Dr. Patrick: Welcome back to another episode of the "FoundMyFitness" podcast. I'm sitting here with Dr. Mark Mattson, who is an adjunct professor of neuroscience at Johns Hopkins University.

Mark, I'm so glad to have you here today. This is a long overdue podcast. I've been a huge fan of your research. As a scientist, you have made decades of contributions to our collective understanding of the benefits of biological stress and the supporting evolutionary theory of why almost all organisms actually need stress to thrive.

There's a variety of topics that I know you to be an expert on, that I'm really excited to talk about with you today, including your understanding the place of plant phytochemicals and our genetic responses to them from a practical and theoretical perspective, your take on how the decades of caloric restriction in animals has panned out, and our attempts to translate that, those research findings, to humans, as well as intermittent fasting as a metabolic switch that has implications for overall health and particularly for brain health.

So perhaps to kick things off today, maybe we could start or maybe you could explain why humans need some biological stress. And how maybe modern-day society has made that difficult to achieve.

Dr. Mattson: Yeah, during evolution, organisms evolved in environments that were very stressful. Even from the simplest of microorganisms like bacteria, where they had to be able to tolerate changes in levels of salinity in the water, exposure to metals that are potentially toxic, like iron and selenium and zinc. And they evolved ways not only that they could resist the toxic effects of these exposures but actually benefit from them.

So, for example, in the case of iron and selenium, we know that now that we need iron and selenium for proper health. But high levels of iron and selenium are actually toxic. And so, cells evolve mechanisms where they actually incorporate iron into proteins and use the iron adaptively in ways that help them cope with stress. In the case of selenium, for example, several of the antioxidant enzymes that is their proteins in our cells that are able to remove free radicals, those proteins themselves, the antioxidant enzymes, have selenium incorporated into them. So, that's one example.

And then, as we move up the evolutionary tree into multicellular organisms and animals, they evolved in stressful environments. Two of the major stresses are actually food scarcity and predation and competition with other organisms. So, individuals that were able to best handle these kinds of stressors, and certainly food scarcity is a stressor and animals will starve to death if they don't get food, but that stress of the food scarcity is actually a motivating factor and nervous systems evolved to overcome food scarcity in many different ways.

So, that is some examples of... And then, the case of exercise, individuals whose bodies function well in a food deprived state and environments where there's potential for predation, who are those that survived and pass their genes on. So, whatever it is those genes did that helped them perform physically well in a, you know, food deprived state had a survival advantage.

Dr. Patrick: So, we, modern day, fast forward, live in a much different world where we have access to food 24 hours a day, all day, all night. We don't, you know, necessarily need to exercise to get our food either. We can just, you know, get in the car and drive somewhere. And we can even have our groceries delivered, you know, to our door. So, you've talked a lot about how this constant access to food and not having these periods of food scarcity, where people are not eating, may have detrimental consequences on overall health.

Dr. Mattson: Yes. One way to look at that is that when we have food available all the time and when we don't have the need to exercise to get through life, our cells become complacent. And they do not maintain their ability to cope with the kinds of stressors that cause disease. Oxidative stress is one key example, inflammation.

So, a good example is muscle cells and exercise. During the exercise, it's a major stress on the cells in the muscles. There's a big increase in free radical production. Cells are electrically active, the muscle cells. So, if they contract, so there's ion fluxes that have to be dealt with.

However, having been exposed to that stress during the exercise, the cells activate gene programs that help them cope with stress and become stronger and more resilient. So, for example, exercise increases antioxidant defenses in muscle cells. It enhances the ability of the muscle cells to clear out damaged proteins, dysfunctional organelles, such as mitochondria, which are the energy-producing organelle in the cell. And as well, there are proteins that are initially called heat shock proteins, but their function is to protect other proteins from being damaged.

So, all of these beneficial mechanisms are stimulated by exercise. So, in a person who's sedentary, they have reduced intrinsic antioxidant defenses. They have accumulation of molecular garbage in their cells, accumulation of mitochondria that aren't functioning well, and accumulation of abnormal proteins.

And this is also true in brain cells, which is the main thing I studied, nerve cells in the brain. There is evidence that's emerging, some from my labs, some from others, that physical exercise, mental exercise, what you and I are doing now, Rhonda, keeping our mind intellectually engaged, we're right now exercising our nerve cells, they're more electrically active. There's more free radicals being produced in our brain cells right now than there would be if we weren't intellectually engaged.

We're right now exercising our nerve cells. They're more electrically active. There's more free radicals being produced in our brain cells right now than there would be if we weren't intellectually engaged. But it's not only okay, it's a good thing because at the same time the cells are beefing up their antioxidant defenses, bolstering their mitochondrial function. In fact, we discovered that... And this was originally described by exercise physiologist and it makes sense. When you exercise regularly, your muscles get bigger, and in the case of endurance muscles, better endurance. And associated with that, there's an increased number of mitochondria, healthy mitochondria, in each muscle cell.

So, that makes sense. The cells then are more able to generate the ATP to support their function. We find a similar thing in nerve cells. And most of this is from animal studies and so we're extrapolating to humans. But in animals, we can look more directly at the brain in kind of an intrusive way. And we find that running-wheel exercise, what we call environmental enrichment where we have the animals in cages where they have essentially like playground-type environment where they can maintain their mind more active.

And under those conditions, exercise, mental exercise, there's an increase in the number of mitochondria in nerve cells. And associated with that, at least in some brain regions, there can even be an increase in the number of synapses between nerve cells, the connections between the nerve cells.

Yeah, so, that's kind of the general thinking that it's important to keep stressing in a good way and an evolutionarily conserved way that is, by stressors that have been normally encountered through millions of years. These transient, short-term, mild, energetic stresses, either the energetic stress of expending a lot of energy during exercise or the more kind of subtle energetic stress of depriving cells of energy for some extended time period.

And we can, I'm sure, we're going to talk about what's going on in terms of signaling pathways and, for example, ketones, which are elevated during fasting and during sustained exercise. And you mentioned you talked to Eric Verdin about his work with enzymes called deacetylases. And his work showing that ketones have signaling functions, in fact, gene expression through modulating these enzymes called deacetylases. So, fasting does the same thing.

Dr. Patrick: Yeah, maybe we can kind of jump into that. So, you know, there's obviously different types of fasting. There's intermittent fasting, time-restricted eating, or even prolonged fasting. Do you want to kind of just maybe briefly describe some of those types of fasting?

Dr. Mattson: Sure. The key thing for your viewers to understand is that when they see intermittent fasting, intermittent fasting is an eating pattern. It's not a diet. Oftentimes, in kind of the lay press and so on, intermittent fasting will be lumped in as a diet. But it's not a diet. It's an eating pattern.

A diet is what you eat and how much you eat. Intermittent fasting is an eating pattern that includes intermittent periods of not eating, sufficient to deplete the glucose stores in the liver and cause a switch to the use of fat from your fat cells and the ketones produced from those fat cells. Right.

So if a person eats breakfast, lunch, and dinner, and doesn't get much exercise, every time they eat they're replenishing the glucose stores in the liver and they may never tap in to the fat stores and, therefore, their ketone levels will remain low because the metabolic switch hasn't occurred. It typically takes at least 10 hours to deplete the glucose in the liver.

So if a person eats breakfast, lunch, and dinner, and then has a snack around 8:00 or 9:00, you know, they may get up and eat breakfast and have not depleted the energy in their liver and have not switched to using fat. So, with intermittent fasting, the approaches that have been used in experimental studies, both in animals and in humans, are as follows:

One, is called daily time-restricted eating, where the time window that one eats is compressed into, say, a six to eight-hour time period. So, that means the person would be fasting for 16 to 18 hours, which is sufficient time for this metabolic switch to have occurred. And scientists think, based on a lot of data, that this metabolic switching is important for health benefits of intermittent fasting, but also maybe even of exercise in some instances. So, the daily time-restricted eating is one approach that can result in daily metabolic switching, daily elevation in ketones.

So, for example, if a person skips breakfast, eats all their food between noon and 6 pm. And if they were to measure their ketones, they'll find that in the morning, they'll start to be elevated. Okay. If they wake up and go for a run in the morning, they're already at or in, the metabolic switch has already occurred. So, they can actually enhance the effect of the fasting in terms of elevation of ketones.

And we think, in terms of beneficial effects on the brain, the cardiovascular system, perhaps even physical performance, which is an area that is being studied now with intermittent fasting, there's very strong evidence that compared to three meals a day plus snacks, intermittent fasting is beneficial for the heart, and the brain, glucose regulation. But it's not completely clear yet whether it's beneficial for athletic performance. There's a lot of interest in that.

Okay. So, let's get back to intermittent fasting eating patterns. Another intermittent fasting eating pattern is one that's now called 5:2 intermittent fasting. And this is where the individual, 2 days a week, they'll only eat one moderate sized meal of, say, 600 calories in those 2 days, then the other 5 days they eat normally.

And so, in that case, 5:2 intermittent fasting, the person will have the metabolic switch occurring two days a week, but not the other five. In fact, this 5:2 intermittent fasting, in a sense, kind of triggered the popularization of intermittent fasting. And I'll just take a few minutes to kind of give a historical perspective.

We'd done a lot of work in the 1990s and early 2000s showing that intermittent fasting was beneficial for the brains of animals. And we can talk about that, some details on that. And then, we'd also publish some work on intermittent fasting reducing resting heart rate and blood pressure and having anti-inflammatory effects.

And then, I was approached by a number of clinical investigators. One was Jim Johnson, who worked with asthma patients. And, in 2007, we published a small study where we found that... These were overweight asthma patients, and we put them on a really rigorous regimen where every other day, they only ate 400 calories. So, that's not something that can be maintained as a lifestyle because it's very hard to maintain your body weight with that.

