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

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

Download, watch or listen to M&M episode 139

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.


Full AI-generated transcript below. Beware of typos & mistranslations!

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 Mattson 1:06:21

Yeah, and that's kind of a so lower dose, much, much lower dose, hundredfold lower doses, we find are neuro protective animal models, and many drugs that humans that humans are prescribed. Now, you can overdose on. I mean, the opioids is we know all about that, right? You can die if you take too much. But there, there are many other drugs that can kill you. So there's always kind of this ideal range. In this case of a drug that's an induce inducing stress. But I think this is an idea in terms of, can we elites mimic some of the effects of exercise or, like restriction by the pharmacological movement? Yeah,

Nick Jikomes 1:07:13

I mean, if you have a Rube review, a review paper on hormesis, that was really interesting. In you know, you've got this really interesting table in there, where you talk about different drugs that seem to have, at least at certain doses have neuroprotective effects that might be able to mimic, you know, the hormesis like effects of things like fasting and stuff. And so this is a really interesting idea. And I want to ask you about some more of these drugs. So you just told us the the example of two for diametral phenol, it actually did help people lose weight, we know the mechanism by which it was doing that, and it had to do with mitochondrial uncoupling stuff you were just talking about. But of course, he then said, you can have too much of a good thing and people started overdosing on it. The other type of drug I want to ask you about because you have it in this table here. And it's also similar, I think, to the ones that are in the news a lot right now. Are these GLP. One, weight loss drugs. So can you tell? Is there anything interesting going on there? And are there any potential words of caution you might have given what you just told us about the other weight loss drug?

Mark Mattson 1:08:18

So one quick comment before the GLP one analogs? Okay, so back in the 1990s, we did the studies with called to deoxy glucose. So it's a molecule very similar to glucose, but it cells cannot use it to produce ATP. And there's, anyway, the bottom line is it competes for glucose in the cell. So if you feed it to an animal, the cells will think they aren't getting enough glucose or as much glucose as they had been. And in fact, if you give it to animals, it will cause them to start producing ketones. It tricks the whole system into thinking that there's not enough glucose around. And so we found that that to deoxy, glucose was beneficial in our animals of stroke, and Parkinson's disease anyway. Okay, so for the GLP one, analogs. So this is an interesting story. And I know a lot about it, because so I was a lab laboratory chief that the National Institute on Aging for 20 years. And so I had a big neuroscience lab with about 50 people in it or more. And one of the investigators in another laboratory, Josephine Egan to POCUS than diabetes, mainly from a clinical standpoint, she developed a GLP one analogue that is a protein that's similar to GLP. One, but its amino acid sequence is a little different. What is GLP? One glucagon like peptide one. It's a hormone that's produced by cells in your gut. It's released into the bloodstream when you eat a meal. And in particular, glucose seems to be the most important stimulator. So it's released into the blood. It does two things that are good for glucose regulation. Well, fairly directly. One is it stimulates insulin production by the beta cells in the pancreas. So GLP, one goes into the blood, that is playing an important role in that rise in insulin, when you eat a meal. So the insulins function is to stimulate cells. So they remove glucose from the blood muscle cells, liver cells and brain cells, whatever. Okay. Second way that GLP one improves glucose regulation, it actually increases the sensitivity of cells to insulin so that it takes less insulin to stimulate removal of glucose from the blood. I see. Okay. So, then,

Nick Jikomes 1:11:45

so is that so is that? Does that mean it improves insulin sensitivity? Yes.

Mark Mattson 1:11:51

Okay. It does. Okay. Yep. acts on your muscle cells, liver cells, even your brain cell to do that. Now, GLP, one itself, it doesn't stay around in the blood very long. The reason is there is a an enzyme called a protease, it cleaves the GLP one protein. And when that enzyme cleaves it, it's no longer able to act on

Nick Jikomes 1:12:20

sets. So your body releases it naturally after meals that are high in glucose. This, this thing improves insulin sensitivity. But it gets enzymatically broken down quickly. So it's not sort of meant to stick around for very long,

Mark Mattson 1:12:35

right. And so these, the, these GLP one analogs, essentially what they did is they changed the amino acids in the region of the protein where the enzyme cleaves. So it can't be cleaved. It can be cleaved. So it stays around for hours, hours, hours. And most of these are given by injection. There's even a once weekly, which is real nice for people with type two diabetes, right? Just subcutaneous once a week. That's it. Yeah.

