Fasting to Benefit Brain Health - with Dr. Matthew Phillips | The Empowering Neurologist EP. 102

Hello everyone, I'm Dr. David Perlmutter. Welcome again to The Empowering Neurologist. Today we're going to have a very interesting conversation with Dr. Matthew Phillips. You may remember him, I've interviewed him before. He wrote a very interesting paper on the use of the ketogenic diet as a treatment for Parkinson's disease. Today we're going to talk about fasting. Now, we've talked quite a bit about fasting. We've talked about the ketogenic diet. Fasting increases ketones, so there's a lot of overlap there. And we're going to talk to Dr. Phillips about specifically the role of fasting in various neurological conditions, including cognitive decline, including Parkinson's, and how fasting is really very— what we call neuroprotective. It has other mechanisms. It increases the production of something called BDNF, brain-derived neurotrophic factor, that increases the growth of new neurons, the connection of neurons. And there are many other activities that are induced by fasting, including something we've also talked about quite a bit called autophagy, whereby our bodies are able to rid themselves of defective cells, as it were. And mitophagy, where we get rid of not, not very good functioning mitochondria, allowing what's called mitochondrial biogenesis, a great term that means enhancing our ability to grow new mitochondria, which as it relates to the brain being such an energy-demanding organ in our bodies is actually very important. Let me tell you a little bit about Dr. Matthew Phillips. He is a full-time clinical and research neurologist at Waikato Hospital in Hamilton, New Zealand. His foremost passion is to explore the potential and feasibility, as well as safety and efficacy, of what are called metabolic therapies, like changing energetics, particularly involved in things like ketogenic diet. We've talked about that before, and as we'll talk about today, fasting. And how these approaches create what are called alternate metabolic states that may improve not only the symptoms but also function and importantly quality of life for people with a variety of neurological issues, be it Alzheimer's, Parkinson's, Huntington's, multiple sclerosis, and others. He will hopefully today touch on even the use of fasting in the treatment of cancer. He did recently publish a paper on that as well. In 2017, his team conducted a first-of-its-type randomized controlled study involving the ketogenic diet as a treatment for Parkinson's disease. We featured him on The Empowered Neurologist talking about that in the past, an excellent episode. In 2020, his team is conducting a first-of-its-kind randomized crossover study of using the ketogenic diet as a treatment in Alzheimer's disease. So, really looking forward to our time together today. Let's jump right into our interview. Hello, Dr. Phillips. How are things in New Zealand?

They are excellent, Dave. Thanks very much for asking.

And congratulations on no COVID-19 anymore. That's quite an accomplishment.

Yep, it's very helpful, especially when you're trying to do trials. It can, it can be a real problem. But no, it's all good here now.

So does that mean there are no restrictions in terms of people going out and doing things? And is it just wide open? Are there restrictions?

Pretty much. There's pretty much no restrictions now. We just moved down to a very, you know, low or no restriction mode. So yeah, I mean, life's pretty much back to normal.

That's great. Well, what we're going to talk about today, I already Our viewers already know, we talked about it in the intro, but— well, that's thunder. We— you and I came together through some incredible serendipity, you must admit, that I ran into your parents while boating in British Columbia, and you live in New Zealand. And, you know, it's kind of a long story, but nonetheless, you've taken an interest in something that I find very, very fascinating. That is basically What's called bioenergetics. What is it that powers our cells, our bodies, our organ systems? And you've applied it to neurology. So on 2 counts, I'm very interested. And you wrote a really incredible paper just a few months ago on the notion of fasting and how that relates to neurological conditions. There's not a lot of people out there talking about it. Yeah. Though I think it's absolutely fascinating. And I just want to say at the beginning of our time together that you did a great job. I know that you're a pioneer in this and, you know, congratulations for sticking with it. Thanks. So you are talking about, as you and I have talked about, targeting the fire and not just the smoke, not just the symptoms. And let's just jump in. You've got this incredible interest in the metabolism aspect of neurological conditions. Let's begin with why in the world would you consider fasting for a patient with a neurological condition?

