evidence is a systematic review of randomised controlled trials where people are basically randomised to this or to that. Or if we're doing an intervention, or classified simply like in this particular case, there would have been a cross-sectional study where there's no intervention is just looking at a snapshot on a given point.

And so, we need to remember by doing that, we are completely neglecting individual response, right? So if I go back to the randomised control trials, by randomising randomly, basically a flick of a coin, we may have responded and non-responded in both groups. So, you put people on fasting and those alternating their fasting, for example, and you put the others on just not fasting, and see what happens. 

But what we completely neglecting here is the different genes, for example, in the apolipoprotein. So the protein that is characteristic to each lipoprotein, so either HDL, LDL, or VLDL. So there is now well recognised different variants in those apolipoproteins that then make somebody, for example, so it's another topic, we can have a conversation about it if you want to on nutritional genomics, and so on.

But I have in mind a very specific study where with a certain variant of the APOA1, I think it was, that people were doing worse on a Mediterranean diet, which was high in monounsaturated fatty acids was actually exacerbating their metabolic syndrome. So when we say Mediterranean diet, everybody should use extra virgin olive oil, and it's just the best, etc. But if we've got that genetic sort of print underneath that is slightly variant, so it's not about bad or good, it's about having a different variant, and it's common to have those variants, right? So it's about understanding, well, maybe that's not the best for me, it's maybe something else I need to... I'm not suggesting they should go for butter. But it's maybe not as much MUFA, monounsaturated fatty acids, perhaps less of it.

Michelle: So I think Valter Longo was talking about that when he was sort of saying we just simply don't have the breadth of research to say that everybody should fast, or that fasting for 12 hours is exactly what we need to do, or 16 hours is exactly the one. And we're probably never going to get that because of just the way that our research says. Like some people, it definitely suits. You've got these anecdotal 103-year-olds that says, "Yes, I've been fasting intermittently for the last 60 years and I'm so well." And so that's exactly what...everybody should be doing it. But everybody doesn't necessarily respond in the same way.

Veronique: No, not in the same way. And I think that really goes well with sort of the study I was saying before the IGF-1 looking at what is a good dose? So, I think that was from the Longo group. And I think they came up with something between 120...what is it? Is it nanogram per mls, is it? To 160, where there was the best association with health and less all-cause mortality, but too little and too high was no good.

So, if we look at that, if that is describing a spectrum of effect on many, many different... It was a huge study with, it was a meta-analysis, I should rephrase, where they looked at, yeah, 19 different studies, very large, looking at all-cause mortality, and correlating that with the IGF-1 levels.

So here we go. 30,000 individuals. So it could be that J curve or that window with the optimal...even 120 to 160 nanograms per mil is still quite a range. So it could be that the response is, again, individual, and depends on that genetic makeup to start with. 

We talk about personalised nutrition, so that's been going on for the last 10 years. Personalised nutrition is the future of nutrition, and so on. That supposes that we are able, in clinical practice, to not just test for five or six genes like some industry companies offer us, like, let's test new genes. And they give you like 10 or 15, maximum things to have variant on the enzyme that metabolises coffee, for example. But that is not enough to give proper prescription for dietary intake. You don't just do 10 to 15 genes, you need to do it on much, much larger.

And then we need to understand, what is the gene-to-gene interactions as well, and the gene-to-gene variant interactions? And on top of it, if you want to make it more confusing, and we have to now because we know the knowledge about the role of the microbiota. So we need to bring that layer as well because our microbiota profile tend to...we know in terms of carbohydrate, for example, make us respond differently to the amount of carbohydrate we're consuming and the type of carbohydrate. So it used to be low GI, high GI and that's the best way to monitor your blood sugar level. But the Israelian study, which I'm sure you're aware of, where they monitored a large population, they monitored with those every five minutes blood glucose monitor attached to...

Michelle: Right.

Veronique: Yeah. And then getting them to monitor everything, poo samples, and activities, sleep pattern, and so on. And get them to eat all sorts of different foods. And where we thought, well, you would think that they would have a low glycemic response, some had a high glycemic response and vice versa. And so, it throws out of the window all those one size fits all kind of recommendation that we come across.

Michelle: It does.

