FoundMyFitness - #066 Dr. Mark Mattson on the Benefits of Stress, Metabolic Switching, Fasting, and Hormesis

Episode Date: August 24, 2021

Dr. Mark Mattson Dr. Mark Mattson is a professor of neuroscience at the Johns Hopkins University School of Medicine and the former chief of the Neuroscience Research Laboratory at the National Institute on Aging. He's one of the most cited neuroscientists in the world, with more than 180,000 citations noted in the scientific literature. Dr. Mattson's work has advanced scientific understanding of brain aging and identified fundamental aspects of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. His most notable work has focused on how the brain responds to mild stressors, such as those associated with exercise and intermittent fasting. In this episode, we discuss... (00:00) Introduction to Dr. Mark Mattson (03:31) Hormetic stressors drive adaptation and prevent physiological complacency (13:00) Intermittent fasting improves health by promoting metabolic switching (16:49) Daily time-restricted eating vs 5:2 weekly fasting  (27:44) A ketogenic diet and intermittent fasting differ in terms of brain effects (34:23) Exercising while intermittent fasting exerts additive effects (52:32) Plant-based bioactive compounds induce hormetic stress (01:10:48) Severe caloric restriction may compromise muscle mass (01:26:25) Intermittent fasting in young vs. old and in men vs. in women (01:35:20) The effects of cortisol differ during a fast versus chronic stress (01:53:36) Fasting-mimetics like resveratrol and spermidine vs actual fasting (02:08:44) How ketone supplementation may improve brain health Join over 300,000 people and get the latest distilled information on circadian insights straight to your inbox weekly: https://www.foundmyfitness.com/newsletter Become a FoundMyFitness premium member to get access to exclusive episodes, emails, live Q+A's with Rhonda and more: https://www.foundmyfitness.com/crowdsponsor

Hello, friends. I'm excited to share a new interview with Dr. Mark Mattson. Dr. Mark Mattson is an adjunct professor of neuroscience at the Johns Hopkins University School of Medicine and the former chief of the neuroscience research laboratory at the National Institute on Aging. He is one of the most cited neuroscientists in the world, with more than 180,000 citations of his work noted in the scientific literature. Dr. Mattson's rigorous work has advanced scientific understanding of brain aging and identified fundamental aspects of age-related neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. His most notable contributions, however, have probably been that of his role as the father of hormesis and intermittent

fasting, for which he is extraordinarily well known. At the start of the interview, you'll hear a little bit more about why I was so excited to have this conversation with Dr. Mattson. We're Trying something new today with this episode and releasing the interview audio here first exclusively on the Found My Fitness podcast feed. For those of you listening who also enjoy our in-depth video interviews, don't worry. We plan to release the full annotated video version of the interview very soon. As many of you already know, the post-production work that goes into our videos is quite intense and we just couldn't wait to share this conversation with you.

On to the important stuff. In this episode, Dr. Mattson and I discuss how hormetic stressors drive adaptation and prevent physiological complacency, how intermittent fasting improves health by promoting metabolic switching, how daily time-restricted eating and five-two weekly fasting compare, how a ketogenic diet and intermittent fasting differ in terms of brain effects, how exercising while intermittent fasting exerts additive effects, how plant-based bioactive compounds, induce hormetic stress. How severe caloric restriction may harm the body and compromise muscle mass.

How older adults, children, women, and pregnant women respond to intermittent fasting. How the effects of cortisol differed during a fast versus chronic uncontrollable stress. How the effects of fasting memetics like resveratrol or spermidine compare with actual fasting. And how ketone supplementation may improve brain health. A couple of quick reminders before we get to the podcast. If you ever find yourself wanting to dive a little deeper on an episode you listen to here, then you should subscribe to my newsletter. It's completely free and we respect your inbox.

I only send it out when we have new, fully research topic pages, exciting upcoming podcast episodes or updates on new research on some of my favorite topics. It's the best place to get distilled research and the most up-to-day information on topics like fasting, fitness, and overall health and longevity. to sign up just head over to found my fitness.com forward slash newsletter that's n e w s L-E-T-T-E-R newsletter. One last thing please keep in mind anything disclosed in this podcast is not in any way intended as qualified medical advice.

If you need qualified medical advice, please seek it out. Now let's get on to it. Welcome back to another episode of the Found My Fitness 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 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, maybe you could explain why humans need some biological stress and how maybe modern day society has made that difficult to achieve. 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, 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, the 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.

And two of the major stresses are actually food scarcity and predation, 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. that 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 those are some examples. And then the case of exercise, individuals whose bodies function well in a food-deprived state and environments where there's potential for predation were those that survived and passed

their genes on. So whatever it is, those genes did that help them perform physically well in a food-deprived state at a survival advantage. 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, we can even have our groceries delivered, you know, to our door. So you've talked a lot about how, you know, 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. 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. 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 that they can 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, their proteins 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, accumulation of abnormal proteins.