Okay, so with any question, I think it's always good to tackle the, the how, but more importantly, the why. And we often in medicine tackle the how. We talk about mechanisms and how, you know, how this works and that works and what these enzymes are doing. I could get into the bioenergetics and talk about how I really like how the idea of flipping your body into an altered metabolic state where you have lower insulin, lowered growth factor, things like IGF-1, upregulated master regulators of metabolism like PGC-1 alpha and AMPK. I could talk about all that stuff. But really, it's the why that matters in these disorders. And if you think of it in an evolutionary framework, then basically, when we were sort of evolving for 2 million years of evolution, we were in a hunter-gatherer mode. Excuse me. And during that time, we would often go without food, and nutrients weren't always available. From an evolutionary perspective, during those times, you actually had to perform better. From a neurological point of view, you had to be able to perhaps think more clearly, have more attention on your prey if you're hunting something, and be able to perhaps even see better and hear better and things like that. Really, my interest in this is about trying to return our bodies for large periods of time to that altered metabolic state, that sort of hunter state, which in theory should have a substantial impact on a lot of these disorders, the most prevalent disorders we're talking about today: Alzheimer's, Parkinson's, cancer, and so on.

So even beyond humans, I mean, it— even single-celled organisms seem to respond appropriately to stress. We call this hormesis. And you made a very interesting comment in your most recent paper that we really haven't had enough time to adapt, perhaps metabolically and genetically, I would say, to this nonstop provision of calories, of nutrients that now kind of since The advent of agriculture pretty much, you know, there are exceptions, characterizes what we experience. When we deprive our bodies of nutrients for a period of time, and we need to talk about what fasting means, what is intermittent fasting, what does it allow, water, etc., but when we do that, it represents a stress. And what are some of the good things that are derived from that stress?

Yeah. So there's a whole host of things because you're really changing the whole metabolism, bioenergetics, and more of the body. So you take a medication that often has one target, right? A medication changes like one pathway often. However, with fasting, you're changing almost everything. You're changing hundreds of pathways. Simultaneously. So you're turning the body into a whole state, and lots of things change. So like your insulin levels go down, for one thing, and that can be, you know, really good because along with that comes an elevation in brain-derived neurotrophic factor, which from a neurological point of view can enhance neurogenesis and remodeling of the synapses and things like that. You elevate other things like PGC-1 alpha, which is a master regulator of mitochondrial metabolism, and so it enhances mitochondria biogenesis. Those are the batteries of our cells, and it can actually make them more efficient at producing energy. There's some evidence that that can happen. You have a master regulator of metabolism called AMPK, and AMPK is a nutrient-sensing enzyme, and it basically induces a lot of processes that make our cells more effective at what they do, including autophagy, which is this really interesting process where the cell selectively degrades junky Proteins and organelles such as aged dysfunctional mitochondria, so that the things can be recycled and used for energy in other ways that make the cell more efficient. Fasting does all these things and a lot more. Really, there's no medication that can compare to that, just absolutely no way. I'm not anti-medication. We use them all the time. However, when you look at the, the power of fasting compared to medications, it's just remarkable. And I really think we should be looking at implementing this more into clinical trials to see just how much we can get out of fasting for our, our most difficult neurological disorders.

So it is a kind of an overseer over the whole process. Yes, there are medications that work at AMP kinase like metformin. Yes, there is mTOR where it even derived its name. There is rapamycin and analogs available that would target that pathway, and even approaches to PGC-1 alpha. But the point is this, what you're saying is that fasting is overriding, encompassing a whole response network in terms of dealing with the stress of nutrient deprivation. That's right. scarcity, allowing the body to preserve itself and even enhance its ability from a, let's say, cognitive perspective right now to do the things necessary to find food. So it's not that we are the strongest or fastest, but suddenly we're tapping into our best resource, which is our brain, which really, you know, more than that, you know, more than anything else, I think distinguishes us from other animals.

Yeah, that's right. We're tapping into an ancient evolutionary mechanism. Fasting has evolved over— I mean, a lot of these master regulators that we're talking about, I didn't talk about mTOR, and there's others, they're very old and ancient enzymatic pathways. We're just taking advantage of something that's been there for a long time in evolution, before we were humans, before humans came on the scene. That's really powerful, potentially.