Veronique: But it doesn't mean we can't do anything, because until we've got this technology to be able to do one blood test, and we know everything, it's going to be a while, right? And until all clinicians are trained for that as well, it will be a while. Does it mean that we should do nothing in between? No, it doesn't mean that. It means that we can try to go for trial and error. And practising fasting in those circumstances, like alternating day or time-restricted eating, for example, that is not going to cause harm to the person, right, the evidence is there now. 

The fear was, for example, that it was going to reduce muscle mass, not just fat mass, and the evidence is now coming, no, it's fine. Muscle mass actually gets protected, for some reasons, when we do it this way. Not when you're doing 15 days of fasting, I'm talking about the alternator.

There is also the evidence coming through that people thought, “Oh, well, as soon as you can eat all what you want the next day, people are going to binge.” And no, the evidence is actually that people naturally tend to consume less on their normal eating day. Not because they're trying to, because there's no restriction, but just naturally they tend to do that.

Michelle: Surely this would shift our appetite genes, our leptin and our ghrelin...

Veronique: Yes, as well.

Michelle: ..as well. And we were talking about how it shifts insulin and insulin-like growth factor, those flow-on effects of appetite suppression and satiety, and even the mental aspects that we'll talk about.

Veronique: Well, the mental aspect is a key one indeed, yeah. So, we know, for example, again that ketone body, beta-hydroxybutyrate has such a depressing effect so that's another one.

Michelle: Right.

Veronique: And so, the mental effect of knowing that, "I just need to try this extreme restriction just for 3 weeks until I lose my 5 kilograms, and then I'll be fine.” Well, there's none of that. And I think that is the biggest breakthrough here when we're talking about weight loss and weight management, is to say, “Hey, there is a way of eating and behaving with food that is very different to what we've been taught so far.”

Michelle: Yeah, that's right.

Veronique: And the thing about we must eat three times a day because breakfast is the most important. Well, no, not for everybody. For everybody, it will be a lot easier to skip breakfast, and to extend that fast until midday. And knowing that this is okay to do so. And then I'm just eating until 8:00, and then I won't be eating anymore, and I know that tomorrow I can eat again. 

Because at the end of the day, any weight loss program can potentially make you lose weight. It's doable, right? But the problem is, it's not about...the big deal is not about losing the weight, the big deal is to then maintain that weight loss over time and be a healthy individual so that you have sufficient energy to be active, build muscle mass, and so on.

And for a number of people, they love that pattern because it's not as daunting as knowing that for the next six months, I'm just going to have this ridiculous amount of food every day, small amounts and when I go out, it's a problem, and all these kind of things. Well, here there's a lot of flexibility. You can just match it according to the schedule as well.

Michelle: Yeah, that's right. You can change the days as well. 

You know, I wanted to really kind of hone in, there's two other aspects of the fasting diet that I thought through our conversation prior to the one we're having today were super fascinating. And that is the effect on immunity. So there's a lot of research about fasting and the health of the white blood cells. I know you're particularly interested in this. Tell us a little bit about how fasting impacts immunity.

Veronique: Okay, so, this is also from the Valter Longo group actually, when they did it in the animal studies. And then they also, well, they've noticed it in the animal studies, and then they tested it in humans as a proof of concept through their fasting-mimicking diet. So it's good because... I'll bring back this in because I don't think I'm explaining that diet very well. 

But, anyway, so what they've noticed is that in the mass models, so through the practice of fasting, that a certain amount...so it was 30% of the white blood cells, were being destroyed in the process of deprived and of, well, not having substrate, being really under this situation of starvation. So that was inducing those genes of autophagy. Autophagy, meaning the cell cleaning itself. So, activating, sorry, expressing enzymes that basically eat away all the old organelles, but also, promoting apoptosis for cells that are too old, or not well functioning, or diseased. 

And that upon receding, through the stem cells, all those white blood cells were basically, or the production of white blood cells were upregulated to replace the ones that died. And through that principle, the hypothesis was that we know that through the ageing process, the autoimmune system becomes less functional and how we see sometimes autoimmune disease appearing in older age, and so on. And so the hypothesis was if we can, through those regular fasting periods through a lifetime, we're actually renewing our immune system on a regular basis, because we're allowing for the old to die out and then for promoting the upregulation of new white blood cells.