And this is also true in brain cells, which is the main thing I study, nerve cells in the brain. There's evidence that's emerging, some from my lab, some from others, that physical exercise, mental exercise, It's what you and I are doing now around to 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. 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 physiologists, 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 when they're active, and most of this is from animal studies, and so we're extrapolating. 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. That's kind of the general

thinking that it's important to keep stressing in a good way in an evolutionarily conserved way, that is, by stresses that have been normally encountered through millions of years, these transient short-term, mild energetic stresses, either the energetic stress of spending 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 diacetylases and his work showing that ketones have signaling functions,

and in fact, gene expression through modulating these enzymes called the acetylases. So fasting does the same thing. 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? Sure. The key thing for your viewers to understand is that when they see 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. Interment 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 fats from your fat cells and the ketones produced from those fat cells. So in a person that 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 or 9 o'clock, 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.

With intermittent fasting, the approaches that have been used in experimental studies, both in animals and 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 a 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 exercise in some instances. So daily time-restricted eating is one approach that can result in daily metabolic switching, daily elevation and ketones. So, for example, if a person skips breakfast, eats all their food between noon and 6 p.m. And if they were to measure their ketones, they'll find that in the morning they'll start to be elevated. 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 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, 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 two days a week, they'll only eat one moderate-sized meal of, say, 600 calories, those two days. then the other five days they eat normally. And so in that case, five-two intermittent fasting, the person will have the metabolic switching occurring two days a week, but not the other five. In fact, this five-two 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've done a lot of work in the 1990s and early 2000 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. 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 airflow 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 Harvey, who's in England and works with women at risk for breast cancer because of their overweight, and they also have a family history.

And she came to my lab. She'd seen our working animals. And there's also some working animals suggesting that fasting can be beneficial in suppressing cancer growth. So anyway, Michelle and I designed a study where we took these women, 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'd normally take in. And because we've 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 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 Walter Longo's lab and Krista Verdi's lab. And then, so that aired on the BBC, and then people in the UK got interested in intermittent fasting. And then all of a sudden, 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 2000, that if you Google Intermittent Fasting, the top hits would actually be scientific papers.

Now if you Google Intermittasting, 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 mine, Rafa de Kabo, 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 sufficient number of human studies of intermittent fasting, particularly in overweight people, to merit coverage of it. But the second reason was that many physicians were 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, you 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 Harvey in England, but also others, clinical people I've talked to, people, if they can get through the first couple 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. 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 the satiety. And we could talk about that. That's a whole other podcast. But one thing we found in pretty much all of our animal studies where we look at the brains, it takes a couple weeks before we see measurable changes in whatever, upregulation of antioxidant

enzyme levels, increased number of mitochondria neurons, increased number of synapses, improvements in learning and memory. Okay, so I'm going to stop talking now. Ronan, let you ask some more questions. Oh, well, this is 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, you know, starting an intermittent fasting sort of regimen and how, you know, you adapt to it and how that, a lot of that has to also do with some of the neuroendocrine changes in the satiety and hunger hormones, I guess, is, you know, grelin and leptin, you know, changing. Is that somehow linked to the production of ketones and this metabolic switching and it happening

easier? 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 is in rats. This was the one I was at the University of Kentucky in Lexington. 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 into 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 like one week of intermittent fasting, two weeks, and then three months. And And then we have these models where we can cause damage to nerve cells in 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 its levels are key. very high levels during red tide seasons where it's dry. And so there was these incidents in an incident in Canada where these people who had eaten shellfish at a restaurant develop memory loss, amnesia. And it turns out scientists traced this back to the first of the shellfish. They'd all eaten the shellfish. And then the shellfish had high levels of this cytotoxin. It's called

demolic acid, and they had high levels because they were 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 prescribed ketogenic diets for patients with epilepsy that don't respond well to the anti-epileptic drugs. Okay, so go ahead. Well, I was going to ask about whether or not you thought, you know, this metabolic switching,

which, you know, you're talking about the metabolism switching from, you know, glucose metabolism to metabolizing fatty acids that are, you know, releasing. from matapose tissue and, you know, in the liver, you know, that produces the ketone bodies, such as beta-hydroxybutyrate, you know, if that is something that can occur on a ketogenic diet, do you, what are your thoughts on the benefits of this metabolic switching from intermittent fasting, you know, in terms of, you know, can you get similar benefits by just doing a ketogenic diet or there are differences between the intermittent fasting and the ketogenic diet? 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, at least in some neural networks. in 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 on where do I go to find a prey animal or to find fruit on trees. you know, based on past, you know, so the ketogenic diet will not cause that increase in neural

network activity. The ketogenic diet, one thing it seems to do is enhance activity of what's called an inhibitory transmitter called GABA. So I'm going to give some like neuroscience 101. Oh, let me ask you, Rhonda. I'll ask you, I ask this question to people, this is not a curiosity and actually writing a book on this now, second book. Name a neurotransmitter besides GABA. Okay, just one, dopamine, serotonin, glutamate. Okay. The third one you name, glutamate is the most important neurotransmitter.

A lot of people have heard of dopamine and serotonin because dopamine links with addiction and serotonin's links with depression, but it turns out that at least 90% of the nerve cells in your brain deploy glutamate as a neurotransmitter. And those neurons are distributed in every brain region throughout the cerebral cortex, other brain regions, hippocampus, brain stem, basically gangly. 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 glutametergic 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 glutametergic neurons 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 glutametergic activity so much that your brain doesn't function well. So an example of that is drugs called benzodiazepines, like Valium. They activate GABA receptors.