Nick Jikomes 1:13:07

And so what So what other effects does GLP one have I? Because, you know, I would imagine, because I don't know all of the biology here, but presumably, it does other things. And are there any potential downsides or hazards that people should think about here? You know, especially given the history of, you know, you told us about the the 240 natural phenol drug earlier, there's been other weight loss drugs in the past that have done cannabinoid receptors, and they help people lose weight. But then later on, we learn, you know, X, Y, or Z goes wrong, and they have to pull it from the market. Yeah,

Mark Mattson 1:13:36

well, I can say there's we'll see what happens. It has been used in and diabetes patients for a decade.

Nick Jikomes 1:13:45

I see. Yeah. Oh, I see. So it has already been used for diabetes, per se. And it's now sort of been rebranded or CO opted in to the weight loss area. Yeah.

Mark Mattson 1:13:56

And the reason is a third action of GLP one, and that's on neurons in the hypothalamus that control appetite. It GLP one suppresses appetite.

Nick Jikomes 1:14:11

Which neurons is this acting up?

Mark Mattson 1:14:14

Ah, oh my gosh, would it be the so is it AGI which is

Nick Jikomes 1:14:22

ERP is the hunger promoting neurons?

Mark Mattson 1:14:26

Okay, so then it's the other ones. It's

Nick Jikomes 1:14:28

acting on pompom seen passing? Yeah, ya. Okay, so it's probably stimulating Pumpsie neurons. Yes, yes. I see. Okay. Yeah. And

Mark Mattson 1:14:40

yeah, so. Okay, so that's how it's acting. It isn't really acting in like a adaptive stress response. I don't, I wouldn't consider it like an adaptive stress response mechanism. On the other When we did find, we started to look at the effects of GLP. One and, and the first analog that was made at Nia called X sanitized or extended for on neurons first and culture and then in animals and found that it did have direct neuroprotective effects. In fact, based on a work that Nigel Gregg, who was in my laboratory, then there have been two clinical trials in patients with Parkinson's disease GLP one analogue and with promising results, they're doing a phase three trial. So I don't know about long term, you know, adverse effects. You know, for example, I don't think there's been much at all done in terms of cancers. So, anyway, so so far, it looks fairly safe, but I'm not promoting it. I promote exercise, eat a healthy diet composition, you know, moderation and calorie intake, maybe intermittent fasting. You know, I think Sun is good, I think the call exposures fine. Those, you know, you and I think are on similar wavelength when you start tweaking with some specific some hormone hormonal signaling pathway like that.

Nick Jikomes 1:16:33

Yeah, there can be unintended consequences. And often, you know, oftentimes, the, the biology is incompletely understood, we understand one piece of it, we don't even realize some larger picture belongs to like, for example, you know, naturally, as, you know, given my scientific background, like when I look at these GLP, one agonists, you know, you mentioned that they they have a specific protein domain that makes them rapidly cleaved by proteases. That evolved for some reason. Yeah, that's, that's not a design flaw. And so I would imagine that keeping these things around around, you know, conservatively, or at least for hours at a time, is probably eventually going to do something else that we don't even know about yet. Yeah. And, yeah, I want to ask you more about behavioral and lifestyle things, including what you do in your own life around diet and exercise. Before we get there. I want to ask you one more question about ketosis. So things that that we've covered. So far, we talked about what ketosis is, we talked about ketones like BHB, how they can be used in place of glucose. We talked about how going into ketosis can lead to a number of beneficial changes, decreases in oxidative stress and free radical production, increases in neuroplasticity, et cetera, et cetera. We talked about a lot of good things. Is there any downside to ketosis if you were to stay into ketosis permanently for days and days and weeks at a time? Are there any detrimental effects?

Mark Mattson 1:18:07

Well, in case of fasting, you know, starvation, you're starting to lose muscle mass when you get too low. But in the case of like ketogenic diet, yeah,

Nick Jikomes 1:18:15

if you're on a ketogenic diet, and you're getting your your caloric needs met, are there any? Yeah? Do those people have any symptoms? Are there downsides?

