Intermittent Fasting and Its Effects on the Brain

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Show Notes

The New York Times interviewed Dr. Mattson for the article "The Benefits of Intermittent Fasting," which was published online on February 17, 2020.

Read "Effects of Intermittent Fasting on Health, Aging, and Disease" published December 26, 2019, in The New England Journal of Medicine. (Free account required.)

Transcript

Intro: I'm Dr. Nathaniel Chin, and you’re listening to Dementia Matters, a podcast about Alzheimer's disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer's disease research and caregiver strategies. Thanks for joining us.

Dr. Nathaniel Chin: Our guest today is Dr. Mark Mattson, a neuroscientist at John Hopkins School of Medicine in Baltimore, Maryland. Dr. Mattson studies the molecular and biochemical causes of degenerative brain diseases, like Alzheimer's Disease and Parkinson's Disease, as well as healthy brain aging at the cellular and molecular levels. Dr. Mattson has done extensive research into intermittent fasting and how it affects brain aging and cognition. The mainstream health media has definitely made intermittent fasting trendy in the last few years, and I'm excited to hear from a scientist if the data supports the hype. Thank you Dr. Mattson for taking the time to join me on Dementia Matters.

Dr. Mark Mattson: Glad to be here, Nathaniel. 

Chin: So can you start out by defining intermittent fasting and explain what happens in the body when someone follows an intermittent fasting lifestyle?

Mattson: Intermittent fasting is an eating pattern in which the individual frequently goes for extended periods of time with no energy intake, periods of time that are sufficient to deplete liver energy stores which is glucose and then switch to using fats and the ketones derived from the fats in your fat cells. The typical American eating pattern is three meals a day plus an evening snack in many cases, and with that eating pattern there's not any time interval between meals sufficient to cause this metabolic switch from glucose to fats and ketones.

Chin: And so that's one of the main concepts is that instead of our body utilizing glucose, in this intermittent fasting you'd be using fats and triglycerides is that right?

Mattson: Yes.

Chin: And how long does it take to make that switch when you mention metabolic switching. How long does one need to go to make it?

Mattson: In a person who's just not exercising and kind of normal daily activities, it takes ten, twelve hours to have that metabolic switch occur. If they, for example, get up in the morning and go running after having slept for eight hours, then probably gonna have the metabolic switch very soon after they begin running.

Chin: I see, and that's a really good point. So it's not really just about the duration in which you're not eating, but it's your other behaviors and lifestyle factors that may influence the actual switch. 

Mattson: Yeah and with exercise, if there's glucose in the liver available, that's preferentially used by your muscle cells and then during fasting your muscle cells will switch to using triglycerides and ketones. From an evolutionary perspective, this allows animals to go extended time periods of many days to even weeks with no food intake. And undoubtedly individuals, animals evolved so that their bodies and brains were able to function very well, perhaps optimally in a food deprived state. Otherwise, they wouldn't have been successful in acquiring food.

Chin: And so you mentioned two key words there. You mentioned fasting and calorie restriction as well as ketones, and so I'm wondering how is this process of intermittent fasting different than our general caloric restriction and this ketogenic diet that we hear about in the news?

Mattson: Yeah, it's possible to have a calorie restricted diet without any metabolic switching occurring. So, for example, if you say you're overweight and you're taking in 2,400 calories a day. If you cut back to 2,000 but you still eat breakfast, lunch, dinner, a snack, then you're not going to deplete the liver glucose stores because every time you eat - if there's carbohydrates that you're eating - then you replenish the liver store. So it's possible to have chloric restriction without the metabolic switch occurring. We think this metabolic switch is important and we can go into more detail on that. Not from just the standpoint of ketones themselves being used as an energy source by ourselves but also there's numerous signaling pathways that are activated that we think, many of them are independent of ketones.

Chin: And so intermittent fasting is different though than a ketogenic diet, is that right?

Mattson: Yes, of course. Ketogenic diet: ketones are elevated, blood glucose remains low, and so cells are using - including brain cells - use a lot of ketones on a ketogenic diet. But some of the signaling pathways, for example, in the brain that we study may be independent of ketone elevation. 