So they quiet down the glutametergic 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 is called, that neurotrophic factor is called BDNF, brain-derived neurotrophic factors. It is the most heavily studied such nerve cell growth factor in the brain. And it is essential for learning in 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 we worry. 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 for cells than glucose. there's less, actually less free radicals generated, well, burning of 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 a good energy source for neurons and they have signaling functions, but those signaling functions are more limited than, then are activated by exercise or intermittent fasting or keeping your brain active. So you mentioned about the different types of metabolic stress, whether that be exercise or intermittent fasting and how, you know, there's an increase in BDNF in the brain.

Do you, in animal studies, and I kind of want to go back. to seeing, you know, what your thoughts are in translating, you know, these animal studies to humans. Obviously, animals have very different metabolic rates than humans. For example, if you were to, you know, fast a rodent for 20 or 48 hours, they lose 20% of their body weight, whereas a human would only lose 2% of their body weight from a 24, or 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? there is evidence that we've obtained that a combination of exercise and intermittent fasting can be better so i'll give you two examples that we publish one was we published a long time ago a former graduate student Alexis stranahan and she it was it's actually relatively simple that studies that design but we had normal mice and we had mice that 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 tells you you're full, stop eating. So these diabetic mice, leptin receptor, mutant mice, they don't get the stop eating signals, 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're fed ad libidin. They can eat as much as they want every day. Then she had a third group that were fed ad libidum,

and they had running wheels in the cages. And then the fourth group, she had ad libidum sedentary, ad libidum running wheels. Then she had every other day fasting sedentary, every other day fasting running wheels. Then she let them go for three months, and 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 in to the hippocampus. And that's where the initial, if you will, associations between a sight and a sound, you know, a bear jumping out on the trail and growling, you hear it's 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 studies is it's a focus of dysfunction

and pathology in Alzheimer's disease, epileptic seizures, even stroke in some instances. And a 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, you know, we put electrodes in the glutametergic neuron here and we stimulate a glutamatergic neuron down here. And we can record. And we can record. that we can activate a gab-ergic 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 that 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 increased 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. And I mentioned BDNF is important for learning in 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. She did not find that in the diabetic mice,

synapse levels came up to the level of normal mice. So there was some beneficial effect, but you couldn't get it back to like they weren't diabetes. Okay, so that's one example. Then the second example has to do with endurance exercise. And this work was done by former post hoc Christina Morosi and a postback fellow Keelan. So this, can you see this?

Yes. Can you see the whole picture? picture? I can. Yeah. So this is a running group from the lab about 2016 or something. Anyway, so the work I'm going to talk about now is done by Keelan, Moell, and Christina Morosi. Christina's not on here. She wasn't fast enough to make our A team. So what they did is they took mice and they had four groups, ad livenom sedentary, these were all normal mice, ad libidum sedentary, ad libidum daily treadmill training for 45 minutes every day for two 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. 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 tests.

How long can the mouth stay on the treadmill without giving up? And they found that, as you'd expect, the animals that had not done treadmill training had much, poor 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 treadmill training. And they measured ketones, which were elevated with intermittent fasting and the exercise. increase the ketone levels much more, almost twice as much, if, you know, when you take their

blood after the end of the treadmill training. And then they took out, they did 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 when you have the combination of the intermittent fasting and the exercise. 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 foods, these athletes were eating before exercising, they're very high in carbohydrates and oftentimes even 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, there was these adaptations were occurring even throughout the day when the people, when the, when the, people were not exercising. And so I've, you know, there was also some effects on, there were some, if people had exercised, fasted, but they were doing a very, very long sort

of endurance training type of activity, then there's some performance issues weren't as good as if they were, if they had exercised while, you know, in the Fed state. But, you know, since reading that meta-analysis, I've tried for the most part, you know, I do typically, I'll do a, you know, a three-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, um, yeah. So it's really interesting that you, your, your experiment that you, Yeah, one point you just mentioned is important, and this can occasionally get lost as these

conversations go on, and that is, it's a switching back and forth intermittently is important. The number, 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 in number of mitochondria. So they're switching back and forth between the metabolic challenge, whether it's fasting or exercise, and the recovery, eating, resting, sleeping. So there's definitely a limit to all of this.

Obviously, with fasting, starvation, 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. You've talked about the importance of what are, you know, called the refeating phase, both, you know, you and Dr. Walter Longa have discussed this in publications

and Walter on the podcast previously. And it's a really, like you mentioned, it's a point that a lot of, you know, people don't focus on that recovery period. How important, like, you know, for the, for the re-feeding 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? Well, these intermittent fasting eating patterns I'm talking about are kind of trivial

from an evolutionary perspective. that is limiting time window you eat to six to eight hours each day. You know, the remaining, whatever, 16 to 18 hours is more than sufficient to recover. If you fasted for, 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, and it's the same with exercise. It's, you know, my understanding is there's quite a few ultramarathoners who,

when they get in their 50s and 60s, start to have a lot of problems. So there, you know, there could be some, you know, 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, you know, any bounds of even getting close to having adverse effects and having to worry about am I recovering or not. But perhaps more of a, of someone doing a more of a prolonged fast, might have to consider, you know, the refeeding and how important.

