Dr. Mark Mattson on the Benefits of Stress, Metabolic Switching, Fasting, and Hormesis

[Dr. Patrick]: Welcome back to another episode  of the "FoundMyFitness" podcast. I'm sitting here   with Dr. Mark Mattson, who is an adjunct professor  of neuroscience at Johns Hopkins University. Mark, I'm so glad to have you here  today. This is a long overdue podcast.   I've been a huge fan of your research.  As a scientist, you have made decades of   contributions to our collective understanding  of the benefits of biological stress and   the supporting evolutionary theory of why almost  all organisms actually need stress to thrive. There's a variety of topics that I know you  to be an expert on, that I'm really excited   to talk about with you today, including your  understanding the place of plant phytochemicals   and our genetic responses to them from a practical  and theoretical perspective, your take on how the   decades of caloric restriction in animals has  panned out, and our attempts to translate that,   those research findings, to humans,  as well as intermittent fasting   as a metabolic switch that has implications for  overall health and particularly for brain health. So perhaps to kick things off today, maybe  we could start or maybe you could explain   why humans need some biological stress.   And how maybe modern-day society  has made that difficult to achieve. [Dr. Mattson]: Yeah, during evolution,  organisms evolved in environments that   were very stressful. Even from the simplest  of microorganisms like bacteria, where   they had to be able to tolerate changes in  levels of salinity in the water, exposure to   metals that are potentially toxic, like iron  and selenium and zinc. And they evolved ways   not only that they could resist the toxic effects  of these exposures but actually benefit from them. So, for example, in the case of iron and selenium,  we know that now that we need iron and selenium   for proper health. But high levels of iron and  selenium are actually toxic. And so, cells evolve   mechanisms where they actually incorporate iron  into proteins and use the iron adaptively in ways   that help them cope with stress. In the case of  selenium, for example, several of the antioxidant   enzymes that is their proteins in our cells that  are able to remove free radicals, those proteins   themselves, the antioxidant enzymes, have selenium  incorporated into them. So, that's one example. And then, as we move up the evolutionary tree  into multicellular organisms and animals,   they evolved in stressful environments. Two of  the major stresses are actually food scarcity   and predation and competition with other  organisms. So, individuals that were able to   best handle these kinds of  stressors, and certainly   food scarcity is a stressor and animals  will starve to death if they don't get food,   but that stress of the food scarcity is actually  a motivating factor and nervous systems evolved   to overcome food scarcity in many different ways. So, that is some examples of... And then, the case  of exercise, individuals whose bodies function   well in a food deprived state and environments  where there's potential for predation, who are   those that survived and pass their genes on. So,  whatever it is those genes did that helped them   perform physically well in a, you know, food  deprived state had a survival advantage. [Dr. Patrick]: So, we, modern day, fast forward,  live in a much different world where we have   access to food 24 hours a day, all  day, all night. We don't, you know,   necessarily need to exercise to get our food  either. We can just, you know, get in the car   and drive somewhere. And we can even have our  groceries delivered, you know, to our door. So,   you've talked a lot about how this constant  access to food and not having these periods   of food scarcity, where people are not eating, may  have detrimental consequences on overall health. [Dr. Mattson]: Yes. One way to look at that is  that when we have food available all the time   and when we don't have the need to exercise to  get through life, our cells become complacent.   And they do not maintain their ability  to cope with the kinds of stressors   that cause disease. Oxidative stress  is one key example, inflammation. So, a good example is muscle cells and exercise.  During the exercise, it's a major stress on the   cells in the muscles. There's a big increase in  free radical production. Cells are electrically   active, the muscle cells. So, if they contract,  so there's ion fluxes that have to be dealt with. However, having been exposed to that stress during  the exercise, the cells activate gene programs   that help them cope with stress and become  stronger and more resilient. So, for example,   exercise increases antioxidant defenses in muscle  cells. It enhances the ability of the muscle   cells to clear out damaged proteins, dysfunctional  organelles, such as mitochondria, which are the   energy-producing organelle in the cell. And  as well, there are proteins that are initially   called heat shock proteins, but their function  is to protect other proteins from being damaged. So, all of these beneficial mechanisms are  stimulated by exercise. So, in a person   who's sedentary, they have reduced intrinsic  antioxidant defenses. They have accumulation of   molecular garbage in their cells, accumulation  of mitochondria that aren't functioning well,   and accumulation of abnormal proteins. And this is also true in brain cells, which is the  main thing I studied, nerve cells in the brain.   There is evidence that's emerging, some from my  labs, some from others, that physical exercise,   mental exercise, what you  and I are doing now, Rhonda,   keeping our mind intellectually engaged,  we're right now exercising our nerve cells,   they're more electrically active. There's  more free radicals being produced in our   brain cells right now than there would  be if we weren't intellectually engaged. We're right now exercising our nerve cells.  They're more electrically active. There's more   free radicals being produced in our brain  cells right now than there would be if we   weren't intellectually engaged. But it's not only  okay, it's a good thing because at the same time   the cells are beefing up their antioxidant  defenses, bolstering their mitochondrial function.   In fact, we discovered that... And this was  originally described by exercise physiologist   and it makes sense. When you exercise  regularly, your muscles get bigger, and   in the case of endurance muscles, better  endurance. And associated with that,   there's an increased number of mitochondria,  healthy mitochondria, in each muscle cell. So, that makes sense. The cells then  are more able to generate the ATP   to support their function. We find  a similar thing in nerve cells.   And most of this is from animal studies and so  we're extrapolating to humans. But in animals,   we can look more directly at the brain in kind of  an intrusive way. And we find that running-wheel   exercise, what we call environmental enrichment  where we have the animals in cages where they have   essentially like playground-type environment  where they can maintain their mind more active. And under those conditions, exercise,  mental exercise, there's an increase in   the number of mitochondria in nerve  cells. And associated with that,   at least in some brain regions, there can  even be an increase in the number of synapses   between nerve cells, the  connections between the nerve cells. Yeah, so, that's kind of the general thinking that   it's important to keep stressing in a good way  and an evolutionarily conserved way that is, by   stressors that have been normally encountered  through millions of years. These transient,   short-term, mild, energetic stresses,  either the energetic stress of   expending a lot of energy during  exercise or the more kind of subtle   energetic stress of depriving cells of  energy for some extended time period. And we can, I'm sure, we're going to  talk about what's going on in terms of   signaling pathways and, for example, ketones,  which are elevated during fasting and during   sustained exercise. And you mentioned you  talked to Eric Verdin about his work with   enzymes called deacetylases. And his work showing  that ketones have signaling functions, in fact,   gene expression through modulating  these enzymes called deacetylases.   So, fasting does the same thing. [Dr. Patrick]: Yeah, maybe we can kind of jump  into that. So, you know, there's obviously   different types of fasting. There's intermittent  fasting, time-restricted eating, or even prolonged   fasting. Do you want to kind of just maybe  briefly describe some of those types of fasting? [Dr. Mattson]: Sure. The key thing  for your viewers to understand is that   when they see intermittent fasting, intermittent  fasting is an eating pattern. It's not a diet.   Oftentimes, in kind of the lay press and so on,   intermittent fasting will be lumped in as a diet.  But it's not a diet. It's an eating pattern. A diet is what you eat and how much you eat.   Intermittent fasting is an eating pattern that  includes intermittent periods of not eating,   sufficient to deplete the glucose stores in  the liver and cause a switch to the use of fat   from your fat cells and the ketones  produced from those fat cells. Right. So if a person eats breakfast, lunch, and dinner,  and doesn't get much exercise, every time they   eat they're replenishing the glucose stores in  the liver and they may never tap in to the fat   stores and, therefore, their ketone levels  will remain low because the metabolic switch   hasn't occurred. It typically takes at least  10 hours to deplete the glucose in the liver. So if a person eats breakfast, lunch, and  dinner, and then has a snack around 8:00 or 9:00,   you know, they may get up and eat breakfast   and have not depleted the energy in their  liver and have not switched to using fat.   So, with intermittent fasting, the approaches that  have been used in experimental studies, both in   animals and in humans, are as follows: One, is called daily time-restricted eating, where  the time window that one eats is compressed into,   say, a six to eight-hour time period. So,  that means the person would be fasting   for 16 to 18 hours, which is sufficient time  for this metabolic switch to have occurred. And   scientists think, based on a lot of data,  that this metabolic switching is important   for health benefits of intermittent fasting, but  also maybe even of exercise in some instances.   So, the daily time-restricted  eating is one approach that can   result in daily metabolic switching,  daily elevation in ketones. So, for example, if a person skips  breakfast, eats all their food between noon   and 6 pm. And if they were to measure their  ketones, they'll find that in the morning,   they'll start to be elevated. Okay. If they  wake up and go for a run in the morning,   they're already at or in, the  metabolic switch has already occurred.   So, they can actually enhance the effect of  the fasting in terms of elevation of ketones. And we think, in terms of beneficial effects on  the brain, the cardiovascular system, perhaps   even physical performance, which is an area that  is being studied now with intermittent fasting,   there's very strong evidence that compared to  three meals a day plus snacks, intermittent   fasting is beneficial for the heart, and the  brain, glucose regulation. But it's not completely   clear yet whether it's beneficial for athletic  performance. There's a lot of interest in that. Okay. So, let's get back to  intermittent fasting eating patterns.   Another intermittent fasting eating pattern is  one that's now called 5:2 intermittent fasting.   And this is where the individual, 2 days a week,  they'll only eat one moderate sized meal of, say,   600 calories in those 2 days, then  the other 5 days they eat normally. And so, in that case, 5:2 intermittent fasting,   the person will have the metabolic switch  occurring two days a week, but not the other five.   In fact, this 5:2 intermittent  fasting, in a sense,   kind of triggered the popularization  of intermittent fasting. And   I'll just take a few minutes to kind  of give a historical perspective. We'd done a lot of work in the 1990s and early  2000s showing that intermittent fasting was   beneficial for the brains of animals. And we  can talk about that, some details on that.   And then, we'd also publish some work  on intermittent fasting reducing resting   heart rate and blood pressure and  having anti-inflammatory effects. And then, I was approached by a number of  clinical investigators. One was Jim Johnson,   who worked with asthma patients. And, in 2007,  we published a small study where we found that...   