Johns Hopkins neuroscientist Mark Mattson shares his insights on what we know — and what we don’t — about intermittent fasting and brain health.
Increasingly, scientists have been focused on various lifestyle choices as strategies to boost brain health and reduce Alzheimer’s risk. When it comes to intermittent fasting, the eating pattern has shown promising benefits in animal studies for a host of health conditions, including obesity, diabetes, cardiovascular disease and neurological disorders like Alzheimer’s. While much more research is needed to determine intermittent fasting’s effects on brain health, these animal studies have since paved the way for research in humans.
Being Patient spoke with Mark Mattson, a neuroscientist at Johns Hopkins University and author of The Intermittent Fasting Revolution: The Science of Optimizing Health and Enhancing Performance (Feb. 2022), about the biological mechanisms that underpin the potential of this approach for boosting brain function and health at large. He also discusses the unknowns that remain about the impacts of intermittent fasting on brain health.
Being Patient: What do we know about intermittent fasting, and why, if at all, is it beneficial for health?
Mark Mattson: We know a lot about intermittent fasting from the perspective of helping people get their weight down and improve their glucose regulation.
Many studies in humans compare three meals a day plus snacks to restricted eating — or another approach we’ve used with a group in England a long time ago [that’s] now called 5:2 intermittent fasting (two days a week eating only one moderate-sized meal each day) — [show that] those [two latter] eating patterns have sufficient time with no food to cause a metabolic switch from using glucose in the liver to using ketones, which come from fats.
Ketones are a good fuel for neurons. We know that for sure. We also know that ketogenic diets and also fasting can suppress epileptic seizures. In fact, ketogenic diets are still used for some patients who don’t respond well to epilepsy drugs. Work in my lab in animals [has] shown what’s going on in the brain to explain that beneficial effect of ketones.
Being Patient: What about for brain health, specifically?
Mark Mattson: I have to get in briefly to a little neuroscience. If I were to ask your listeners or viewers what neurotransmitters they have heard of, they might say dopamine or serotonin. But it turns out the most abundant and important neurotransmitter in the brain is glutamate. It’s an amino acid — an excitatory transmitter — and over 90 percent of the neurons throughout the brain use glutamate. Those glutamatergic neurons degenerate in Alzheimer’s disease.
Actually, it turns out that Alzheimer’s patients have increased incidence of seizures, like 20- to 30-fold over age-matched people without Alzheimer’s. There’s this hyper-excitability — unconstrained, improperly regulated activity in those excitatory circuits. What intermittent fasting does is it quiets those neurons by actually increasing the activity of inhibitory neurons. They use the neurotransmitter GABA.
A lot of studies in animals have shown that compared to ad libitum feeding, intermittent fasting can enhance learning and memory, and even has an anti-anxiety effect once the animals are adapted to the new intermittent fasting eating pattern.
Being Patient: Glucose is the normal fuel of our brains, but we can switch energy sources to ketones. So, is changing energy sources better for our brains, or is it that ketones are a better source of fuel for our brains?
Mark Mattson: Both are true: those aren’t mutually exclusive. You said that our brain cells normally use glucose. That’s true if we’re eating diets that have carbs in them. If we’re eating a ketogenic diet, or if we’re fasting, the neurons switch from using glucose to ketones. That’s been clearly demonstrated in humans by Steve Cunnane where he had people switch to ketogenic diet and he measured both glucose and ketone utilization and showed there’s that switch.
With Alzheimer’s, neurons have problems using glucose. That’s been known for decades and decades. Based on Dr. Cunnnane’s work and some of our’s in animals, we think that neurons are still able to use ketones even in humans and animals that are symptomatic with Alzheimer’s disease.
Being Patient: The idea is that by keeping our brains well fed, we create an environment where things are less likely to go wrong, such as the build-up of beta-amyloid plaques and tau tangles; if we have a healthy level of energy source, then perhaps it will be harder to reach that tipping point where the neurodegenerative process or pathology begins. Is that correct?
Mark Mattson: Very well said. Experimentally, one can show that if you compromise the energy levels in neurons, and this is in animal studies or neurons in a dish, then they produce more amyloid beta peptide and they’re more vulnerable to being damaged by the amyloid. They’re also more vulnerable to hyperexcitability and what we call excitotoxic damage.
Being Patient: What is the state of the research in intermittent fasting?
Mark Mattson: I’m really excited about all this because just in the last five to seven years, there has been an exponential increase in the number of human studies.
I was invited with a colleague of mine to write an article for the New England Journal of Medicine a few years ago. They had two reasons for inviting us to do it. One was there’s not enough data from humans, particularly people with obesity or insulin resistance, to merit a review article. But also, a lot of physicians hadn’t heard of intermittent fasting or they had no idea that there’s actually a lot of science, including an increasing number of clinical trials.
Now, if you go on ClinicalTrials.gov, which is where you go to find all the ongoing trials, and if you put in the words intermittent fasting, there’s like 150 trials ongoing, ranging from various cancers, diabetes, obesity. mild cognitive impairment and some inflammatory neurological disorders like multiple sclerosis.
What happened was that the animal research really didn’t start till the late ’80s, early ’90s. It took a couple of decades to get a lot of animal data. Then, human studies started and they’re taking off now.
Being Patient: Looking ahead, what more do we need to know about intermittent fasting?
Mark Mattson: For normal people who don’t have Alzheimer’s disease, we don’t know much at all, except that they can undergo this metabolic switch from glucose to ketones in terms of neurons in their brain using them.
We have a trial that’s almost done at the National Institute on Aging, where we took people between the ages of 55 and 70 with obesity. They’re also insulin resistant. We put them on either 5:2 intermittent fasting or [a] control eating pattern, which [are] breakfast, lunch and dinner. Before we started them in the study and then at the end of two months, we did a bunch of cognitive tests and other psychological tests. We’re doing functional magnetic resonance imaging to look at neural network activity in their brains. And we’re doing some other things, for example, analyzing their cerebrospinal fluid to see if some of the things we saw change in the brain in animals with intermittent fasting also change in humans. I can’t say anything about it yet — because the study’s not done, we haven’t published it — except that it’s looking encouraging.
But, more study is needed. There needs to be studies focusing on the brain and humans. There are a lot of anecdotal things where people will say they skip breakfast and it’s been a couple months now; in the morning hours, they feel like they’re really productive and they’re able to think clearly and so on. But from humans, it’s a lot of anecdotal things and not any true scientific data.
Being Patient: Without fasting, can we use ketones supplements like beta-hydroxybutyrate as an energy source for the brain?
Mark Mattson: The beta-hydroxybutyrate ester, a colleague of mine at NIH (National Institutes of Health) developed that ketone ester. This was when I was a lab chief at NIH. I was a lab chief there for 20 years and then I retired, and now I’m on the faculty at Hopkins. We tested that ketone ester in our mouse model of Alzheimer’s disease. It had beneficial effects.
Then, it’s now being tested by Steve Cunnane in patients with Alzheimer’s disease, and also a neurologist that I mentored is going to test it in patients with mild cognitive impairment or early Alzheimer’s disease.
Being Patient: In the meantime, what is your advice for improving one’s brain health?
Mark Mattson: Number one: physical exercise. [Then, there’s] cognitive exercise — particularly what you and I are doing now, engaging in intellectually challenging things — and moderation in calorie intake and eating a healthy diet.
The interview has been edited for length and clarity.
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