Yeah. I know. There's a, in Europe, for example, in Germany, there are clinics where, People go in for a couple weeks and they'll fast for 10 days to two weeks under, 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. And 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 pass for longer time periods,

what frequency would be reasonable for long-term health? You've interviewed Walter 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 size 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, incorporated in their lifestyle? And 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 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, it, it you skip breakfast, then you can still have lunch with people at work and dinner with people where to, if you're doing something else, maybe like falters 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. So, yeah. Right.

It's a lot more challenging. One thing I want to get into, and you mentioned early, very, very. early on in the introduction, and I think we're getting there is diet composition and the question of if, well, there's good evidence. Yes, eating vegetables and fruits is good for hell. And why is that? and the emerging evidence that has kind of turned the load up on antioxidant idea on its head. So during evolution, it was two, we're omnivores, and the same would be true with other animals that are omnivores or herbivores. it is advantageous to be able to eat plant materials, fruits, nuts, roots, leaves, because they have energy. And 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 most plants, the most vital parts of the plants in terms of propagation of the species, if you were to eat those, they have a bitter taste. So, for example, the skin of grapes or apples and broccoli, you know, seed producing part, 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 is what they are. The plants are producing their own pesticides. So that's, 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 bitter taste. The second way is vomiting. third way, which is interesting from 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 cytocrine 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 sulfurophane, 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 it is is it activates antioxidant defenses in ourselves. 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 offenses. 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, 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 contrast with sugar or whatever, you know, any, a lot of other highly palatable addictive foods.

So anyway, I wrote, 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 there 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 stop up. free radicals because actually free radicals are important in ourselves for normal signaling and in our adaptive responses to stress. Instead, the chemicals that are good for health seem to be

acting by triggering mild adaptive stress responses in ourselves that overlap quite a bit with exercise and fasting. Yeah, and these are, these chemicals, again, they're concentrated in the exposed parts of the fruits, like the skin of the fruits. Yeah, oh, here's a really interesting thing, green tomatoes. All right, so bugs usually don't eat the 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 tomatoine that's highly concentrated in the green tomatoes,

and then levels of tomato deen declined 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 if, I guess mainly this applies to birds, but, so say a bird, 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. And they may poop out the seeds, you know, whatever, half a mile away. So now the tomato plants are, and that's, you know, so these are all evolutionary mechanisms that give advantages to one or both of the species. during their co-evolution. Is there, can you, if a person is exercising regularly and also doing some form of intermittent fasting and they're getting these activation of some of these stress response pathways and the beneficial effects and the 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 the, to eat the plant compounds because I'm exercising and I'm doing intermittent fasting.

I wouldn't, I wouldn't do that or say that. What hasn't been done, though, Ronda, is there, and the reason is it's, it's expensive. There haven't been studies where within a study,

they do all these various combinations, you know, of, okay, we're going to do this study with, we'll have some people intermittent fast, we'll have some exercise, we'll have some do both, we'll have some, whatever, take in sulfurophane or, and then we'll have them do sulfurophane 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, in 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. It's better to eat fish than red meat. And so complex carbohydrates are better than simple. I think that people shouldn't say, well, I can just eat at McDonald's every day if I exercise an intermittent fast because they would be better off than having been intermittent fasting and exercising. you know, if they're going to eat at McDonald's and don't want to give that up,

then exercise and intermittent fasting and will counteract that somewhat, but it's still kind of stupid. The way I also think about it is, you know, you have something like sulfurophane, which we've talked quite a bit about on the podcast. Yeah, I know, Jed, he's at Hopkins. Yeah, he's a good friend of mine. And so, you know, you have something like sulfuric.

that's activating the NRF2 pathway, which has, you know, you know, all these downstream effects on phase two, detoxification enzymes, you know, activating those and inhibiting the phase one biotransformation enzymes, which are involved in potentially making a pro-carcinogen, an actual carcinogen, you know, and all these, 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, there's, it seems as though different types of stressors do have a more robust effect on certain types of stress response pathways. Yes. And so getting, why wouldn't you want to diversify? Yep, that makes sense. Yep. Although I should, I should say that,

so go back to sulfur-fane and then I have to ARE pathway. That is activated by exercise. and fasting. And so I would say these chemicals that are in the plants are more targeted in what they do. Compared to exercise and fasting, those chemicals affect the more limited number of pathways. In other words, you can't just take sulfur-fane and it's going to substitute for exercise or intermittent fasting. Kind of shifting back just for a moment to the, to the fasting topic, do you, we've talked a lot about metabolically unhealthy people, 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? 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 all. always fed ad libidim and they're sedentary. So really in the animal studies,

the control group is couch potatoes. And that's why, you know, we look at, 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, you know, 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, is that applied to humans or a normal weight. What there have been, 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 and people already have a healthy body weight are going to be less than in people who are overweight. And the effects on improving glucose regulation in people with the people that are type to diabetes already have insulin resistance are going to be much quantitatively much greater than in 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.

Is that makes sense? It does, like difficult to even measure, you know, because as you've been discussed, 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, you know, also, you know, producing less reactive oxygen species because they're, you know, more energetically favorable or, you know, used easier by the mitochondria. It seems as though activating autophagy, as you mentioned, the, you know, the clearing away of, you know, damaged stuff and organelles and things like, you know, within a cell.

