Metabolic Switching, Fasting, Ketosis, Neuroplasticity, Diet & Neurodegenerative Disease | Mark Mattson

About the Guest: Mark Mattson, PhD is a semi-retired neuroscientist at Johns Hopkins who ran a research lab at the NIH for many years. He wrote the book, "The Intermittent Fasting Revolution."

Episode Summary: Nick and Dr. Mattson discuss: intermittent fasting & diet; ketosis & metabolic switching; aging & neurodegenerative disease; exercise, stress, and neuroplasticity; and more.

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Mark Mattson 4:45

When I started reading literature on aging, and there had been Malson rat studies showing that daily caloric restriction, cutting back on calories in extended lifespan of rats When mice, by law if it's initiated when the animals are young, by kind of decreasing increments of its lifespan extension, the later it started in life. And then there were I'd also seen a paper from a group at National Institute on Aging, where I eventually ended up actually, where they showed that every other day food deprivation or every other day fasting, extended lifespan of rats and mice. And so, we had animal models that are relevant to Alzheimer's, Parkinson's, and stroke. And if you're interested and go the details, but anyway, the bottom line, we have models, either their genetic or neurotoxin based or in the case of stroke, it's actually a surgical procedure where you shut up the blood supply trenchantly to the brain. We found if we maintain rats or mice on every other day fasting, we started out by doing three months, and then we found we have to do it a minimum of two weeks to a month. But if we have them on intermittent fasting, and then for example, expose their brains to excitotoxins, in models of Parkinson's, or Huntington's disease, that neurons are resistant to the degenerating and the functional outcome is

Nick Jikomes 6:32

it's preserved. So being in the fasted state is protective against neurodegeneration.

Mark Mattson 6:40

Ah, yes, but we found it can be just a one time fast it, it has to be cumulative over a period of time. And we wait can get to a later but in all of our studies, and other people are finding this too. And it's even true to some extent in human studies that takes two weeks to a month of intermittent fasting to see robust effects on the brain and the heart. And, yeah, so anyway, we can talk about what's happening during those two weeks. Yeah,

Nick Jikomes 7:18

well, let's say let's say like, let's just start out with two simple things to orient people here. So first, can you just give us a simple definition of intermittent fasting, and then, you know, let's, let's say that someone starts intermittent fasting today, and they're gonna go for several weeks, let's just say they're gonna go weeks and weeks daily intermittent fasting, walk us through those several weeks in terms of what some of the major physiological changes are going to be?

Mark Mattson 7:43

Okay, good. So intermittent fasting, what it snot is a diet and diet is what you eat composition of your diet, and how much intermittent fasting is an eating pattern. And it's any eating pattern that results in frequent, often periodic periods without any foods sufficient to cause a metabolic switch from glucose, to fats and ketones. So in humans, that takes about 12 to 14 hours. If you're not exercising, this kind of normal daily activities. If you exercise a lot of people do this actually say you get up in the morning, after having not needing anything right now before and you go out the door and go on a run for an hour at some time during that run. So during the night, when you're sleeping, you'll be systems using glucose. And when you go on the run, initially, you'll be using glucose because you've only been fasting, say eight or eight to 10 hours. And then at some point in Iran, you're gonna it's gonna start switching the ketones and that are derived from the fats. Actually, I was kind of a amateur an endurance athlete. And this is kind of my explanation of some people, endurance events, they'll be they'll start to race. And they'll be feeling pretty good. And then there'll be some time period where there's like, a decrement in their performance. And then they'll get they'll get their second wind. So of course, I don't think it's a second one. I think it has to do with energy metabolism. So if you if you start the event, in not in a ketogenic state, and then you you're during the time you're switching from glucose to ketones. That takes time it doesn't happen like one second. Your cells are using glucose next year using ketones. There's got to be signaling that the The system essentially the liver, senses, depletion of glucose. And then fat released fatty acids into the blood. And that go into the liver converted to ketones. So that takes many, many minutes. 10s of minutes,

Nick Jikomes 10:18

submit so So from the point where you're actually running out of glucose, it's taking minutes before your body sort of senses that depletion and then switches you over to, to using ketones.

Mark Mattson 10:30

Yeah, many minutes, 10s of minutes. But anyway, so intermittent fasting, I'll give you a couple examples of for humans, typical intermittent fasting eating patterns that people are used, and a lot of clinical studies that we can talk about. One is a daily time restricted eating, where the individual eats all of their food with only say within, say, a six to eight hour time window. So they're fasting for 16 to 18 hours, which is enough to cause the metabolic switch to occur. I skipped breakfast. I've done that since I was a graduate student at the University of Iowa actually, and, and I exercise before ate lunch usually. So, you know,

Nick Jikomes 11:22

you're going, you're going at least partially into ketosis every day when you have that kind of pattern.