Chin: Okay, and so actually late last year the New England Journal of Medicine published an article in which you offered this extensive review of the scientific literature relating to the effects of intermittent fasting on health, aging, and disease. I know you were just alluding to this and so I'm wondering, what did you find in regards to intermittent fasting and its effect specifically on brain health and cognition?

Mattson: Well, as is usually the case, there's many more studies being done in animals than humans and the New England Journal, of course, focuses on humans. So from the human perspective there's solid evidence that in people who are obese or overweight that switching their eating pattern to an intermittent fasting eating pattern can enable them to lose weight and particularly lose fat and improve their glucose regulation, improve insulin sensitivity. So there's been now dozens of studies in overweight or obese humans. There have been fewer studies in normal weight humans, and the studies that have been done actually focused on resistance training and whether people who do weight lifting can build muscle mass well on an intermittent fasting eating pattern. The answer is yes. And then - but as far as human diseases, some clinical trials have been done in certain disorders; asthma, multiple sclerosis, which are inflammatory disorders as are a lot of diseases. There's also numerous trials going on in cancer. there's a lot of evidence from animal studies and just knowledge of cancer cells and their energy requirements that suggest that drugs that people are given in their chemotherapeutic treatments or radiation treatments - the vulnerability of cancer cells to those toxic treatments can be enhanced if the person is in a fasting state or an intermittent fasting eating regimen so yeah. And then also in human studies, there's pretty strong evidence of - let's say solid evidence - that cardiovascular risk factors, blood pressure and blood lipid profiles, can be improved by switching from normal eating pattern to intermittent fasting.

Chin: And in your paper in the New England Journal, you mentioned that there have been some studies to show cognitive benefits of people who are doing intermittent fasting and that their performance on some memory tests like verbal memory actually improved during the intermittent fast.

Mattson: Yeah, the studies are limited. There's one study in Germany, which I think the one that I cited in the New England Journal article. There's other studies ongoing, including one that my colleague Dimitrios Kapogiannis at the National Institute on Aging is heading, where what we're doing is - it turns out that overeating and diabetes and insulin resistance are risk factors for cognitive impairment and Alzheimer's disease. So in the study we're doing at the NIA, we're taking subjects at risk for cognitive impairment and A.D. because of their age - they're between 55 and 70 years old  - and their metabolic status - they’re obese and insulin resistant - and then we randomly assign them to either Control, arm which is advice for a healthy eating, or intermittent fasting arm, which is two days a week, eating only 500 calories on those two days which is not near enough to keep the liver glucose stores supplied. And so there's two days a week they're in a ketogenic state. Study’s almost done, but we can't really say anything about the results yet.

Chin: You do mention in your paper that there is evidence, as far as neurodegenerative disorders, that intermittent fasting and caloric restriction can improve sort of brain resilience or can improve the brain's health. Could you speak to some of those mechanisms of how intermittent fasting could actually help the brain?

Mattson: Yes, and this is based on animal studies and animal models of A.D. and Parkinson's so there's multiple mechanisms. One is that intermittent fasting can enhance neurotrophic factor signaling particularly brain derived neurotrophic factor, BDNF, which is known to be important for cognition and - actually it's important also because it has kind of an antidepressant effect. The most commonly used antidepressant drugs are mediated by BDNF so that's one mechanism. BDNF is known to enhance the resistance of neurons to stress and to promote the formation and maintenance of synapses. Okay, so then another mechanism is that the intermittent fasting... what it does - during the fasting period nerve cells in the brain, they reduce their overall uptake of proteins and production of new proteins. They go into kind of “conserve resources” mode where they're not actually growing during the fasting period but they're reducing protein synthesis by suppressing a pathway called the MTOR pathway. And then at the same time they're increasing a process called autophagy, which is a mechanism whereby the nerve cells recycle molecules in the cells or even mitochondria, the energy producing compartment of the cells. Then during the feeding period, the cell goes into a growth mode. We think from the animal studies that that's when actually new synapses are formed and the nerve cells grow and enhance connections so forth. A third mechanism is to enhance DNA repair. There's some evidence that - well there's a lot of evidence - during aging, there's increased accumulation of damaged DNA in our genome. This is why cancer risk increases during aging, at least part of the reason why that there's increased mutations in cells that aren't repaired and therefore there's increased chances of a cell becoming cancerous. We found intermittent fasting and exercise enhanced DNA repair in the brain as well.