Mark Mattson 1:18:26

Well, if those people are eating a lot of saturated fat, there's downsides for the cardiovascular system? I think it's the my looking at the data. And there have been a lot of studies on this is not good. On the other hand, if you're eating good fats, omega three fatty acids, for example? I don't know. But I would think that you're not getting the stress recovery effects that you see with intermittent fasting. In other words. You're not really stressing, you know, you're

Nick Jikomes 1:19:15

only getting sort of one one side of the coin. Yeah. So I mean, it's based on everything that you studied. And we've talked about so far, it seems like you know, a lot of people get obsessed with trying to think about the right diet, like, should I be on the ketogenic diet? Or should I be on a high carb diet or some other diet? It seems like your point of view is probably that it's not so much about having a diet, it's about going through this pattern of challenging and then recovering and going through this sort of intermittent metabolic switching pattern. And, you know, perhaps the details of what your diet is, don't matter as much as making sure that you have that sort of back and forth pattern.

Mark Mattson 1:19:59

Now The details of the diet matter some. But regardless of the, of the composition, the diet, the intermittent fasting is beneficial in animal studies, for example, we put rats or mice on a diet were very high in saturated fat, but fructose in their drinking water, right? So it's like, and they become obese and diabetic, if we put them on intermittent fasting, that can, that has a very clear beneficial effect. On the other hand, if one looks at lifespan, the first of all animals on a McDonald's type diet, have a short lifespan, intermittent fasting can get to stand that somewhat, but it doesn't extend it as much as it does in rats and mice that are on a healthier diet.

Nick Jikomes 1:20:58

Let's see. So So in other words, you can you can extend the lifespan through intermittent fasting, even if you maintain a poor diet. So even if you're continuing junk food, if you just add the intermittent fasting can be longevity benefits, they're just not going to be as big as if you also change the diet.

Mark Mattson 1:21:15

That's true. But I'm not saying it's okay to eat.

Nick Jikomes 1:21:21

You know, so it's like, oh, you know, yeah, I'm not saying you're advocating that but like, let's say someone eats a very poor Western diet right now. Step one could just be start intermittent fasting. And step two can be then slowly start to substitute for different foods, and that each of those steps would move you in a good direction.

Mark Mattson 1:21:39

Yeah, that's right. Okay. And exercise. And keep your mind intellectually challenged.

Nick Jikomes 1:21:49

What? So you mentioned earlier, a few things about yourself. You said that, you know, you've been, I think, a runner for many years. And it sounds like you do daily intermittent fasting. Can you just talk a little bit more about what your current sort of eating and fasting schedule and exercise schedule is and how long you've been maintaining that?

Mark Mattson 1:22:09

Yeah, so I get up well, since I retired, I get up about seven in the morning. Then I write, or I have a podcast too, I do that. Anyway, that the mornings I kind of keep my mind intellectually challenged while I'm in a fasted state, then I exercise, usually for an hour between 11 and 12. And then I eat a meal. And then usually in mid afternoon, I'll have some healthy thing, the simple thing, Apple carrots, sometimes some whole grain, they go with olive oil or something and then dinner about six. And the composition my diet is it's mainly vegetables, nuts, fruits, fish. I do eat whole grains I mentioned. When we eat, I eat oatmeal. I'm you know, there's there's a lot of chatter, that you know that any grains is bad for you. But I'm on board with that. If you look at these blue zones, which I'm sure you've heard of these are spots in the world where the people living there have exceptional longevity. You know, these are, there's a number of these different Blue Zones. And, you know, so there's people with different genetic makeup and it's not just their, or whatever, Japanese or Asian heritage, but as far as diet goes, uniformly, those blue zones, their diet is mainly complex carbohydrates. Like 70 to 80% of their calories is complex carbohydrates in root things like sweet potatoes, beans, and, you know, vegetables, maybe some fruits now and they're, they're living 90 100 years old, there's a lot of centenarians and that so just from that alone, from the standpoint of humans suggests that you know, eating a diet that has a lot of carbs as long as you know, essentially no simple sugars can be healthy. So anyway, that's kind of composition. A then what else but then in in 2019, I had a I used to run a lot. Do a lot of trail running, I love running on hiking trail, and And I started to have some knee problems. So I switched to mountain biking and I had a crash on my I crashed my mountain bike. So this is 2019. And you know, so I'm in, in my 60s, right, and I'm riding on these highly technical trails I probably shouldn't have been riding on but you're, as you get older, Nick, you're young, still. But as you get older, you'll find that your your mind you still think you're young, but your reaction time you're Yeah, you're saying that your your balance coordination, they're declining, even though you don't necessarily notice it that much. But anyway, I had, I had to have three surgeries, and my my core muscles. And then that screwed up my gait, and then I get tendinitis in my tendons. And then this kind of a interesting story. It's just a personal story doesn't really have anything to do with intermittent fasting. But I've had pain issues in my whole life. Like, I've had to sit on a doughnut cushion for many decades, I even when I was in graduate school, I had like, really bad heartburn that seemed, even had endoscopy, and it didn't really look like any big things. And then I have the surgeries and, and the doctors were saying, Well, we're surprised you're having such severe pain, given what looks like on MRI or whatever. And so we did genome wide exome sequencing on me, that means I took my DNA and sequenced all the genes. And i Turns out I have a mutation in a gene that encodes a voltage dependent sodium channel that's highly expressed in neurons that convey pain, the nociceptive neurons. And this mutation, it's called a gain of function mutation. The bottom line is that the sodium channel which controls the depolarization of nerves, it opens more easily than a norm. You know,