But in these overweight asthma patients, over two months, it had profound beneficial effects in improving their symptoms, their air flow in their lungs. My lab, we measured indicators of oxidative stress and inflammation in the blood, which went down not right away but between two and four weeks of initiating that every-other-day metabolic switching regimen.

Okay. So, we published that study. Then, I was approached by Michelle Harvie, who was in England, and works with women at risk for breast cancer because they're overweight and they also have a family history. And she came to my lab, she'd seen our work in animals. And there's also some work in animals suggesting that fasting can be beneficial in suppressing cancer growth.

So, anyway, Michelle and I designed a study where we took these 100 women, and we randomly assigned them to either what's now called 5:2 intermittent fasting or we had a control group where we had them eat breakfast, lunch and dinner, but each meal had 25% fewer calories than they normally take in.

And because we had done a calculation that the long-term calorie intake would be similar in the two groups, the group eating 600 calories two days a week versus the group eating three meals every day but reducing their calorie intake.

Over six months, both groups of women lost about 8% of their initial body weight. And both groups had improvements in glucose regulation and other health indicators. But the women on 5:2 intermittent fasting had a greater improvement in insulin sensitivity and lost more belly fat compared to the group that was counting calories, if you will, every meal.

Then what happened is a producer at the BBC, Michael Mosley, picked up on that study when we published it in 2010 or '11. And he did a documentary for the BBC, which aired in 2013 or '14. He came to my lab, and Valter Longo's lab, and Krista Varady's lab. So, that aired on the BBC.

And then, people in the UK got interested in intermittent fasting. And then, all of a sudden, like, there's all sorts of things showing up on the internet on intermittent fasting. So, it used to be, before the work in the early 2000s, that if you if you google intermittent fasting, the top hits would actually be scientific papers. Now, if you google intermittent fasting, it's just like a bunch of random people who have some angle on it or so on.

But the good thing about that is there's now a lot of interest from mainstream medicine. And I wrote an article, well, the end of 2019, together with a former postdoc of mine, Rafael de Cabo, a review article on intermittent fasting for "The New England Journal of Medicine."

And the editors invited us to write the article for two reasons. One, there had accumulated a sufficient number of human studies of intermittent fasting, particularly, in overweight people to merit, you know, coverage of it.

But the second reason was that many physicians are being approached by patients, asking the physicians about intermittent fasting. And in some cases, maybe many cases, the physicians really don't know much about it. They don't know that there's actually quite a bit of science behind it, both basic and clinical. And from a practical standpoint, they don't know how to prescribe intermittent fasting to a patient, and then follow up with them to try to help them switch their eating pattern.

It turns out that in the studies, the ones I mentioned, particularly the ones we did with Michelle Harvie in England but also other clinical people I've talked to, people, if they can get through the first couple of weeks of switching their eating pattern, say two weeks to a month, they will no longer be hungry and irritable and maybe can't concentrate well during the time period that they've previously been eating.

So, for example, if they decide, "Okay, I'm going to start skipping breakfast." For the first number of days, even a week or so, they're going to be very hungry, irritable in the morning. And the reason is, it takes time for your whole system, everything, to adapt to the new eating pattern. And a lot of that has to do with changes in the brain and the neuroendocrine systems that control hunger and satiety. And we could talk about that. That's a whole another podcast.

But one thing we found in pretty much all of our animal studies where we look at the brains, it takes a couple of weeks before we see measurable changes in whatever upregulation of antioxidant enzyme levels, increased number of mitochondria in neurons, increased number of synapses, improvements in learning and memory. Okay, so I'm going to stop talking now, Rhonda, and let you ask some more questions.

Dr. Patrick: Oh, absolutely, I have so many questions. You've brought up so many important and interesting points. But just to kind of speak to what you were just talking about, this sort of adaptation to perhaps starting an intermittent fasting sort of regimen and how you adapt to it. And a lot of that has to also do with some of the neuroendocrine changes in the satiety and hunger hormones, I guess, you know, ghrelin and leptin, you know, changing that. Is that somehow linked to the production of ketones and this metabolic switching and it happening easier or...?

Dr. Mattson: Yes, there is a link with ketones. And it's a very interesting one. In hindsight, it goes back to the first studies we published with intermittent fasting, which was in rats. This was the one when I was at the University of Kentucky in Lexington.

So, what we did is we took rats and we randomly assigned them to either every other day fasting. And the way that's done is one day you go in to the animal's cage. You remove their food completely. The next day, you go in. You put back food, you know, as much or more than they want to eat. Then the next day, you go back in. You remove all their food.

So they're going 24 hours no food, 24 hours food, 24 hours no food. Don Ingram, who's a colleague of mine when I was at the NIA, had shown that every-other-day fasting can extend lifespan up to 50% in rats, when it's initiated when they're young adults.

So, we took rats and had them either intermittent fasting or not. And we did a study where we did one week of intermittent fasting, two weeks, and then three months. And then, we have these models where we can cause damage to nerve cells and brain regions, where nerve cells degenerate in Alzheimer's or Parkinson's or with epileptic seizures.

And we found that the most striking effect was in the model of epileptic seizures where we administer what's called an excitotoxin. It's a very interesting story. It's a naturally occurring chemical that's produced in algae. And it accumulates very high levels during red tide seasons where it's dry.

And so, there was these incidents, an incident in Canada where these people who had eaten shellfish at a restaurant develop memory loss, amnesia. And it turns out that the scientists trace this back first to the shellfish. They'd all eaten the shellfish. And then, the shellfish had high levels of this excitotoxin, it's called domoic acid. And they had high levels because they are eating the algae that had high levels.

So, as you go up the food chain, toxins accumulate. Anyway, to make a long story short, the intermittent fasting protected against epileptic seizures and protected the neurons from being excited to death. And we now know that there's a role for ketones in protecting nerve cells against epileptic seizures. In fact, clinicians, neurologists in some cases, still prescribe ketogenic diets for patients with epilepsy that don't respond well to the antiepileptic drugs. Okay. Go ahead.

Dr. Patrick: Well, I was gonna ask about whether or not you thought this metabolic switching, which, you're talking about metabolism switching from glucose metabolism to metabolizing fatty acids that are released from adipose tissue and the liver that produces the ketone bodies, such as beta-hydroxybutyrate.

If that is something that can occur on a ketogenic diet, what are your thoughts on the benefits of this metabolic switching from intermittent fasting, in terms of...? Can you get similar benefits by just doing a ketogenic diet? Are there differences between the intermittent fasting and the ketogenic diet?

Dr. Mattson: My opinion is that you can get some but not all the benefits of intermittent fasting with a ketogenic diet. Early on, I talked about how increased activity in neural networks is good for neurons. And with intermittent fasting, there is evidence that during the fasting, there's actually some increase based on some neural networks and activity in neural networks.

I guess that kind of makes sense from an evolutionary perspective that if you're an animal, and you haven't been able to get food for a long time, your brain cells better be active. Your brain better be alert. You better be motivated. And you better be thinking cognitively, "Where do I go to find a prey animal or to find fruit trees?" you know, based on that.

You know, so the ketogenic diet will not cause that increase in neural network activity. So, you know, the ketogenic diet, one thing it seems to do is enhance activity of what's called an inhibitory neurotransmitter called GABA. So, I'm going to give some like Neuroscience 101.

Let me ask you, Rhonda. I ask this question to people just out of curiosity. And I'm actually writing a book on this, a second. Name a neurotransmitter besides GABA.

Dr. Patrick: Okay. Just one? Dopamine, serotonin, glutamate.

Dr. Mattson: Okay. The third one you named, glutamate, is the most important neurotransmitter. A lot of people have heard of dopamine and serotonin because dopamine links with addiction and serotonin links with depression. But it turns out that least 90% of the nerve cells in your brain deploy glutamate as neurotransmitter. And those neurons are distributed in every brain region: throughout the cerebral cortex, other brain regions, hippocampus, brainstem, basal ganglia.

Whereas, the neurons that produce dopamine and serotonin are few in number and they're located in discrete regions in the brainstem. They're important, but the only way those neurotransmitters affect behavior is by acting on glutamatergic neurons.

Okay. And then, the main inhibitory neurotransmitter is GABA. And neurons that deploy GABA are distributed throughout the brain. And their main role is to kind of control excitability of glutamatergic neurons, you know, throughout the brain. So, if you were to block the function of GABA-producing neurons, your brain circuits would fry themselves.

On the other hand, if you have too much GABA, then it can quiet down the glutamatergic activity so much that your brain doesn't function well. So, an example of that is drugs called benzodiazepines, like Valium. They activate GABA receptor. So, they quiet down the glutamatergic neurons. But if you take too much Valium... If you were an animal in the wild, and you hadn't gotten food in a long time, you don't want to take Valium. You want your nerve cell circuits to function.

Anyway, so, the intermittent fasting is similar to intermittent exercise. You get this activation neural networks. One of the main effects that I haven't even talked about yet in the brain of exercise, intermittent fasting, and intellectual engagement is to increase the production of proteins that are called nerve cell growth factors or neurotrophic factors.

One of those proteins that's produced in response to activity in neural networks and in response to the metabolic stresses of exercise and fasting, that neurotrophic factor is called BDNF, brain-derived neurotrophic factor. It is the most heavily studied such nerve cell growth factor in the brain. And it is essential for learning and memory.

You can't knock out the BDNF gene in mice. They'll die. You can reduce levels genetically and then that will impair learning and memory. Actually, interestingly, if you reduce levels of BDNF by about 50%, the animals will overeat and become obese. So, BDNF is also involved in regulating appetite.

Okay. So, let's see, where were we. Right. So, ketogenic diet, it will, definitely, your neurons will switch from using glucose to ketones. We think that's good because, essentially, ketones is a more efficient energy source per cell than glucose. And there is actually less free radicals generated in the burning, if you will, burning ketones compared to glucose.