Mark Mattson 11:27

Yeah, that's right. And that eating patterns in people have a low body weight, or, you know, not much body fat, like me, you can get plenty of calories to maintain your body weight with 90 within a six hour time window each day. One meal, I can't really do its thing get enough calories to keep my body weight at. And, yeah, another example is that it's actually in a way led to the popularization of intermittent fasting being a thing on the internet. And it's called a five to five to intermittent fasting where a person two consecutive days a week, they eat only about five 600 calories. The other five days eat normally. So five to 600 calories is not enough to keep your your liver glycogen, which is glucose stores replete. So you'll be ketogenic on those two days. And so we did a study in collaboration with a group in England, in overweight women, genetically or based on family history anyway, at risk for breast cancer. So they're being overweight as a risk factor in itself. And they were randomly assigned to five to intermittent fasting or daily reduction in calories. But in that control group that people ate breakfast, lunch, dinner, and each meal had about 20% fewer calories than they would normally eat. So they're 20% calorie restriction.

Nick Jikomes 13:23

So they're eating, they're eating throughout the waking period, but they're doing portion control. So they're eating 20% less, and then the other people are on this five to schedule, but they can eat as much as they want, except on those two days. That's right.

Mark Mattson 13:34

And, and we figured kind of did a calculation that the weekly calorie intake of both groups should be about the same. And it apparently was because over a six month period of the study, their body weights decreased by the close to the same amount, about 8% of their initial pay to 10% of their initial body weight. So we saw improvements, a lot of health indicators in both groups, improved glucose regulation, improved markers of inflammation, so reduce inflammation, but the group and five to intermittent fasting had statistically significantly better improvement in insulin sensitivity and glucose regulation. So we published a paper in 2011. And then a producer at the BBC, named Michael Mosley is an MD. He saw, you know, he kept up on the literature, particularly things coming from the UK. And he picked up on that paper when it came out. And he did a documentary on intermittent fasting and aired on the BBC in 2013. I think it's called Well eat fast live longer. So he came to my lab. And Valter Longo was lab in California and crystal clarity up in Chicago and and he ended up doing the he tried, like doing this five days, consecutive days a month don't need hardly anything. And he didn't like he kind of liked that five to invest. He didn't. We didn't he didn't do the daily time restricted eating, which I think is easier for people to incorporate into their daily routine. Particularly if you're skipping breakfast, you just get up go to work. You can still you can still, you know, have lunch, and maybe a dinner at least early dinner with people and still get get the benefits. Yeah. So anyway, this metabolic switch from glucose to ketones defines whether an eating pattern is an intermittent fasting meeting. Yeah,

Nick Jikomes 16:05

so so so it's all based on Yeah, if you make the switch from using glucose to fuel your cells to using ketones, that's, you know, if you're not getting to that ketogenic state, then you're not actually fasting, you haven't gone long enough. Right? What so so I have a couple of questions here. Just to give people a sense for like the energetics and and how these different fuel sources are working. So you can use sugar glucose to run your cells, you can use ketones to run your cells. So question one is why? Why is glucose the default? Why do our cells sort of prefer to use glucose first, if they're given the choice of both?

Mark Mattson 16:46

Yeah, that's a good question. If it had, I think it's an evolutionary thing. You know, I mentioned it takes a while to mobilize the ketones. And a lot of this has to do like if you can sit or you're a prey animal. And there's a predator, and you have to escape from that predator, right? You don't

Nick Jikomes 17:08

have 10 minutes to get yourself together.

Mark Mattson 17:12

No, you don't have 10 minutes, it has to be really rapid in these hormones. I didn't mention adrenaline, or epinephrine. So when you're under stress, as you well know, Nick, your brain controls that stress response and causing release of adrenaline and cortisol from the adrenal glands, that happens very quickly, in less than a minute, and matter of over a period of seconds, it's starting to go. And the the adrenaline and the cortisol kind of work together. One thing that the cortisol do does is it kind of helps it, it promotes an increase in blood glucose. And so you get that rapid energy source available. So kind of the bottom line is, the glucose seems to be like a key thing in acute stress responses and survival under those conditions that the using fats and ketones is more of a long term survival mechanism, when an organism hasn't been able to acquire food for days or weeks or some animals, humans can go for a month or more without,

Nick Jikomes 18:40

you know, glucose can can be burned for energy more quickly. So in cases where you know you're in a life or death situation out in the wild, as a prey animal or something, then you need to suddenly use a lot of a lot of energy right now to engage in like a ballistic movement to escape a predator. Glucose would naturally be preferred, because it's going to enable you to do that quicker.

Mark Mattson 19:02

Yeah. And then in the case of athletes, then kind of one extrapolation of that is that sprinters and people who are doing things that require short bursts of energy, you know, they aren't gonna benefit much from being in a ketogenic state. Is

Nick Jikomes 19:25

that true? Yeah. Because the prediction would be that, you know, if you were a sprinter, you know, you're not going to break the world record if you're in ketosis.