These were overweight asthma patients,  and we put them on a really rigorous   regimen where every other day, they only ate 400  calories. So, that's not something that can be   maintained as a lifestyle because it's very  hard to maintain your body weight with that. But in these overweight asthma patients, over  two months, it had profound beneficial effects   in improving their symptoms, their air flow in  their lungs. My lab, we measured indicators of   oxidative stress and inflammation in the  blood, which went down not right away but   between two and four weeks of initiating that  every-other-day metabolic switching regimen. Okay. So, we published that study. Then, I was  approached by Michelle Harvie, who was in England,   and works with women at risk for breast  cancer because they're overweight and they   also have a family history. And she came to  my lab, she'd seen our work in animals. And   there's also some work in animals suggesting that   fasting can be beneficial in  suppressing cancer growth. So, anyway, Michelle and I designed a  study where we took these 100 women,   and we randomly assigned them to either  what's now called 5:2 intermittent fasting   or we had a control group where  we had them eat breakfast,   lunch and dinner, but each meal had 25%  fewer calories than they normally take in. And because we had done a calculation  that the long-term calorie intake would   be similar in the two groups, the group  eating 600 calories two days a week   versus the group eating three meals every  day but reducing their calorie intake. Over six months, both groups of women lost  about 8% of their initial body weight.   And both groups had improvements in   glucose regulation and other health indicators.  But the women on 5:2 intermittent fasting   had a greater improvement in insulin  sensitivity and lost more belly fat   compared to the group that was counting  calories, if you will, every meal. Then what happened is a producer at the BBC,   Michael Mosley, picked up on that study  when we published it in 2010 or '11.   And he did a documentary for the BBC, which  aired in 2013 or '14. He came to my lab,   and Valter Longo's lab, and Krista  Varady's lab. So, that aired on the BBC. And then, people in the UK got interested in  intermittent fasting. And then, all of a sudden,   like, there's all sorts of things showing  up on the internet on intermittent fasting.   So, it used to be, before the work in the early  2000s, that if you if you google intermittent   fasting, the top hits would actually be scientific  papers. Now, if you google intermittent fasting,   it's just like a bunch of random people  who have some angle on it or so on. But the good thing about that is there's now  a lot of interest from mainstream medicine.   And I wrote an article, well, the end of  2019, together with a former postdoc of mine,   Rafael de Cabo, a review article on intermittent  fasting for "The New England Journal of Medicine." And the editors invited us to write  the article for two reasons. One, there   had accumulated a sufficient number of  human studies of intermittent fasting,   particularly, in overweight people  to merit, you know, coverage of it. But the second reason was that many  physicians are being approached   by patients, asking the physicians  about intermittent fasting.   And in some cases, maybe many cases, the  physicians really don't know much about it.   They don't know that there's actually quite a bit  of science behind it, both basic and clinical.   And from a practical standpoint, they don't  know how to prescribe intermittent fasting   to a patient, and then follow up with them to  try to help them switch their eating pattern. It turns out that in the studies, the  ones I mentioned, particularly the ones   we did with Michelle Harvie in England but  also other clinical people I've talked to,   people, if they can get through the first couple  of weeks of switching their eating pattern,   say two weeks to a month, they will  no longer be hungry and irritable and   maybe can't concentrate well during the time  period that they've previously been eating. So, for example, if they decide,   "Okay, I'm going to start skipping breakfast."  For the first number of days, even a week or so,   they're going to be very hungry, irritable in  the morning. And the reason is, it takes time for   your whole system, everything, to  adapt to the new eating pattern.   And a lot of that has to do with changes  in the brain and the neuroendocrine systems   that control hunger and satiety. And we could  talk about that. That's a whole another podcast. But one thing we found in pretty much all of  our animal studies where we look at the brains,   it takes a couple of weeks before  we see measurable changes in   whatever upregulation of antioxidant  enzyme levels, increased number of   mitochondria in neurons, increased number of  synapses, improvements in learning and memory.   Okay, so I'm going to stop talking now,  Rhonda, and let you ask some more questions. [Dr. Patrick]: Oh, absolutely, I have so many  questions. You've brought up so many important   and interesting points. But just to kind of speak  to what you were just talking about, this sort of   adaptation to perhaps starting an intermittent  fasting sort of regimen and how you adapt to it.   And a lot of that has to also do with some of the  neuroendocrine changes in the satiety and hunger   hormones, I guess, you know, ghrelin and leptin,  you know, changing that. Is that somehow linked to   the production of ketones and this metabolic  switching and it happening easier or...? [Dr. Mattson]: Yes, there is a link with  ketones. And it's a very interesting one.   In hindsight, it goes back to the first  studies we published with intermittent fasting,   which was in rats. This was the one when I was  at the University of Kentucky in Lexington. So, what we did is we took rats and we randomly  assigned them to either every other day fasting.   And the way that's done is one day you go in  to the animal's cage. You remove their food   completely. The next day, you go in. You  put back food, you know, as much or more   than they want to eat. Then the next day,  you go back in. You remove all their food. So they're going 24 hours no food, 24 hours  food, 24 hours no food. Don Ingram, who's a   colleague of mine when I was at the NIA,  had shown that every-other-day fasting   can extend lifespan up to 50% in rats, when  it's initiated when they're young adults. So, we took rats and had them either intermittent  fasting or not. And we did a study where we did   one week of intermittent fasting, two  weeks, and then three months. And then,   we have these models where we can cause  damage to nerve cells and brain regions,   where nerve cells degenerate in Alzheimer's  or Parkinson's or with epileptic seizures. And we found that the most striking effect  was in the model of epileptic seizures where   we administer what's called an excitotoxin. It's a  very interesting story. It's a naturally occurring   chemical that's produced in algae.   And it accumulates very high levels  during red tide seasons where it's dry. And so, there was these incidents,  an incident in Canada where   these people who had eaten shellfish at a  restaurant develop memory loss, amnesia.   And it turns out that the scientists trace this  back first to the shellfish. They'd all eaten the   shellfish. And then, the shellfish had high levels  of this excitotoxin, it's called domoic acid.   And they had high levels because they are  eating the algae that had high levels. So, as you go up the food chain,   toxins accumulate. Anyway, to make a long  story short, the intermittent fasting protected   against epileptic seizures and protected the  neurons from being excited to death. And we now   know that there's a role for ketones in protecting  nerve cells against epileptic seizures. In fact,   clinicians, neurologists in some  cases, still prescribe ketogenic diets   for patients with epilepsy that don't respond  well to the antiepileptic drugs. Okay. Go ahead. [Dr. Patrick]: Well, I was gonna  ask about whether or not you thought   this metabolic switching, which, you're  talking about metabolism switching from   glucose metabolism to metabolizing fatty acids  that are released from adipose tissue and   the liver that produces the ketone  bodies, such as beta-hydroxybutyrate. If that is something that can  occur on a ketogenic diet,   what are your thoughts on the benefits of this  metabolic switching from intermittent fasting,   in terms of...? Can you get similar  benefits by just doing a ketogenic   diet? Are there differences between the  intermittent fasting and the ketogenic diet? [Dr. Mattson]: My opinion is that   you can get some but not all the benefits of  intermittent fasting with a ketogenic diet.   Early on, I talked about how increased activity  in neural networks is good for neurons. And   with intermittent fasting, there is  evidence that during the fasting,   there's actually some increase based on some  neural networks and activity in neural networks. I guess that kind of makes sense  from an evolutionary perspective that   if you're an animal, and you haven't  been able to get food for a long time,   your brain cells better be active.  Your brain better be alert.   You better be motivated. And you better  be thinking cognitively, "Where do I go   to find a prey animal or to find  fruit trees?" you know, based on that. You know, so the ketogenic diet will not cause  that increase in neural network activity.   So, you know, the ketogenic  diet, one thing it seems to do is   enhance activity of what's called an  inhibitory neurotransmitter called GABA.   So, I'm going to give some like Neuroscience 101. Let me ask you, Rhonda. I ask this question to  people just out of curiosity. And I'm actually   writing a book on this, a second.  Name a neurotransmitter besides GABA. [Dr. Patrick]: Okay. Just one?  Dopamine, serotonin, glutamate. [Dr. Mattson]: Okay. The third one you named,  glutamate, is the most important neurotransmitter.   A lot of people have heard of dopamine and  serotonin because dopamine links with addiction   and serotonin links with  depression. But it turns out that   least 90% of the nerve cells in your brain  deploy glutamate as neurotransmitter.   And those neurons are distributed  in every brain region:   throughout the cerebral cortex, other brain  regions, hippocampus, brainstem, basal ganglia. Whereas, the neurons that produce  dopamine and serotonin are few in number   and they're located in discrete regions  in the brainstem. They're important,   but the only way those neurotransmitters affect  behavior is by acting on glutamatergic neurons. Okay. And then, the main  inhibitory neurotransmitter   is GABA. And neurons that deploy GABA are  distributed throughout the brain. And their   main role is to kind of control  excitability of glutamatergic neurons,   you know, throughout the brain. So,  if you were to block the function of   GABA-producing neurons, your brain  circuits would fry themselves. On the other hand, if you have too much GABA, then  it can quiet down the glutamatergic activity so   much that your brain doesn't function well. So, an  example of that is drugs called benzodiazepines,   like Valium. They activate GABA receptor. So,  they quiet down the glutamatergic neurons.   But if you take too much Valium... If you were  an animal in the wild, and you hadn't gotten food   in a long time, you don't want to take Valium.  You want your nerve cell circuits to function. Anyway, so, the intermittent fasting is similar  to intermittent exercise. You get this activation   neural networks. One of the main effects that  I haven't even talked about yet in the brain of   exercise, intermittent fasting, and intellectual  engagement is to increase the production   of proteins that are called nerve cell  growth factors or neurotrophic factors. One of those proteins that's produced in  response to activity in neural networks   and in response to the metabolic stresses of  exercise and fasting, that neurotrophic factor   is called BDNF, brain-derived neurotrophic  factor. It is the most heavily studied   such nerve cell growth factor in the brain.  