And then, the ketones have these signaling functions affecting gene expression that glucose doesn't have. So, I guess two things. The ketones are good energy source for neurons and they have signaling functions. But those signaling functions are more limited than are activated by exercise or intermittent fasting or keeping your brain active.

Dr. Patrick: So, you mentioned about, you know, the different types of metabolic stress, whether that be exercise or intermittent fasting, and how there's an increase in BDNF in the brain in animal studies. And I kind of want to go back to seeing what your thoughts are in translating these animal studies to humans. Obviously, animals have very different metabolic rates than humans. For example, if you were to fast a rodent for 48 hours, they lose 20% of their body weight, whereas a human would only lose 2% of their body weight from a 48-hour fast.

But I also want to ask you, have you seen additive effects in your studies on animals? Or have you looked at additive effects of animals that are constantly exercising or routinely, you know, so a physically active animal with their little exercise wheel. But you also expose them to these periods of food scarcity, intermittent fasting. Are the two combined better than just one type of metabolic stress?

Dr. Mattson: There is evidence that we've obtained that combination of exercise and intermittent fasting can be better. I'll give you two examples that we published. One was, we published a long time ago, a former graduate student Alexis Stranahan. And it's actually relatively simple, the studies of design.

But we had normal mice and we had mice that have type 2 diabetes. And they have type 2 diabetes because they're genetically engineered to have a defective leptin receptor. Leptin is a hormone that when you eat a meal and your stomach gets full, it's released into the blood. And it travels up to your brain, a region called the hypothalamus. And, essentially, it tells you you're full, stop eating.

So, these diabetic mice, leptin-receptor mutant mice, they don't get the stop-eating signal. So, they're presumably always hungry. Okay. So, then what Alexis did is she divided these normal mice and diabetic mice into four groups. The normal laboratory conditions, which is they're sedentary in relatively small cages, no running wheels. And then, they are fed ad libitum. And they can eat as much as they want every day.

And she had a third group that were fed ad libitum. And they had running wheels in the cages. And then, the fourth group... What a minute, what did I say? Yeah, sorry. I figured what to say. So, she had ad libitum/sedentary, ad libitum/running wheels. And then, she had every-other-day fasting/ sedentary, every-other-day fasting/ running wheels.

And she let them go for three months. And then, she took out their brains. And there's a brain region called the hippocampus, which is in many respects the most intensively studied brain region for several reasons.

One, it's critical for learning and memory. It's kind of all the information from our eyes, our ears, our other senses, funnels into the hippocampus. And that's where the initial, if you will, associations between a sight and sound. You know, a bear jumping out on the trail and growling, you hear its growl. The next time you go walking on the trail, you hear a bear growl, you don't have to see it to have a mental image of a bear. So, the hippocampus is critical for these initial associations.

And then, a second reason the hippocampus is heavily studied is it's a focus of dysfunction and pathology in Alzheimer's disease, epileptic seizures, even stroke in some instances.

And the third reason is, it's easy to study because the circuitry is actually relatively simple compared to the cortex. So, we can put electrodes in the glutamatergic neurons here. And we stimulate glutamatergic neurons down here, and we can record that, we can activate a GABAergic neuron and record reduction in activity.

So, anyway, what Alexis found was that... First, what she did is she measured the number of synapses along the dendrites, the part of the neuron that receives information coming from another neuron. So, she simply counted. Not simply, it actually takes a lot of work, but counted synapses and found two things.

One, the diabetic mice, regardless of whether they were intermittent fasting or had running wheels in their cages, had smaller number of synapses than did the normal mice. And then, she found that the running-wheel exercise and the intermittent fasting increase the number of synapses. And the combination of intermittent fasting plus running wheel got a further increase in the number of synapses. Okay. So, that suggests that intermittent fasting can enhance the effects of running on increasing number of synapses between neurons.

And then, she took the other hippocampus from the brain and measured BDNF levels. I mentioned BDNF is important for learning and memory. It's actually also important for formation of new synapses. And she found that the intermittent fasting and the exercise, each alone, increased BDNF levels and the combination got a further boost to BDNF levels.

But she did not find that in the diabetic mice, synapse levels came up to the level of normal mice. You know, so there was some beneficial effect, but you couldn't get it back like they had never been diabetic. Okay. So, that's one example.

Then the second example has to do with endurance exercise. And this work was done by former postdoc Krisztina Marosi, and a postdoc fellow Keelin. I'm actually looking at it. Can you see this?

Dr. Patrick: Yes.

Dr. Mattson: Can you see the whole picture?

Dr. Patrick: I can, yeah.

Dr. Mattson: So, this is about a running group from the lab about 2016 or something. Anyway, so the work I'm going to talk about now is done by Keelin Moehl and Krisztina Marosi. Krisztina is not on here. She wasn't fast enough to make our 18.

So, what they did is they took mice and they had four groups, these are all normal mice, ad libitum/sedentary, ad libitum/daily treadmill training for 45 minutes every day for 2 months. Then she had a group every-other-day fasting/ no treadmill training. And then, the final group was daily treadmill training while they're on every-other-day fasting for two months.

And then, at the end of the two months, they did a maximum endurance test. Sorry. So, 45 minutes a day on the treadmill, and then every week, they increased either the speed of the treadmill or the incline. So, they're actually, you know, increasing the work over the two months.

So, they did maximum endurance and test, how long can the mouse stay on the test treadmill without giving up. And they found that, as you'd expect, the animals that have not done treadmill training had much poorer endurance than the animals that did treadmill training, regardless of whether they were on intermittent fasting or not.

But there was a statistically significantly better endurance in the mice that were on intermittent fasting during the two months of the treadmill training. And they measured ketones, which were elevated with intermittent fasting, and the exercise increased the ketone levels much more, almost twice as much, when you take their blood after the end of the treadmill training.

And then, they got a lot of analysis of the blood. They did something called metabolomics. And then, they took out muscle cells from the soleus muscle, which is an endurance muscle in the leg of the mice. And they did some measurements that suggested that intermittent fasting and the exercise increased the number of mitochondria in the muscle cells. And that the increase was the most on the other combination of intermittent fasting and the exercise.

Dr. Patrick: Very cool. I remember reading a meta-analysis a few years back looking at human studies, people that exercised either fasted or in a fed state, which, unfortunately, there's a bit of a confounder because if you look at the dietary composition of most of the food these athletes were eating before exercising, they're very high in carbohydrates and oftentimes even, you know, refined carbohydrate, where you have like some toast and jam or something like that.

But regardless, there was a variety of metabolic adaptations that, for example, mitochondrial fatty acid oxidation was enhanced, mitochondrial biogenesis. These things were somewhat blunted in people that exercised in a fed state. Whereas, if they had done it in a fasted state, these adaptations were occurring even throughout the day when the people were not exercising.

And so, you know, there were also some effects on... If people had exercised, fasted, but they were doing a very, very long sort of endurance-training type of activity, then there are some performance issues, weren't as good as if they had exercise while in the fed state. But, you know, since reading that meta-analysis, I've tried for the most part... You know, typically, I'll do a, you know, a 3-mile run or I'll get on my Peloton and do a 20-minute high-intensity, you know, Tabata or something, training. And I try, I do it fasted.

And I definitely have adapted to it over time. But I do it because I'm thinking to myself, "Well, I want those mitochondrial adaptations." So, it's really interesting that your experiment that you mentioned.

Dr. Mattson: Yeah, one point that you just mentioned is important. And this can occasionally get lost as these conversations go on. And that is, it's the switching back and forth intermittently, is important.

For example, in the muscle cells with exercise, the number of mitochondria doesn't increase during the exercise, it increases during the rest period. But if you had never exercised, you would have never gotten a stimulus that triggers what's called mitochondrial biogenesis, the increase the number of mitochondria.

So, the switching back and forth between the metabolic challenge, whether it's fasting or exercise, and the recovery, well, you know, eating, resting, sleeping, you know. And there's definitely a limit to all of this. Obviously, with fasting, starvation. You know, if you start to lose muscle mass, then you're fasting too much. And, as you mentioned, you can overdo it with exercise too and sometimes get diminishing returns. So, it's important to have these recovery periods.

Dr. Patrick: You've talked about the importance of what are called the refeeding phase. Both, you know, you and Dr. Valter Longo have discussed this in publications and Valter on the podcast previously. Like you mentioned, it's a point that a lot of, you know, people don't focus on that recovery period.

For the refeeding period, you know, how important is that? And how long is that window? Do we know? You know, is it like a week? Is it just a couple of days?

Dr. Mattson: Well, with these intermittent fasting eating patterns I'm talking about are kind of trivial from an evolutionary perspective. That is limiting time window you eat six to eight hours each day. You know, the remaining, whatever, 16 to 18 hours is more than sufficient to recover. If you fasted or if you tried to do fasting for five days, one day recovery, fast another five days, one day recovery, and keep that up. It won't be long before you're going to start to have problems.

So, it's the same with exercise. You know, my understanding is there's quite a few ultra marathoners who, when they get in their 50s and 60s started to have a lot of problems. So, you know, there could be some long-term consequences of overdoing it, whether it's with fasting or exercise. And what you and I are talking about today is well within any bounds of even getting close to having adverse effects and having to worry about, "Am I recovering or not?"

Dr. Patrick: But perhaps more of someone doing more of a prolonged fast might have to consider, you know, the refeeding and how important, I know...

Dr. Mattson: In Europe, for example, in Germany, there are clinics where people go in for a couple of weeks and they'll fast for 10 days to 2 weeks and they're, you know, supervised. It's kind of like a resort, actually, you know. And everybody else there is doing the same thing.

And they're collecting a lot of data and starting to publish. They see a lot of improvements in health indicators even within that, you know, two-week fasting period. But they don't have really good data on long-term effects. And in talking to the people who run these centers, oftentimes, a person will only do this once a year.

And so, they may be overweight and, you know, have insulin resistance. And they'll go in, and they'll show some, even during that short period, a little bit of improvement in their insulin sensitivity. But then, they'll come back a year later. And they're back where they were or worse.