Mark Mattson 19:32

Right? But, but on the other hand, endurance, if you're an endurance athlete, the converse may be true, and there's evidence for this and we can talk about why a lot of endurance athletes, especially ones that are making money, are using ketone ester. That's kind of a big thing now. Meaning

Nick Jikomes 19:56

like they're supplementing with ketones. Yeah. Okay. Yeah. Interesting. So, so fasting is defined by the switch from using glucose to using ketones. We just talked about sort of why the body might want to use one versus the other it has something to do maybe with you know, the dynamics of energy use whether or not you need it immediately right now all at once or or not. What is going on? When this metabolic like in the cells when this metabolic switch is happening? What are some of the more salient things that are happening at the cellular level when it comes to things like, say, inflammation, or, or getting into what's going on in neurons?

Mark Mattson 20:41

Okay, so I can there I can talk about changes that occur with during, like a single period of being in a ketogenic state versus intermittent metabolic switching over periods of weeks and months. Okay. So the ketones, as you said, are fuel for the cells. And couple of things happen. One is so called ketones and glucose, are used in the mitochondria to produce ATP. When ketones are used, they're less free radicals produced by the mitochondria, per amount of ATP, produce

Nick Jikomes 21:35

ketones. So if I start fasting today, when I'm going into ketosis, you know, 10 1214 hours later, there's going to be a reduction in the amount of free radicals that mitochondria produce.

Mark Mattson 21:46

Yeah. And there's also signaling. This is evolutionarily thinking, it's kind of an interesting thing, that there's a lot of evidence now that ketones, they're not just an energy source for neurons for ourselves, like neurons or whatever. So there are also have signaling functions, that is to say they can affect the expression of genes. In cells, they can either turn them on or off. So ketones can turn off or on genes. And a number of genes are being identified. You know, hopefully, we'll talk a lot about the brain, which is what my expertise is. My own lab. Well, let's go back, there's there's a scientist out in California Eric Burdon, who he was like, one of the first people to recognize their signaling functions for these ketones, they affect gene expression. And he has evidence that these ketones actually affect kind of the organization of the structure of the DNA, I guess you'd say in the nucleus by modifying proteins are called histones. And so that's one thing we found that keep main ketone, beta hydroxy, butyrate, or BHB. It will activate two transcription factors. In neurons, one is called crab and the other is called NF kappa B. Crab is very interesting from the standpoint of neurons because it's well known to blame play important roles in neuroplasticity, the learning and memory, the formation of new synapses, or even a process called neurogenesis where new neurons are produced from stem cells.

Nick Jikomes 23:48

That's it. So crab Crab is like a signal that tippet anything that induces something like neuroplasticity, creb will often turn on creb will be the thing that sort of turns on the genes you need for that plasticity, the things that are going to result in like more protein in the synapses. So you're saying the ketones can directly trigger that cascade of

Mark Mattson 24:05

events? That's right. And NF kappa B is an interesting story. It was initially I'm discovered and talked a lot about by people who study blood cells. And there it was, does it can have a pro inflammatory effect, it can promote inflammation, but it turns out, it can also, interestingly, prevent cell death. So it's kind of makes sense. And we, we've found in cultured neurons that if we activate NF kappa b by pre treating them with a inflammatory cytokine, called TNF tumor necrosis factor that that will actually protect the neurons against excitotoxicity protect them against metabolic stress. And so the previous work on NF kappa B and mainly they had shown associations between activation of NF kappa V, and bad things going on in a tissue like inflammation. But that association didn't establish cause and effect. And scientists, even scientists can jump to conclusions like this. They could say, oh, NF kappa B is activated in these inflamed tissues that must be causing or contributing to the inflammation or be a bad thing. But it turns out it's, it's actually an adaptive stress response. The NF kappa B activation, the cells are responding in the case the neurons to t and f which can potentially cause problem in a way that make the neurons more resistant to stress in general. Anyways, so the ketones, we found keto and the way it activate, we found that it increases the production of BDNF, which is a neurotrophic factor a protein produced and released from neurons that promotes the growth and survival of the neurons that release it or adjacent neurons. With it interacting with we found that ketones induce production of BDNF, BDNF.

Nick Jikomes 26:41

I see. So in general, it seems like the ketones are turning on pathways in the cell that have to do with growth

Mark Mattson 26:48

and plasticity. Yes, and stress resistance, stress resistance, yep.

Nick Jikomes 26:55

Okay, so you've got more plasticity, you've got more stress resistance or resilience of the cells. And then that's also coming with less oxidative stress because you've got fewer free radicals.

Mark Mattson 27:06

Yeah. And these are kind of the cute things that are happening, well, relatively cute over many, many minutes, two hours in a ketogenic state. But then I mentioned early on that. It takes, for example, improvements in insulin sensitivity, reductions in blood pressure, we can talk about that neuroprotective effects we've seen in my lab. Those, we don't see these for these two weeks to a month after the initiation of intermittent fasting.