And it is essential for learning and memory. You can't knock out the BDNF gene in mice. They'll  die. You can reduce levels genetically and then   that will impair learning and memory. Actually,  interestingly, if you reduce levels of BDNF   by about 50%, the animals will overeat and  become obese. So, BDNF is also involved in   regulating appetite. Okay. So, let's see, where were  we. Right. So, ketogenic diet,   it will, definitely, your neurons will  switch from using glucose to ketones.   We think that's good because, essentially,  ketones is a more efficient energy source   per cell than glucose. And there is  actually less free radicals generated   in the burning, if you will,  burning ketones compared to glucose. And then, the ketones have these signaling  functions affecting gene expression that   glucose doesn't have. So, I guess two things.  The ketones are good energy source for neurons   and they have signaling functions. But those  signaling functions are more limited than   are activated by exercise or intermittent  fasting or keeping your brain active. [Dr. Patrick]: So, you mentioned about, you  know, the different types of metabolic stress,   whether that be exercise or intermittent  fasting, and how there's an increase in BDNF   in the brain in animal studies. And I kind of  want to go back to seeing what your thoughts   are in translating these animal studies to humans.  Obviously, animals have very different metabolic   rates than humans. For example, if you were  to fast a rodent for 48 hours, they lose 20%   of their body weight, whereas a human would only  lose 2% of their body weight from a 48-hour fast. But I also want to ask you,  have you seen additive effects   in your studies on animals? Or have you looked at  additive effects of animals that are constantly   exercising or routinely, you know, so a physically  active animal with their little exercise wheel.   But you also expose them to  these periods of food scarcity,   intermittent fasting. Are the two combined  better than just one type of metabolic stress? [Dr. Mattson]: There is evidence  that we've obtained that   combination of exercise and  intermittent fasting can be better.   I'll give you two examples that we published.  One was, we published a long time ago, a   former graduate student Alexis Stranahan. And it's  actually relatively simple, the studies of design. But we had normal mice and we had   mice that have type 2 diabetes. And they have type  2 diabetes because they're genetically engineered   to have a defective leptin receptor. Leptin  is a hormone that when you eat a meal   and your stomach gets full, it's released into the  blood. And it travels up to your brain, a region   called the hypothalamus. And, essentially,  it tells you you're full, stop eating. So, these diabetic mice, leptin-receptor mutant  mice, they don't get the stop-eating signal. So,   they're presumably always hungry.  Okay. So, then what Alexis did is   she divided these normal mice and  diabetic mice into four groups. The normal   laboratory conditions, which is they're sedentary  in relatively small cages, no running wheels. And   then, they are fed ad libitum. And they  can eat as much as they want every day. And she had a third group that were fed ad  libitum. And they had running wheels in the cages.   And then, the fourth group... What  a minute, what did I say? Yeah,   sorry. I figured what to say. So, she had ad  libitum/sedentary, ad libitum/running wheels. And   then, she had every-other-day fasting/ sedentary,  every-other-day fasting/ running wheels. And she let them go for three months.   And then, she took out their brains. And there's  a brain region called the hippocampus, which   is in many respects the most intensively  studied brain region for several reasons. One, it's critical for learning and memory.   It's kind of all the information from  our eyes, our ears, our other senses,   funnels into the hippocampus. And that's where  the initial, if you will, associations between   a sight and sound. You know, a bear jumping out  on the trail and growling, you hear its growl.   The next time you go walking on the trail, you  hear a bear growl, you don't have to see it to   have a mental image of a bear. So, the hippocampus  is critical for these initial associations. And then, a second reason the hippocampus is  heavily studied is it's a focus of dysfunction   and pathology in Alzheimer's disease, epileptic  seizures, even stroke in some instances. And the third reason is, it's easy to study  because the circuitry is actually relatively   simple compared to the cortex. So, we can put  electrodes in the glutamatergic neurons here.   And we stimulate glutamatergic neurons  down here, and we can record that,   we can activate a GABAergic neuron  and record reduction in activity. So, anyway, what Alexis found was that... First,   what she did is she measured the number of  synapses along the dendrites, the part of   the neuron that receives information coming  from another neuron. So, she simply counted.   Not simply, it actually takes a lot of work,  but counted synapses and found two things. One, the diabetic mice, regardless of whether they  were intermittent fasting or had running wheels in   their cages, had smaller number of synapses than  did the normal mice. And then, she found that   the running-wheel exercise  and the intermittent fasting   increase the number of  synapses. And the combination   of intermittent fasting plus running wheel got  a further increase in the number of synapses.   Okay. So, that suggests that intermittent  fasting can enhance the effects of running   on increasing number of synapses between neurons. And then, she took the other hippocampus  from the brain and measured BDNF levels.   I mentioned BDNF is important for learning  and memory. It's actually also important for   formation of new synapses. And she found that  the intermittent fasting and the exercise,   each alone, increased BDNF levels and the  combination got a further boost to BDNF levels. But she did not find that in the diabetic mice,  synapse levels came up to the level of normal   mice. You know, so there was some beneficial  effect, but you couldn't get it back like   they had never been diabetic.  Okay. So, that's one example. Then the second example has  to do with endurance exercise.   And this work was done by former postdoc  Krisztina Marosi, and a postdoc fellow   Keelin. I'm actually looking at   it. Can you see this? [Dr. Patrick]: Yes. [Dr. Mattson]: Can you see the whole picture? [Dr. Patrick]: I can, yeah. [Dr. Mattson]: So, this is about a running  group from the lab about 2016 or something.   Anyway, so the work I'm going to  talk about now is done by Keelin   Moehl and Krisztina Marosi. Krisztina is not  on here. She wasn't fast enough to make our 18. So, what they did is they took mice and they  had four groups, these are all normal mice,   ad libitum/sedentary, ad libitum/daily treadmill  training for 45 minutes every day for 2 months.   Then she had a group every-other-day fasting/ no  treadmill training. And then, the final group was   daily treadmill training while they're on  every-other-day fasting for two months. And then, at the end of the two months, they  did a maximum endurance test. Sorry. So,   45 minutes a day on the treadmill, and then every  week, they increased either the speed of the   treadmill or the incline. So, they're actually,  you know, increasing the work over the two months. So, they did maximum endurance and test, how long  can the mouse stay on the test treadmill without   giving up. And they found that, as you'd expect,  the animals that have not done treadmill training   had much poorer endurance than the  animals that did treadmill training,   regardless of whether they were  on intermittent fasting or not. But there was a statistically significantly better  endurance in the mice that were on intermittent   fasting during the two months of the treadmill  training. And they measured ketones, which   were elevated with intermittent fasting, and the  exercise increased the ketone levels much more,   almost twice as much, when you take their  blood after the end of the treadmill training. And then, they got a lot of analysis of the  blood. They did something called metabolomics.   And then, they took out muscle cells from  the soleus muscle, which is an endurance   muscle in the leg of the mice. And they  did some measurements that suggested   that intermittent fasting and the exercise  increased the number of mitochondria   in the muscle cells. And that  the increase was the most   on the other combination of  intermittent fasting and the exercise. [Dr. Patrick]: Very cool. I remember reading a  meta-analysis a few years back looking at human   studies, people that exercised either fasted or  in a fed state, which, unfortunately, there's a   bit of a confounder because if you look at the  dietary composition of most of the food these   athletes were eating before exercising, they're  very high in carbohydrates and oftentimes even,   you know, refined carbohydrate, where you have  like some toast and jam or something like that. But regardless, there was a variety of metabolic  adaptations that, for example, mitochondrial fatty   acid oxidation was enhanced, mitochondrial  biogenesis. These things were somewhat   blunted in people that exercised in a fed state.  Whereas, if they had done it in a fasted state,   these adaptations were occurring even throughout  the day when the people were not exercising. And so, you know, there were also some  effects on... If people had exercised,   fasted, but they were doing a very, very long  sort of endurance-training type of activity, then   there are some performance issues, weren't as good  as if they had exercise while in the fed state.   But, you know, since reading that meta-analysis,  I've tried for the most part... You know,   typically, I'll do a, you know, a 3-mile  run or I'll get on my Peloton and do a   20-minute high-intensity, you know, Tabata or  something, training. And I try, I do it fasted. And I definitely have adapted to it over time.  But I do it because I'm thinking to myself,   "Well, I want those mitochondrial adaptations."   So, it's really interesting that  your experiment that you mentioned. [Dr. Mattson]: Yeah, one point that you  just mentioned is important. And this   can occasionally get lost as these  conversations go on. And that is,   it's the switching back and forth  intermittently, is important. For example, in the muscle cells with exercise,  the number of mitochondria doesn't increase   during the exercise, it increases during the  rest period. But if you had never exercised,   you would have never gotten a  stimulus that triggers what's   called mitochondrial biogenesis, the  increase the number of mitochondria. So, the switching back and forth between the  metabolic challenge, whether it's fasting   or exercise, and the recovery, well,  you know, eating, resting, sleeping,   you know. And there's definitely a limit to all  of this. Obviously, with fasting, starvation.   You know, if you start to lose muscle  mass, then you're fasting too much. And,   as you mentioned, you can overdo it  with exercise too and sometimes get   diminishing returns. So, it's important  to have these recovery periods. [Dr. Patrick]: You've talked about the importance  of what are called the refeeding phase. Both,   you know, you and Dr. Valter Longo  have discussed this in publications   and Valter on the podcast previously. Like  you mentioned, it's a point that a lot of,   you know, people don't focus  on that recovery period. For the refeeding period, you know, how important  is that? And how long is that window? Do we know?   You know, is it like a week?  Is it just a couple of days? [Dr. Mattson]: Well, with  these intermittent fasting   eating patterns I'm talking about are kind of  trivial from an evolutionary perspective. That is   limiting time window you eat six to eight  hours each day. You know, the remaining,   whatever, 16 to 18 hours is more than sufficient  to recover. If you fasted or if you tried to do   fasting for five days, one day recovery,  fast another five days, one day recovery,   and keep that up. It won't be long before  you're going to start to have problems. So, it's the same with exercise.   You know, my understanding is there's quite  a few ultra marathoners who, when they get   in their 50s and 60s started to have a lot of  problems. So, you know, there could be some   long-term consequences of overdoing it,  whether it's with fasting or exercise.   