Chin: So it seems that intermittent fasting not only helps the whole body by improving insulin sensitivity, helping with weight loss, reducing blood pressure and risk for diabetes, but then there are some very specific effects that can happen within the brain. 

Mattson: One thing we found is really interesting. Very recently, we had a paper in a journal called Nature Communications where we found that intermittent fasting - well this is very important for the people listening - it takes people several weeks to a month to adapt to an intermittent fasting eating pattern so that they are no longer hungry and irritable during the time period with their previous eating pattern that they would have been eating. For example, if someone wants to adopt an intermittent fasting eating pattern where they skip breakfast and eat all their food between noon and six or seven PM each day so that they're fasting for 16-17 hours a day, then when they first start that skipping breakfast they're going to be very hungry in the morning and irritable, maybe not even - having maybe having trouble concentrating. But by two weeks to a month, those initial side effects if you will, or adaptations, will disappear. We found by looking at the brains of mice that, with the same time course, there's an enhancement of activity of an inhibitory neurotransmitter called GABA, which has an anti-anxiety effect. It turns out in Alzheimer's disease - and really my lab was the the first one way back in the late ‘80s early ‘90s to provide evidence for that - and Alzheimer's disease, there's a problem with nerve cell networks in the brain controlling their excitability so that certain circuits become uncontrollably excited, hyper-excited, and in fact patients with Alzheimer's disease, they have a greatly increased incidence of epileptic seizures compared to age-match control subjects. And that's because we think there's impairment in GABA, the inhibitory neurotransmitter, signaling or even death of the neurons - they use GABAs and neurotransmitters. So intermittent fasting will constrain excitability within normal limits and protect neurons against what we call excitotoxicity, which gets a little more complicated. But in the brain and Alzheimer's, of course, a lot of focus is on the Amyloid-Beta peptide, which forms the plaques and intracellular TAU tangles. My own opinion is that A-Beta and certainly TAU are downstream. That is, occur after other important changes that contribute to the increased accumulation of the amyloid. But once the amyloid starts to accumulate then it makes neurons even more vulnerable to hyperexcitability and what we call excitotoxicity. In fact one of the one of the drugs that's used to treat Alzheimer's patients is a drug that blocks a certain type of excitatory glutamate receptor. That's a drug called memantine. 

Chin: And you know, you mentioned that this first month of an intermittent fast is difficult for people. I notice that you put that in your paper as well as far as practical considerations. But you also speak to the research referencing brain evolution and how this practice of intermittent fasting is meant to optimize our brain function. However the modern lifestyle kind of gets in the way of that, and so what is it about our modern lifestyles that make it difficult to do intermittent fasting or actually negatively impact our brain?

Mattson: What makes it hard to do is that most of us, including me, we were raised in family where the normal eating pattern was three meals a day and oftentimes ice cream after dinner. As everyone knows what you learn when you're a kid you tend to stick with, whether it's... you know anything, religion, or just habits, you know. Exercise, in general kids who are brought up in families where the parents exercise, they're more likely to exercise. So yeah this is a long-standing eating pattern that arose way back probably nine, ten thousand years ago when the agricultural revolution took hold and people settled down and farmed domesticated plants and animals and were able to store food so that they could wake up in the morning and they'd have food to eat. On the other hand, from an evolutionary perspective, breakfast is the least likely meal. That is to say, animals in the wild don't wake up and breakfast is waiting for them. They have to work for it.

Chin: You also mentioned, too, that one of the potential barriers to intermittent fasting is that most healthcare providers are not really trained to provide specific interventions, intermittent fasting interventions. You do mention some of the options and you mentioned them here today in the podcast of this, having two days a week where you restrict how many calories. But there are other options, too, where you do not eat for 16 to 18 hours. Is there any evidence that one is better than the other?