Nick Jikomes 27:44

I see so so most of the effects you're talking about. If you go into ketosis once, like today, you won't necessarily see all the those things happening, you need to be doing this day by day for an extended period.

Mark Mattson 27:56

Yeah. And, and we've written a lot of papers on this kind of maybe the most important one was the New England Journal of Medicine review article that I wrote with a colleague of mine raffled, acabo. And that was in 2019. And one point we made in there is, we think, and elsewhere, we publish that the reason it takes so much time, weeks, months or more, let's see, you know, see the kinds of changes you want to see when you go to the clinic and talk to your doctor and he does blood work, you know, major glucose measures or measure your blood pressure and so on. So, these intermittent periods or daily time restricted eating, for example, sell for a certain time period each day, say four to six hours are in the ketogenic state. And during that time, pathways are activated in neurons that other cell types have put kind of enhance their stress resistance and also help them conserve resources. For example, proteins protein synthesis goes down. That's because mTOR pathway which maybe people have heard about, goes down. So in the fasted state cells go on to conserve resources, stress resistance mode autophagy is increased mTOR, which is kind of a key pathway where amino acids are that stimulates amino acid uptake and protein synthesis that's turned down and but then in the recovery period eating after fasting, then things are switched back into a growth and plasticity mode. Protein synthesis goes up. So cells can produce a new protein as they need to grow. Since our atomic energy was increased during the fasting period, garbage has been cleared out. We think during the recovery periods when mitochondrial biogenesis occurs increase in the number of new mitochondria, in cells, sort of switching back and forth between conserve resources, stress, resistance, and growth and plasticity mode over time, is what can help optimize health. And this is analogous to exercise, Nick, I mean, so your muscle cells don't get bigger. During exercise, they get bigger during the recovery. But if you don't get exercise, they're not going to get bigger, stronger and healthier.

Nick Jikomes 30:53

During the recovery phase. During the recovery phase. It's all about these repeated bouts of stress, rest, stress rest.

Mark Mattson 31:02

Yep. And in the case of fasting, it's a it's a stress, you know, mild, moderate, it's something that we've about to experience, same as exercise, right. And for those reasons, those two particular things we can do seem to have robust effects on health and disease resistance. And it's because those are, probably I'd make the case the two most important things that that we had to be that organisms have to be able to do when they're in a stressful condition, no food. Right? They have to be able to resist that stress, keep but keep functioning at a high level. Yep. Right. So we're geared for that. Yeah. And also, in the case of neurons dislike when you exercise your muscles, when your neurons are active, that's a stress on them. There's big sodium influx calcium influx free radical production, you know, there's a big increase in energy demand.

Nick Jikomes 32:24

Yeah, so I mean, almost, I think almost what you're saying is, you know, at a cellular molecular level, you know, studying really hard thinking very hard problem solving, using your neurons is almost analogous to, you know, resistance training or exercise of your muscle cells.

Mark Mattson 32:38

It's aerobic, or aerobic training, or aerobic training.

Nick Jikomes 32:42

Yeah. So it's this acute stress, that if it's coupled with being followed by this rest period, which you know, for your brain would literally mean going to sleep at some point. That's where that's where the growth actually happens. So it has to be sort of triggered initially with the stressor, the active use of either the muscle cell or the neurons. But that growth will only happen afterwards in the rest phase.

Mark Mattson 33:07

Yeah, exactly. Yeah.

Nick Jikomes 33:11

And so what can you I want to you've written a lot about this, and it's fascinating. And I think that helps people think about, like, why things are set up this way. You know, like, why do we even have these different metabolic modes? We go into? Why do we have to, you know, acutely go into Active mode, and then rest mode? You know, is it because all of this stuff was baked in to our behavior naturally, so if we think about humans living as traditional hunter gatherers, and they're basically in their wild state, when we think about wild animals, they don't have civilization, they don't have this infinite abundance of food. So they're constantly, you know, going out and exercising in order to get their food, and they're stopping to eat their food. And just based on the natural cycles of feast and famine out in the wild, people were forced to engage in intermittent fasting, whether they wanted to or not, is that how we start to think about why our biology works this way? Yes,

Mark Mattson 34:06

I think that's an important way to think about it. It's always important to go back and try to ask the question, Well, what was a vantage, or, you know, what explains why things are the way they are? And in biology and life actually, you gotta go back to our evolutionary roots. And also, you know, so I would consider eating breakfast, lunch and dinner and an evening snack, very abnormal. From an evolutionary perspective and our genetic constitution. We didn't evolve with that eating pattern. So it's very unnatural. And our systems what essentially what I've used the word ourselves As an organ systems become complacent they aren't. They're essentially in the growth and growth mode all the time. And they're never having, you know, the stress resistance, conserve resources mode. So. So for example, we talked about oxidative stress. And this is done in animals where we can directly look at the cells and look at Mount of oxidative stress in the cells. But when animals are fed ad libitum, they have food available all the time. And particularly as they age, the ability of the cells to remove free radicals is comp is not good as they age. But if you put them on daily calorie restriction or every other day of fasting, as they get old, their ability to get rid of free radicals is maintained. And what I'm talking about specifically there is that we have genes that encode proteins that their job is to remove free radicals, the antioxidant enzymes, and both. Interestingly, both exercise and fasting will stimulate those genes.

