00:00:00[Dr. Patrick]: Welcome back to another episode of the "FoundMyFitness" podcast. I'm sitting here with Dr. Mark Mattson, who is an adjunct professor of neuroscience at Johns Hopkins University. Mark, I'm so glad to have you here today. This is a long overdue podcast. I've been a huge fan of your research. As a scientist, you have made decades of contributions to our collective understanding of the benefits of biological stress and the supporting evolutionary theory of why almost all organisms actually need stress to thrive.
00:00:37There's a variety of topics that I know you to be an expert on, that I'm really excited to talk about with you today, including your understanding the place of plant phytochemicals and our genetic responses to them from a practical and theoretical perspective, your take on how the decades of caloric restriction in animals has panned out, and our attempts to translate that, those research findings, to humans, as well as intermittent fasting as a metabolic switch that has implications for overall health and particularly for brain health.
00:01:13So perhaps to kick things off today, maybe we could start or maybe you could explain why humans need some biological stress. And how maybe modern-day society has made that difficult to achieve. [Dr. Mattson]: Yeah, during evolution, organisms evolved in environments that were very stressful. Even from the simplest of microorganisms like bacteria, where they had to be able to tolerate changes in levels of salinity in the water, exposure to metals that are potentially toxic, like iron and selenium and zinc. And they evolved ways
00:02:03not only that they could resist the toxic effects of these exposures but actually benefit from them. So, for example, in the case of iron and selenium, we know that now that we need iron and selenium for proper health. But high levels of iron and selenium are actually toxic. And so, cells evolve mechanisms where they actually incorporate iron into proteins and use the iron adaptively in ways that help them cope with stress. In the case of selenium, for example, several of the antioxidant enzymes that is their proteins in our cells that are able to remove free radicals, those proteins
00:02:55themselves, the antioxidant enzymes, have selenium incorporated into them. So, that's one example. And then, as we move up the evolutionary tree into multicellular organisms and animals, they evolved in stressful environments. Two of the major stresses are actually food scarcity and predation and competition with other organisms. So, individuals that were able to best handle these kinds of stressors, and certainly food scarcity is a stressor and animals will starve to death if they don't get food,
00:03:44but that stress of the food scarcity is actually a motivating factor and nervous systems evolved to overcome food scarcity in many different ways. So, that is some examples of... And then, the case of exercise, individuals whose bodies function well in a food deprived state and environments where there's potential for predation, who are those that survived and pass their genes on. So, whatever it is those genes did that helped them perform physically well in a, you know, food deprived state had a survival advantage.
00:04:30[Dr. Patrick]: So, we, modern day, fast forward, live in a much different world where we have access to food 24 hours a day, all day, all night. We don't, you know, necessarily need to exercise to get our food either. We can just, you know, get in the car and drive somewhere. And we can even have our groceries delivered, you know, to our door. So, you've talked a lot about how this constant access to food and not having these periods of food scarcity, where people are not eating, may have detrimental consequences on overall health.
00:05:06[Dr. Mattson]: Yes. One way to look at that is that when we have food available all the time and when we don't have the need to exercise to get through life, our cells become complacent. And they do not maintain their ability to cope with the kinds of stressors that cause disease. Oxidative stress is one key example, inflammation. So, a good example is muscle cells and exercise. During the exercise, it's a major stress on the cells in the muscles. There's a big increase in free radical production. Cells are electrically
00:06:00active, the muscle cells. So, if they contract, so there's ion fluxes that have to be dealt with. However, having been exposed to that stress during the exercise, the cells activate gene programs that help them cope with stress and become stronger and more resilient. So, for example, exercise increases antioxidant defenses in muscle cells. It enhances the ability of the muscle cells to clear out damaged proteins, dysfunctional organelles, such as mitochondria, which are the energy-producing organelle in the cell. And as well, there are proteins that are initially
00:06:50called heat shock proteins, but their function is to protect other proteins from being damaged. So, all of these beneficial mechanisms are stimulated by exercise. So, in a person who's sedentary, they have reduced intrinsic antioxidant defenses. They have accumulation of molecular garbage in their cells, accumulation of mitochondria that aren't functioning well, and accumulation of abnormal proteins. And this is also true in brain cells, which is the main thing I studied, nerve cells in the brain.
00:07:34There is evidence that's emerging, some from my labs, some from others, that physical exercise, mental exercise, what you and I are doing now, Rhonda, keeping our mind intellectually engaged, we're right now exercising our nerve cells, they're more electrically active. There's more free radicals being produced in our brain cells right now than there would be if we weren't intellectually engaged. We're right now exercising our nerve cells. They're more electrically active. There's more free radicals being produced in our brain cells right now than there would be if we
00:08:02weren't intellectually engaged. But it's not only okay, it's a good thing because at the same time the cells are beefing up their antioxidant defenses, bolstering their mitochondrial function. In fact, we discovered that... And this was originally described by exercise physiologist and it makes sense. When you exercise regularly, your muscles get bigger, and in the case of endurance muscles, better endurance. And associated with that, there's an increased number of mitochondria, healthy mitochondria, in each muscle cell.