Like those, you know, sorts of effects happening, even if they're not, like, if the magnitude isn't as great, it seems as though, like, that needs, that has to be beneficial long term in terms of, like, activating stress response pathways and that are, they're going to help you deal with the stresses of aging better. Yeah, I agree. One thing that's being found is it's important to maintain muscle mass as you age. So I think people need to be a little bit careful to take insufficient energy to maintain their muscle mass. So, for example, the people in the calorie restriction society may be overdoing it.

then you know the story of Roy Walford, who was in Biosphere 2? You can tell the story. Okay. I can't remember exactly when it was 70s or 80s or 1980s. I can't remember. There's something called Biosphere where his two people down in Arizona, essentially they built this bubble and they grew plants in there. and the goal was see if they could be self-sustating 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 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 Windrick at University of Wisconsin,

showing that calorie restriction can extend lifespan. And then Roy Walford, what was it? So as you get older, your perception of, time is messed up. Roy Fawford died in, I'd like to say, like 15 years ago or something. ALS. Lugarig's disease. It's a muscle wasting disease involving degeneration of the neurons that innervate those muscles. And that was really interesting because, I mentioned these studies that we've done with intermittent fasting in 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 that made it worse. So, of course, these mice are destined to have ALS, so the kind of 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 I was 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 of dominoous muscle off my pubic bone and had adduct. partially coming off. I had to have three surgeries and I've had other issues now. So I've lost muscle mass, particularly my legs during this ordeal. And I'm having trouble. I'm building it back up. So in hindsight, it's 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 the 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, hey, as people started doing cross-string stuff, I didn't pick up on, hey, I should be working my core, and I should be, you know, keeping some muscle mass. You know, so all these years I was mainly just doing the same thing.

But anyway, so that's just like a personal anecdote. And, you know, so I guess what I'm saying is having a little body weight can be good, but you have to be a little careful during aging to make sure that you have a good muscle bass as part of that. Like the main, well, I guess I was mostly muscle mass anyway, but still, yeah, more muscle mass. It brings up a good point on some of the safety concerns with practicing intermittent fasting and certainly a prolonged fasting and whether or not elderly people, someone over the age of 70, can do a 5-2 type of fast or even daily time restricted eating and maybe they should be doing that along with resistance training if they even should do it. Do you have any thoughts on that? My thoughts are that exercise and a healthy diet would be more important for them. We don't know. The answers we don't know.

There have not been, there needs to be studies in elderly people of intermittent fasting, starting it in the elderly. So it's just not clear. So right now, the main focus, at least from mainstream medicine, is on people who are overworked. weight or with insulin resistance, there is some interest in, and also people at risk for cancers. 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, in as much 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 they're 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 a 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 then gets both the parents and the kid to switch their eating pattern. And he's had success in helping some of these kids get their body weight down by switching their eating pattern to interme. mid-pastity? Pregnant women, we don't know, but I would say if the woman is already doing intermittent

fasting, you can probably keep doing it during pregnancy. You know, it used to be that OBGYNs would tell women that are pregnant, okay, you should take it easy, don't overdo it. You know, you don't want to do much exercise. eyes. That's actually the way cardiologist used to deal with patients who have had a heart attack is take it easy on your heart. But we now know that it's actually good for pregnant women to get some exercise during pregnancy. And certainly if they're overweight, you know, that's not good. That's something I'm interested in. We publish an article on it.

So women with obesity and type 2 diabetes, there's increased risk of autism or having a child who's that is on the autism spectrum disorder compared to normal weight, healthy women. And that's very interesting. and I can send, I don't know, you can put stuff up on your website, Rhonda, right? Absolutely. 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? Yeah, and we also post them on the video. We put the figures and study titles and information. So whatever you're talking about, we're going to find. So, what? So when one looks at, 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 the 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 interactions, 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 increased incidence of autism and the increase in maternal obesity and type 2 diabetes, it tracks really well. You know, through the, you know, from very little maternal obesity in the 70s and 80s and then increase and increase autism. then 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 the mTORis

like the persons, if they have obesity, type two diabetes, they're undoubtedly not exercising or, you know, calorie-restricted. And so they never have the metabolic switching 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 hyper-exhaitability 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. Now, 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 increase 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 you bunch of other mice, the mouse goes in the corner and doesn't want to interact with the other mice. So you can kind of measure this propensity to interact, so kind of social withdrawal. And those mice in their brains, they have hyperactivity of glutametergic neuroses. runnal networks. So there is some evidence that kids with autism exercise can help them.

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 are, 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 the GABA tone. And ketogenic diets will do that too.

So it'll be interesting, I think it would be interesting to try intermittent fasting in kids with autism. Or perhaps a ketogenic diet as well. Very, very interesting, Mark. 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, you know, if women, you know, should fast or if it affects their cycle, menstrual cycle, or hormones like thyroid, things like that,

whether we're talking about like an intermittent fast that's more longer than time restricted eating something more like a maybe 24 to 48 hour or perhaps even a more prolonged fast. Do you have any thoughts about that? Yeah, major calorie restriction. So I'll start with animals then go to humans. So in animals, for example, had one, postdoc Bronwyn Martin in 2005 or something, she took rats and she put them on ad libidum 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 then she followed them over time. And then the females, She essentially did vaginal swab 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 ester cycles. The rats were with 40% calorie restriction. And this was over a period of like four or six months. they shut down.