So, you know, one question then is if someone wants to fast for longer time periods, what frequency would be reasonable for long-term health? You've interviewed Valter Longo before, and he's done a lot of work with this eating pattern where the subjects, five consecutive days a month, they'll eat only one moderate-sized meal. And then, the other days of the month, eat normally. And that seems to be beneficial.

The key thing is, you know, how long can people maintain this in their lifestyle, incorporate it in their lifestyle? Daily time-restricted eating, for example, seems to be easy for a lot of people to do for years and years and years. You know, maybe five days a month, that's perhaps... But at some point, you have to think about it that way, looking kind of a long view of what can you...?

And then, another thing is, what about...? You know, so daily time-restricted eating, if you skip breakfast, then you can still have lunch with people at work and dinner with people. Where, if you're doing something else, maybe, like Valter's maybe five days a month, you're not going to be able to... You may go out to dinner with somebody and say, "Well, I can't eat anything today." Yeah.

Dr. Patrick: Right. It's a little bit challenging.

Dr. Mattson: One thing I want to get into, and you mentioned early, very early on in the introduction, I think we're getting there, is diet composition. Well, there's good evidence, yes, eating vegetables and fruit is good for health. And why is that?

And the emerging evidence that has kind of turned that "load up on antioxidant" idea on its head. And so, yeah, so during evolution, we're omnivores. And the same would be true with other animals that are herbivores. It is advantageous to be able to eat plant materials: fruits, nuts, roots, leaves, because they have energy.

However, it's not necessarily advantageous to the plants that we eat them. In fact, it's generally not. And we know that in the case of insects, but it's also true with herbivores and so on.

So, in most plants, the most vital parts of the plants, in terms of propagation of the species, if you already eat those, they have a bitter taste. So, for example, the skin of grapes or apples and, you know, broccoli, the seed-producing part of the broccoli and so on, they have a bitter taste. And so, the thinking is that it was to our advantage to be able to eat these even though they have a bitter taste and have these naturally occurring pesticides. It's what they are. The plants are producing their own pesticides.

So, in fact, one of the reasons plants produce so many of the chemicals is that many of those chemicals, their function is to dissuade insects and other organisms from eating them. That's their main function. Okay. So we co-evolved with these plants. And as we co-evolved with them, we evolved several ways to protect ourselves from overdosing on these pesticides that the plants normally produce.

So, one way is a bitter taste. The second way is vomiting. A third way, which is interesting from a human environmental health standpoint, is we have evolved enzymes in our liver that rapidly remove these potentially toxic chemicals when we eat them. They're called cytochrome P450s. Okay. But the fourth way is that the individual cells in our body have evolved to respond to some of these chemicals by, for example, enhancing their antioxidant defenses or enhancing their ability to even extrude the chemicals.

So, I'll give you a few specific examples. I mentioned broccoli. Many of your viewers probably, if they're into health, they've probably heard of sulforaphane, which is a chemical that's in broccoli. And there's quite a bit of evidence that it can be good for health. And one of the ways is it activates antioxidant defenses in our cells.

So, it's similar to exercise and fasting, which are stressors. The stress of this chemical that's in the broccoli that we consume. The stressor is the chemical. It's activating antioxidant defenses. Another example is curcumin, which is in turmeric root, which in Indian food is very common. And it also activates antioxidant defenses.

The most commonly consumed plant toxin by your viewers, very likely, is caffeine. So, if you were to take powdered, if you were to take concentrated caffeine and put it on your tongue, it has extremely bitter taste. It's possible to overdose and die from caffeine. And there have been some documented cases of actually people essentially eating caffeine powder.

If you take tea leaves, coffee beans, you know, ground coffee beans, put them on your kitchen table in the summer, assuming you don't have an ant-free house, and there's ants crawling on the table, you'll notice that they avoid the coffee and tea leaves. And they're avoiding caffeine and other naturally occurring good toxins in them. So, that contrasts with sugar or whatever, you know, a lot of other highly palatable, addictive foods.

Yeah. So, anyway, I was invited to write an article for "Scientific American" on this general notion that the reason fruits and vegetables are good for our health is not because they are free-radical-scavenging things like vitamin E or C can help in certain ways, getting rid of free radicals. That's not the answer. The answer isn't that we want to swamp ourselves with things that sop up free radicals because, actually, free radicals are important in our cells for normal signaling and then our adaptive responses to stress.

Instead, the chemicals that are good for health seem to be acting by triggering mild adaptive stress responses in our cells that overlap quite a bit with exercise and fasting. Yeah, these chemicals, again, they're concentrated in the exposed parts of the fruit, like the skin of the fruits.

So, yeah. Here's a really interesting thing. Green tomatoes. All right. So, bugs usually don't eat tomatoes until they start to turn red in the garden. Okay. So, why is that? The reason is they like the taste of the red ones better than the green ones.

So, it turns out, there's this chemical that's been called tomatidine that's highly concentrated in the green tomatoes. And then levels of tomatidine decline dramatically as the tomato turns red. Okay. By the time the tomato starts turning red, the seeds in the tomato that have the potential to give rise to another tomato plant and propagate the species, they're ready to go.

So, I guess, mainly this applies to birds. So, birds won't eat green tomatoes either. So, let's go with that. So, the bird eats the red tomato and they may eat some of the seeds. The seeds can resist going through their digestive system, then they poop out the seeds, and the seeds can grow.

You know, and they might poop out the seeds, you know, whatever, half a mile away. So, now the tomato plants are... You know, so these are all evolutionary mechanisms that give advantages to one or both of the species during their co-evolution.

Dr. Patrick: If a person is exercising regularly and also doing some form of intermittent fasting and they're getting this activation of some of these stress response pathways and the beneficial effects, you know, metabolic switching, is there any need to also take in these plant phytochemicals that are also activating, you know, perhaps the same or different or both, you know, stress response pathways? In other words, like, can you just say, "Well, I don't need to eat the plant compounds because I'm exercising and I'm doing intermittent fasting."?

Dr. Mattson: I wouldn't do that or say that. What hasn't been done though, Rhonda, is other... And the reason is, it's expensive. There haven't been studies where within a study, they do all these various combinations. You know, okay, we're gonna do this study with...well, some people intermittent fast, we'll have some exercise, we'll have some do both, we'll have some, whatever, taking sulforaphane, and then we'll have them do sulforaphane plus intermittent fasting, and so on and so on.

And my view on diet composition is one that I think makes sense from data from epidemiological studies, the Blue Zone, where, you know, certain places where people have exceptional longevity. And all of them have diets that are mostly plant based. And then, the evidence that simple sugar is bad for health is overwhelming. The saturated fat, I think, the evidence is pretty strong. So, it's better to eat fish than red meat. And so, complex carbohydrates are better than simple.

I think that, you now, people shouldn't say, "Well, I can just eat at McDonald's every day if I exercise and do intermittent fasting because it's..." They would be better off than having been intermittent fasting and exercising... You know, if they're if they're going to eat at McDonald's and don't want to give that up, then exercise and intermittent fasting will counteract that somewhat, but it's still kind of stupid.

Dr. Patrick: The way I also think about it is, you know, you have something like sulforaphane, which we've talked quite a bit about in the podcast. I've interviewed Jed Fahey.

Dr. Mattson: Yeah, I know, him. Jed, he's at Hopkins.

Dr. Patrick: Yeah, he's a good friend of mine. And so, you know, you have something like sulforaphane that's activating the NRF2 pathway, which has, you know, you know, all these downstream effects on phase II detoxification enzymes, you know, activating those, inhibiting the phase I biotransformation enzymes, which are involved in potentially making a procarcinogen an actual carcinogen. You know, there's all these pathways that, you know, I don't know how much exercise and/or intermittent fasting, you know, activates those pathways, I'm sure to some degree.

But you know, it seems as though different types of stressors do have a more robust effect on certain types of stress response pathways. And so, why wouldn't you want to diversify?

Dr. Mattson: Yeah, that makes sense. Yep. Although I should say that... So, going back to sulforaphane and the NRF2-ARE pathway. That is activated by exercise and fasting. And so, I would say this. These chemicals that are in the plants are more targeted in what they do. Compared to exercise and fasting, those chemicals affect a more limited number of pathways. In other words, you can't just take sulforaphane and it's going to substitute for exercise or intermittent fasting.

Dr. Patrick: Right. Kind of shifting back just for a moment to the to the fasting topic, we've talked a lot about metabolically unhealthy people with Type 2 diabetes, or perhaps obesity, or animal models of such, and the benefits of intermittent fasting in those, you know, people or animals. How much can, you know, a healthy person who perhaps is not, you know, at risk for obesity or metabolic syndrome benefit from intermittent fasting?

Dr. Mattson: Yeah, that's a complicated answer. I'll expand a little bit how much and in what ways. There have been far fewer studies in humans of intermittent fasting on normal weight, you know, healthy people. In animals, the control group is always fed ad libitum and they're sedentary. So, really, in the animal studies, the control group is couch potatoes.

And that's why, I would say in extrapolating the animal data to humans, I'm very comfortable in saying intermittent fasting will have very clear, measurable, highly significant benefits for overweight people. But since all the animal studies, the control group is couch potatoes, and we're seeing good effects on the couch potatoes, we can't say, you know, that does apply to humans of normal weight.

But there have been studies in normal weight healthy humans. Looking at some health indicators, blood glucose levels and insulin, and looking at ability to maintain and build muscle mass, so resistance training studies, several published studies where they found that with daily time-restricted eating, people were able to maintain and build muscle just as well as people who weren't on daily time-restricted eating.

But it's undoubtedly, the magnitude of any beneficial effects on health in people that already have a healthy body weight are going to be less than on people who are overweight. And the effects on improving glucose regulation in people with Type 2 diabetes, who already have insulin resistance, are going to be quantitatively much greater than people who have, you know, already have normal insulin sensitivity. So, you know, I would say that there will be some benefits, but it's going to be quantitatively less. Does that make sense?