On our Facebook site, we've been doing some fasting with several— with thousands of people at a time. I don't know. It's hard for me to know how many, but probably tens of thousands of people have joined us to do 24, 36-hour fasts. We've been doing that, I think— it brings up an interesting point, but we've been doing it sort of to enhance autophagy in hopes of maybe providing a little bit of senolytic therapy so we can maybe have a younger population of immune cells that might serve us well during these immunologically challenging times. Leave it at that. But that said, you know, there's an interesting thought that you brought up, the idea that fasting increases BDNF. Yes, it's good for neurogenesis. Yes, it's good for neuroplasticity, but we know Studies have demonstrated people coming into the hospital with head trauma, for example, and stroke, who have higher levels of BDNF tend to do better. So it also is insulating and reparative as it relates to neurons that have been traumatized. So even interestingly, from a preventive medicine perspective, fasting may be a way of increasing BDNF and therefore helping to insulate the brain, you know, the cells from as significant damage in comparison to what they might otherwise have experienced, like in stroke.

Absolutely. I mean, and if you look at the animal studies with, you know, rodents, rodents that are fasted, you know, for a period of time, I think it's 3 months or so, sort of time-restricted feeding fasting or alternate daily fasting before a stroke is induced in them, Compared to animals that are not fasted, those animals that have been fasted have final strokes that are less than half the size. The infarcts are less than half the size of the ones that were not fasted. And yeah, they have more neurogenesis and things like that going on. So of course, you can't automatically apply that to humans. That's the problem with translational medicine, and that's why it's so important we do human studies. To complement our animal research. But it's very tempting to say, well, what if—

Why not? At least we can talk about it. That's for sure.

Yeah, absolutely. But what if you were on a serious fasting regimen, and they're not that hard, as you and I know, to do that and incorporate them into your lifestyle, and would that protect you if you had a stroke? I see strokes all the time. I see them almost every day. Would that make your final infarct smaller? Obviously, the thing is, of course, would it prevent you from— make it less likely you were going to have a stroke in the first place? It's very exciting.

I would say that a couple other mechanisms that you might want to think about downstream might be tumor necrosis factor alpha and IL-6 that are also downregulated in the fasting state, again, through the AMP kinase mTOR pathway. We know that higher levels of both of those cytokines does tend to correlate with worse outcome.

Definitely. Fasting has powerful effects on suppressing inflammatory mediators such as IL-6 and TNF-alpha, as you mentioned. That's why it could apply to other inflammatory-based disorders, of which there are many. Such as multiple sclerosis and cancer in people.

Well, there's a great segue. I want to come back to our topic, but— or maybe we'll leave it for later. You recently wrote a paper dealing with a patient with a metastatic thymoma treated with, I believe, with fasting?

Yeah. I'll just give a brief outline of that one. Basically, a young lady, 37, and she was diagnosed with a metastatic thymoma. about the size of a small football invading her lung and her lung pleura, which is the lining around the lung. And it was actually invading the pericardium around the heart a little bit too. And it was not surgically resectable. And she was offered palliative chemo. Radiotherapy was not an option. And her oncologist, quite frankly, said, you have about 1 year tops. He was being perhaps a little more cautious than the literature would suggest, but still not a good outcome prognostically with the conventional road. So, what she did was we did a 2-year pro— well, it turned out to be 2 years. It was, you know, at the start we were like, it's as long as it takes. We're going to do this. What she did was 1 week of fluid-only fasting, so allowing water, tea, or coffee every 1 to 2 months. She started it off with a 12-day fast. The first was a 12-day. She did that for 2 years. In the interim, in the feeding period, she went on a fairly strict ketogenic diet. That's basically what she did. She had no chemo. Radiotherapy or surgery for this. As you know, the result was fairly remarkable.

I would invite our viewers to— we've done several podcasts on ketogenic approach to malignancy or cancer, and very interesting information. Let's get back to neurological conditions. There's one study that came to mind. As we were talking about autophagy or clearing out cellular debris, There was a recent paper that talked about the failure of the lysosome, deficiencies of lysosomal activity. That's, let's say, what digests this, helps to digest the cellular debris. A failure or deficiency of lysosomal activity in Parkinson's as it relates to digesting some of this abnormal protein and raised the idea that there may be medication to enhance lysosomal But we've got that covered right now. We can increase autophagy by things like fasting. Do you suspect this, along with what you've described before, and your results were outstanding, do you think fasting is going to play or could play a role in Parkinson's treatment?