Nick Jikomes 36:25

I see. So we have now we have natural antioxidants that get triggered to to do what they do when we stress our bodies, either through fasting or exercise, which is kind of interesting, because normally people think about antioxidants as only things that you eat. You're saying that we have endogenous antioxidants that actually come bubble up from the inside?

Mark Mattson 36:51

Yeah, so there are chemicals a few and and fruits and vegetables that can directly squelch free radicals. But there aren't very many vitamin D is one vitamin A. But these other chemicals that people sell the the food supplement, dietary supplement industry that kind of have it right, but not exactly. So you'll see on the shelves now. sulforaphane, or curcumin? Yep. Right? Resveratrol, yep, et cetera. And they have antioxidant on the bottle. But those chemicals don't directly squelch free radicals. In fact, what they do is they, they cause a stress on the cells. And the cells increase production of their own antioxidant enzyme.

Nick Jikomes 38:03

I see. And so I guess the two things come to mind there. So one will so just to sort of repeat what you said and reiterate what you said, you're saying that many of these things marketed as antioxidants like resveratrol, which is like the the so called red wine molecule. They're not actually antioxidants, per se. They're stressing the cells so that the cell uses its own endogenous antioxidants. The two things that come to mind there for me are one, I know that a lot of these compounds, including resveratrol, actually have very low bioavailability. So whether they can do this is one thing, but if they're not actually getting into our bodies, they're not doing it as much as we think they are. And then coupled to that is what you just told us about fasting. So fasting is an exercise reliable ways to get this endogenous antioxidant production up. And I think that's really important to emphasize, because those are reliable behavioral methods to do use these antioxidants that we haven't dodged, honestly, but people are sort of used to and trained to think about, oh, to get antioxidants, I have to go buy a supplement or I have to eat something.

Mark Mattson 39:10

Yeah, they're trained that well, they're trained by the advertisements, right? And, you know, I wrote a, there's a whole interesting evolutionary thing with this coevolution of plants and animals that eat plants, insects, herbivores, omnivores like us. And I wrote an article for Scientific American in 2015. And kind of the take home message is that many of the chemicals that are in the skin of fruits are the kinds of sensitive parts of that vegetables, vulnerable parts like broccoli sprouts or heads. The reason those chemicals are in Well, first of all, they have a bitter taste. And second, the reason they're in the plants is to keep insects and us for meeting any or much of that plant, right. And

Nick Jikomes 40:14

that's what the bitter taste really is, right? From an evolutionary perspective, it means don't eat too much of this.

Mark Mattson 40:18

Yeah, and even caffeine, you know, is a really good insect anti feed. And if you put tea leaves or coffee beans, or even, you know, smash up the coffee beans, or certainly if you put pure caffeine on your kitchen table, the ants aren't gonna go anywhere near him. And, but sell sulfur Fein has probably been the most studied with regards to this. So as a bitter taste, it's in, you know, if you've ever eaten broccoli sprouts, they're pretty bitter taste right? And right, but there's been a lot of research on sulforaphane and very convincing evidence that y y is good for sales imposes oxidative stress on the cells. And they respond by activating genes that encode antioxidant enzymes. And specifically, there is a what's called a transcription factor that is a protein that stimulates genes. That transcription factor is called NRF. Two. And sulforaphane essentially activates by causing oxidative stress activates that transcription factor that then bolsters antioxidant defenses. So that's one clear example where there's this chemical that definitely acts through this pathway. So for things contrast, or is very child's a little bit more bioavailable. That means that, when we eat it, a lot of it gets into our system, and our cells will be exposed to it. So yeah.

Nick Jikomes 42:16

So when we think about sort of this intermittent metabolic switching, so you know, it sounds like the ancestral state, or the natural state of human beings, and probably pretty much all animals is some level or some pattern of intermittent metabolic switching, you know, animals out in the wild, don't have all of the food they need all of the time. So in some sense, we're not built to just live in that state of food surplus. Thinking about I want to get back to ketosis. So we sort of talked about intermittent fasting going into and out of ketosis, you know, every day or two, let's say, What happens if you go into ketosis and you stay there for more extended period of time. And the first sort of piece of this I want to ask you about is, you know, I'll remind people who don't know, the ketogenic diet has actually been known, I think, for a long time going back to the ancient Greeks to be a way to treat epilepsy. And so it's clearly it's been known for a long time, it's doing something in the brain, and it has this effect on epilepsy. Before you get into the details there, let me just ask you, if somebody just goes into just through dieting, goes into ketosis for one day, two day, three days, maybe several days, what does it feel like? Does this what are sort of the psychoactive effects here? Is your mind affected in terms of your ability to feel like you have mental clarity or mental energy? What does it actually feel like subjectively?