And what you and I are talking about today is  well within any bounds of even getting close to   having adverse effects and having to  worry about, "Am I recovering or not?" [Dr. Patrick]: But perhaps more of  someone doing more of a prolonged fast   might have to consider, you know, the  refeeding and how important, I know... [Dr. Mattson]: In Europe, for example, in  Germany, there are clinics where people go   in for a couple of weeks and they'll fast for 10  days to 2 weeks and they're, you know, supervised.   It's kind of like a resort, actually, you know.  And everybody else there is doing the same thing. And they're collecting a lot of data and  starting to publish. They see a lot of   improvements in health indicators even within  that, you know, two-week fasting period. But   they don't have really good data on  long-term effects. And in talking to the   people who run these centers, oftentimes,  a person will only do this once a year. And so, they may be overweight and, you know, have  insulin resistance. And they'll go in, and they'll   show some, even during that short period, a  little bit of improvement in their insulin   sensitivity. But then, they'll come back a year  later. And they're back where they were or worse. So, you know, one question then is if someone  wants to fast for longer time periods,   what frequency would be reasonable for long-term  health? You've interviewed Valter Longo before,   and he's done a lot of work with this  eating pattern where the subjects,   five consecutive days a month, they'll  eat only one moderate-sized meal.   And then, the other days of the month, eat  normally. And that seems to be beneficial. The key thing is, you know, how long can  people maintain this in their lifestyle,   incorporate it in their lifestyle? Daily  time-restricted eating, for example, seems to be   easy for a lot of people to do for  years and years and years. You know,   maybe five days a month, that's perhaps... But at  some point, you have to think about it that way,   looking kind of a long view of what can you...? And then, another thing is, what about...?  You know, so daily time-restricted eating,   if you skip breakfast, then you can still have  lunch with people at work and dinner with people.   Where, if you're doing something else,  maybe, like Valter's maybe five days a month,   you're not going to be able to... You may go  out to dinner with somebody and say, "Well,   I can't eat anything today." Yeah. [Dr. Patrick]: Right. It's  a little bit challenging. [Dr. Mattson]: One thing I want to  get into, and you mentioned early,   very early on in the introduction, I think  we're getting there, is diet composition. Well,   there's good evidence, yes, eating vegetables  and fruit is good for health. And why is that? And the emerging evidence that has kind of turned  that "load up on antioxidant" idea on its head.   And so, yeah, so during evolution, we're  omnivores. And the same would be true with   other animals that are herbivores.  It is advantageous to be able to eat   plant materials: fruits, nuts, roots,  leaves, because they have energy. However, it's not necessarily advantageous to the  plants that we eat them. In fact, it's generally   not. And we know that in the case of insects,  but it's also true with herbivores and so on. So, in most plants, the most vital parts of the  plants, in terms of propagation of the species,   if you already eat those,  they have a bitter taste.   So, for example, the skin of grapes or apples and,  you know, broccoli, the seed-producing part of the   broccoli and so on, they have a bitter taste. And  so, the thinking is that it was to our advantage   to be able to eat these even though they have a  bitter taste and have these naturally occurring   pesticides. It's what they are. The  plants are producing their own pesticides. So, in fact, one of the reasons plants produce  so many of the chemicals is that many of those   chemicals, their function is to dissuade  insects and other organisms from eating them.   That's their main function. Okay. So we co-evolved  with these plants. And as we co-evolved with them,   we evolved several ways to protect  ourselves from overdosing on these   pesticides that the plants normally produce. So, one way is a bitter taste. The second way  is vomiting. A third way, which is interesting   from a human environmental health standpoint,  is we have evolved enzymes in our liver that   rapidly remove these potentially toxic chemicals  when we eat them. They're called cytochrome P450s.   Okay. But the fourth way is that the  individual cells in our body have   evolved to respond to some of these chemicals by,  for example, enhancing their antioxidant defenses   or enhancing their ability to  even extrude the chemicals. So, I'll give you a few specific examples.  I mentioned broccoli. Many of your   viewers probably, if they're into health,  they've probably heard of sulforaphane,   which is a chemical that's in broccoli. And  there's quite a bit of evidence that it can   be good for health. And one of the ways is it  activates antioxidant defenses in our cells. So, it's similar to exercise and  fasting, which are stressors.   The stress of this chemical that's  in the broccoli that we consume.   The stressor is the chemical. It's  activating antioxidant defenses.   Another example is curcumin, which  is in turmeric root, which in Indian   food is very common. And it also  activates antioxidant defenses. The most commonly consumed plant toxin by  your viewers, very likely, is caffeine.   So, if you were to take  powdered, if you were to take   concentrated caffeine and put it on your  tongue, it has extremely bitter taste.   It's possible to overdose and die from  caffeine. And there have been some   documented cases of actually people  essentially eating caffeine powder. If you take tea leaves, coffee  beans, you know, ground coffee beans,   put them on your kitchen table in the summer,  assuming you don't have an ant-free house,   and there's ants crawling on the table, you'll  notice that they avoid the coffee and tea leaves.   And they're avoiding caffeine and other  naturally occurring good toxins in them. So,   that contrasts with sugar or whatever, you know,  a lot of other highly palatable, addictive foods. Yeah. So, anyway, I was invited to write  an article for "Scientific American"   on this general notion that the reason fruits and  vegetables are good for our health is not because   they are free-radical-scavenging things like  vitamin E or C can help in certain ways, getting   rid of free radicals. That's not the answer. The  answer isn't that we want to swamp ourselves with   things that sop up free radicals because,  actually, free radicals are important   in our cells for normal signaling and  then our adaptive responses to stress. Instead, the chemicals that are good for  health seem to be acting by triggering   mild adaptive stress responses in our cells that  overlap quite a bit with exercise and fasting.   Yeah, these chemicals, again, they're concentrated  in the exposed parts of the fruit, like the skin   of the fruits. So, yeah. Here's a really interesting  thing. Green tomatoes. All right. So,   bugs usually don't eat tomatoes until  they start to turn red in the garden.   Okay. So, why is that? The reason is they like the  taste of the red ones better than the green ones. So, it turns out, there's this  chemical that's been called   tomatidine that's highly concentrated in the  green tomatoes. And then levels of tomatidine   decline dramatically as the tomato turns red.   Okay. By the time the tomato starts turning  red, the seeds in the tomato that have the   potential to give rise to another tomato plant  and propagate the species, they're ready to go. So, I guess, mainly this applies to birds. So,  birds won't eat green tomatoes either. So, let's   go with that. So, the bird eats the red tomato  and they may eat some of the seeds. The seeds can   resist going through their digestive system, then  they poop out the seeds, and the seeds can grow. You know, and they might poop out the seeds,  you know, whatever, half a mile away. So,   now the tomato plants are... You know,  so these are all evolutionary mechanisms   that give advantages to one or both of  the species during their co-evolution. [Dr. Patrick]: If a person is exercising regularly  and also doing some form of intermittent fasting   and they're getting this activation of  some of these stress response pathways   and the beneficial effects, you know, metabolic  switching, is there any need to also take in these   plant phytochemicals that are also activating,  you know, perhaps the same or different or both,   you know, stress response pathways? In other  words, like, can you just say, "Well, I don't   need to eat the plant compounds because I'm  exercising and I'm doing intermittent fasting."? [Dr. Mattson]: I wouldn't do that or say that.   What hasn't been done though, Rhonda,  is other... And the reason is,   it's expensive. There haven't been studies  where within a study, they do all these various   combinations. You know, okay, we're gonna do this  study with...well, some people intermittent fast,   we'll have some exercise, we'll have some do both,  we'll have some, whatever, taking sulforaphane,   and then we'll have them do sulforaphane plus  intermittent fasting, and so on and so on. And my view on diet composition is  one that I think makes sense from   data from epidemiological studies, the  Blue Zone, where, you know, certain   places where people have exceptional longevity.  And all of them have diets that are mostly   plant based. And then, the evidence that simple  sugar is bad for health is overwhelming. The   saturated fat, I think, the evidence is pretty  strong. So, it's better to eat fish than red meat.   And so, complex carbohydrates  are better than simple. I think that, you now,  people shouldn't say, "Well,   I can just eat at McDonald's every day if I  exercise and do intermittent fasting because   it's..." They would be better off than having  been intermittent fasting and exercising...   You know, if they're if they're going to eat at  McDonald's and don't want to give that up, then   exercise and intermittent fasting will counteract  that somewhat, but it's still kind of stupid. [Dr. Patrick]: The way I also think about it is,  you know, you have something like sulforaphane,   which we've talked quite a bit about in  the podcast. I've interviewed Jed Fahey. [Dr. Mattson]: Yeah, I know,  him. Jed, he's at Hopkins. [Dr. Patrick]: Yeah, he's a good friend of  mine. And so, you know, you have something   like sulforaphane that's activating the NRF2  pathway, which has, you know, you know, all these   downstream effects on phase II detoxification  enzymes, you know, activating those, inhibiting   the phase I biotransformation enzymes, which are  involved in potentially making a procarcinogen   an actual carcinogen. You know, there's all these  pathways that, you know, I don't know how much   exercise and/or intermittent fasting, you know,  activates those pathways, I'm sure to some degree. But you know, it seems as though different types  of stressors do have a more robust effect on   certain types of stress response pathways.  And so, why wouldn't you want to diversify? [Dr. Mattson]: Yeah, that makes sense. Yep.  Although I should say that... So, going   back to sulforaphane and the NRF2-ARE pathway.  That is activated by exercise and fasting. And   so, I would say this. These chemicals that are  in the plants are more targeted in what they do.   Compared to exercise and fasting, those chemicals  affect a more limited number of pathways.   In other words, you can't just take sulforaphane   and it's going to substitute for  exercise or intermittent fasting. [Dr. Patrick]: Right. Kind of shifting back  just for a moment to the to the fasting topic,   we've talked a lot about metabolically  unhealthy people with Type 2 diabetes,   or perhaps obesity, or animal models of such, and  the benefits of intermittent fasting in those,   you know, people or animals. How much can,  you know, a healthy person who perhaps is not,   you know, at risk for obesity or metabolic  syndrome benefit from intermittent fasting? [Dr. Mattson]:   Yeah, that's a complicated answer. I'll  expand a little bit how much and in what ways.   There have been far fewer studies in humans  of intermittent fasting on normal weight,   you know, healthy people. In animals, the  control group is always fed ad libitum and   they're sedentary. So, really, in the animal  studies, the control group is couch potatoes. And that's why, I would say in  extrapolating the animal data   to humans, I'm very comfortable in saying  intermittent fasting will have very clear,   measurable, highly significant  benefits for overweight people.   