Definitely. As you know, we published that randomized controlled trial a couple years back on a keto diet and Parkinson's. And really, the way I think about the keto diet is it mimics— it makes the body go into a pseudo-fasting-like state. And that's, to me, the main power of the keto diet. I think fasting has more potential. At the time, getting ethical approval for a study in people with a neurodegenerative disorder It was hard enough to get it for a keto diet. To get it for fasting, I really didn't think that was going to be feasible. However, we've just completed a randomized crossover in Alzheimer's, which is hopefully going to be published soon, of a keto diet in Alzheimer's. And so now with the evidence building up for keto diets in these neurodegenerative disorders, I think it is a nice time perhaps to introduce the the concept that maybe we can start introducing fasting periods for these disorders in people and see if that can help. For someone with Alzheimer's or Parkinson's, I would introduce a very gentle kind of fasting. There's different ways to do it, as you know. Probably the easiest one is time-restricted feeding, where you could just say do a 16:8, which is like they fast for 16 hours a day and then they eat for 8 hours a day, sort of whatever you want, although I would probably make it more along the lines of the keto diet, and just do that. And yes, I would love to see what that does in terms of autophagy. In theory, that should really upregulate autophagy and make it more effective at clearing these junky proteins, you know, such as Lewy bodies in Parkinson's. And then, you know, with Alzheimer's, you've got tau and the others that are these diseases. appear to be associated with quite strongly. It would be very, very interesting to see what happens.

Well, along the lines of the ketogenic diet, and certainly brought on by fasting, is the creation of ketone bodies. I think one that gets a lot of interest, of course, is beta-hydroxybutyrate. I think most of the attention on beta-hydroxybutyrate has been from its fuel perspective, that it really— I wouldn't say it's a It's not the perfect fuel, but its ability to produce energy, ATP, with less production of free radicals, etc. There are multiple highlights in the fuel area that people talk about, but in your paper, you call attention to beta-hydroxybutyrate from other perspectives, like as a signaling molecule. Tell us a little bit about that.

Yeah, so this actually opens the door to a much bigger topic. Sort of paradigm, paradigm. So yes, beta-hydroxybutyrate is the main blood ketone that is produced mainly by the liver, but elsewhere in the body too, from fat. And it has several bioenergetic advantages over glucose, which is the main fuel that people normally use for the brain. So BHB produces— Dr. Veech. who unfortunately passed away just a few months ago, showed us that compared to glucose, BHB produces more energy, more ATP, and probably consumes less oxygen as well. And then, so that's some of the bioenergetic advantages, but yes, it's also got advantages as a signaling metabolite. And this introduces the concept of epigenetics. where your DNA, you can, although your sort of genetic code is fixed, you can alter how it is read. And that's a really underdone area of medicine. I can't begin to explain how underappreciated I think epigenetics is. And it's— you can actually alter the expression of other genes. other factors involved in metabolism via BHB, and that's just so exciting. You can actually alter how the genetic code is read and introduce many other changes beyond just its direct role in energy.

Yeah, it's been said that genetics loads the gun and environment pulls the trigger. We are very empowered to think that we have a big role to play in our genetic destiny. Sure, a far cry from what we were told in medical school. We were told that our DNA lived in a glass case, and that it was the sole determinant of everything in the future. Absolutely, yeah. How empowering, and what a lot of responsibility now we have when we understand what a role this plays in our lifestyle choices. It takes me to another area, and that is kind of this food. funneling of information as it relates to one area that we know that fasting is, and the ketogenic diet for that matter, extremely effective for, and that is the actual intervention treatment of metabolic syndrome, and specifically as it relates to insulin resistance and glucose homeostasis. Perhaps we can talk about that in the context

