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

Mark Mattson: the father of hormesis and intermittent fasting research

Dr. Mattson's work identified how intermittent fasting protects against brain aging, Alzheimer's, and Parkinson's through hormetic stress responses.

"Dr. Matson's rigorous work has advanced scientific understanding of brain aging and identified fundamental aspects of age-related neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. His most notable contributions, however, have probably been that of his role as the father of hormesis and intermittent fasting, for which he is extraordinarily well known. At the start of the interview, you'll hear a little bit more about why I was so excited to have this conversation with Dr. Mattson. We're trying something new today with this episode and releasing the interview audio here first, exclusively on the Found My Fitness podcast feed. For those of you listening who also enjoy our in-depth video interviews, don't worry. We plan to release the full annotated video version of the interview very soon. As many of you already know, the post-production work that goes into our videos is quite intense, and we just couldn't wait to share this conversation with you. On to the important stuff. In this episode, Dr. Matson and I discuss how hormetic stressors drive adaptation and prevent physiological complacency, how intermittent fasting improves health by promoting metabolic switching, how daily time-restricted eating and 5-2 weekly fasting compare, how a ketogenic diet and intermittent fasting differ in terms of brain effects, how exercising while intermittent fasting exerts additive effects, how plant-based bioactive compounds induce hormetic stress, how severe caloric restriction may harm the body and compromise muscle mass, how older adults, children, women, and pregnant women respond to intermittent fasting, how the effects of cortisol differ during a fast versus chronic uncontrollable stress, how the effects of fasting mimetics like resveratrol or spermidine compare with actual fasting, and how ketone supplementation may improve brain health. A couple of quick reminders before we get to the podcast. If you ever find yourself wanting to dive a little deeper on an episode you listen to here, then you should subscribe to my newsletter. It's completely free and we respect your inbox. I only send it out when we have new fully researched topic pages, exciting upcoming podcast episodes, or updates on new research on some of my favorite topics. It's the best place to get distilled research and the most up-to-date information on topics like fasting, fitness, and overall health and longevity. To sign up, just head over to foundmyfitness.com forward slash newsletter. That's N-E-W-S-L-E-T-T-E-R, newsletter."

Key distinction: intermittent fasting vs time-restricted eating vs prolonged fasting

IF alternates fasting/feeding periods. TRE limits daily eating window. Prolonged fasting (2+ days) activates stem cell regeneration.

"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? 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 fats from your fat cells and the ketones produced from those fat cells. So in a person that 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 eight or nine o'clock, 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. With intermittent fasting, the approaches that have been used in experimental studies, both in animals and 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 a sufficient time for this metabolic switch to have occurred. And scientists I just 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 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 p.m., and if they were to measure their ketones, they'll find that in the morning they'll start to be elevated. 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 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, 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, two days a week, they'll only eat one moderate-sized meal of, say, 600 calories, those two days. Then the other five days, they eat normally. And so in that case, 5-2 intermittent fasting, the person will have the metabolic switching 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've 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. 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 airflow 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 Harvey, who's in England and works with women at risk for breast cancer because of their overweight, and they also have a family history. And she came to my lab. She'd seen our working animals. And there's also some working animals suggesting that fasting can be beneficial in suppressing cancer growth. So anyway, Michelle and I designed a study where we took these women, 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'd normally take in. And because we'd 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."

Hormesis: mild stress from fasting activates protective cellular pathways

Like a tomato producing toxins to protect seeds, fasting stress activates cellular repair and protection - the hormesis principle.

"Is there, can you, if a person is exercising regularly and also doing some form of intermittent fasting and they're getting these activation of some of these stress response pathways and the beneficial effects and you're getting the 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?"

IF helped Alzheimer's and Parkinson's models but worsened ALS in mice

Every-other-day fasting helped Alzheimer's, Parkinson's, and epilepsy mouse models but worsened ALS - fasting isn't universal.

"And that was really interesting because, you know, I mentioned these studies that we'd done with intermittent fasting in 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."

Fasting and exercise both boost GABA - potential for autism research

Exercise and intermittent fasting both upregulate GABAergic tone, as does keto. Shared mechanism suggests potential for autism.

"And then the exercise and intermittent fasting upregulate the GABA tone. And ketogenic diets will do that too."

Paradox: fasting raises cortisol yet extends lifespan in animals

Animals on calorie restriction have elevated cortisol yet live longer. Intermittent stress may be adaptive, unlike chronic stress.

"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."

Exercise may have more profound mental health benefits than fasting alone

Mattson says exercise has more profound mental health effects than fasting. Observational data supports exercise; combining both is optimal.

"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 on, you know, I mentioned my blood pressure is now up."

Neurons use up to 50% of ATP just to pump ions - ketones provide an efficient alternative fuel

Active neurons use up to 50% of ATP driving ion pumps. Ketone bodies provide efficient alternative fuel that may protect neurons.

"My PhD work was mostly cancer metabolism, mitochondrial function. I did a lot. So in neurons, like up to, 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 and 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 this tendency for hyper excitability. And so anyway, that's the destroyer part of the sculptor and destroyer. How much of a role would the GABA production from being in ketosis help negate that? Well, that's important. That's a good question. I think that from a drug standpoint, drugs that enhance GABA tone could be beneficial. The trick is it's a tricky business because glutamate is critical for learning and memory. And it's, 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 that function isn't optimal. What about testing that with something like a ketone ester to see transiently? No, we've done that. So Richard Veitch in – I can't remember what year again. Anyway, bottom line is he sent a pulse doc up to my lab and what was his name? Kashi, a Japanese postdoc. And together with people in my lab in a mouse model Alzheimer's disease, they gave the 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, and learning and memory. And the ketone ester was beneficial. and no I think the ketone ester is very promising a friend of mine up in Canada, Steve Cunan, has done some really nice work with pad imaging. All right. So one can get images of relative levels of utilization of glucose by brain cells or of ketones. So Steve Kannon, he had radiolabel glucose, 2-deoxyglucose, and radiolabeled, he used acetoacetate, but it doesn't matter. He didn't use beta-hydroxybutyrate. Okay. So he had – these were just normal, initially normal people, but he's doing studies in people with mild cognitive impairment and Alzheimer's. So he had them – so 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 had shown that very early on, people with mild cognitive impairment, 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, Steve, that at least in people with early Alzheimer's disease, even though the 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 the – why am I blanking on her name? Kieran Clark's work at Oxford with ketone ester and the elite British cyclist. So, yeah, that's a big deal in the endurance athletes. And, 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."