Dr. Patrick: Quantitatively difficult. It does. Like, difficult to even measure, you know, because as you've been discussing throughout the podcast, the benefits of metabolic switching, the production of ketone bodies like beta-hydroxybutyrate, and their signaling effects on BDNF, you know, increasing BDNF, and also producing less reactive oxygen species, because they're more energetically favorable or easier by the mitochondria. It seems as though activating autophagy, as you mentioned, you know, the clearing away of damaged stuff and organelles and things within a cell.

Like those, you know, sorts of effects happening, even if the magnitude isn't as great. It seems as though like that has to be beneficial long term in terms of like activating stress response pathways, that are going to help you deal with the stresses of aging better.

Dr. Mattson: Yeah, I agree. One...

Dr. Patrick: Do you think that...? Sorry.

Dr. Mattson: Go ahead.

Dr. Patrick: No, go ahead.

Dr. Mattson: One thing that's being found that it's important to maintain muscle mass as you age. So, I think people need to be a little bit careful, you know, to take in sufficient energy to maintain their muscle mass. So, for example, the people in the Calorie Restriction Society may be overdoing it. And, you know, the story of Roy Walford, who was in the Biosphere 2.

Dr. Patrick: I do. You can tell the story.

Dr. Mattson: Okay. I can't remember exactly when it was, '70s or '80s, or 1980s. I can't remember. There's something called Biosphere where these two people down in Arizona, essentially, they built this bubble. And they grew plants in there. And the goal was to see if they could be self-sustaining for long-term.

And so, what happened was they were all right for a while. And then, after a while, they started not being able to generate sufficient food and they lost a lot of body weight. And, you know, essentially, on the point of starvation. And so, they had to finally come out of the biosphere.

And one of them was Roy Walford, who had also done a lot of important work on calorie restriction. Actually, a lot of very important early work with Rick Weindruch at the University of Wisconsin, showing that calorie restriction can extend lifespan.

And then, Roy Walford... So, as you get older, your perception of time is messed up. Roy Walford died in, I like to say, like 15 years ago or something, ALS, Lou Gehrig's disease. That's a muscle-wasting disease involving degeneration of the neurons that innervate those muscles.

And that was really interesting because I mentioned the study that we've done with intermittent fasting and animal models of Alzheimer's, Parkinson's, epilepsy, and we found it was beneficial. But we also tried, every-other-day fasting in a mouse model of ALS. And what we found is, it made it worse.

So, of course, these mice are destined to have ALS, so the abnormal processes are already in motion when we put the animals on intermittent fasting, but their motor function, we have ways of testing their motor function, declined much more precipitously when they were on intermittent fasting. So, I think that's the important...

And then, my own personal case. So, I've always had a low BMI. And I started doing daily time-restricted eating like 30 years ago, not eating breakfast. And as kind of an endurance semi-athlete, trail running, mountain bike riding. Actually, when I was a kid, I used to race motocross.

But, anyway, I did a lot of running. And so, my BMI is always around, it's very low, like 18, 18.5, you know, somewhere there. And then, two years ago, I had a mountain bike accident. And not to be too gory but, essentially, tore my rectus abdominis muscle off my pubic bone, and had adductor partially coming off. I had to have three surgeries, and I've had other issues.

So I've lost muscle mass, particularly in my legs, during this ordeal. And I'm having trouble building it back up. So, like, hindsight is always 20/20. And like, you know, I couldn't have predicted I'd have a mountain bike accident and have all this going on. But in hindsight, I probably would have been better off...and I didn't really do any resistance training.

Because when I was running, when I started running in the '70s like there was no such thing as cross training. It was like runners, the training is you run. You stretch and you run. And, somehow, I guess because I'm stupid. I didn't pick up on, you know, people start doing cross training stuff. I didn't pick up.

"Hey, I should be working my core. And I should be, you know, keeping some muscle mass." You know, so all these years, I've mainly just been doing the same thing. But, anyway, so that's just like a personal anecdote. And, you know, I guess what I'm saying is having a low bodyweight can be good, but you have to be a little careful during aging to make sure that you have a good muscle mass as part of that like the main... Well, I guess I was mostly muscle mass anyway but, still, yeah, more muscle mass.

Dr. Patrick: It brings up a good point on some of the, you know, safety concerns with practicing intermittent fasting and certainly prolonged fasting. You know, whether or not elderly people, someone over the age of 70, can do you know, a 5:2-type of fast or certainly, you know, even, you know, daily time-restricted eating, and maybe they should, you know, doing that along with resistance training, if they even should do it. Do you have any thoughts on that?

Dr. Mattson: My thoughts are that exercise and a healthy diet would be more important for them. Yeah. And, you know, the answer is we don't know. There need to be studies in elderly people of intermittent fasting starting in the elderly. So, it's just not clear. So, right now, the main focus, at least from mainstream medicine, is people who are overweight or with insulin resistance. There is some interest in also people at risk for cancers because well, there's really strong...

As you know, being overweight is a risk factor for a lot of different types of cancer in both men and women. So, inasmuch as intermittent fasting can keep your body weight down, that's good. But there's also evidence that intermittent fasting can actually, in animals, it definitely suppresses the formation of tumors, spontaneous formation of tumors. And it can greatly reduce the growth of cancer cells implanted into animals. And it can enhance the killing of cancer cells by chemotherapy drugs and radiation.

But, anyway, so elderly people, if they have good muscle mass and are physically active, I don't know, they can try intermittent fasting. If they have the same overall calorie intake, then they're not going to lose body weight. You know, whether they're eating all their food within an eight-hour time window or not or two days a week, if they make up for the calories.

Then another group would be little kids that are growing fast. Children who are overweight with obesity, maybe there's interest by pediatricians in this. And I've had several contact me, one up in New York who... What he's had some success with is kids with obesity. He gets his parents to buy into it. And get both the parents and the kid to switch their eating pattern. Then he's had success in helping some of these kids get their body weight down by switching their eating pattern to intermittent fasting.

So, women with obesity and Type 2 diabetes, there's increased risk of autism or having a child that is on the autism spectrum disorder compared to normal weight, healthy women. And that's very interesting. I can send... I don't know, you can put stuff on your website, Rhonda, right?

Dr. Patrick: Absolutely.

Dr. Mattson: So, I don't need a website. I just go through you. So, I'll send you a few articles that you could post on your website. Is that okay?

Dr. Patrick: Yeah. And we also post them on the video. We put the figures and study title, and information. So, whatever you're talking about, we're going to find.

Dr. Mattson: Anyway, I'll send you this one on autism. So, we know that in the 1970s, and '80s, autism was kind of... A lot of people never heard what's autism? What's autism? I didn't. When I went to high school, I never heard anything at school or from my parents about autism.

And then, beginning in, around late '80s, '90s and then, more so there's increased incidence of autism, some of that's due to increased recognition that the kids are having trouble concentrating, they're avoiding social interaction, and so on. But that doesn't seem to explain all of the increase.

It turns out, there's a nice... If you track the increase incidence of autism and the increase in maternal obesity and type two diabetes, it tracks really well. You know, from very little maternal obesity in the '70s and '80s, and then increased autism.

So, the neuroscientists have good evidence that in autism, during brain development in the embryo, in the uterus, the brain grows more rapidly than normal. And probably because their mTOR pathways like, just, you know... The persons, if they have obesity and Type 2 diabetes, they're undoubtedly not exercising or, you know, calorie restricted. And so, they never have the metabolic switching, the mTOR pathway, which is the growth mode is on.

And so, nerve cells, the neural stem cells proliferate more rapidly, neurons grow more rapidly, connections start forming. And then, what happens is there seems to be hyperexcitability of neural networks. And this has been documented by doing what's called functional magnetic resonance imaging in kids with autism. Kids with autism have a huge increase in incidence of seizures.

And I should say, not all kids with autism are born to women with obesity or Type 2 diabetes. Not all kids with autism have seizures. But there's a big increased incidence. That is more kids with autism have seizures than kids that don't have autism.

And then, in animal studies, there are some genetic models that are actually pretty good for autism. There's something called Fragile X syndrome. And the gene is known for that. And when that gene abnormality is put in mice, and then you put the mouse in a cage which a bunch of other mice, the mouse goes in the corner and doesn't want to interact with other mice, and kind of measure this propensity to interact, so kind of social withdrawal.

And those mice, in their brains, they have hyperactivity of glutamatergic neuronal networks. So, there is some evidence that kids with autism, exercise can help them. And certainly, we know, I know, I used to coach high school cross country and my kids ran. And I know that during the cross-country season, the kids, their mood is much better than when they're not running. They're more relaxed, less ornery.

And so, right, and then the exercise and intermittent fasting upregulate their GABA tone. Ketogenic diets will do that too. So, I think it would be interesting to try intermittent fasting in kids with autism.

Dr. Patrick: Or perhaps a ketogenic diet as well, very interesting, Mark. So, to kind of shift back to the women part of this story. There's been a lot of questions about whether or not fasting affects women differently, different than men. And if women should fast or if it affects their cycle, menstrual cycle or hormones like thyroid, things like that. Whether we're talking about like intermittent fast that's like longer than time-restricted eating, something more like a maybe 24 to 48 hour, or perhaps even more prolonged fast. Do you have any thoughts about that?

Dr. Mattson: Yeah. Major calorie restriction, so, I'll start with animals then go to humans. So, in animals, for example, I had one postdoc Bronwen Martin in 2005 or something, she took rats and she put them ad libitum feeding, 20% daily calorie restriction, 40% daily calorie restriction, which is a lot, or every-other-day fasting. And she had both males and females.