They stopped cycling. And they lost a lot of body fat during over those months. Then the rats on every other day fasting, they kept cycling, but there was some increase in irregularity of the timing, 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, the males, even having 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 during over these months. So then she looked at act like this, 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 of the article. Okay, in the wild, if there's 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. If they get pregnant, there's no food that support, you know, development, their baby. So they shut down their cycling. They become more active looking for food. The males, the males, before the males starved the nest, it would be advantageous to them to be able to inseminate as, many females as possible before they die of starbations. So they stay for, so that's my interpretation of that.

You know, the female has the egg that's the potential passing the genes on. And, you know, so I don't know. But, and then, 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 kind of an obsessive, compulsive, like psychiatric disorder? The answer is we don't know. We just don't know. From an evolutionary perspective, you would think that would be selected against And it's not clear. I guess I don't know enough about anorexia nebosa, but, you know, how back in human recorded history,

how 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 Anineorexia, Abosa would be something that would not be strongly selected against during evolution. Right, because, and these girls,

they've usually quit cycling too. So I guess we just don't know. On the one hand, intuitively, it wouldn'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 it seems like it may be okay, but we just don't know. You're talking about with adolescent girls?

Yeah. Well, so what about women that are not adolescent? and are, 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 amenoretic 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? Well, in animals, that's what happens. So, for example, if we're to take these rats and do 40% calorie restriction for three months or four months, so that they stop cycling, and then you put them back, add libidum feeding, 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 this. Speculation. This is just thinking and not anything that's approaching 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 where this is a big thing that's lacking in this field is studying hormones, except for like simple things like leptin and gurellin. So for example, F-S-H-L-H-Oxytocin, anything to produce. Oh, we do know 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, Jay Wan Lee, who was a graduate student, when I was Kentucky, and then he came to Baltimore when they 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 into your cells. It could be a muscle cell, nerve cell, doesn't matter. and they bind to the receptor, 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,

geez, I'm blanking on the knee, they should know that Sue discovered this. Okay, so I mentioned there's two receptors for cortisol. One is called the gluca corticoid 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, whether it's 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 receptor, the MR, and an increase in GR. So the way that the cells are responding to the cortisol is changing, not just the cortisol levels. 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 libidum 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 to respond to bad types of stress, chronic uncontrollable stress. 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 alternative day fasting. You know, I think that's a really important point. distinguish because, you know, in the context what we were talking about with women's cycle, there wasn't really, you know, much of an effect on the cycle, alternate day fasting, which, by the way, in rodents is a much stronger, like a woman doing a 24-hour fasting and then alternate day would be probably much more significant of a fast in rodents, right? But anyways, the differences between and uncoupling the benefits.

and, you know, or just even... Wait a minute. I think you said it backwards. So it's a more significant fast in the rodents. Yes, it's a more 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 more. Yeah, much more. As you mentioned, mice, they die if they don't have food. if you 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. That's a big difference. So I'd say, you know, a day complete fasting could be, equivalent to like five days or something. I don't know anyway. Right. Well you know what I don't know if this makes sense to you Mark but if you look at some of

the work from for example Volta Longo when they've looked at 48 hour fast and the drop in IGF1 levels goes to about 50%. And in humans you know looking at what it takes to drop IGF1 to 50% it's in the order between 5 to 7 days

so, you know, perhaps that sort of thing. Yeah, and even with ketones, it's true that in the animals, ketones go up within an hour or two of fasting. Wow. Whereas in humans, it's obviously dependent on the exercise. 10 to 12, right. Yeah, so what I was sort of wanting to just touch on, for one, it seems as though intermittent fasting in the context of certainly daily time-restricted

eating and perhaps even, you know, doing, doing a 24-hour fast or 48-hour fast, shouldn't have much of an effect in most women that aren't caloricly restricting in addition to that and perhaps aren't doing, you know, running marathons or, you know, running 15 miles a day, you know, so, you know, so there's obviously a spectrum here when you're, when you're, 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, you know, if you're, if you're restricting your calories at the same time, it seems like that's right. That's right. 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 caloric restriction. Perhaps it depends on the, if you're doing something like a fasting mimicking diet or it's a pretty severe caloric restricted diet or if you're doing something like these caloric restriction societies do. It's very interesting. I don't know if you have you met Rafi de Cabo?

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. He 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, it takes, take 20 animals, you divide them into two groups, you over a period of a week or two determine how many food pellets each animal eats each day. Okay, then, 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, and 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 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 that are 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 eat pretty much twice as much food as they normally eat. And so they may, 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 pear feeding. But anyway, the bottom line is what we found is that we see, in those studies as the brain, we saw clear beneficial effects of intermittent fasting on the brain that were in the brain. independent of calorie intake.