Yeah. So, well, the metabolic syndrome is a risk factor for so many other disorders. And for— I'm sure most of your viewers know this, but the metabolic syndrome is like this sort of conglomeration of factors. So sort of obesity, but it's sort of visceral and particularly involves fat. fat buildup in the liver, and associated with type 2 diabetes, and hypertension, and abnormalities in the cholesterol profile. Now, that is a risk factor for many neurological diseases, such as stroke being the obvious one, but also things like Alzheimer's, and Parkinson's, neurological cancers, and so on. So, if you can hammer away at metabolic syndrome, you will reduce the risk of getting neurological disorders in general. There is no better way to hammer away at metabolic syndrome than with fasting. We have known for 100 years that fasting flat out cures type 2 diabetes. Dave, this is another thing we were not told in medical school, but we were told type 2 diabetes is a chronic degenerative, chronic process. You're always going to have it, and it's just going to keep getting worse. It's simply flat out not true. It can absolutely be reversed in the majority of cases. I have seen it, and we have done it. Yeah. And and you know other people have done it a lot more, like Jason Fung, for example. So and then with regards to obesity, well fasting obviously is I mean I don't think I need to go into the mechanisms. If you can implement a regular fasting regimen, it has marked effects on obesity. And you can just you can you know again I'll quote Jason Fung. Go ahead and read one of his books and he can. He has done a lot of work on that, him and Megan Ramos, I should add. In terms of hypertension, fasting improves that tremendously as well. Now, you have to get into the longer fasts to really hammer away at hypertension. You have to do what we call periodic fasting if you really want to get it down, and that involves several days of fasting at a time. Now, that's— you need a little more guidance, so perhaps from someone, a medical professional who knows about it. But if you really want to get blood pressure down, you can. That's the point. I think the smaller fasting periods would help, too. Those are 3 of the biggest factors of the metabolic syndrome. If you can fast, if you can make this a part of your life, and it's not difficult, I mean, I'll never go back to not having fasting as a regular part of my life. It just has so many benefits that if you can do that, according to the data, you really should drastically lower your risk of getting a neurological disease. They're some of the worst diseases, in my opinion, the worst. Yeah.

Well, we look at the big players in the world in terms of what is causing death, and these are chronic degenerative conditions. It's not infectious agents, it's not trauma, it's not war. It's the chronic degenerative, meaning lifestyle choice related, we talked about issues. And cancer. Yeah, and cancer, which is also, as you say, related very much to nutrition.

Definitely.

We had Dr. Sarah Hallberg on the program a couple of years back showing reversal and in fact curing patients of type 2 diabetes with a ketogenic diet over a 1-year period of time. And I recently gave a lecture to a group of doctors here in the States, and I went around the room and asked, how do you treat type 2 diabetes? And basically every drug was mentioned. And I said, well, please understand that none of you is, by these answers, treating type 2 diabetes. You're treating the manifestations, as you and I mentioned earlier. You're treating the smoke, not treating the fire.

Treating the smoke.

Nothing you do is treating the diabetes. The moment you stop the metformin or whatever drug you think is best, that following day the blood sugar starts to go back up. So you really haven't done anything. You suppressed one part of the story, Which is the blood sugar, or if they're measuring the A1C.

Exactly, yeah.

But what you're talking about is really treating the problem. And while some may challenge the relationship to neurological conditions of fasting, of ketogenic diet, no one can deny this powerful relationship of metabolic syndrome to risk for neurological degeneration, and therefore, I think if we have to connect 2 dots to get between fasting and ketogenic diet to neurologic diseases, so be it.

Definitely. Yeah, with regards to diabetes, the smoke is the blood glucose level, and the fire is the insulin resistance. In the diabetes world, we're constantly treating the smoke. We're getting that blood glucose down. It makes us feel good, and yet the patient comes back a year later, and the medications need to be upped. If you're giving insulin to the patient, well, the more insulin you give, the worse you're going to make that insulin resistance. You're making things— you're getting rid of the smoke in the short term, but in the long term, the fire's just smoldering away and getting bigger and bigger. Like you said, Dave, the diabetes is not being treated. If you really want to hammer away at it, address the insulin resistance fast. Reduce the body's need for insulin. Get rid of the glucose. Wow, the HbA1c and the insulin resistance, they will lower and it will reverse. I mean, it's just the way to go if you really want to cure your diabetes.

Interestingly, in January, in the Journal of the American Medical Association, there was a terrific overview article really finally focusing on the fact that Alzheimer's is primarily a bioenergetic issue, that it's not fundamentally an accumulation of beta amyloid-caused disease. And you think of the billions of dollars spent on developing anti-amyloid therapy when now we understand that the genesis is highly influenced by what we're talking about, bioenergetics.