00:08:48So, that makes sense. The cells then are more able to generate the ATP to support their function. We find a similar thing in nerve cells. And most of this is from animal studies and so we're extrapolating to humans. But in animals, we can look more directly at the brain in kind of an intrusive way. And we find that running-wheel exercise, what we call environmental enrichment where we have the animals in cages where they have essentially like playground-type environment where they can maintain their mind more active.
00:09:33And under those conditions, exercise, mental exercise, there's an increase in the number of mitochondria in nerve cells. And associated with that, at least in some brain regions, there can even be an increase in the number of synapses between nerve cells, the connections between the nerve cells. Yeah, so, that's kind of the general thinking that it's important to keep stressing in a good way and an evolutionarily conserved way that is, by stressors that have been normally encountered through millions of years. These transient,
00:10:21short-term, mild, energetic stresses, either the energetic stress of expending a lot of energy during exercise or the more kind of subtle energetic stress of depriving cells of energy for some extended time period. And we can, I'm sure, we're going to talk about what's going on in terms of signaling pathways and, for example, ketones, which are elevated during fasting and during sustained exercise. And you mentioned you talked to Eric Verdin about his work with enzymes called deacetylases. And his work showing that ketones have signaling functions, in fact,
00:11:20gene expression through modulating these enzymes called deacetylases. So, fasting does the same thing. [Dr. Patrick]: Yeah, maybe we can kind of jump into that. So, you know, there's obviously different types of fasting. There's intermittent fasting, time-restricted eating, or even prolonged fasting. Do you want to kind of just maybe briefly describe some of those types of fasting? [Dr. Mattson]: Sure. The key thing for your viewers to understand is that when they see intermittent fasting, intermittent fasting is an eating pattern. It's not a diet.
00:12:08Oftentimes, in kind of the lay press and so on, intermittent fasting will be lumped in as a diet. But it's not a diet. It's an eating pattern. A diet is what you eat and how much you eat. Intermittent fasting is an eating pattern that includes intermittent periods of not eating, sufficient to deplete the glucose stores in the liver and cause a switch to the use of fat from your fat cells and the ketones produced from those fat cells. Right. So if a person eats breakfast, lunch, and dinner, and doesn't get much exercise, every time they
00:12:57eat they're replenishing the glucose stores in the liver and they may never tap in to the fat stores and, therefore, their ketone levels will remain low because the metabolic switch hasn't occurred. It typically takes at least 10 hours to deplete the glucose in the liver. So if a person eats breakfast, lunch, and dinner, and then has a snack around 8:00 or 9:00, you know, they may get up and eat breakfast and have not depleted the energy in their liver and have not switched to using fat. So, with intermittent fasting, the approaches that have been used in experimental studies, both in
00:13:51animals and in humans, are as follows: One, is called daily time-restricted eating, where the time window that one eats is compressed into, say, a six to eight-hour time period. So, that means the person would be fasting for 16 to 18 hours, which is sufficient time for this metabolic switch to have occurred. And scientists think, based on a lot of data, that this metabolic switching is important for health benefits of intermittent fasting, but also maybe even of exercise in some instances.
00:14:44So, the daily time-restricted eating is one approach that can result in daily metabolic switching, daily elevation in ketones. So, for example, if a person skips breakfast, eats all their food between noon and 6 pm. And if they were to measure their ketones, they'll find that in the morning, they'll start to be elevated. Okay. If they wake up and go for a run in the morning, they're already at or in, the metabolic switch has already occurred. So, they can actually enhance the effect of the fasting in terms of elevation of ketones.
00:15:34And we think, in terms of beneficial effects on the brain, the cardiovascular system, perhaps even physical performance, which is an area that is being studied now with intermittent fasting, there's very strong evidence that compared to three meals a day plus snacks, intermittent fasting is beneficial for the heart, and the brain, glucose regulation. But it's not completely clear yet whether it's beneficial for athletic performance. There's a lot of interest in that. Okay. So, let's get back to intermittent fasting eating patterns.