Mark Mattson 43:45

Are you making a distinction between ketosis due to, you know, in a fasted state of ketosis induced by essentially eating a lot of fat? But

Nick Jikomes 44:01

well, I mean, I'm not sure let's just assume it's let's assume it's through fasting initially, but if there's a difference there, I think that's that's worth talking about.

Mark Mattson 44:08

Yeah. If the person normally. So for example, if you normally breakfast, and you've done that for years and years, and then tomorrow, you don't eat breakfast, you're gonna feel hungry and irritable in the morning, maybe can't concentrate. And that's true. And this has also gets back to this two week to a month situation. If you are adapted to intermittent fasting over a period of several weeks. Then in the morning, they're adapted to not eating breakfast. You will, you won't feel hungry. You'll be more alert, better able to concentrate and focus on what you're doing. Many people will find that but you have to get adapted to it takes time. You studied neuro endocrine system, right? Yes. And those those changes. There's all sorts of hormones involved in rigging up regulating appetite, right? Leptin, and ghrelin, leptin, tells you your, your fall, don't eat any more ghrelin goes to your hypothalamus. All these changes occur, and yeah, you perceive your, yeah,

Nick Jikomes 45:31

it takes time, it takes time for all these systems to switch and to orchestrate all the changes that will get you to the next steady state.

Mark Mattson 45:39

Yeah. How's it does with exercise? If you've been sedentary, and you go out and try to run, even three miles, you probably won't be able to do it, you, you won't feel good. And you may say, Well, I don't like that I'm not going to do that anymore. Right? Right. It's kind of same idea with fasting, you know, you got to kind of stick with it and get, get adapted to it. And then once you're adapted, feel your brain will function really well. It's very true with exercise. And what kind of the nother way to look at this, Nick, is that everybody knows this, that after you eat a meal, particularly if there's carbs in it, you feel sleepy off, right? Yes, a big carb heavy meal, right? So sleepy is the opposite of your brain being sharp and functioning? Well, so they can focus on what you're doing. So, you know, just looking in again, get back to evolution, that makes sense that, okay, and animals, whatever, wolves have killed a buffalo and eaten, you know, they can just, they can sleep for a while, and they, their brain doesn't have to, they're good to go for quite a while. So again, this all kind of makes sense. But, and then, you know, for us, we don't like to feel hungry. And but that's hunger is there for a reason, right? It's kind of a motivator. Yeah. Yeah. motivator to get food. But But interestingly, once you're adapted the short, very short term fast, right? Whatever, 16 hours, once you're adapted to that, you won't feel hungry. Actually, I think a lot of people I've talked to myself included, you'll appreciate the food more when you do eat it. Yeah.

Nick Jikomes 47:40

Yeah. I mean, it's like, I think everyone. It's easy to forget this. But I think everyone knows it from experience. It's also just kind of common sense. Right? Like, the more you're deprived of something the the sweeter it is once you get it. Yeah, that's right. Yeah. I mean, yeah, when you're dying of thirst, that glass of water is, you know, like, unlike anything else. And you know, likewise, if you force yourself to be a little bit hungry, hungrier for longer and more frequently, when you do sit down to eat the the tastes are just enhanced, literally.

Mark Mattson 48:09

Yeah, we're intelligent beings, we can put off a reward if we know that it benefits us to put off the reward.

Nick Jikomes 48:19

That's right. Yeah. So the other thing, so I want to ask you about here that's related to metabolic switching, and ketosis. All the stuff that we've been talking about is, if we think about the average American today, the average American, you know, for many, many decades at this point, is been eating, you know, the so called Western diet, which just means it's calorie dense, and it's freely available. We're essentially never the average American eating, the average American diet is essentially never fasting. So we always have glucose in the system to use as energy. We're never going into ketosis. If we're like the average person, what is the connection there, if anything to chronic disease in general, but neurodegenerative disease in particular, things like Parkinson's, things like Alzheimer's, you were getting into that earlier, but is there a connection between never being in intermittent metabolic switching never being in ketosis and developing these neurodegenerative diseases later in life?