So, and then she followed them over time. And then, the females, she essentially did vaginal swabs to do staging of the cycle. And so, as far as that goes, the rats with 20% daily calorie restriction, there was no change in their estrous cycle. The rats with 40% calorie restriction, and this was over a period of like 4 or 6 months, they shut down, they stopped cycling. And they lost a lot of body fat over those months.

Then, the rats on every-other-day fasting, they kept cycling but there was some increase in irregularity of, you know, the timing between the cycles, but they were still presumably fertile.

Then, she did all sorts of stuff. She tested their learning and memory. Oh, then, interestingly in males, even at the 40% daily calorie restriction. So, the males, their sperm count didn't change. And they didn't lose as much body weight as the females over these months.

And she looked at like this though, the activity of the rats moving around the cage. And the females, when they're on major calorie restriction, became very active. Like, they're moving around the cage a lot. Looking for food, maybe?

So, my interpretation of this. And we had like a few sentences in the discussion on the article. Okay. In the wild, if animals are getting to the point of starvation, so that would be the 40% calorie restriction. The females, they don't want to get pregnant. Or if they get pregnant, there's no food to support, you know, development, their baby. So they shut down their cycling, they become more active looking for food.

The males, before the male starve to death, it will be advantageous to them to be able to inseminate as many females as possible before they die of starvation. So, they stay fertile. So that's my interpretation. You know, the female has the egg that's the potential passing the genes on. You know, so I don't know.

But with the intermittent fasting, they kept cycling. And their activity in the cage increased a little bit, but they maintain pretty good body fat compared to the 40% calorie restriction.

One issue is, and this applies mainly to adolescent girls, if an adolescent girl goes to intermittent fasting eating pattern, would she be more prone to developing anorexia nervosa, which is a kind of obsessive compulsive like psychiatric disorder? The answer is we don't know. We just don't know.

So, from an evolutionary perspective, you would think that would be selected against. But, you know, and it's not clear. I guess, I don't know enough about anorexia nervosa. But, you know, back in human recorded history, is anorexia nervosa even common? Or is this something that has arisen more as girls are more conscious of their body image and so on?

And, you know, therefore, there's this psychological factor that I don't know if that's something that... I guess what I'm saying, it doesn't make sense to me that anorexia nervosa would be something that will not be strongly selected against during evolution. And these girls often, they usually quit cycling, too. You know, so, yeah, I guess we just don't know.

On the one hand, intuitively, I'd say, it won't be a good idea to recommend this to adolescent girls. But if they're with obesity or overweight, I don't know. We just don't know. I think that seems like maybe okay, but we just don't know.

Dr. Patrick: You're talking about with adolescent girls?

Dr. Mattson: Yeah.

Dr. Patrick: Well, so what about women that are not adolescent and, you know, do not have an eating disorder and are perhaps even normal weight, not obese or overweight? Is there a concern with other hormonal imbalances? I don't even know, necessarily, is it a bad thing? I mean, if you're amenorrheic for a short period of time, and you go back to eating normal calories, what does that mean? Do you delay your reproductive lifespan longer? Or is there even implications that...?

Dr. Mattson: Well, in animals, that's what happens. So, for example, we're going to take these rats and do 40% calorie restriction for 3 months or 4 months so that they stop cycling. And then, you put them back ad libitum feeding again, they gain their body weight back. They start cycling. These aren't our studies. These are other studies.

Then, those rats will be able to have, keep cycling to an older age than they would have previously stopped cycling. So, in other words, in theory, maybe you could extend age of menopause by shutting down cycling for 10 years. I don't know. This is like just...

Dr. Patrick: Speculation.

Dr. Mattson: This is just thinking and not anything that's approaching it coming close to even encouraging someone to do something like that, which would be crazy. But it's an interesting thing to think about. I don't know. There haven't been studies. This is a big thing that's lacking in this field is studying hormones, except for simple things like leptin and ghrelin. So, for example, FSH, LH, oxytocin, yeah, anything to produce.

Oh, we do know, in animals anyway, there seems to be increased activation of the hypothalamic, pituitary, adrenal stress response system. And that's the system that results in increased levels of cortisol. And this was something that was noted early on in the animal studies.

The animals live longer when they're on calorie restriction or intermittent fasting. But they have elevated cortisol levels, which is usually, you know, in the clinical arena, that's not a good thing because it can suppress the immune system. However, so the animals are living longer.

And we did a study, Jaewon Lee was a graduate student, went out in Kentucky and then he came to Baltimore with me when I moved. So, this gets a little bit into endocrinology. Cortisol, there's two receptors for cortisol, two proteins inside the cell that bind the cortisol. And those cortisol-binding proteins are transcription factors.

So, cortisol comes from the blood in your cells. It could be a muscle cell, a nerve cell doesn't matter. And they bind to the receptor. And then, which is a transcription factor, it then goes into the nucleus and affects the expression of certain genes. In fact, the Nobel Prize was given to the person who... Oh, Jesus, I'm blanking on the name. I should know who discovered this.

Okay. So, I mentioned there's two receptors for cortisol. One is called the glucocorticoid receptor or GR. The other is called the mineralocorticoid receptor or MR. And, okay, so there's been a lot of studies on cortisol in relation to chronic, uncontrollable psychosocial stress. So,people who are, you know, whether it's, you know, their work or life situation, they're chronically stressed out, they have elevated cortisol levels.

And it's been shown that, in that case, in the brain, nerve cells in the brain have a decreased level of one of the cortisol receptors, the MR, and an increase in GR. So, the way that the cells are responding to the cortisol is changing, not just the cortisol.

So, we did a study where we measured levels of GR and MR, the two different receptors for cortisol, in the hippocampus of mice that had been on every-other-day fasting, or ad libitum control feeding. And what we found is that, in contrast to chronic uncontrollable stress, the intermittent fasting caused a decrease in levels of GR and a sustained level of MR.

So, the take home message is there's increased activation of stress response pathways with intermittent fasting. But the ways your cells respond to the stress is different than the bad ways your cells will respond to bad types of stress, chronic uncontrollable stress.

Dr. Patrick: That's really important. That's a very important point to make. Kind of just going back to one thing you were talking about, comparing your severely caloric-restricted animals to like alternate-day fasting.

You know, I think that's a really important point to distinguish because, you know, in the context of what we were talking about with women's cycle, there wasn't really, you know, much of an effect on the cycle in alternate-day fasting, which by the way, in rodents is a much stronger, like, the woman doing a 24-hour fasting. And then an alternate day would be possible, probably much more significant of a fast in rodents, right? But anyways, the differences between and uncoupling the benefits and or just even...

Dr. Mattson: Oh, wait a minute. I think you said it backwards. So, it's a more significant fast in rodents.

Dr. Patrick: Yes, it's a more a significant, exactly. Yes. Thank you. Yeah, 24-hour fast in rodent would be, I'm not even sure, would it be like 72 hour or something in humans? Much, much more?

Dr. Mattson: Yeah, much more. As you mentioned, the mice, they die, if they go beyond three days or so. They will die. You know, so that's kind of... You know, so one day is a third of that, right? So, I would say, you know, a human can live, it depends on their initial body fat, but they can live maybe two months without food.

Dr. Patrick: That's a big difference.

Dr. Mattson: So, I'd say, you know, a day of complete fasting could be equivalent to, like...

Dr. Patrick: Five days?

Dr. Mattson: I don't know.

Dr. Patrick: Right. Well, you know, I don't know if this makes sense to you, Mark. But if you look at some of the work from, for example, Valter Longo, when they've looked at a 48-hour fast and the drop in IGF-1 levels, it goes to about 50%. And in humans, you know, looking at what it takes to drop IGF-1 to 50%, it's anywhere between 5 to 7 days. So, you know, perhaps, that sort of that just...

Dr. Mattson: And even with ketones, it's true that in the animals, the ketones go up within an hour or two of fasting.

Dr. Patrick: Wow. Whereas in humans, it's obviously, depending on exercise.

Dr. Mattson: So, 10 to 12.

Dr. Patrick: Ten to 12. Right. Yeah. So, what I was sort of wanting to just touch on. For one, it seems as though that intermittent fasting in the context of certainly daily time-restricted eating, and perhaps even, you know, doing a 24-hour fast or 48-hour fast, shouldn't have much of an effect in most women that aren't calorically-restricting, in addition to that. And perhaps aren't, you know, running marathons or, you know, running 15-miles a day.

You know, so there's, there's obviously a spectrum here, when you're thinking about the effects on a woman's cycle. It seems as though it's the actual caloric load that's important. So, if you're restricting your calories, at the same time, it seems like...

Dr. Mattson: That's right.

Dr. Patrick: But also in terms of just general benefits of intermittent fasting in terms of the overlap between caloric restriction. You know, it sounds as though there is some uncoupling. I don't know how much metabolic switching occurs with calorie restriction, perhaps it depends on if you're doing something like a fast mimicking diet, where it's a pretty severe calorie restricted diet, or if you're doing something like this Caloric Restriction Societies do.

Dr. Mattson: It's very interesting. I don't know if you have you met Rafa de Cabo?

Dr. Patrick: I would love to have a conversation with him. I'm familiar with his work, but him and I have not... We were supposed to meet at a conference a couple years ago, but that didn't work out.

Dr. Mattson: Yes. So, it turns out that most, perhaps all of the rodent studies with rats and mice of calorie restriction are also intermittent fasting studies. And the reason is the way they did the studies, they take 20 animals, they divide them into two groups, you, over a period of a week or two, determine how many food pellets each animal eats each day. Sorry. You do that before you divide them into two groups.

So, essentially, you get, for each animal, their daily calorie intake. And then, you divide them into two groups. In the calorie restricted group, you give, say, 20% fewer pellets than they would have normally eaten each day. And you give it to them all at once.

It turns out, when that's done, because they're calorie is restricted, they eat all of their food in a short time period, like within four to six hours. So, they're actually fasting for up to 20 hours.