But since all the animal studies, the control  group is couch potatoes, and we're seeing good   effects on the couch potatoes, we can't say, you  know, that does apply to humans of normal weight. But there have been studies in  normal weight healthy humans.   Looking at some health indicators,  blood glucose levels and insulin, and   looking at ability to maintain and build muscle  mass, so resistance training studies, several   published studies where they found that with  daily time-restricted eating, people were able to   maintain and build muscle just as well as people  who weren't on daily time-restricted eating. But it's undoubtedly, the magnitude of any  beneficial effects on health in people that   already have a healthy body weight are going  to be less than on people who are overweight.   And the effects on improving glucose  regulation in people with Type 2 diabetes, who   already have insulin resistance, are  going to be quantitatively much greater   than people who have, you know, already  have normal insulin sensitivity. So,   you know, I would say that there will be some  benefits, but it's going to be quantitatively   less. Does that make sense? [Dr. Patrick]: Quantitatively difficult.   It does. Like, difficult to even measure,  you know, because as you've been discussing   throughout the podcast, the benefits of metabolic  switching, the production of ketone bodies   like beta-hydroxybutyrate, and their signaling  effects on BDNF, you know, increasing BDNF, and   also producing less reactive oxygen species,  because they're more energetically favorable   or easier by the mitochondria. It seems as  though activating autophagy, as you mentioned,   you know, the clearing away of damaged stuff  and organelles and things within a cell. Like those, you know, sorts of effects  happening, even if the magnitude isn't   as great. It seems as though like that has to be  beneficial long term in terms of like activating   stress response pathways, that are going to  help you deal with the stresses of aging better. [Dr. Mattson]: Yeah, I agree. One... [Dr. Patrick]: Do you think that...? Sorry. [Dr. Mattson]: Go ahead. [Dr. Patrick]: No, go ahead. [Dr. Mattson]: One thing that's being found that  it's important to maintain muscle mass as you   age. So, I think people need to be a little bit  careful, you know, to take in sufficient energy   to maintain their muscle mass. So, for example,  the people in the Calorie Restriction Society   may be overdoing it. And, you know, the story  of Roy Walford, who was in the Biosphere 2. [Dr. Patrick]: I do. You can tell the story. [Dr. Mattson]: Okay. I can't remember  exactly when it was, '70s or '80s, or   1980s. I can't remember. There's something  called Biosphere where these two people   down in Arizona, essentially, they built  this bubble. And they grew plants in there.   And the goal was to see if they could  be self-sustaining for long-term. And so, what happened was they were all right for  a while. And then, after a while, they started   not being able to generate sufficient food and  they lost a lot of body weight. And, you know,   essentially, on the point of starvation. And so,  they had to finally come out of the biosphere. And one of them was Roy Walford, who had also done  a lot of important work on calorie restriction.   Actually, a lot of very important early  work with Rick Weindruch at the University   of Wisconsin, showing that calorie  restriction can extend lifespan. And then, Roy Walford... So, as you  get older, your perception of time   is messed up. Roy Walford died in, I like  to say, like 15 years ago or something, ALS,   Lou Gehrig's disease. That's a muscle-wasting  disease involving degeneration of the neurons that   innervate those muscles. And that was really interesting because I  mentioned the study that we've done with   intermittent fasting and animal models  of Alzheimer's, Parkinson's, epilepsy,   and we found it was beneficial. But we also tried,  every-other-day fasting in a mouse model of ALS.   And what we found is, it made it worse. So, of course, these mice  are destined to have ALS,   so the abnormal processes are already  in motion when we put the animals on   intermittent fasting, but their motor function,  we have ways of testing their motor function,   declined much more precipitously when  they were on intermittent fasting.   So, I think that's the important... And then, my own personal case.  So, I've always had a low BMI. And   I started doing daily time-restricted eating  like 30 years ago, not eating breakfast. And as   kind of an endurance semi-athlete,  trail running, mountain bike riding.   Actually, when I was a kid,  I used to race motocross. But, anyway, I did a lot of running. And so, my  BMI is always around, it's very low, like 18,   18.5, you know, somewhere there. And then,  two years ago, I had a mountain bike accident.   And not to be too gory but, essentially, tore my  rectus abdominis muscle off my pubic bone, and had   adductor partially coming off. I had to have  three surgeries, and I've had other issues. So I've lost muscle mass, particularly in my  legs, during this ordeal. And I'm having trouble   building it back up. So, like, hindsight is  always 20/20. And like, you know, I couldn't   have predicted I'd have a mountain bike accident  and have all this going on. But in hindsight,   I probably would have been better off...and  I didn't really do any resistance training. Because when I was running, when  I started running in the '70s   like there was no such thing as cross  training. It was like runners, the training is   you run. You stretch and you run. And,  somehow, I guess because I'm stupid.   I didn't pick up on, you know, people start  doing cross training stuff. I didn't pick up. "Hey, I should be working my core. And I should  be, you know, keeping some muscle mass." You know,   so all these years, I've mainly just  been doing the same thing. But, anyway,   so that's just like a personal anecdote. And,   you know, I guess what I'm saying is  having a low bodyweight can be good, but   you have to be a little careful during aging  to make sure that you have a good muscle mass   as part of that like the main... Well, I  guess I was mostly muscle mass anyway but,   still, yeah, more muscle mass. [Dr. Patrick]: It brings up a good point on  some of the, you know, safety concerns with   practicing intermittent fasting and certainly  prolonged fasting. You know, whether or not   elderly people, someone over the age of 70, can  do you know, a 5:2-type of fast or certainly,   you know, even, you know, daily time-restricted  eating, and maybe they should, you know, doing   that along with resistance training, if they even  should do it. Do you have any thoughts on that? [Dr. Mattson]: My thoughts are that exercise and  a healthy diet would be more important for them.   Yeah. And, you know, the answer is we don't know.   There need to be studies in elderly people of  intermittent fasting starting in the elderly. So,   it's just not clear. So,  right now, the main focus,   at least from mainstream medicine, is people  who are overweight or with insulin resistance.   There is some interest in also people at risk for  cancers because well, there's really strong... As you know, being overweight is a risk factor  for a lot of different types of cancer in both   men and women. So, inasmuch as intermittent  fasting can keep your body weight down,   that's good. But there's also evidence  that intermittent fasting can actually,   in animals, it definitely suppresses the formation  of tumors, spontaneous formation of tumors.   And it can greatly reduce the growth  of cancer cells implanted into animals.   And it can enhance the killing of cancer  cells by chemotherapy drugs and radiation. But, anyway, so elderly people, if they have  good muscle mass and are physically active,   I don't know, they can try intermittent fasting.  If they have the same overall calorie intake,   then they're not going to lose body weight.  You know, whether they're eating all their food   within an eight-hour time window or not or two  days a week, if they make up for the calories. Then another group would be  little kids that are growing fast.   Children who are overweight with obesity, maybe  there's interest by pediatricians in this. And   I've had several contact me, one up in New York  who... What he's had some success with is kids   with obesity. He gets his parents to buy  into it. And get both the parents and the   kid to switch their eating pattern. Then he's  had success in helping some of these kids   get their body weight down by switching  their eating pattern to intermittent fasting. So, women with obesity and Type 2 diabetes,  there's increased risk of autism or   having a child that is on the  autism spectrum disorder compared to   normal weight, healthy women.  And that's very interesting.   I can send... I don't know, you can put  stuff on your website, Rhonda, right? [Dr. Patrick]: Absolutely. [Dr. Mattson]: So, I don't need a website. I just  go through you. So, I'll send you a few articles   that you could post on your website. Is that okay? [Dr. Patrick]: Yeah. And we also post  them on the video. We put the figures and   study title, and information. So, whatever  you're talking about, we're going to find. [Dr. Mattson]: Anyway, I'll send you this one on  autism. So, we know that in the 1970s, and '80s,   autism was kind of... A lot of people never  heard what's autism? What's autism? I didn't.   When I went to high school, I never heard anything  at school or from my parents about autism. And then, beginning in, around  late '80s, '90s and then,   more so there's increased incidence of autism,  some of that's due to increased recognition   that the kids are having  trouble concentrating, they're   avoiding social interaction, and so on. But that  doesn't seem to explain all of the increase. It turns out, there's a nice... If you  track the increase incidence of autism   and the increase in maternal obesity and type  two diabetes, it tracks really well. You know,   from very little maternal obesity in the  '70s and '80s, and then increased autism. So, the neuroscientists have  good evidence that in autism,   during brain development in the embryo, in the  uterus, the brain grows more rapidly than normal.   And probably because their mTOR pathways  like, just, you know... The persons,   if they have obesity and Type 2 diabetes,  they're undoubtedly not exercising or,   you know, calorie restricted. And so,   they never have the metabolic switching, the  mTOR pathway, which is the growth mode is on. And so, nerve cells, the neural  stem cells proliferate more rapidly,   neurons grow more rapidly, connections  start forming. And then, what happens is   there seems to be hyperexcitability of neural  networks. And this has been documented by   doing what's called functional magnetic  resonance imaging in kids with autism.   Kids with autism have a huge  increase in incidence of seizures. And I should say, not all kids with  autism are born to women with obesity   or Type 2 diabetes. Not all kids with autism  have seizures. But there's a big increased   incidence. That is more kids with autism have  seizures than kids that don't have autism. And then, in animal studies, there are some  genetic models that are actually pretty good   for autism. There's something  called Fragile X syndrome.   And the gene is known for that. And when  that gene abnormality is put in mice,   and then you put the mouse in a  cage which a bunch of other mice,   the mouse goes in the corner and doesn't want to  interact with other mice, and kind of measure this   propensity to interact, so  kind of social withdrawal. And those mice, in their brains, they have  hyperactivity of glutamatergic neuronal networks.   So, there is some evidence that kids  with autism, exercise can help them.   And certainly, we know, I know, I used to coach  high school cross country and my kids ran.   And I know that during the  cross-country season, the kids,   their mood is much better than when they're  not running. They're more relaxed, less ornery. And so, right, and then the exercise and  intermittent fasting upregulate their GABA   tone. Ketogenic diets will do that too. So,   I think it would be interesting to try  intermittent fasting in kids with autism. [Dr. Patrick]: Or perhaps a ketogenic  diet as well, very interesting,   Mark. So, to kind of shift back to the women part  of this story. There's been a lot of questions   about whether or not fasting affects women  differently, different than men. And if women   should fast or if it affects their cycle,  menstrual cycle or hormones like thyroid,   things like that. Whether we're talking  about like intermittent fast that's like   longer than time-restricted eating,  something more like a maybe 24 to 48 hour,   or perhaps even more prolonged fast.  