Nick Jikomes 1:27:20

I see. So you have you have hyper, you have hyper excitable pain neurons. Yeah.

Mark Mattson 1:27:25

So I have a lot of pain issues now. So I've had them I guess I'm saying all that time, I've kind of had that modify my exercise accordingly. So now it's more just walking in and stationary bike where I can get my heart rate up, like 130, and sweat and stuff, and then I do some kind of other muscle toning stuff. Well,

Nick Jikomes 1:27:51

while we're talking about exercise, too, you know, we talked about the importance of going from, you know, challenging the body to recovery phase, right, so exercising your muscles, allowing them to rest, stimulating your neurons, allowing them to take a break, that that that pattern is very important when it comes to the challenge side, for your muscles and your cardiovascular system. So when you're exercising, I assume that you can exercise too much. And so what does that actually look like? And how does someone know if they are pushing their body too hard or too often?

Mark Mattson 1:28:29

I guess you can look at a single bout of exercise. So evolution did a good job in selecting out individuals who would die if they exercise in one bout of exercise. And that's you know, anybody who has been endurance athletes knows even endurance athletes, you your body and mind isn't going to let you go so far that you actually die, like acutely. It's very rare that happens. Sometimes it can happen in people but up usually they have some underlying cardiovascular problem, for example. But as far as, you know, training and how much is too much over time. You know, I'm not an expert on this actually. But kind of key thing is you don't want to injure yourself, right? You can get overuse injuries. I've had a number of those things. Mostly with me, it's a common thing, whatever, plantar fasciitis or this or that? Well,

Nick Jikomes 1:29:43

I mean, there's I guess there's two things here. I think there's probably just the common sense side like right, if you're doing something so much that you're in pain, you probably have gone too far. Yeah, the piece maybe that you can speak to more is, you know, we talked when we talked about intermittent fasting going on off On Off, is there something to be said about, say not doing? Let's say you're doing resistance training, you're lifting weights or something, is there a benefit, you know, having rest days in between exercise days versus having like two or three days of hard exercise in a row.

Mark Mattson 1:30:18

My understanding, and I'm not expert on that is yes, that is a benefit that have a long, particularly for resistance training, where you're, like, straining, actually physically damaging your muscles during that, and that's been shown, it may take several days, to get full recovery and grow, you know, build up the muscle fibers and strength and mitochondrial biogenesis. And all that aerobic exercise seems to be more amenable to daily, you know, fairly hard sessions. You know, so typically, endurance athletes will, I used to coach high school cross country, so I made the training weekly schedule there. And usually, it's like, you mix it up, you do, you know, some long runs that kind of just a moderate intensity, and then you will maybe do one day, you know, intervals, you know, at high intensity and those intervals, and then maybe throw in a one long run at higher intensity week. And I think those are just kind of standard ways that have been. And I think that's true, you know, that, far as injury goes. You know, if you do too much of speed, speed workouts, as runners, they're much more likely to get injured, particularly these high school kids who may not even be training in the offseason much. So and you got to build up, you know, they come in, in the file. And some of them they're supposed to, but they may not have run much during the summer. So like, the first three weeks to a month, you're mainly just going on long runs, and maybe there's some moderate, you know, short intervals, and then you kind of build up, because there's a lot of things going on there. It's not just your cardiovascular and respiratory systems, it's your muscles and tendons and, you know, their whole, the whole chain of things that are connected and how much stress they're being put on, relative to what they've been experiencing. You know, prior to starting,

Nick Jikomes 1:32:53

you know, we've we've covered a lot of ground when it comes to, you know, fasting and a lot of the underlying biology and stuff. When it comes to daily intermittent fasting. You know, how would you how would you summarize for the average person why or why not, they should do that, and what the major potential benefits are, if they start intermittent fasting, if they are used to the standard American pattern of just eating all day.

