Mark Mattson is the current Chief of the Laboratory of Neurosciences at the National Institute on Aging. He is also a professor of Neuroscience at The Johns Hopkins University. Mattson is one of the foremost researchers in the area of cellular and molecular mechanisms underlying neurodegenerative disorders such as Alzheimer’s Disease, Parkinson’s Disease, and amyotrophic lateral sclerosis.

Thanks, Brian. I am at the National Institute on Aging, and as many of you know– people are getting older, and there have been advances in cancer research, cardiovascular disease research– many people who would have died in their 50s and 60s from those diseases are living into the danger zone for Alzheimer’s and Parkinson’s diseases. It’s projected that by 2050, the number of people with Alzheimer’s disease will triple from what it is today. It’s 5 million today, it’ll be 5 million by 2050.
In my lab, we use a number of different animal models that are relevant to age-related neurodegenerative disorders. We have mice that accumulate amyloid in their brain as they get older, and they have learning and memory problems. We have mice that have damage to dopamine producing neurons, that control body movements– that’s Mylo-Parkinson’s disease. And we also have models of stroke, which is again another major-rate problem and cause of death. Well, it has been known for a long time that one way to extend the life span of laboratory animals is simply to reduce their energy intake. And, in rats and mice one can increase their life span by 30 or 40%.
We started looking at the effects of energy restriction on the brain in the context of age-related neurodegenerative disorders, and found that we could slow down, for example, the abnormal accumulation of amyloid, or the degeneration of dopamine neurons in the Alzheimer’s and Parkinson’s myel by reducing energy intake.
Now, there’s a number of ways you can reduce energy intake. You can simply eat less at each meal, or you can do what we call intermittent fasting. So, reduce the frequency of the meals. And, what I am going to tell you today is that fasting does good things for the brain. In the animals we have insight into a lot of the neurochemical changes that are occurring in the brain that we think explain why fasting is good for the brain.
But I am going to start out and talk a little bit about anecdotal evidence that fasting is good for the brain, and also evolutionary prospective on why fasting might be good for the brain. OK. So everybody knows that in certain religions people will fast periodically. Down through history many famous people with good brains have fasted regularly. Up on the top here is a quote from Plato, he fasted for greater physical and mental efficiency. There are some quotes there, including one from about 6,000 years ago, an Egyptian pyramid inscription that says, “Humans live on one-quarter of what they eat; on the other three-quarters live their doctors.”
And in this country, as you know, being overweight is a big problem. It’s not only a risk factor for cardiovascular disease and diabetes, certain cancers, but emerging evidence suggests that it’s also a risk factor for age-related cognitive impairment, and possibly Alzheimer’s disease.
In the lower right, there is a reference to a book written over a hundred years ago by Upton Sinclair. Many of you may know Upton Sinclair is the author of “The Jungle”, a book on meatpacking industry, but he also wrote and published the book that you can find in the full text online, it’s called “The Fasting Cure”. In that book he interviewes 250 people who had some ailment and went on fast for various lengths of time, and except in a handful of cases, their health condition improved.
OK, before I focus on the brain, which will be the main part of my talk, I just want to point out that there is evidence not just from animals, but from humans that fasting is good for the body. It will reduce inflammation, it will reduce oxidative stress in organ systems throughout the body, and one thing that happens when you fast, that does not happen when you eat three meals a day, is that your energy metabolism shifts so that you start burning fats.
Every time you eat a meal the energy goes into your liver and it’s stored in the form of glycogen– and it’s always tapped into first. And it takes about 0 to 2 hours before you deplete the glycogen stores in your liver. So, if you eat three meals a day you never deplete the glycogen stores in your liver, although if you exercise you can. And once you deplete the glycogen stores in your liver then you start burning fats, and you produce what are called ketone bodies.
It turns out ketone bodies are very good for your brain, and I’ll talk about that in a minute. Now, we’ve done a lot of work on animals in the 90s, between 5 and 20 years ago, showing that intermittent fasting was good for the brain, then we started collaborating with some investigators, did some human studies looking at effects on the body, some that were shown on the last slide.
And then a producer at the BBC named Michael Mosley made a program on intermittent fasting that was aired on the BBC, it’s been aired on PBS. He wrote a book called “The Fast Diet”. And just in the last two years there’s been a flurry of books on intermittent fasting for health, and it’s becoming what, I think– some people may think it’s a fad, but hopefully people find some of these– What do I mean by intermittent fasting, and intermittent energy restriction? There’s a lot of variations, that there’ve been on used on this. One sort– a harsh one is every other day only eat 500 calories. And in our human studies we’ve been doing what’s called the 5:2 diet, where 2 days a week you only eat 500 calories, the other 5 days you eat normally. Eat healthy if you can. In this book called “The 8-Hour Diet” there’s evidence that if you restrict the time window that you eat each day to 8 hours or less, it’ll have health benefits, again, that’s long enough to shift the energy metabolism.
OK, why does fasting bolster brain power? During development of your brain, but also in the adult, neurons are generated from stem cells. They grow out their axons and dendrites, they form connections with each other, synapses, and communicate with each other. During aging, many people– their brain ages successfully, they stay cognitively intact, whereas, unfortunately, others develop diseases. We think the reason, the main take-home message of this talk, is fasting is a challenge to your brain, and your brain responds to that challenge of not having food by activating adaptive stress response pathways that help your brain cope with stress, and resist disease.