Do you have any thoughts about that? [Dr. Mattson]: Yeah. Major calorie restriction,  so, I'll start with animals then go to humans.   So, in animals, for example, I had one  postdoc Bronwen Martin in 2005 or something,   she took rats and she put them ad libitum feeding,  20% daily calorie restriction, 40% daily calorie   restriction, which is a lot, or every-other-day  fasting. And she had both males and females. So, and then she followed them  over time. And then, the females,   she essentially did vaginal swabs to do staging  of the cycle. And so, as far as that goes,   the rats with 20% daily calorie restriction,  there was no change in their estrous cycle.   The rats with 40% calorie restriction, and  this was over a period of like 4 or 6 months,   they shut down, they stopped cycling. And  they lost a lot of body fat over those months. Then, the rats on every-other-day fasting, they  kept cycling but there was some increase in   irregularity of, you know, the timing between the  cycles, but they were still presumably fertile. Then, she did all sorts of stuff. She tested their  learning and memory. Oh, then, interestingly in   males, even at the 40% daily calorie restriction.  So, the males, their sperm count didn't change.   And they didn't lose as much body  weight as the females over these months. And she looked at like this though, the  activity of the rats moving around the   cage. And the females, when they're on major  calorie restriction, became very active.   Like, they're moving around the  cage a lot. Looking for food, maybe? So, my interpretation of this. And we had like a  few sentences in the discussion on the article.   Okay. In the wild, if animals are  getting to the point of starvation,   so that would be the 40% calorie  restriction. The females,   they don't want to get pregnant. Or if they get  pregnant, there's no food to support, you know,   development, their baby. So they shut down their  cycling, they become more active looking for food. The males, before the male starve to death,   it will be advantageous to them to be able  to inseminate as many females as possible   before they die of starvation. So, they stay  fertile. So that's my interpretation. You know,   the female has the egg that's the potential  passing the genes on. You know, so I don't know. But with the intermittent fasting, they kept  cycling. And their activity in the cage increased   a little bit, but they maintain pretty good body  fat compared to the 40% calorie restriction. One issue is, and this applies  mainly to adolescent girls,   if an adolescent girl goes to intermittent  fasting eating pattern, would she be   more prone to developing anorexia nervosa,  which is a kind of obsessive compulsive   like psychiatric disorder? The answer  is we don't know. We just don't know. So, from an evolutionary perspective, you  would think that would be selected against.   But, you know, and it's not clear. I guess, I  don't know enough about anorexia nervosa. But,   you know, back in human recorded history, is  anorexia nervosa even common? Or is this something   that has arisen more as girls are more  conscious of their body image and so on? And, you know, therefore, there's this  psychological factor that I don't know if that's   something that... I guess what I'm saying,  it doesn't make sense to me that anorexia   nervosa would be something that will not be  strongly selected against during evolution.   And these girls often, they usually  quit cycling, too. You know, so,   yeah, I guess we just don't know. On the one hand, intuitively, I'd say,   it won't be a good idea to recommend  this to adolescent girls. But if they're   with obesity or overweight, I don't  know. We just don't know. I think   that seems like maybe okay,  but we just don't know. [Dr. Patrick]: You're talking  about with adolescent girls? [Dr. Mattson]: Yeah. [Dr. Patrick]: Well, so what about women  that are not adolescent and, you know,   do not have an eating disorder and are perhaps  even normal weight, not obese or overweight?   Is there a concern with other hormonal  imbalances? I don't even know, necessarily,   is it a bad thing? I mean, if you're  amenorrheic for a short period of time,   and you go back to eating normal  calories, what does that mean? Do you   delay your reproductive lifespan longer?  Or is there even implications that...? [Dr. Mattson]: Well, in animals, that's what  happens. So, for example, we're going to take   these rats and do 40% calorie restriction for  3 months or 4 months so that they stop cycling.   And then, you put them back ad libitum  feeding again, they gain their body weight   back. They start cycling. These aren't  our studies. These are other studies. Then, those rats will be  able to have, keep cycling   to an older age than they would have  previously stopped cycling. So, in other words,   in theory, maybe you could extend age  of menopause by shutting down cycling   for 10 years. I don't know. This is like just... [Dr. Patrick]: Speculation. [Dr. Mattson]: This is just thinking  and not anything that's approaching it   coming close to even encouraging someone to do  something like that, which would be crazy. But   it's an interesting thing to  think about. I don't know.   There haven't been studies. This is a big thing  that's lacking in this field is studying hormones,   except for simple things like leptin and  ghrelin. So, for example, FSH, LH, oxytocin,   yeah, anything to produce. Oh, we do know, in   animals anyway, there seems to be increased  activation of the hypothalamic, pituitary, adrenal   stress response system. And that's the system  that results in increased levels of cortisol.   And this was something that was  noted early on in the animal studies. The animals live longer when they're on  calorie restriction or intermittent fasting.   But they have elevated cortisol  levels, which is usually,   you know, in the clinical  arena, that's not a good thing   because it can suppress the immune system.  However, so the animals are living longer. And we did a study, Jaewon Lee was a graduate  student, went out in Kentucky and then he came   to Baltimore with me when I moved. So,  this gets a little bit into endocrinology.   Cortisol, there's two receptors for  cortisol, two proteins inside the cell   that bind the cortisol. And those cortisol-binding  proteins are transcription factors. So, cortisol comes from the  blood in your cells. It could   be a muscle cell, a nerve cell doesn't  matter. And they bind to the receptor.   And then, which is a transcription factor,  it then goes into the nucleus and affects   the expression of certain genes. In fact, the  Nobel Prize was given to the person who...   Oh, Jesus, I'm blanking on the name.  I should know who discovered this. Okay. So, I mentioned there's two  receptors for cortisol. One is called   the glucocorticoid receptor or GR. The other  is called the mineralocorticoid receptor or MR.   And, okay, so there's been a lot of  studies on cortisol in relation to chronic,   uncontrollable psychosocial stress. So,people  who are, you know, whether it's, you know,   their work or life situation, they're chronically  stressed out, they have elevated cortisol levels. And it's been shown that, in that case,  in the brain, nerve cells in the brain   have a decreased level of one of the cortisol  receptors, the MR, and an increase in GR. So,   the way that the cells are responding to the  cortisol is changing, not just the cortisol. So, we did a study where we measured levels of GR  and MR, the two different receptors for cortisol,   in the hippocampus of mice that had been on  every-other-day fasting, or ad libitum control   feeding. And what we found is that, in  contrast to chronic uncontrollable stress,   the intermittent fasting caused a decrease  in levels of GR and a sustained level of MR. So, the take home message is   there's increased activation  of stress response pathways   with intermittent fasting. But the  ways your cells respond to the stress   is different than the bad  ways your cells will respond   to bad types of stress,  chronic uncontrollable stress. [Dr. Patrick]: That's really important.  That's a very important point to make.   Kind of just going back to one thing  you were talking about, comparing your   severely caloric-restricted animals  to like alternate-day fasting. You know, I think that's a really important  point to distinguish because, you know,   in the context of what we were talking about  with women's cycle, there wasn't really,   you know, much of an effect on the cycle  in alternate-day fasting, which by the way,   in rodents is a much stronger, like, the woman  doing a 24-hour fasting. And then an alternate   day would be possible, probably much more  significant of a fast in rodents, right?   But anyways, the differences between and  uncoupling the benefits and or just even... [Dr. Mattson]: Oh, wait a minute.  I think you said it backwards.   So, it's a more significant fast in rodents. [Dr. Patrick]: Yes, it's a more a  significant, exactly. Yes. Thank you.   Yeah, 24-hour fast in rodent would be,   I'm not even sure, would it be like 72 hour  or something in humans? Much, much more? [Dr. Mattson]: Yeah, much more.  As you mentioned, the mice,   they die, if they go beyond three days or so.  They will die. You know, so that's kind of...   You know, so one day is a third of that,  right? So, I would say, you know, a human   can live, it depends on their initial body fat,  but they can live maybe two months without food. [Dr. Patrick]: That's a big difference. [Dr. Mattson]: So, I'd say, you know, a day of  complete fasting could be equivalent to, like... [Dr. Patrick]: Five days? [Dr. Mattson]: I don't know. [Dr. Patrick]: Right. Well, you know, I  don't know if this makes sense to you,   Mark. But if you look at some of the  work from, for example, Valter Longo,   when they've looked at a 48-hour fast and the  drop in IGF-1 levels, it goes to about 50%.   And in humans, you know,  looking at what it takes to drop   IGF-1 to 50%, it's anywhere between 5 to 7 days.  So, you know, perhaps, that sort of that just... [Dr. Mattson]: And even with ketones,  it's true that in the animals, the   ketones go up within an hour or two of fasting. [Dr. Patrick]: Wow. Whereas in humans,  it's obviously, depending on exercise. [Dr. Mattson]: So, 10 to 12. [Dr. Patrick]: Ten to 12. Right. Yeah. So, what I  was sort of wanting to just touch on. For one, it   seems as though that intermittent fasting in the  context of certainly daily time-restricted eating,   and perhaps even, you know, doing  a 24-hour fast or 48-hour fast,   shouldn't have much of an effect in most women  that aren't calorically-restricting, in addition   to that. And perhaps aren't, you know, running  marathons or, you know, running 15-miles a day. You know, so there's, there's obviously a  spectrum here, when you're thinking about the   effects on a woman's cycle. It seems as though  it's the actual caloric load that's important.   So, if you're restricting your calories,  at the same time, it seems like... [Dr. Mattson]: That's right. [Dr. Patrick]: But also in terms of just general  benefits of intermittent fasting in terms of the   overlap between caloric restriction. You know,  it sounds as though there is some uncoupling. I   don't know how much metabolic switching occurs  with calorie restriction, perhaps it depends on   if you're doing something like a fast mimicking  diet, where it's a pretty severe calorie   restricted diet, or if you're doing something  like this Caloric Restriction Societies do. [Dr. Mattson]: It's very interesting. I  don't know if you have you met Rafa de Cabo? [Dr. Patrick]: I would love to have a conversation   with him. I'm familiar with his  work, but him and I have not...   We were supposed to meet at a conference a  couple years ago, but that didn't work out. [Dr. Mattson]: Yes. So, it turns  out that most, perhaps all of the   rodent studies with rats and mice of calorie  restriction are also intermittent fasting studies.   And the reason is the way they did the studies,  they take 20 animals, they divide them into   two groups, you, over a period of a week or two,  determine how many food pellets each animal eats   each day. Sorry. You do that before  you divide them into two groups. So, essentially, you get, for each  animal, their daily calorie intake.   