00:16:18Another intermittent fasting eating pattern is one that's now called 5:2 intermittent fasting. And this is where the individual, 2 days a week, they'll only eat one moderate sized meal of, say, 600 calories in those 2 days, then the other 5 days they eat normally. And so, in that case, 5:2 intermittent fasting, the person will have the metabolic switch occurring two days a week, but not the other five. In fact, this 5:2 intermittent fasting, in a sense, kind of triggered the popularization of intermittent fasting. And
00:17:06I'll just take a few minutes to kind of give a historical perspective. We'd done a lot of work in the 1990s and early 2000s showing that intermittent fasting was beneficial for the brains of animals. And we can talk about that, some details on that. And then, we'd also publish some work on intermittent fasting reducing resting heart rate and blood pressure and having anti-inflammatory effects. And then, I was approached by a number of clinical investigators. One was Jim Johnson, who worked with asthma patients. And, in 2007, we published a small study where we found that... These were overweight asthma patients, and we put them on a really rigorous
00:17:58regimen where every other day, they only ate 400 calories. So, that's not something that can be maintained as a lifestyle because it's very hard to maintain your body weight with that. But in these overweight asthma patients, over two months, it had profound beneficial effects in improving their symptoms, their air flow in their lungs. My lab, we measured indicators of oxidative stress and inflammation in the blood, which went down not right away but between two and four weeks of initiating that every-other-day metabolic switching regimen.
00:18:45Okay. So, we published that study. Then, I was approached by Michelle Harvie, who was in England, and works with women at risk for breast cancer because they're overweight and they also have a family history. And she came to my lab, she'd seen our work in animals. And there's also some work in animals suggesting that fasting can be beneficial in suppressing cancer growth. So, anyway, Michelle and I designed a study where we took these 100 women, and we randomly assigned them to either what's now called 5:2 intermittent fasting
00:19:35or we had a control group where we had them eat breakfast, lunch and dinner, but each meal had 25% fewer calories than they normally take in. And because we had done a calculation that the long-term calorie intake would be similar in the two groups, the group eating 600 calories two days a week versus the group eating three meals every day but reducing their calorie intake. Over six months, both groups of women lost about 8% of their initial body weight. And both groups had improvements in
00:20:18glucose regulation and other health indicators. But the women on 5:2 intermittent fasting had a greater improvement in insulin sensitivity and lost more belly fat compared to the group that was counting calories, if you will, every meal. Then what happened is a producer at the BBC, Michael Mosley, picked up on that study when we published it in 2010 or '11. And he did a documentary for the BBC, which aired in 2013 or '14. He came to my lab, and Valter Longo's lab, and Krista Varady's lab. So, that aired on the BBC.
00:21:06And then, people in the UK got interested in intermittent fasting. And then, all of a sudden, like, there's all sorts of things showing up on the internet on intermittent fasting. So, it used to be, before the work in the early 2000s, that if you if you google intermittent fasting, the top hits would actually be scientific papers. Now, if you google intermittent fasting, it's just like a bunch of random people who have some angle on it or so on. But the good thing about that is there's now a lot of interest from mainstream medicine.
00:21:47And I wrote an article, well, the end of 2019, together with a former postdoc of mine, Rafael de Cabo, a review article on intermittent fasting for "The New England Journal of Medicine." And the editors invited us to write the article for two reasons. One, there had accumulated a sufficient number of human studies of intermittent fasting, particularly, in overweight people to merit, you know, coverage of it. But the second reason was that many physicians are being approached by patients, asking the physicians about intermittent fasting.
00:22:36And in some cases, maybe many cases, the physicians really don't know much about it. They don't know that there's actually quite a bit of science behind it, both basic and clinical. And from a practical standpoint, they don't know how to prescribe intermittent fasting to a patient, and then follow up with them to try to help them switch their eating pattern. It turns out that in the studies, the ones I mentioned, particularly the ones we did with Michelle Harvie in England but also other clinical people I've talked to,
00:23:23people, if they can get through the first couple of weeks of switching their eating pattern, say two weeks to a month, they will no longer be hungry and irritable and maybe can't concentrate well during the time period that they've previously been eating. So, for example, if they decide, "Okay, I'm going to start skipping breakfast." For the first number of days, even a week or so, they're going to be very hungry, irritable in the morning. And the reason is, it takes time for your whole system, everything, to adapt to the new eating pattern.
00:24:07And a lot of that has to do with changes in the brain and the neuroendocrine systems that control hunger and satiety. And we could talk about that. That's a whole another podcast. But one thing we found in pretty much all of our animal studies where we look at the brains, it takes a couple of weeks before we see measurable changes in whatever upregulation of antioxidant enzyme levels, increased number of mitochondria in neurons, increased number of synapses, improvements in learning and memory.
00:24:53Okay, so I'm going to stop talking now, Rhonda, and let you ask some more questions. [Dr. Patrick]: Oh, absolutely, I have so many questions. You've brought up so many important and interesting points. But just to kind of speak to what you were just talking about, this sort of adaptation to perhaps starting an intermittent fasting sort of regimen and how you adapt to it. And a lot of that has to also do with some of the neuroendocrine changes in the satiety and hunger hormones, I guess, you know, ghrelin and leptin, you know, changing that. Is that somehow linked to
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, zu diesem Thema vielleicht in drei Jahren wieder. Ne, Witz, aber ich habe nach Sachen gesucht die ich lesen könnte und da auch etwas vor.
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