Mark Mattson 49:22

Yeah, there's, well, I can kind of divide this up into animal studies and human studies. So in humans, epidemiological studies, pretty convincing now that people with obesity and insulin resistance are at increased risk for Alzheimer's and age related cognitive impairment. Of course, they're also bigger risk for stroke because of the cardiovascular effects atherosclerosis and And they're, they're in a state of chronic inflammation. They're in a state where their cells are not able to deal with free radicals very well, that can actually increase risk for cancer. So that's one thing that's very clear, this western type eating pattern being in navigating into a ketogenic state. That's a big risk factor for most cancers, we are the major cancers, cardiovascular disease, diabetes. And in the case, so Parkinson's, the data is far as the data a little less clear, but we do see in our animal models that intermittent fasting protects the dopamine producing neurons. So

Nick Jikomes 50:54

just a quick question on the cancer side. IE, is it fair to I mean, it seems common sensical to make that connection? To me, it seems very natural to think, Okay, if we're always in feeding mode, if we're always supplying our body with all this energy, well, cancer is just unrestricted growth. So if we're always in growth mode, we're going to be more likely to push things in the cancer direction is that essentially what you just said there?

Mark Mattson 51:20

That and also, there's this two stage model for cancer development that's kind of generally accepted as that. Step one is there has to be some damage to genes, some mutation, that that mutation is in a gene that's involved in controlling cell growth and survival. And so that's step one. And then step two is that there has to be a mechanism to keep the cells in a growth mode. So I guess step one is mutation and then go into this continuous growth mode. If you deprive cancer cells of glucose, in a in a ditch, then in a culture dish, they can be very easily it will inhibit their growth, they can be easily killed by radiation or chemotherapy. I see. So it's not up to you if you give them ketones in case a mouse cancer is not all there. They're still susceptible to being killed by that. The radiation? Yeah, so the

Nick Jikomes 52:44

cancer cells, maybe even more, so the non cancer cells really want to use glucose. So if you don't put you know, even even if the cancer is there, like you've created, you've created the cancer through mutation, if it doesn't have the fuel to power that hypergrowth it's much more easily susceptible to being taken out either by the immune system or by radiation or some some kind of medical treatment.

Mark Mattson 53:10

Yeah, and that it's been shown clearly in animals you can in animals, you just you take cancer cells, and you put them into the animal under the skin and a tumor will fall on them are in case like glioblastoma, brain cancer, you can put glioblastoma cells in the brain and tumor will form and, and and the intermittent fasting and daily calorie restriction will slow the growth of the cancers. And there's many human clinical trials ongoing now. Dozens actually,

Nick Jikomes 53:48

where they're actually using fasting as part of the treatment itself.

Mark Mattson 53:52

Yeah, yeah.

Nick Jikomes 53:53

Why wouldn't like so I've rarely heard this talked about outside of conversations like this with people like you. You know, I, I've seen people with cancer. You know, I've talked to many people who know people who've had cancer or have had cancer themselves. I've never encountered someone out in the wild who's had cancer and survived it. Or you know, someone who's, you know, who I've known who's had cancer. I've never encountered a situation where their physicians were telling them anything about diet or recommending fasting or anything like that. Is that just not part of the normal medical for today? Or is the evidence there? Yes.

Mark Mattson 54:36

It's so in our western medicine, predicting the United States is probably the worst health care system around in a major industrialized country. That's our profit driven throughout, unfortunately. And so you've got big pharma making drugs You've got the fast food industry, making things that elevate our glucose and probably do other bad things to us. And then you've got congressmen being lobbied being lobbied by these industries, and then the healthcare system themselves, is it scared? There's no prevention in mind or risk disease risk reduction, your insurance won't cover your whatever going to a gym every day or you know, whatever. For example, in, in people in lower socio economic status, particularly in inner cities, right. They can't even get vegetables, very high a car, you know, they're relatively expensive, and so on. So there's no insurance that will, you know, help them have a healthy and the affordable,

Nick Jikomes 56:06

the affordable and available foods are exactly the foods that will cause chronic disease. Yeah,

Mark Mattson 56:11

that's right. And there's not there's no mechanism, there's a lot of industries pushing that in a way that task food industry directly the pharmaceutical kind of indirectly, in that they won't make any money if people don't get sick. Right, they, they make money by someone getting a cancer being diagnosed with whatever. diabetes or cardiovascular disease, you know, yeah.

Nick Jikomes 56:44

Yeah, they do the best when there's an extended treatment that requires many, many interventions over time. Right.

Mark Mattson 56:52

Right. So, you know, education is, you know, what you're doing right now? I mean, it's, it seems like we're kind of fighting a insurmountable battle, but, you know, people can be educated and motivated, and kind of encouraged that to change that. One part of this too now is it's transgenerational, right. So kids, that they grow up, if their parents, you know, for whatever reason, you know, don't exercise and eat mostly junk food. Those kids are highly likely to adopt the same patterns. Yep. Right. And what you learned during those formative years, often sets the stage for the rest of your life. So there has to be some mechanism, method mechanism put in place to address that. You know,

Nick Jikomes 58:04

you know, switching gears a little bit, or at least on the theme of staying on the theme of, you know, thinking about prevention, and the maintenance of health. You know, we've talked about intermittent fasting and fasting in general, we've talked about exercise, how if you stress the body in the right way, in the right pattern, it can actually have adaptive effects. I think the technical term for this is where Mises and you've written about this, but on this general subject of hormesis, and challenging the body in intermittent fashion. Another type of challenge, I think, is really interesting. And you're definitely seeing this in certain parts of the culture has to do with things like temperature and hypoxic stress. So I want to talk about temperature for a minute and how that affects things like just physiology in general, but things like mitochondrial health, and metabolism. A lot of people are getting really into things like ice baths, you know, going into the cold on purpose. They're getting into things like saunas going into the heat on purpose. Is this a type of stressor that's analogous to things like exercise that will have actually potentially adaptive, beneficial effects?