And then, you divide them into two groups. In  the calorie restricted group, you give, say, 20%   fewer pellets than they would have normally eaten  each day. And you give it to them all at once. It turns out, when that's done,  because they're calorie is restricted,   they eat all of their food in a short time period,   like within four to six hours. So, they're  actually fasting for up to 20 hours. So, we did, I think it was the first  study published, where we asked,   are there effects of intermittent fasting  better, different, or quantitatively   greater or less with intermittent  fasting and calorie restriction? So,   there's a certain strain of mouse that when  we put them on every-other-day fasting,   on the day they do have food, they ate pretty  much twice as much food as they normally eat.   And so, they remain, over time,  they don't lose any weight.   Okay. So, they're intermittent  fasting, but no calorie restriction. And then, we had calorie restriction group. And  another group we called pair feeding. But, anyway,   the bottom line is, what we found is that  we see no studies on the brain. We saw   clear, beneficial effects of intermittent fasting  on the brain that are independent of calorie   intake. You know, so we had animals that were on  intermittent fasting, no change in calorie intake,   and still saw, actually, did the epilepsy  model, it showed that it still protected   them against epileptic seizures, protected  the neurons. We still saw decrease in IGF-1.   I can't remember all the details. Yeah, and then I mentioned the study with  Michelle Harvie in England. That was really,   we dissociated. Remember, we had a group that  was counting calories each meal, and then we had   group 5:2 intermittent fasting. And they  both lost the same amount of body weight,   and over six months, their  calorie intake was the same. Yet the women on 5:2 intermittent fasting lost  more belly fat, and had a significantly greater   improvement in insulin sensitivity. So, that's, I  think, the first human study to show at least some   benefit that can't be accounted  for by reduction in calorie intake. [Dr. Patrick]: What about uncoupling benefits  of weight loss from intermittent fasting? [Dr. Mattson]: We did that in the mouse study. [Dr. Patrick]: Of the brain, yeah. [Dr. Mattson]:   Yeah. That study could be done in humans.  You just have to... It hasn't been done. [Dr. Patrick]: I think there was  a time-restricted-eating study   done by, was it Varaday? University of Chicago? [Dr. Mattson]: Oh, yeah, Krista Varady. [Dr. Patrick]: Perhaps, I think, there  was no weight loss. And there were some   benefits. There was, you know, metabolic benefits.   I can't recall all of them. But, again, coming  down to knowing what you've discussed with these   stress response pathways and cytoprotective  mechanisms. And you know, these adaptations   and the metabolic switching and the  importance of all that. What are your...? [Dr. Mattson]: I have to leave pretty soon.  But I want to mention one thing that's kind   of interesting. So, we found in rats. So, we  implanted rats with essentially transmitters   where we could record in real time 24/7  their heart rate and blood pressure.   And then, we switch them from ad lib to either  daily 30% calorie restriction or every-other-day   fasting. And we found that their heart rate and  blood pressure went down over a period a lot, went   down over a period a couple of weeks, a little  bit more down by a month and then stayed down. Then we switched them back to ad  libitum feeding. And at about two weeks,   the resting heart rate and blood pressure, going  back up and by a month, it was back to where   it was before, you know,  way back at the beginning. So, a couple of things. So, people who do  aerobic exercise tend to have low-resting   heart rate, low blood pressure, and  increased heart rate variability.   Heart rate variability is the variability in  the time interval between individual heartbeats. So, for example, if your heart  rate was 60 and mine was 60,   that doesn't mean that each of us  there's, you know, every second,   exactly every second, there's a beat. It could  be 0.8 seconds, then 1.2 seconds, then 0.9. So,   initially, like, I guess, it's kind of  counterintuitive that it's a good thing to have   variability, between the time interval  between beats, but actually it is. So, endurance athletes have high heart rate  variability. And, essentially, what it means is   their heart regulation number,  their heart is more adaptable   to stress and other changes. And so, what happens   is, and this has been known for exercise  and particularly aerobic exercise, that   the reason it causes a reduction in heart  rate and blood pressure and increased heart   rate variability is that the exercise over time  will enhance what's called the parasympathetic   nerves that innervate the heart.  And the parasympathetic nerves   slow down heart rate. The sympathetic  nervous system increases heart rate. So, we found the same thing with intermittent  fasting. It enhances the parasympathetic   nervous system. That will also. And that's sort  of the vagus nerve, which is this big nerve   coming down here. It innervates  the heart, slows down heart rate.   It can increase blood flow, dilation of blood  vessels. And it can also enhance gut motility. So, I guess, I kind of want to throw that  out there. It's kind of an interesting   effect that I haven't talked about intermittent  fasting on the cardiovascular system that's   very similar to exercise. It takes a few  weeks to a month to see the clear effects.   Then, if you stop doing it, you stop exercising,   stop intermittent fasting, it doesn't take  long for things to go back the way they were. And people, like me, who, you know,  you exercise regularly. And then,   in my case, for an accident and surgery, I  had to stop exercising. So within a month,   my blood pressure went from like 100 over  60, and resting heart rate of like low 50s   to blood pressure like 135 over 85. And my  resting heart rate's up like to 70, you know. [Dr. Patrick]: So, I know that you might... [Dr. Mattson]: So, you got  to stick with it, if you can. [Dr. Patrick]: Yeah, I just want to mention  sauna use, real quick, because that's also been   shown to do the same thing with parasympathetic  activity and heart rate variability and blood   pressure and all these things. And it mimics  cardiovascular, particularly aerobic exercise.   And it's very useful for people that are injured  and can't go out and get that exercise. It also   helps maintain muscle mass that's been  shown in both animal and human studies. [Dr. Mattson]: I should do that. [Dr. Patrick]: Keep that in mind and also... You  should. And if you don't have access to a sauna,   hot baths can also... And I can  send you some of this information.   Hot baths can also increase heat  shock proteins, which have been   shown to help maintain muscle mass, and  then heart rate, your heart rate elevates. [Dr. Mattson]: Surprise, surprise,  hot bath can increase heat shock. [Dr. Patrick]: Right. So, I know you have to  leave, I just wanted to ask you really two quick   questions. One, your just rapid-fire  thoughts on some of these so-called   caloric restriction or fasting mimetics like  resveratrol or spermidine or hydroxy citrate,   things that have been shown to increase  autophagy or polyphenols from coffee. And maybe   doing that in combination with intermittent  fasting and what your speculation would be. But also what your intermittent fasting  routine looks like, maybe before and   after your injury? And if they're, you  know, different. And then that's it. [Dr. Mattson]: Well, the answer the last  part is easy. Not different. I eat all my   food within a six-hour time window and it's  no simple sugars, virtually no saturated fat,   mostly plant based. That's vegetables, some  fruits, fish. I do eat whole grains. I'm not   so convinced that, you know, whole wheat is bad  for you. I don't think I have any gluten. Okay. [Dr. Patrick]: Do you do prolong fast ever  or longer than a daily-time restricted? [Dr. Mattson]: Surprisingly, I  haven't. And then, but, you know,   trying to mimic the effects of fasting. We've  worked on this a little bit with 2-deoxyglucose   and with something called DNP, which is a  mitochondrial uncoupler. 2-deoxyglucose,   it's glucose that doesn't have a hydroxyl group  that's glucose. That's why it's called to 2-deoxy. But anyway, 2-deoxyglucose will be  taken up in cells just like glucose is,   but it cannot be used to produce ATP. And it  competes with an enzyme called hexokinase. That's   like the first enzyme involved in the metabolism  of glucose that leads to ATP production. So, the bottom line is if you   feed an animal or a human 2-deoxyglucose,  cells in the animal will think,   they will experience the effects of glucose  deprivation because there's less glucose   coming in. And, in fact, it will increase  some of these protein chaperones, one called   GRP78, glucose-regulated protein 78.  It's kind of like a heat shock protein. And we'd found that if we give  2-deoxyglucose every other day,   it can be neuroprotective in some of our models,  and we published that. Don Ingram, he wants to see   if 2-deoxyglucose with increased lifespan. So,  he put it in the diet of animals. And actually,   it shortens their lifespan. It had some adverse  effects, long-term on the cardiovascular system.   So, now, that's kind of  mimicking calorie restriction   at kind of fundamental global  way, you know, way upstream. The things you mentioned are, you  know, can you activate pathways,   like certain pathways, autophagy, and  others that are maybe kind of downstream?   And I don't know. I think the thing  is, it's kind of tricky business   knowing how to know what amount of  anything that mimics fasting is enough. For example, you may see some short-term  benefit in whatever endpoint you're looking at.   So, for example, ketones. The 2-deoxyglucose  will increase ketone levels because cells   think there's less glucose in the blood  when there's actually not. And so,   ketones are produced. But, you  know, long term, it's not good. So, you know, my advice is to stick with  exercise. I think intermittent fasting   can be helpful for a lot of people. Keeping your  mind intellectually engaged, eating good diet.   There's just not sufficient data to support the  use of any of these things, you know, whether it's   nicotinamide riboside, or rapamycin seems like  it's something that in animal studies looks pretty   interesting, but I've been kind of hesitant to  take rapamycin myself, just given that what it's   prescribed for is suppressing the immune system.  And long-term in humans, we don't know. So, yeah. [Dr. Patrick]: I'm so sorry to have to ask you  one more question. But I feel like we need another   podcast. Just because you're so knowledgeable in  this field, I would just love to know what your   thoughts are, do you think, for example, a type  of, you know, daily time-restricted eating, maybe   something similar to what you're doing or eating,  you eat within a six-hour window or in eight-hour   window every day, would have an effect on human  lifespan or, at the very least, healthspan? [Dr. Mattson]: I would predict it would. And this  is in comparison to three meals a day plus snacks. [Dr. Patrick]: And what if the  three meals a day plus snacks,   you're still exercising and healthy  and you're still metabolically healthy? [Dr. Mattson]: Say that again. [Dr. Patrick]: If, let's say, the person eating  the three meals are eating high-quality meals   and maybe eating some nuts or  something for a snack and they're   also physically active. So they're  lean and metabolically healthy? [Dr. Mattson]: I think maybe because I don't know  if that's true for humans, we don't know. But   in animals, exercise alone, without  calorie restriction or intermittent fasting   has minimal next to no effect on lifespan, maybe  like a 5% increase. So, in animals, and in animals   that are herbivores, calorie restriction,  intermittent fasting have a striking ability   to extend lifespan. Running-wheel exercise, and  animals run quite a bit every day, not much. You know, but the animals don't die from  cardiovascular disease, typically, or diabetes.   They died from cancers and kidney disease are kind  of the two main causes of death. So, inasmuch as   exercise is really going to  affect the cardiovascular system   and glucose regulation. I wouldn't  be comfortable extrapolating,   you know, the animal to the humans, because  I think exercise is really important. [Dr. Patrick]: Yeah, if you look  at the observational studies,   you know, exercise between a hundred... [Dr. Mattson]: And my own personal  experience is that the exercise for me   has more profound beneficial effects.  