Mark Mattson 1:33:22

And when you start again, you'll you'll feel hungry and irritable during the time you hadn't previously been eating, that will dissipate. And within two weeks to four months, you will feel feel more alert, more productive, particularly during the fasting period, you're going to find you know, better mental clarity able to focus. If you start looking at health indicators that you have, they're overweight, particularly, you'll be losing fat and particularly belly fat, that abdominal fat around your waist, which is the bad fat, you'll have better glucose regulation. And you'll your blood pressure should go down, maybe resting heart rate go down somewhat. So you'll these are the benefits that you'll reap long term health benefits of better function and disease resistance of multiple organ systems plus, you know, better brain function over time. So you can be more productive in your job, which most people today Well, I would say, you know, they have to use their brain a lot and so it's really important to habit functioning well. Sounds

Nick Jikomes 1:34:47

like there's there's many benefits to doing daily intermittent fasting beyond just weight loss. So if you but the key thing to remember if in order to get there is that it's going to take at least a couple of weeks. Before your body gets used to it, and it doesn't kind of feel like a struggle and a pain in the ass, for your mind to just kind of learn to ignore those those hunger signals, it's, it's the only reason they're really there is because you've been eating food all the time up until this point. That's

Mark Mattson 1:35:15

right. And also another tip is to that you can deal with friends or workers or say, oh, let's let's do this together and like, talk about it now. And then I, back a number of years ago, soon after intermittent fasting became like a viral thing on the internet. There's multiple companies in Silicon Valley, where a lot of people are very health conscious. And they they just adopt the intermittent fasting eating patterns and kind of do it together. Some of that exercise, right? If you're dealing with someone else, often it's faster and easier to do than just doing it alone.

Nick Jikomes 1:36:04

Yep. Is there anything else? You know, anything that we talked about that you want to reiterate? Or do you that you think is worth mentioning again, so that so that people just keep it top of mind?

Mark Mattson 1:36:16

Yeah, if you have a few friends or relatives have some medical condition that evidence indicates is intermittent fasting can benefit, you might want to tell them about it. So there'll be obesity, type two diabetes. And also, there are many clinical trials going on. Now over 200 clinical trials of intermittent fasting are ongoing in various diseases, a lot of different cancers, a lot of inflammatory disorders, inflammatory bowel disorder, bills, disorders, like Crohn's, for example. What else, some looking at the brain, we actually have a study that was just submitted for publication where we looked at effects of intermittent fasting on the brains of people at risk for cognitive impairment, because they had obesity and insulin resistance. And we did a battery of cognitive tests, psychological tests, we did imaging their brain to look at size of different brain regions, and maybe more interestingly, at neural network activity using something called functional MRI. And then we did a lot of, we're doing a lot of blood work, and also are many of the subjects they agreed to pay us to do a spinal tap, where we can take the so called cerebral spinal fluid that bathes the brain. So we have measured some things in there and but there are other studies ongoing. So I think people Oh, and also talk to your physician about it. Increasingly, physicians have heard about intermittent fasting. And if they're not up on the science, if you're, if you're, say primary care physician is not up on the science, maybe you can get them up to date by sending them some articles or links to my book, but I'm various

Nick Jikomes 1:38:28

what is that? Is that the book behind you? What's What's the title? Oh,

Mark Mattson 1:38:32

yeah, that's the intermittent fasting revolution.

Nick Jikomes 1:38:37

Okay, great. The intermittent fasting Revolution by Mark Matson. Yep.

Mark Mattson 1:38:42

And, yeah, I that came out last year, when I was at the NIH that I mentioned at the big lab, I didn't have time to write a book on science, intermittent fasting, because I was so busy with lab and keeping things going and now the writing and so on. So even though we started the research in the 1990s, you know, I finally got around to writing books. So this is this is a science with like a couple 100 references and so on. So it's, I tried to write it so layperson can understand and hopefully, that there was a level that people can understand most of it and yet, you know, learn a lot, a lot of new things by reading.

Nick Jikomes 1:39:31

All right, well, Dr. Mark Mattson thank you for your time. This was fascinating and I definitely learned quite a bit.

Mark Mattson 1:39:38

Thanks, Nick. I enjoyed it. Take care and keep up the good work

Mind & Matter
Mind & Matter
Whether food, drugs or ideas, what you consume influences who you become. Learn directly from the best scientists & thinkers about how your body & mind react to what they're fed. New episodes weekly. Not medical advice.