You know, so we had animals that were on intermittent fasting, no change in calorie intake, and still saw. Actually, we did the epilepsy model and showed that it still protected the neuron, them against epileptic seizures, protected the neurons we still saw, decreases IGF1. I can't remember all the details, but yeah. And then I mentioned the study with Michelle Harvey 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 a reduction in calorie intake. What about uncoupling benefits of weight loss from intermittent fasting? We did that in the mouse study. Oh, the brain, yeah. Yeah. Yeah, that study could be done in humans.

You just have to, it hasn't been done. I think there was a time-restricted eating study done by, was it Veridae, University of Chicago. Oh, yeah, Krista Verdeh. 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 the cytoprotective mechanisms and, you know, these, you know, the adaptations and the metabolic

switching and the importance of all that. What are your... I'm going to 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 switched 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 libidum 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 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 and the time interval between individual heartbeats. So, for example, if your heart rate was 60 and mine was 60, that doesn't mean that, you know, 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. and then, you know. So,

initially, I guess it's kind of counterintuitive that it's a good thing to have variability between, then 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 of their heart is more adaptable to, change to stress and other changes. And so what happens, what happens is, and this has been known for exercise and particularly aerobic exercise, that the reason it causes 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 nerve slow down heart rate, the sympathetic nervous system increases heart rate. Okay, so we found the same thing with intermittent fasting. It enhances the parasympathetic nervous system. That will also, and that's through the vagus nerve, which is this big nerve coming down here, it intervates 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 hadn't talked about of 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 who, like me, who, you know, you exercise, regularly and then on 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 rates up like to 70. You know, so you got to stick with it if he can. Yeah, I just want to mention sauna use real quick because that's also been shown to do the same thing with the 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. So keep that in mind, but also just... I should do that. 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

with preserving the muscle mass, and then heart rate, your heart rate elevates. Surprise, surprise. Yeah. How bath can increase heat shock protein. Right. So, but I know you have to leave. I just wanted to ask you really two quick questions. questions. One, you're just rapid-fire thoughts on some of these so-called caloric restriction

or fasting memetics like resveratrol or spermidine or hydroxycitrate, 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. Well, the answer to the last part is easy. It's not different. I eat all my food within a six-hour time window,

and it's no simple sugars, you know, virtually no saturated fat, mostly plant-based, not vegetables, some fruits, fish. I do eat whole grains. I'm not so convinced that, You know, whole weed is bad for you. I don't think I have any gluten. Okay, then...

Do you do prolong fast ever, or longer than a daily time? Surprisingly, I haven't. Uh-uh. And then about, you know, trying to mimic effects of fasting, we've worked on this a little bit with two-deoxy glucose and with something called DNP. which is a mitochondrial uncoopler. 2Doxy glucose is a, it's glucose that it has a, it doesn't have a hydroxyl group that

glucose does. That's what it's called 2Doxy. But anyway, 2Doxy glucose 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 human, two deoxy glucose, cells in the animal, will think, they will experience effects of glucose deprivation because there's less glucose coming in.

And in fact, it will increase some of these protein chaperones, one called GRP 78, glucose-regulated protein 78. It's kind of like a heat shock protein. And we'd found that if we give two deoxy glucose every other day, it can be neuroprotective in some of our models, and we publish that. And then with Don Ingram, no, not with Don Ingram,

it was Don Ingram. He wanted to see if 2D oxygly glucose would increase lifespan. So he put it in the diet of animals, and actually it shortened their lifespan. It had some adverse effects long term on the cardiovascular system. So, now,

That's kind of mimicking calorie restriction at a 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 any thing 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 2deoxy glucose 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, I'm kind of, my advice is to stick with exercise, I think, intermittent fasting. can be helpful for a lot of people at keeping your mind intellectually gauge, 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, you know, rapamycin seems like it's something that in animal studies looks pretty interesting, but I'd be 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. 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 daily time restricted eating, maybe something similar to what you're doing or eating you eat within a six hour window or eight hour window every day would have an effect on human lifespan or at the very least health span? I would predict it would. And this is, again, this is in comparison to three meals a day plus snacks. And what if the three meals a day plus snacks are still exercising and healthy and you're still

metabolically healthy? Say that again? 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 at a lean, they're lean and metabolically healthy. 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, in animals that are herbivores, calorie restriction intermittent fasting,

have a striking ability to extend lifespan, running wheel exercise, and the animals run quite a bit every day. Not much. But the animals don't die from cardiovascular disease typically or diabetes. They die from cancer, cancers, kidney disease are kind of the two main cause of the death.

So inasmuch as exercise has really good effects on the cardiovascular system and glucose regulation. I wouldn't be comfortable extrapolating, you know, the animals to the humans because I think exercise is really important. Yeah. If you look at the observational studies, exercise. 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 on, you know, I mentioned my blood pressure is now up. It's not like, you know, high clinically, but it's high compared to, 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. Yeah, right. Thank you. Well, I 100% agree. When I exercise, it's almost, almost exclusively for the brain benefits. and mood for sure. And the other things are kind of healthy side effects for me. 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 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 and plants. You know, I've followed some of your podcast and video cast over the years and enjoy them. I think you're doing a big service to the general public and we need more people like you

are, you know, presenting things, you know, interviewing scientists and trying to present things and what's known, what's not known. There's a lot of garbage on the internet. And just like in an, so you are, you're beefing up the internet autophagy, maybe help clean up a little bit of the garbage. And I appreciate that. I appreciate that. I appreciate that a lot. Mark, and I know that you're in the process of writing a book, which is, you know, waiting for your proofs back. So I look forward to... Yeah, it's written. I'm done. I'm just waiting for the proofs. I'm looking forward to reading that and sharing it.