Michelle: It's almost similar to that beta-hydroxybutyrate. It activates those pathways for sort of detoxification and regeneration. And almost it's like working on that regulation of the inflammatory pathways, our immune system as well.

Veronique: Exactly.

Michelle: It's just fascinating that different mechanisms, but ultimately, the same sort of simplicity of like, okay, well, we need to clean out here, just like we could clean out our cupboards and clean our houses from time to time.

Veronique: Exactly. Yes, from time to time, yeah.

Michelle: Amazing.

Veronique: So that autophagy pathway, so autophagy being the process of cleaning the cell and so yes, upregulating detoxification enzymes, upregulating enzyme that basically digest all the old organelles in the cell. So this process is upregulated by beta-hydroxybutyrate. So you need the presence of the ketone body for that.

Then, how do you produce a ketone body? Well, it is many ways. You basically need to utilise fat stores as a source of energy. Actually, I should rephrase that. Ketone bodies are produced when fat is a principal source of energy. So whether it be either our own fat stores through energy restriction, we end up having to use our fat stores, like I explained before. Or be it through a diet where there's not as much carbohydrate but more of the fat.

So, this is how in that particular fasting-mimicking diet, it's not completely low carbohydrate like a ketogenic diet, it's just more reduced carbohydrate, but a bit more fat proportionally, right? But it's also, just a parenthesis, it's also how the ketogenic diet aims to explain certain benefits, or for example, all those supplements, those MCT oil, so medium-chain triglyceride. So, the idea with medium-chain triglycerides is that they are medium-chain, so they only have between 6 to 12 carbon long as opposed to 18, 20, 24.

And so, upon intake, so upon absorption in the intestinal tract, they're not taking...normally fat, after absorption, is transported through the lymphatic system through chylomicrons. But short-chain and medium-chain fatty acids are actually entering the bloodstream straightaway in the portal vein, bound to albumin, taken straightaway to the liver, and so being basically metabolised much more quicker.

And so, if we consume these medium-chain triglycerides...I mean, you've got to handle it to start with because it's digestible. But people when they take it as a supplement, the aim is to produce the ketone bodies because the liver is going to metabolise it. And if we consume quite a fair bit of it, some of it will be directed to produce those ketone bodies.

So anyway, back to the fasting-mimicking diet. So what they did then they tested that in humans to see whether they would also notice the benefits on those white blood cells. So the fasting-mimicking diet, like as I explained before, it's like a five-day protocol. And the idea is to do it for five days, then have one-month normal eating, another five days, one-month normal eating, and another five days. So do it three times. And they recommend three times once a year in that kind of pattern. 

So obviously, glucose was regulated, ketone bodies. IGF-1 was decreased after, so I'm looking at the thing here, after the third cycle even was very low. So they were measuring after each cycle of five days. And then the last measure was done after the end of the one month, eating normally, right? So five days one-month food normal eating, five days one-month normal eating, five days, and then normal eating and they were taking the last measurement through that last month. So, in other words, when people were back to normal eating.

Michelle: Yeah, back to normal, yeah.

Veronique: Yeah. And so the IGF-1 was still lower than baseline. The IGF-1 binding protein was a little bit upregulated. So the binding protein is the one that holds on to IGF-1. So IGF-1 cannot have that growth hormone effect because it stays bound to the protein in the blood.

And then looking at all sorts of body fat, body composition, and so on and CRP, so as a marker of inflammation, CRP was significantly decreased even on that very last, after one month. So then it was mesenchymal, the special cells, they're used as...stem cells as being then used for. So whether they've been used specifically for the white blood cells is not specified here, but that is what they used as a surrogate marker to show that. And so that was upregulated. Clearly, we can see that after the second cycle, and then still after one month of eating normal, yeah.

Michelle: Even just through this brief conversation to realise there is some significant changes in your underlying biochemistry by doing, whether it's time-restricted eating, intermittent fasting, the fasting-mimicking diet. Those kinds of interventions seemingly having some significant biochemistry, long-lasting effects on things like inflammation, immune cell, detoxification, regeneration, changing the way that our hormones work, changing our signalling. So, really, some fascinating areas of research. I mean, I don't think yet we know the fully long-term impacts on longevity but it seems that it does have a relationship in some ways, like even using things like body composition, balance, reflex response, issues like fatty liver disease, etc.