So, we did, I think it was the first study published, where we asked, are there effects of intermittent fasting better, different, or quantitatively greater or less with intermittent fasting and calorie restriction? So, there's a certain strain of mouse that when we put them on every-other-day fasting, on the day they do have food, they ate pretty much twice as much food as they normally eat. And so, they remain, over time, they don't lose any weight. Okay. So, they're intermittent fasting, but no calorie restriction.

And then, we had calorie restriction group. And another group we called pair feeding. But, anyway, the bottom line is, what we found is that we see no studies on the brain. We saw clear, beneficial effects of intermittent fasting on the brain that are independent of calorie intake. You know, so we had animals that were on intermittent fasting, no change in calorie intake, and still saw, actually, did the epilepsy model, it showed that it still protected them against epileptic seizures, protected the neurons. We still saw decrease in IGF-1. I can't remember all the details.

Yeah, and then I mentioned the study with Michelle Harvie in England. That was really, we dissociated. Remember, we had a group that was counting calories each meal, and then we had group 5:2 intermittent fasting. And they both lost the same amount of body weight, and over six months, their calorie intake was the same.

Yet the women on 5:2 intermittent fasting lost more belly fat, and had a significantly greater improvement in insulin sensitivity. So, that's, I think, the first human study to show at least some benefit that can't be accounted for by reduction in calorie intake.

Dr. Patrick: What about uncoupling benefits of weight loss from intermittent fasting?

Dr. Mattson: We did that in the mouse study.

Dr. Patrick: Of the brain, yeah.

Dr. Mattson: Yeah. That study could be done in humans. You just have to... It hasn't been done.

Dr. Patrick: I think there was a time-restricted-eating study done by, was it Varaday? University of Chicago?

Dr. Mattson: Oh, yeah, Krista Varady.

Dr. Patrick: Perhaps, I think, there was no weight loss. And there were some benefits. There was, you know, metabolic benefits. I can't recall all of them. But, again, coming down to knowing what you've discussed with these stress response pathways and cytoprotective mechanisms. And you know, these adaptations and the metabolic switching and the importance of all that. What are your...?

Dr. Mattson: I have to leave pretty soon. But I want to mention one thing that's kind of interesting. So, we found in rats. So, we implanted rats with essentially transmitters where we could record in real time 24/7 their heart rate and blood pressure. And then, we switch them from ad lib to either daily 30% calorie restriction or every-other-day fasting. And we found that their heart rate and blood pressure went down over a period a lot, went down over a period a couple of weeks, a little bit more down by a month and then stayed down.

Then we switched them back to ad libitum feeding. And at about two weeks, the resting heart rate and blood pressure, going back up and by a month, it was back to where it was before, you know, way back at the beginning.

So, a couple of things. So, people who do aerobic exercise tend to have low-resting heart rate, low blood pressure, and increased heart rate variability. Heart rate variability is the variability in the time interval between individual heartbeats.

So, for example, if your heart rate was 60 and mine was 60, that doesn't mean that each of us there's, you know, every second, exactly every second, there's a beat. It could be 0.8 seconds, then 1.2 seconds, then 0.9. So, initially, like, I guess, it's kind of counterintuitive that it's a good thing to have variability, between the time interval between beats, but actually it is.

So, endurance athletes have high heart rate variability. And, essentially, what it means is their heart regulation number, their heart is more adaptable to stress and other changes. And so, what happens is, and this has been known for exercise and particularly aerobic exercise, that the reason it causes a reduction in heart rate and blood pressure and increased heart rate variability is that the exercise over time will enhance what's called the parasympathetic nerves that innervate the heart. And the parasympathetic nerves slow down heart rate. The sympathetic nervous system increases heart rate.

So, we found the same thing with intermittent fasting. It enhances the parasympathetic nervous system. That will also. And that's sort of the vagus nerve, which is this big nerve coming down here. It innervates the heart, slows down heart rate. It can increase blood flow, dilation of blood vessels. And it can also enhance gut motility.

So, I guess, I kind of want to throw that out there. It's kind of an interesting effect that I haven't talked about intermittent fasting on the cardiovascular system that's very similar to exercise. It takes a few weeks to a month to see the clear effects. Then, if you stop doing it, you stop exercising, stop intermittent fasting, it doesn't take long for things to go back the way they were.

And people, like me, who, you know, you exercise regularly. And then, in my case, for an accident and surgery, I had to stop exercising. So within a month, my blood pressure went from like 100 over 60, and resting heart rate of like low 50s to blood pressure like 135 over 85. And my resting heart rate's up like to 70, you know.

Dr. Patrick: So, I know that you might...

Dr. Mattson: So, you got to stick with it, if you can.

Dr. Patrick: Yeah, I just want to mention sauna use, real quick, because that's also been shown to do the same thing with parasympathetic activity and heart rate variability and blood pressure and all these things. And it mimics cardiovascular, particularly aerobic exercise. And it's very useful for people that are injured and can't go out and get that exercise. It also helps maintain muscle mass that's been shown in both animal and human studies.

Dr. Mattson: I should do that.

Dr. Patrick: Keep that in mind and also... You should. And if you don't have access to a sauna, hot baths can also... And I can send you some of this information. Hot baths can also increase heat shock proteins, which have been shown to help maintain muscle mass, and then heart rate, your heart rate elevates.

Dr. Mattson: Surprise, surprise, hot bath can increase heat shock.

Dr. Patrick: Right. So, I know you have to leave, I just wanted to ask you really two quick questions. One, your just rapid-fire thoughts on some of these so-called caloric restriction or fasting mimetics like resveratrol or spermidine or hydroxy citrate, things that have been shown to increase autophagy or polyphenols from coffee. And maybe doing that in combination with intermittent fasting and what your speculation would be.

But also what your intermittent fasting routine looks like, maybe before and after your injury? And if they're, you know, different. And then that's it.

Dr. Mattson: Well, the answer the last part is easy. Not different. I eat all my food within a six-hour time window and it's no simple sugars, virtually no saturated fat, mostly plant based. That's vegetables, some fruits, fish. I do eat whole grains. I'm not so convinced that, you know, whole wheat is bad for you. I don't think I have any gluten. Okay.

Dr. Patrick: Do you do prolong fast ever or longer than a daily-time restricted?

Dr. Mattson: Surprisingly, I haven't. And then, but, you know, trying to mimic the effects of fasting. We've worked on this a little bit with 2-deoxyglucose and with something called DNP, which is a mitochondrial uncoupler. 2-deoxyglucose, it's glucose that doesn't have a hydroxyl group that's glucose. That's why it's called to 2-deoxy.

But anyway, 2-deoxyglucose will be taken up in cells just like glucose is, but it cannot be used to produce ATP. And it competes with an enzyme called hexokinase. That's like the first enzyme involved in the metabolism of glucose that leads to ATP production.

So, the bottom line is if you feed an animal or a human 2-deoxyglucose, cells in the animal will think, they will experience the effects of glucose deprivation because there's less glucose coming in. And, in fact, it will increase some of these protein chaperones, one called GRP78, glucose-regulated protein 78. It's kind of like a heat shock protein.

And we'd found that if we give 2-deoxyglucose every other day, it can be neuroprotective in some of our models, and we published that. Don Ingram, he wants to see if 2-deoxyglucose with increased lifespan. So, he put it in the diet of animals. And actually, it shortens their lifespan. It had some adverse effects, long-term on the cardiovascular system. So, now, that's kind of mimicking calorie restriction at kind of fundamental global way, you know, way upstream.

The things you mentioned are, you know, can you activate pathways, like certain pathways, autophagy, and others that are maybe kind of downstream? And I don't know. I think the thing is, it's kind of tricky business knowing how to know what amount of anything that mimics fasting is enough.

For example, you may see some short-term benefit in whatever endpoint you're looking at. So, for example, ketones. The 2-deoxyglucose will increase ketone levels because cells think there's less glucose in the blood when there's actually not. And so, ketones are produced. But, you know, long term, it's not good.

So, you know, my advice is to stick with exercise. I think intermittent fasting can be helpful for a lot of people. Keeping your mind intellectually engaged, eating good diet. There's just not sufficient data to support the use of any of these things, you know, whether it's nicotinamide riboside, or rapamycin seems like it's something that in animal studies looks pretty interesting, but I've been kind of hesitant to take rapamycin myself, just given that what it's prescribed for is suppressing the immune system. And long-term in humans, we don't know. So, yeah.

Dr. Patrick: I'm so sorry to have to ask you one more question. But I feel like we need another podcast. Just because you're so knowledgeable in this field, I would just love to know what your thoughts are, do you think, for example, a type of, you know, daily time-restricted eating, maybe something similar to what you're doing or eating, you eat within a six-hour window or in eight-hour window every day, would have an effect on human lifespan or, at the very least, healthspan?

Dr. Mattson: I would predict it would. And this is in comparison to three meals a day plus snacks.

Dr. Patrick: And what if the three meals a day plus snacks, you're still exercising and healthy and you're still metabolically healthy?

Dr. Mattson: Say that again.

Dr. Patrick: If, let's say, the person eating the three meals are eating high-quality meals and maybe eating some nuts or something for a snack and they're also physically active. So they're lean and metabolically healthy?

Dr. Mattson: I think maybe because I don't know if that's true for humans, we don't know. But in animals, exercise alone, without calorie restriction or intermittent fasting has minimal next to no effect on lifespan, maybe like a 5% increase. So, in animals, and in animals that are herbivores, calorie restriction, intermittent fasting have a striking ability to extend lifespan. Running-wheel exercise, and animals run quite a bit every day, not much.

You know, but the animals don't die from cardiovascular disease, typically, or diabetes. They died from cancers and kidney disease are kind of the two main causes of death. So, inasmuch as exercise is really going to affect the cardiovascular system and glucose regulation. I wouldn't be comfortable extrapolating, you know, the animal to the humans, because I think exercise is really important.