Mark Mattson 59:17

The short answer is yes. They are the benefits of heat or cold exposure. You know, intermittent heat and cold exposure relative to exercise and fasting I think are not as great. But there are benefits Wait, we've got a sauna, infrared sauna, and I usually do it every other day. Or so for like 4550 minutes get up to like 130 140 degrees. So you sweat. So I'll start with heat. So there are some there's these proteins called Heat Shock proteins are very well known. Huge literature on this and they were discovered, it's pretty simple people. They, they had cultured cells, and essentially put them in, they'd have one incubator at, like normal body temperature. Yep. And then another incubator, it's a would be the equivalent number like 105 degrees Fahrenheit body temperature. So that's not outside, that's the actual body temperature. And then I just, they looked at changes in gene expression. And they found the certain set of genes, heat shock genes that are responsive to this, they call it a shock, Ki Chung, heat stress. And this happens pretty quickly, within 10s of minutes of changing temperatures, these heat shock proteins go up. And then the function of these heat shock proteins is pretty interesting. It prevents the formation and accumulation of misfolded proteins. In Alzheimer's disease, Parkinson's disease, Huntington's disease, one clear problem is that the neurons are accumulating misfolded proteins, misfolded proteins. And so that's pretty interesting. You know, we never did that. We, I don't think those experiments have been done of like taking a mouse model of Alzheimer's or Parkinson's, and then, you know, doing what, kind of the equivalent of a human, you know, get once a day or whatever it get. Elevate the outdoor temperature. So that,

Nick Jikomes 1:01:57

yeah, daily mouse

Mark Mattson 1:01:59

side, and then and then do that long term and see, but it would be interesting.

Nick Jikomes 1:02:04

Well, the prediction, I guess the prediction would be that if you were to do this before the development of disease, you would either prevent it or push it

Mark Mattson 1:02:14

out in time. Yes, that's right. Yeah, what about cold calling is interesting, too. Right. So there, I'll talk about some proteins called mitochondrial uncoupling proteins, or ucps. I'll try to streamline this as well as I can. So rats and mice, they don't force some animals don't shiver in the cold. They will actually generate heat. And specifically, they're these cells called brown fat cells that are producing the heat when the temperature goes down, outside lot. And well, essentially, when the body temperature starts to go down. So what's happening there is when the body temperature starts to go down, the genes that produce proteins called uncoupling proteins are turned on and the uncoupling protein, what it does is it causes the mitochondria to produce heat instead of ATP, or produce heat, in addition to some ATP, okay. Okay, so these brown fat cells, which these rodents and other animals have, a lot of humans don't have much of these brown fat cells. Interestingly, we found that in neurons, it kind of did the opposite experiment, I talked about putting cultured cells in a hat we took, we took cultured neurons from the brain Varone brads. And we put them in the refrigerator. Alright, and then our we had controls that we didn't put in the refrigerator, and then we took them out of the refrigerator. And then we I can't remember how long we incubated them for a while longer. Then we looked at gene expression, and we found that uncoupling protein was increased. Okay, but then, we found that using a drug that activates uncoupling protein, in the absence of any change in temperature, okay, so we take temperature out of the equation, if we activate the uncoupling protein directly, it ProAct protects neurons. against a variety of types of stress. And in fact, there's there's a company now that's doing clinical trials of this drug. It's actually a very well known drug in chemistry. And it's called to for die nitro phenol or DNP. And people actually used to take this to lose weight. Now, because they cause uncoupling, so there'll be essentially, the calories that will be used for generating heat, and their body temperature goes up, they lose weight. But a few of these people had the bright idea, okay, I'm taking this amount of DNP. And I'm losing, whatever, two pounds a week. Hey, I'll take a lot more and I'll lose. You know, in two weeks, I can lose 40 pounds. And they

Nick Jikomes 1:05:58

died. Because they just overheated.

Mark Mattson 1:06:01

Yeah, essentially, they Yeah, yeah.

Nick Jikomes 1:06:04

So okay, yeah. So there's a weight loss, there was a weight loss drug to for die nitro phenol, it affected mitochondrial uncoupling protein, it did cause them to lose weight. But you can't have too much of a good thing. So people were essentially overdosing on this drug and overheating.

Mark