Veronique: And to keep in mind the ultimate studies that could demonstrate that, they're not doable from a human point of view because we're not rats, and we can't be under control. And there are so many other factors that influence our long-term health anyway. However, what you just mentioned here is these molecules that are responding to fasting, so molecules as in those genes and those transcription factors that are responding, that are being activated, or suppressed, all these kinds of pathways, that they are used as surrogate markers.

So, we are then inferring that if the inflammasome is suppressed, or the NLRP3 is suppressed through beta-hydroxybutyrate, then we know that systemic inflammation is more going to be dampened. And so, in the long term, when we know that systemic inflammation interferes with insulin signalling, or will be damaging the endothelium of the cardiovascular system, and so on. So we can infer that the insulin resistance will not likely take place, or less so, and that there is protection on the cardiovascular system.

So it's all about inferring, based on those observations that I made. And is it good enough? Is it not good enough? Well, we don't know. But you're right, we'll never know for sure. That's for sure.

Michelle: Veronique, I just want to thank you so much for joining us today to discuss all these facets of intermittent fasting. It just has what feels to me so much potential to affect our health in so many different ways, from gut health, to metabolic health, to immune health, to the effects on brain, the nervous system, and the list goes on. And I think even practitioners who are well-versed in this area will have found some clinical pearls to implement in their practices after today's episode. So thank you so much.

Veronique: I don't know if we covered everything that we should have but I'm happy to come back if necessary.

Michelle: Thank you so much.

Veronique: Because you're right. I just pick up on the word gut health. So there is often a question, “Oh, what happens to the gut microbiota when you're fasting?” right? So the evidence shows that actually, the pathogenic bacteria, there is a shift, shall we say, into the composition of the bacteria where the pathogenic bacteria don't have the substrate, so they don't handle that period of fasting, and so they tend to be diminishing.
And then when we talk about intermittent fasting, so the alternation whatever you do, whether it's hourly, or week, whatever, or per day, it's the idea of fasting and feasting. And so that switch is, I didn't say that, but that switch is what has been really identified as being the beneficial aspect because compared to permanent calorie restriction, which we talked about at the start, the permanent calorie restriction doesn't have that switch, okay, it's permanent, permanent.

And there is the theory that there is some adaptation taking place and that the body then learns to do with what little it has. Over a long time, does it really create the same benefit as the alternating? So, when we talk about brain health, and shown in the animal data, there was really brain-derived neural growth factor that is promoted also by beta-hydroxybutyrate...

Michelle: The fasting/feasting. Fantastic.

Veronique: ...by the way. And so that means protecting, well, having new neural cells but also protecting the neurons. And so that switch was not so much when it was constant calorie restriction, but a lot more when there was that fasting/feasting cycle.

Michelle: Yeah, fantastic.

Veronique: So that's something to think about. Anyway, there we go.

Michelle: Yeah. Amazing.

Veronique: But it's a pleasure and anytime, Michelle, if we want to talk again, I'm very happy to.

Michelle: Thanks, everyone, for listening today. Don't forget that you can find all the show notes, transcripts, and other resources from today's episode on the FX Medicine website. I'm Dr. Michelle Woolhouse, and thanks for joining us. We'll see you next time.

About Dr. Veronique Chachay

Veronique Chachay is the coordinator and lecturer of the nutrition science courses in the undergraduate nutrition major Programs, and the applied food science for dietetics course in the Master on Dietetics Studies, in the School of Human Movement and Nutrition Sciences. Her nutrition science expertise is applied in a wide range of research fields, including regulation of energy expenditure via brown fat activation, dietary factors modulating alpha diversity in inflammatory bowel disease, and energy intake meeting requirements in motor neuron disease.


The information provided on FX Medicine is for educational and informational purposes only. The information provided on this site is not, nor is it intended to be, a substitute for professional advice or care. Please seek the advice of a qualified health care professional in the event something you have read here raises questions or concerns regarding your health.

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