Mattson: No. In humans, there's been no studies yet within the same study that directly compared, you know in other words, have three arms to the study control five-two intermittent fasting or daily time-restricted eating approach and, you know, so same group of people and look at same endpoints. So that hasn’t been done. But we do know that definitely sedentary overindulgent lifestyles are not good for the brain just like they're not good for other organ systems. It makes sense that the converse is true; that is exercise and moderation and energy intake and intermittent fasting compared to normal eating pattern will be beneficial. We don't  - it'll be interesting to do studies in normal healthy subjects, normal weight, say people who exercise to see if there's any additional benefits of intermittent fasting for endpoints of that interest, whether it's cognition or endurance. There's a lot of interest in the exercise community in intermittent fasting now. Because it's emerging that at least with endurance events, marathon certainly, Tour de France type things, that if you start the event in a fasted state where you've already switched to using the fats coming from your fat cells then you're able to maintain performance throughout the event. Whereas if you're taking essentially glucose, carbohydrates, you know if you, before the event and then different times during the event, it causes these well - first of all the ketones don't go up but then if you do deplete the glucose then you go into a period of poor performance until the metabolic switch takes hold. So I've had some interest in that. And we did studies in animals running on treadmills daily for two months with them on either intermittent fasting or ad libitum feeding eating patterns. At the end of the two months, the animals that were on the intermittent fasting eating pattern had better endurance when we tested their maximum, how far and how long can they run on the treadmill. 

Chin: That's a pretty important finding. So not only are we talking about preventing disease, but potentially talking about enhancing one's performance in their current state.

Mattson: Yeah, yeah.

Chin: Do we know the long-term consequences of intermittent fasting and metabolic switching?
Mattson: In animals, we do, but there's a caveat with this, more than one. So in animals, if we start with young or even middle-aged rats or mice and you put them on intermittent fasting eating pattern - the most commonly used one in the rodents is every other day fasting, 24-hours fasting, 24-hours food is always available and this keeps switching back and forth - they can live up to 50 percent longer if they're on the intermittent fasting eating pattern. However the control eating pattern in all animal studies is ad libitum feeding, that is they always have food available and they actually overeat and become fat. If you look at lab rats and mice, particularly as they get middle-aged, they gain a lot of weight and a lot of fat. The animal studies are really asking the question, if you take an obese or overweight and fairly sedentary animal and you switch them to intermittent fasting eating pattern, they live longer. We have found - we did do some studies where we compared daily calorie restriction to intermittent fasting, both of which are beneficial, and we did find greater improvement in insulin sensitivity with the intermittent fasting compared to daily calorie restriction. So I guess you know the take home message there with humans - and in normal weight humans we don't know for sure, but maybe they might benefit from intermittent fasting as they age well.

Chin: I guess, you know, one of the questions I like to ask my interviewees during this podcast, Dr. Mattson, is what they do in their own life. And with you being an expert in this field, I wonder do you practice intermittent fasting and are there other things that you do to maintain brain health and reduce your risk of neurodegenerative disease?

Mattson: I don't eat breakfast and most days I eat all my food within, it varies but, six to seven or eight hour time window, usually it's about six to seven hours. I spread it out so I'll, you know, eat around lunch time or so and then late afternoon. I don't eat everything at once, I kind of spread it out so I can get enough calories to maintain my body weight which is low to start with. Then exercise is very good for the brain. Unfortunately for me now, I got in a mountain bike accident and I'm recovering from surgeries and so I haven't been able to get much aerobic exercise. I can tell, as well as anyone else who exercises regularly and then isn't able to kind of test that, there's a big effect of exercise on the brain. So those are the two things. Then, of course, for Alzheimer's disease keeping your mind intellectually and socially engaged is important. There's good epidemiological evidence for that and that's consistent with what we know from animal studies as well.

Chin: And so likely a combination of all of these things will make a difference. With that, you know, I'd really like to thank you for being on Dementia Matters and as more of these studies come out, I hope to have you back on the show.

Outro: Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center. The Wisconsin Alzheimer's Disease Research Center combines academic, clinical, and research expertise from the University of Wisconsin School of Medicine and Public Health and the Geriatric Research Education and Clinical Center of the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. It receives funding from private university, state, and national sources, including a grant from the National Institutes of Health for Alzheimer's Disease Centers. This episode was produced by Rebecca Wasieleski and edited by Bashir Aden. Our musical jingle is "Cases to Rest" by Blue Dot Sessions. Check out our website at adrc.wisc.edu. You can also follow us on Twitter and Facebook. If you have any questions or comments email us at dementiamatters@medicine.wisc.edu. Thanks for listening.

Updated on March 25, 2024