At least, on my mental health than   intermittent fasting. And I think, also,  you know, I mentioned my blood pressure is   now up. It's not like, you know, high  clinically, but it's high compared... You know,   so without exercise, even though I'm doing daily  time-restricted eating and my body weights down,   I'm still, you know, showing these bad  changes without the exercise. Yeah. [Dr. Patrick]: Yeah. Right. Thank you.  Well, I, 100% agree. When I exercise,   almost exclusively for the brain  benefits and you know. Sure. And   the other things are kind of  healthy side effects for me. GAP I know that you're in the process  of writing a book, which is,   you know, waiting for proofs  back. So, I look forward to... [Dr. Mattson]: Yeah, it's written. I'm  done. I'm just waiting for the proofs. [Dr. Patrick]: I'm looking forward  to reading that and sharing it. [Dr. Mattson]: And the second book is actually,   you know, in the general public, I'm kind of best  known for work on intermittent fasting, but that's   just a part of my research over the  years. So my second book is called   "Sculptor and Destroyer: The Story of Glutamate,  the Brain's Most Important Neurotransmitter." My postdoc work, I showed glutamate  played an important role in   controlling the formation of synapses during  brain development. At that time, in the 1980s,   it wasn't recognized that neurotransmitters  have an important role before their   synapses form. They always thought, okay, the  nervous system gets wired up, there's synapses,   and now there's neurotransmitters. But, yeah,  so we showed glutamate plays an important role. And then, so that's the sculptor.  And then, glutamate is important in   synaptic remodeling and learning and  memory. So, that's the sculpting part. Then the destroyer is... So, I mentioned  epilepsy and excitotoxicity. There's a lot   of evidence that in Alzheimer's, Parkinson's,  definitely stroke, traumatic brain injury, ALS,   all of those excitotoxicity is a factor that is  neurons continuing to be excited by glutamate   when they're in a compromised state,  energetically, for example, with a stroke, or   we think more subtly in Parkinson's or  Alzheimer's, where there's mitochondrial   dysfunction that's occurring. And then the  neurons continue to be excited even though the   mitochondria aren't producing enough ATP to run  the ion pumps that pump sodium and potassium back. Your PhD work was what? [Dr. Patrick]:   My PhD work was mostly cancer metabolism,  mitochondrial function. I did a lot on... [Dr. Mattson]: So, in neurons, like it's been  estimated that in neurons that are active, during   normal activity, up to 50% of the ATP is used  to drive the sodium pump and the calcium pump to   pump those ions back out after the neuron is  fired. So, when the neuron fires an action   potential, when it's active, the sodium  and calcium rush in, then you get a voltage   change across the membrane. And then, that's  propagated. And it's important to rapidly   remove the sodium, potassium so that the charge  across the membrane gets back to where it was. And so, yeah, during normal aging,  Alzheimer's, Parkinson's, if the mitochondria   aren't working even a little bit less  well than they are, there's a tendency for   hyperexcitability. And so, anyway, that's the  destroyer part of the "Sculptor and Destroyer." [Dr. Patrick]: How much of a role would the GABA  production from being in ketosis help negate that? [Dr. Mattson]: Well, that's important. That's  a good question. I think that, from a drug   standpoint, drugs that enhance GABA tone could  be beneficial. It's a tricky business because   glutamate is critical for learning and  memory. And, you know, all our circuits,   essentially, are glutamatergic. So, you  don't want them to go out of control,   but you don't want the activity to go  too low so the function isn't optimal. [Dr. Patrick]:   What about testing that with something like  a ketone ester to see, you know, transiently? [Dr. Mattson]: No, we've done  that. So, Richard Veech in,   I can't remember what year again. Anyway, bottom  line is he sent Paul to come to my lab and   what was his name, Kashi [SP], a Japanese  postdoc. And together with people in my lab,   in a mouse model Alzheimer's disease.  They gave animals in the food ketone ester   or not, and then we had isocaloric. And then, we looked at the amyloid accumulation,  the neurofibrillary tangle, tau in learning and   memory. And the ketone ester was beneficial. And  now, I think the ketone ester is very promising.   A friend of mine up in Canada, Steve Cunnane,  has done some really nice work with PET imaging. So, all right, so one can get   images of relative levels of utilization  of glucose by brain cells or of ketones.   So, Steve Cunnane, used the radiolabeled  glucose, 2-deoxyglucose, and radiolabeled,   he used acetoacetate, but it doesn't  matter. He didn't use beta-hydroxybutyrate. Okay. So, these are just initially normal  people but he's doing studies on people with   mild cognitive impairment and Alzheimer's. So,  he had them, when they're eating carbohydrates,   brain cells use mainly glucose. When they go on  a ketogenic diet, the brain cells switch. They   clearly switch. It's very clear. They use a lot  more ketones, maybe still using some glucose. And then, in Alzheimer's disease, other  investigators, decades ago, have shown that very   early on, you know, people with mild cognitive  imapairment, even somewhat during normal aging   there's reduced glucose utilization by brain  cells. And however, we think, based on some   of our animal studies, and some preliminary  studies in Alzheimer's patients of Steve's that,   at least, in people with early Alzheimer's  disease, even though their brain cells have   problems using glucose, they still  seem to be using ketones very well. So, this is something that I'm excited about.  And there's a neurologist that was under me   at NIA that he's actually finishing up a study  of intermittent fasting and people at risk for   cognitive impairment. And he may be one of the  places where these ketone ester studies are done.   And then, you know, Kieran Clarke's work at Oxford  with ketone ester and elite British cyclists. So, yeah, that's a big deal in endurance athletes.  You know, the cost, right, for the average person,   the cost of the ketone ester is  way too much to make it practical.   And we don't know for sure. What would  be interesting to do like a comparison of   someone, you know, fasting versus  ketone ester. You know, then you could   maybe sort out whether any endurance-enhancing  effect of intermittent fasting   is in addition to ketone ester,  or if it's all due to the ketones.   But, yeah, bottom line is, I  think that's really promising. [Dr. Patrick]:   As you mentioned, the cost is very prohibitive for  most people. And I think of it. So, I can tell you   from just anecdotally, and I'm so sorry, I know  you have to go. It's great speaking with you. As a   sort of a foot in the door to like maybe someone  who is not motivated to try a ketogenic diet,   perhaps they have cognitive decline or dementia,  or maybe even you know, early-stage Alzheimer's,   when they notice a beneficial effect from  the ketone ester, and that's a lot more   motivating for a person to have  a real-world piece of evidence   where they feel an effect and say, "Okay,  well, maybe I can try this diet. That's not,   you know, that quite easy to do." But  they may be more motivated to do it. [Dr. Mattson]: You know, before he passed  away, Richard Veech he interacted with,   like he had a friend who had Parkinson's disease,  and he took the ketone ester and claimed that had   really clear beneficial effects on his Parkinson's  symptoms that are fairly rapid, so, you know... [Dr. Patrick]: Thank you for telling me this.  My father was diagnosed with Parkinson's like... [Dr. Mattson]: People can try it.  I mean, it's not gonna hurt them. [Dr. Patrick]: Yep. I'll tell you  anecdotally. So, two things. One,   my father was diagnosed with Parkinson's about,  I don't know, three and a half years ago, and   I have these ketone esters, and I've been  sort of trying to get him to try it and   the pandemic happened and all this stuff.  And so, I'm trying to go back to that point. But my mother has a different type of motor  disorder. She has both orthostatic tremor,   and essential tremor. Orthostatic tremors when she  stands still, her legs will shake very rapidly,   but if she walks, that doesn't happen. She's  fine if she's moving. And the essential tremor   is if she's like, you know, eating or like  has her arm out, you know, it'll shake. [Dr. Mattson]: How old is she? [Dr. Patrick]: She is 63. She's  had this, I mean, it pretty much   started to go badly after her menopause. She  went through menopause. And all of a sudden,   her orthostatic tremors got to the  point where she couldn't stand. Whereas,   when I was growing up, she could stand  without, you know, her legs trembling so bad. So, now it's like, if she's in line, she  has to have something to sit, you know,   where she can move fine, but like standing... [Dr. Mattson]: What about your  grandparents? Did they have that?   You know, any of them have Parkinson's or...? [Dr. Patrick]: No. Not that we're aware of, no. [Dr. Mattson]: Okay. Well, that's good. [Dr. Patrick]: But I was gonna tell you  that that I have convinced my mother to   try the ketone ester. And it does  improve both her orthostatic tremor   and her essential. Mostly, it improves her  essential tremor. But I'm using that as... [Dr. Mattson]: Did you do a blind study? [Dr. Patrick]: No. I need to do that. We've  done it several times. And it's worked. But   it's hard because it tastes so bad that  there's just no way she would not know.   She often has to taste it with some  something like a little bit of orange   juice or something like that. So, until  the ketone esters...you know, it is hard. So, there's definitely potential  for a placebo effect. But,   you know, knowing what we know about the epilepsy  and seizures, and it seems very reasonable that it   would help with motor dysfunction and certainly  what we know about mitochondrial dysfunction.   So, anyways, I've got these ketone  esters, and I've been sort of trying to   convince both of my parents  to try a ketogenic diet. My father, though, he's actually sort of always  naturally done some sort of intermittent fasting.   It's just that's sort of what he's naturally done,   slash maybe even a little bit of  caloric restriction, you know, [Dr. Mattson]: So, he's around the same age? [Dr. Patrick]: He is 72. [Dr. Mattson]: Okay. So,  yeah, when was he diagnosed? [Dr. Patrick]: When he was  around, I would say, 68,   about 68. Yeah. And so, I've been, you know,  exercise and all these things in the lifestyle,   I'm trying to, like, help optimize, you know.  But I really am wanting to see if there's an   effect of the ketogenic diet. And I think the way  to do that is to look to ketone esters. That's   how can you instantaneously put someone in ketosis  without a lot of work? That would be it, you know. But I really want to thank you, Mark, for the  discussion and just the wealth of knowledge and   all the research you have done over the years.  I mean, I have like alluded to your research,   I mean, just hundreds of times through public  speaking and podcasts and YouTube videos and   articles. And so, you know, you've really had  a major influence on my thinking, you know,   in the field of biological stress in general and  intermittent fasting and the effects on the brain.

Channel: FoundMyFitness

Views: 269,322

Keywords: intermittent fasting, fasting, time-restricted eating, ketosis, metabolic switch, ketone ester, ketogenic diet, caloric restriction, fasting mimetics, caloric restriction mimetics, hormesis, xenohormesis, mark mattson, fasting benefits, calorie restriction, keto diet, mark mattson fasting, fasting science, mark mattson intermittent fasting, fasting benefits for the brain, 16/8 fasting, 16/8 fasting benefits, water fasting, time-restricted eating benefits

Id: dhjZcFbKFdM

Length: 149min 50sec (8990 seconds)

Published: Thu Oct 07 2021

Reddit Comments

[u/Epitaphi]

That was a fantastic interview, I don't normally have the ability to watch so long but I was riveted for the full duration. Lots of information being shared and talked about!