Dr. Patrick: Yeah, if you look at the observational studies, you know, exercise between a hundred...

Dr. Mattson: And my own personal experience is that the exercise for me has more profound beneficial effects. At least, on my mental health than intermittent fasting. And I think, also, you know, I mentioned my blood pressure is now up. It's not like, you know, high clinically, but it's high compared... You know, so without exercise, even though I'm doing daily time-restricted eating and my body weights down, I'm still, you know, showing these bad changes without the exercise. Yeah.

Dr. Patrick: Yeah. Right. Thank you. Well, I, 100% agree. When I exercise, almost exclusively for the brain benefits and you know. Sure. And the other things are kind of healthy side effects for me.

GAP

I know that you're in the process of writing a book, which is, you know, waiting for proofs back. So, I look forward to...

Dr. Mattson: Yeah, it's written. I'm done. I'm just waiting for the proofs.

Dr. Patrick: I'm looking forward to reading that and sharing it.

Dr. Mattson: And the second book is actually, you know, in the general public, I'm kind of best known for work on intermittent fasting, but that's just a part of my research over the years. So my second book is called "Sculptor and Destroyer: The Story of Glutamate, the Brain's Most Important Neurotransmitter."

My postdoc work, I showed glutamate played an important role in controlling the formation of synapses during brain development. At that time, in the 1980s, it wasn't recognized that neurotransmitters have an important role before their synapses form. They always thought, okay, the nervous system gets wired up, there's synapses, and now there's neurotransmitters. But, yeah, so we showed glutamate plays an important role.

And then, so that's the sculptor. And then, glutamate is important in synaptic remodeling and learning and memory. So, that's the sculpting part.

Then the destroyer is... So, I mentioned epilepsy and excitotoxicity. There's a lot of evidence that in Alzheimer's, Parkinson's, definitely stroke, traumatic brain injury, ALS, all of those excitotoxicity is a factor that is neurons continuing to be excited by glutamate when they're in a compromised state, energetically, for example, with a stroke, or we think more subtly in Parkinson's or Alzheimer's, where there's mitochondrial dysfunction that's occurring. And then the neurons continue to be excited even though the mitochondria aren't producing enough ATP to run the ion pumps that pump sodium and potassium back.

Your PhD work was what?

Dr. Patrick: My PhD work was mostly cancer metabolism, mitochondrial function. I did a lot on...

Dr. Mattson: So, in neurons, like it's been estimated that in neurons that are active, during normal activity, up to 50% of the ATP is used to drive the sodium pump and the calcium pump to pump those ions back out after the neuron is fired. So, when the neuron fires an action potential, when it's active, the sodium and calcium rush in, then you get a voltage change across the membrane. And then, that's propagated. And it's important to rapidly remove the sodium, potassium so that the charge across the membrane gets back to where it was.

And so, yeah, during normal aging, Alzheimer's, Parkinson's, if the mitochondria aren't working even a little bit less well than they are, there's a tendency for hyperexcitability. And so, anyway, that's the destroyer part of the "Sculptor and Destroyer."

Dr. Patrick: How much of a role would the GABA production from being in ketosis help negate that?

Dr. Mattson: Well, that's important. That's a good question. I think that, from a drug standpoint, drugs that enhance GABA tone could be beneficial. It's a tricky business because glutamate is critical for learning and memory. And, you know, all our circuits, essentially, are glutamatergic. So, you don't want them to go out of control, but you don't want the activity to go too low so the function isn't optimal.

Dr. Patrick: What about testing that with something like a ketone ester to see, you know, transiently?

Dr. Mattson: No, we've done that. So, Richard Veech in, I can't remember what year again. Anyway, bottom line is he sent Paul to come to my lab and what was his name, Kashi [SP], a Japanese postdoc. And together with people in my lab, in a mouse model Alzheimer's disease. They gave animals in the food ketone ester or not, and then we had isocaloric.

And then, we looked at the amyloid accumulation, the neurofibrillary tangle, tau in learning and memory. And the ketone ester was beneficial. And now, I think the ketone ester is very promising. A friend of mine up in Canada, Steve Cunnane, has done some really nice work with PET imaging.

So, all right, so one can get images of relative levels of utilization of glucose by brain cells or of ketones. So, Steve Cunnane, used the radiolabeled glucose, 2-deoxyglucose, and radiolabeled, he used acetoacetate, but it doesn't matter. He didn't use beta-hydroxybutyrate.

Okay. So, these are just initially normal people but he's doing studies on people with mild cognitive impairment and Alzheimer's. So, he had them, when they're eating carbohydrates, brain cells use mainly glucose. When they go on a ketogenic diet, the brain cells switch. They clearly switch. It's very clear. They use a lot more ketones, maybe still using some glucose.

And then, in Alzheimer's disease, other investigators, decades ago, have shown that very early on, you know, people with mild cognitive imapairment, even somewhat during normal aging there's reduced glucose utilization by brain cells. And however, we think, based on some of our animal studies, and some preliminary studies in Alzheimer's patients of Steve's that, at least, in people with early Alzheimer's disease, even though their brain cells have problems using glucose, they still seem to be using ketones very well.

So, this is something that I'm excited about. And there's a neurologist that was under me at NIA that he's actually finishing up a study of intermittent fasting and people at risk for cognitive impairment. And he may be one of the places where these ketone ester studies are done. And then, you know, Kieran Clarke's work at Oxford with ketone ester and elite British cyclists.

So, yeah, that's a big deal in endurance athletes. You know, the cost, right, for the average person, the cost of the ketone ester is way too much to make it practical. And we don't know for sure. What would be interesting to do like a comparison of someone, you know, fasting versus ketone ester. You know, then you could maybe sort out whether any endurance-enhancing effect of intermittent fasting is in addition to ketone ester, or if it's all due to the ketones. But, yeah, bottom line is, I think that's really promising.

Dr. Patrick: As you mentioned, the cost is very prohibitive for most people. And I think of it. So, I can tell you from just anecdotally, and I'm so sorry, I know you have to go. It's great speaking with you. As a sort of a foot in the door to like maybe someone who is not motivated to try a ketogenic diet, perhaps they have cognitive decline or dementia, or maybe even you know, early-stage Alzheimer's, when they notice a beneficial effect from the ketone ester, and that's a lot more motivating for a person to have a real-world piece of evidence where they feel an effect and say, "Okay, well, maybe I can try this diet. That's not, you know, that quite easy to do." But they may be more motivated to do it.

Dr. Mattson: You know, before he passed away, Richard Veech he interacted with, like he had a friend who had Parkinson's disease, and he took the ketone ester and claimed that had really clear beneficial effects on his Parkinson's symptoms that are fairly rapid, so, you know...

Dr. Patrick: Thank you for telling me this. My father was diagnosed with Parkinson's like...

Dr. Mattson: People can try it. I mean, it's not gonna hurt them.

Dr. Patrick: Yep. I'll tell you anecdotally. So, two things. One, my father was diagnosed with Parkinson's about, I don't know, three and a half years ago, and I have these ketone esters, and I've been sort of trying to get him to try it and the pandemic happened and all this stuff. And so, I'm trying to go back to that point.

But my mother has a different type of motor disorder. She has both orthostatic tremor, and essential tremor. Orthostatic tremors when she stands still, her legs will shake very rapidly, but if she walks, that doesn't happen. She's fine if she's moving. And the essential tremor is if she's like, you know, eating or like has her arm out, you know, it'll shake.

Dr. Mattson: How old is she?

Dr. Patrick: She is 63. She's had this, I mean, it pretty much started to go badly after her menopause. She went through menopause. And all of a sudden, her orthostatic tremors got to the point where she couldn't stand. Whereas, when I was growing up, she could stand without, you know, her legs trembling so bad.

So, now it's like, if she's in line, she has to have something to sit, you know, where she can move fine, but like standing...

Dr. Mattson: What about your grandparents? Did they have that? You know, any of them have Parkinson's or...?

Dr. Patrick: No. Not that we're aware of, no.

Dr. Mattson: Okay. Well, that's good.

Dr. Patrick: But I was gonna tell you that that I have convinced my mother to try the ketone ester. And it does improve both her orthostatic tremor and her essential. Mostly, it improves her essential tremor. But I'm using that as...

Dr. Mattson: Did you do a blind study?

Dr. Patrick: No. I need to do that. We've done it several times. And it's worked. But it's hard because it tastes so bad that there's just no way she would not know. She often has to taste it with some something like a little bit of orange juice or something like that. So, until the ketone esters...you know, it is hard.

So, there's definitely potential for a placebo effect. But, you know, knowing what we know about the epilepsy and seizures, and it seems very reasonable that it would help with motor dysfunction and certainly what we know about mitochondrial dysfunction. So, anyways, I've got these ketone esters, and I've been sort of trying to convince both of my parents to try a ketogenic diet.

My father, though, he's actually sort of always naturally done some sort of intermittent fasting. It's just that's sort of what he's naturally done, slash maybe even a little bit of caloric restriction, you know,

Dr. Mattson: So, he's around the same age?

Dr. Patrick: He is 72.

Dr. Mattson: Okay. So, yeah, when was he diagnosed?

Dr. Patrick: When he was around, I would say, 68, about 68. Yeah. And so, I've been, you know, exercise and all these things in the lifestyle, I'm trying to, like, help optimize, you know. But I really am wanting to see if there's an effect of the ketogenic diet. And I think the way to do that is to look to ketone esters. That's how can you instantaneously put someone in ketosis without a lot of work? That would be it, you know.

But I really want to thank you, Mark, for the discussion and just the wealth of knowledge and all the research you have done over the years. I mean, I have like alluded to your research, I mean, just hundreds of times through public speaking and podcasts and YouTube videos and articles. And so, you know, you've really had a major influence on my thinking, you know, in the field of biological stress in general and intermittent fasting and the effects on the brain.