Yeah, so let's talk about smoke and fire again. The smoke in Alzheimer's is the amyloid, the tau, and the sort of proteins that accumulate. I'm not, you know, Using autophagy to address that is a very good thing. However, the fire, in my opinion, is the mitochondrial damage in those diseases, and I don't think you'd disagree. I hope— well, I don't think you would. The mitochondria are really damaged in Alzheimer's and Parkinson's and other neurodegenerative disorders, as they are damaged in cancer. And so, these diseases, you know, it's in medical school— we keep going back to medical school, but why not? So, we often learn about things at the genetic—

I went back to medical school.

Yeah, I would too. Yeah, we learned about things at the genetic level, the cell level, the organ level, and the organism level, you know, behavior and then even a bit of ecology. But we skipped the organelle level. We never learned much about the organelles. Yeah, we learned about mitochondria and the endoplasmic reticulum and that a little bit, but we didn't really get into the nuts and bolts of the mitochondria. And that is where it gets really exciting. This is the problem. This is a problem. There are many other problems in how we're being taught and learning. If you want to really understand Alzheimer's and Parkinson's, in my opinion, you must know more about the mitochondria. They are damaged heavily, and keto diets and fasting directly address this problem. Same with cancer. I think if you really want to hammer away at cancer, you really have to think about the mitochondria. Dysregulated metabolism has only very recently become one of the hallmarks of cancer, which is unbelievable since, you know, Otto Warburg has been describing this stuff— had described this stuff almost 100 years ago. So, yeah.

Well, you call attention to Edward Dewey in the 1800s talking about virtually all of our diseases are due to the fact that we're overfed. So, you know, this isn't entirely new stuff. I mean, I was talking about 20 years ago that I used the term acquired mitochondropathy for Alzheimer's and Parkinson's, because back then we began to recognize that mitochondria were the arbiters of apoptosis or pre-programmed cell death, that it was actually mitochondrial dysfunction that triggered the apoptosis caspase-3 pathway that led to then the cell destroying itself. Yeah. So, we've come a long way. I wanted to let our viewers know that you and I are writing a book chapter for Dr. Timothy Noakes, who is, I think, a hero to all of us in terms of the low-carb world after what he went through in South Africa. So, I'm looking forward to working on that with you. That sounds— Likewise. Well, anyway, I want to wish you the best. I think we're getting ready for a big storm here, so I don't want to lose you. But I do want to thank you for spending time with us today and say hi to your parents. I met them before I met you. I haven't actually met you yet, but anyway, someday.

Yeah, I will. Thanks a lot, Dave.

All right, my friend. Talk to you soon. Well, that was a very, very interesting interview. What a welcomed approach to the treatment, and I would say probably the prevention, you know, if you do it intermittently, of these neurological conditions for which we really don't have much going on in the way of meaningful therapy. It's interesting to note that Dr. Phillips describes some really nice results as it relates to things like Parkinson's. We've talked about that before, and as you see, his upcoming study now dealing with using fasting as a treatment in Alzheimer's disease, or at least, at the very least, using what's called a ketogenic diet. I want to read to you the conclusion of his recent paper called Fasting as a Therapy in Neurological Disease that he published in October 2019. Here is the conclusion: An overview of the mechanisms of fasting. In an era of rising healthcare costs and increasing prevalence Of neurological disease, the introduction of a self-empowering, cost-free, effective therapeutic option for a range of neurological disorders would be a welcome addition to the armamentarium of physicians. Today, most common neurological disorders are fundamentally characterized by defective metabolism on many levels. Given that fasting is a simple, multi-targeted, and essentially metabolic therapy, With a healthy track record for treating a variety of neurological diseases in animals, it holds promise as a treatment for analogous diseases in humans. Despite this promise, the state of the evidence in humans is extremely limited. Many more studies are needed before the actual clinical efficacy of fasting as a therapy in human neurological disorders can be ascertained. Yet if these studies can be prioritized, Perhaps the day will come when fasting regimens are prescribed alongside medication-based approaches, culminating in the inception of a unified metabolic approach, not only treating the symptoms but also the natural course of the most common disabling neurological diseases in existence. Really opening the door for us to really embrace A new way to conceptualize how we deal with these challenging disorders. Thanks for watching today. I'm Dr. David Perlmutter. Thank you for watching The Empowering Neurologist. We will be back soon. Bye for now.