The second book is actually, you know, in the general public, I'm kind of best known through work on intermittent fasting, but that's like not... That's just the part of research over the year. So my second book is called sculpting. and destroyer, the story of glutamate, the brain's most important neurotransmitter. My postdoc work, I showed glutamate played an important role in and 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 the synapses form.

It was thought, okay, the nervous system gets wired up, there's synapses, and now there's neurotransmitters. But, yeah, so we showed glutamate pays an important role. And then, so that's the sculptor, and then glutamate's important in synaptic remodeling and learning in 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 the sodium and potassium back. What was your, your Ph.D. work was what? My PhD work was mostly cancer metabolism, mychondrial function. I did a lot on...

So in neurons, like, up to... It's been estimated 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 those ions back out after the neuron is fine. 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 and 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 this tendency for hyper-excitability. So anyway, that's a destroyer part of the sculptor and deseroyer. How much of a role would the GABA production from being in ketosis help negate that? Well, that's important. That's a good question. I think that from a drug standpoint, drugs that enhance gabatone could be beneficial. The trick is, it's a tricky business because glutamate is critical for learning and memory and it's, you know, all our circuits essentially are glutametergic,

so you don't want them to go out of control, but you don't want the activity to go too low, function isn't optimal. What about testing that with something like a ketonester to see, you know, transiently? No, we've done that. We, so Richard Veach in, I can't remember what year again. Anyway, bottom line is he sent a postdoc up to my lab and, what was his name, Kashi, Japanese postdoc.

And together with people in my lab, in a mouse model Alzheimer's disease, they gave the animals in the food, ketone ester or not. And then we had isochloric. And then we looked at the amyloid accumulation, the neurofibrilloid tangle, tau, and learning in memory. And the ketone ester was beneficial. And, no, I think the ketone ester is very promising. A friend of mine up in Canada, Steve Kunan, has done some really nice work with pat imaging. All right. So one can get images of relative levels of utilization of glucose by brain cells.

or of ketones. So Steve Kinnon used, he had radio-labeled glucose, two-deoxy glucose, and radio-labeled, he used acetoacetate, but it doesn't matter. He didn't use beta-hydroxybutyrate. Okay, so he had, these were just normal, initially normal people, but he's doing studies in people with mild cognitive impairment and Alzheimer's. So he had them, so 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, had shown that very early on, you know, people with mild cognitive impairment, 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 the 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 And he may be one of the places where these ketone ester studies are done. And then you know the, why am I blanking on her name? Karen Clark's work at Oxford with ketone ester and the elite British cyclist. So, yeah, that's a big deal in the endurance athlete. endurance athletes.

And, 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. It would be interesting to do, like a comparison of, you know, someone, you know, fasting versus ketone ester. You know, then you could sort out, you could maybe start 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, the bottom line is I think that's a really promising thing to focus. As you mentioned it, 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. I just, it's great. It's great speaking with you. So as a sort of 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 ketonester, 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. There's also, you know, before he passed away, Richard Veach, 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. Thank you for telling me this.

My father was diagnosed with Parkinson's. People can try it. I mean, it's not going to hurt them. 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've been, 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 going to try 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 will shake. 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 the standing. What about your grandparents? Did they have, you know, any of them have parking?

instance or the... No, not that we're aware of, no. Okay. Well, that's good. But I was going to tell you that I have convinced my mother to try the ketone ester and it does improve both her orthostatic tremor and her essential. Mostly it approves her essential tremor. But I use, I'm using that as...

Did you do a blind study? That is a great, 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 that she's getting it. She often has to taste it with something like a little bit of orange juice or something like that. So until the ketone esters, you know, it's just, it is hard. So there's definitely a potential for a placebo effect. But knowing what we know about the epilepsy and seizures and it seems very reasonable that it would help with motor displeasure.

and certainly what we know about mitochondrial dysfunction. So anyways, I'm, I've got these keystone 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. I just, that's sort of what he's naturally done, slash maybe even a little bit of caloric restriction, you know. So he's around the same age? He is 72. Okay. Yeah. And he was diagnosed. When was he diagnosed? When he was around, I would say 68. Yeah. About 68. Yeah. And so I've been, you know, exercise and all these things in the lifestyle that I'm trying to like help optimize, you know.

Yeah. 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 at the ketone esters. How can you instantaneously put someone in ketosis without a lot of work? That would be it, you know? So that's my little anecdotal. Okay, Rhonda. Well, anyways, yes, thank you so much, Mark. I will let you get to your next thing you have to do.

But can we please have another podcast and talk all about your destroyer and what was the second part? A sculptor. Sculptor. Thank you. And just, I really enjoyed speaking with you. It's really great to have conversation with you all about science. So I'd love to do it again if you're willing. Okay.

Maybe your colleagues there that are doing this learned a little too. Oh, I'm sure they're going to be super excited. Okay. So thanks so much, Mark. Okay. Bye, Rhonda. Bye. I want to take a moment to say a huge thank you to talk.

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