Does this make sense in evolutionary terms? Anything we talk about in biology, we always have to ask the question, “Why is it that way? Why when we take animals and put them on an intermittent fasting diet, are their neurons protected, in mice, of Alzheimer’s and Parkinson’s disease? Why do they perform better when we test their learning and memory?” It amazes. Well, if you’re hungry and haven’t found food, you better figure out how to find food. You don’t want your brain to shut down if you’re hungry. And, in fact, that’s what we find in the animals: Nerve cell circuits are more active. Some of the changes in the brain that occur with intermittent fasting also occur with vigorous exercise.
Now, most people, and Jeff this morning gave a nice talk on showing the benefits of exercise on him. I think you probably found that it benefited your brain too? OK. So, when we start looking at what are the neurochemical changes in the brain with intermittent fasting. They are very similar to exercise.
Now on this slide, in the upper left picture, the third boy on the right running, that’s my son, he is in the audience. You can tell by the faces of the 3 kids– they are in a cross-country race, that’s a challenge, right? They are probably saying to themselves during the race– I used to run races myself, I still occasionally do– “Why am I doing this?” However, when they get done with the race, they feel great, and they feel relaxed. During the cross-country season my wife and I– It’s very obvious our son’s mood was better. On the right, my daughter is in the white. Her mood was better during cross-country season.
Why is that? Exercise and intermittent fasting both increase the production of proteins in the brain that are called neurotrophic factors. We discovered this many years ago, back when I was a postdoc in Colorado in 1980s. We found that these neurotrophic factors, such as FGF, and one called BDNF, brain-derived neurotrophic factor, promote the growth of neurons, promote the connection of neurons, and the strengthening in synapses. OK, so here is the idea: Challenges to you brain, whether it’s intermittent fasting, vigorous exercise, or what we are doing now, hopefully if you haven’t fallen asleep, is cognitive challenges.
When this happens, neurocircuits are activated, levels of neurotrophic factors such as BDNF increase. That promotes the growth of the neurons, the formation and strengthening of synapses. Also shown in the lower left, it turns out both, exercise and intermittent fasting, and using your neurons, using your brain can increase the production of new nerve cells from stem cells, at least in one region of your brain, called the hippocampus, which is shown here. I mentioned ketones, which come from burning fat, and that happens during fasting.
The Romans discovered ketones even though they had no idea, they haven’t taken any chemistry course, or didn’t know what it was. People with epileptic seizures back then, they thought they were possessed by demons. And they found if they take these people and shut them in a room, and don’t feed them, the demons will go away. What’s happening is: ketones go up, and it’s well known that ketons suppress seizures, and in fact, ketogenic diets are used to treat, even today, patients with severe epilepsy. We are doing my work in my lab trying to understand why ketones are good for neurons. One reason is they provide an alternative fuel for the neurons, they boost the energy levels in the neurons.
Recently we discovered that fasting, by increasing BDNF levels in the brain, as a neurotrophic factor, can increase the number of mitochondria in your nerve cells. And I am not going to go into details of this slide, but the mechanism is very similar to the mechanism where by exercising your muscles increases the number of mitochondria in your muscles. The fasting is a mild energetic stress, and the neurons respond adaptively by increasing mitochondria, which helps them produce more energy, and in this paper cited down here, “Nature Communications”, we recently showed that by increasing the number of mitochondria in neurons, it can increase the ability of the neurons to form and maintain synapses, and thereby increase learning and memory ability. In addition to the increasing neurotrophic factors and increasing neuronal bioenergetics, we’ve found that intermittent fasting will enhance the ability of your nerve cells to repair DNA, so right now– and also probably exercise, and also intellectual challenges.
And again, what’s happening in this case when you are using your neurons, exercising your neurons, it causes a mild oxidative stress, and at the same time that there is increased oxidative stress the cells are enhancing their ability to repair oxidative damage to DNA.
Why is it that the normal diet is three meals a day plus snacks? It isn’t that it’s the healthiest way, eating pattern, and that’s my opinion, but I think there’s a lot of evidence to support that. There are a lot of pressures to have that eating pattern. There’s a lot of money involved. The food industry, are they going to make money from skipping breakfast like I did today? No, they are going to lose money. If people fast the food industry loses money. What about the pharmaceutical industries? What if people do some intermittent fasting, and exercise periodically, and they are very healthy? Is the pharmaceutical industry going to make any money on healthy people? So, one challenge for a society, and this is one of the purposes of these TED Talks, hopefully, is that communication is the way to improve health.
People understanding what they can do to improve their health and then taking action, like Jeff talked about in his own talk this morning. So, I would urge you to communicate, and spread the word that there are ways for people to be healthy, and maybe we can do this even with– Of course, I am working for NIH, and one thing about NIH is we are using your tax payer’s money to try to help your health. We don’t have a profit motive.
So, really one of the main reasons I’ve got interested in things like intermittent fasting, exercise, trying to understand at the cellular molecular level, what’s happening in the brain. This is research that isn’t commonly done, and it’s not done at all by pharmaceutical industries, and it’s not done so much. So, I am going to end with this slide. And thank you very much for your attention. And try it out, you can just play around with these kinds of diets, and you may find…
What we found in our human studies though is it’s kind of like exercise: if you’ve never exercised before, and you go and run 3 miles, you are not going to feel good. If you eat 3 meals a day, and all of a sudden you go all day not eating anything that day you are going to feel irritable, and ornery, and so on. But it turns out if you can kind of force yourself to do that, maybe one day a week for a month, and then two days a week, you get used to it, and after a month or two many people can adapt to that kind of diet with no problem and you’ll find that on the days when you don’t eat so much you are more productive. Thank you. (Applause)

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