Live Like a Girl with Dr. Mindy Pelz - Dr. David Perlmutter on Protecting Your Brain, Metabolism & Menopause

Episode Date: August 24, 2026

Women are far more likely than men to develop Alzheimer’s disease, and Dr. David Perlmutter believes one of the most important pieces of that story is metabolic health.In this episode of Live Like a Girl, Dr. Perlmutter joins Dr. Mindy to explain what happens when the brain’s immune cells shift from protective to destructive, why menopause may increase vulnerability, and how blood sugar, insulin resistance, visceral fat, inflammation, mitochondrial health, and lifestyle all influence brain aging.They also discuss HRT, GLP-1 medications, ketones, fasting, fiber, exercise, BNDF, sleep, and what women can begin doing in their 30s, 40s, and 50s to support long-term cognitive health.In This Episode, You’ll LearnWhy women face a higher risk of Alzheimer’sHow menopause may affect brain metabolismWhy belly fat and insulin resistance matter for brain healthThe blood markers Dr. Perlmutter watches most closelyWhat emerging research says about GLP-1 drugs and the brainThe lifestyle habits Dr. Perlmutter prioritizes for preventionResources MentionedBrain DefendersTanzi StudyCochrane ReviewMore on Dr. David Perlmutterhttps://drperlmutter.com/http://braindefenders.com/https://www.instagram.com/davidperlmutter/https://www.youtube.com/user/DavidPerlmutterMDhttps://x.com/davidperlmutterlinkedin.com/in/david-perlmutter-mdFor more resources related to today’s episode, visit the podcast episode page: https://www.drmindypelz.com/ep363/Connect with Dr. Mindy:Join Reset AcademyWatch the episodes on YouTubeFollow Dr. Mindy on InstagramSubscribe to Dr. Mindy’s newsletterDisclaimer: This podcast is intended for educational and informational purposes only and is not a substitute for professional medical advice. Always consult a qualified healthcare professional before making changes to your diet, fasting routine, or lifestyle.

How many of you felt your brain go offline the minute you hit your 40s? When my brain started to go offline in my early 40s, I was crazy scared. I went from being the woman who could hold everything together to not being able to get through a full workday. The positive thinking that had always been my superpower, it just disappeared. Worst case scenarios replaced it. Anxiety I didn't recognize. A version of myself, I didn't sign up for.

I thought something was deeply wrong with me. And then I went looking for answers. What I found didn't just help me. It changed the entire way I understand what it means to be a woman moving through this season of life. Your brain is not broken. It's remodeling. That's why I wrote, age like a girl, to really lay that out for all of you.

It's part science. It's part my own story. the messy, humbling, ultimately beautiful story of a woman who had to fall apart a little before she could figure out who she actually was. If you're in that right now, I want you to know you are not alone, and this is not the end. It might just be the beginning of the most powerful chapter of your life. So age like a girl, it's available now at Dr. Mindy Pells.com slash books. And please know, I am always cheering you on.

Hey, Dr. Mindy here, and welcome to the Live Like a Girl podcast, where I bring you icons, disruptors, educators, scientists, and doctors that show you what can be possible when you love and celebrate the female body you are blessed to live in. Let's dive in. Two out of every three people diagnosed with Alzheimer's are women. That is twice the risk for men. This is a statistic that as a society, we should be incredibly concerned about. Why women? What is happening to a woman that sets us up for cognitive decline? Recently, a large piece of this Alzheimer's conversation for women

has centered around the loss of estrogen. Get on hormone replacement therapy and your chances of Alzheimer's diminishes. Today's guest has been studying the brain for decades and has a whole lot more to say about why women are more prone to Alzheimer's than men. And it's not centered around hormone replacement therapy. He actually brings to the table an expert. as to why the belly fat that appears during your menopausal years might be the greatest predictor of cognitive decline. Now, hear me out for a moment because this conversation is not there to set

you up for shame. It's here to help you widen your lens as to the importance of why metabolic flexibility may not only help you lose weight, but sets you up for better brain aging. For years, the belly fat, so many women fight in perimenopause has been treated like a vanity problem, something to shrink for the mirror, for the genes, for how we feel at the beach. But what if the belly fat is actually a warning light for your brain? here's what I learned. The fat gathering around your waist during perimenopause doesn't just sit there. It's metabolically active and it's pumping out inflammatory signals that travel straight to your brain. Once there, they can flip your brain's own immune cells from protectors of your brain cells into destroyers.

cells that start dismantling the very connections they're supposed to defend. And in women, that flip gets an extra push from falling estradiol, which starts to send its own signal telling those cells to start tearing things down. It is in every functional sense your body turning on itself, a bit like an autoimmune condition for the brain. So that waistline that you're concerned about, I promise you it is more than just cosmetic. It's a metabolic marker, and it may be one of the most powerful predictors we have for Alzheimer's risk, more useful than any brain scan. So this is why I have brought you Dr. David Perlmutter.

Dr. Pearlmutter is a board-certified neurologist and author of the New York Times best-selling book Grain Brain, which I highly recommend. His new book, Brain Defenders, lays out exactly how these brain immune cells decide whether to protect you or turn against you, and how the same lifestyle that works on shrinking your waistline can protect your mind. In this, conversation, we get into why your waist to hip ratio might tell you more than any test in a neurologist's office. And why prevention, not a future cure, is where your real power lies. I love this conversation. I hope you are inspired by what you hear. I hope it motivates you to go into not just wanting to become more metabolically flexible so you have.

feel good and you look good, but so you can finally prevent cognitive decline. So without further ado, let's dive in, Dr. David Perlmutter. Dr. Pramutter, let me just start off by saying welcome to my podcast. I'm really excited to have this conversation. And for your viewers and listeners, we've already had a really nice conversation, so I know we're going to have a great time today. Yeah. Here's what I'm really curious about.

Two-thirds of Alzheimer's happens to women. Yet in all the research I've seen, there is no real solution for these women. And yet, perhaps the solution isn't in medication. The solution is in lifestyle. Help us understand the difference when we're treating a brain condition like Alzheimer's between taking a medication and actually putting the work in your life. lifestyle. The most important things to consider about what is going on in the Alzheimer's brain is it is a manifestation of a shift in the brain's immune cells away from being supportive,

what we call brain defender cells, to being destructive. These exact cells can either be on your side and helping your brain remain healthy or they can shift and turn their backs on you and lead to the destruction of synapses. And to be fair, that process has to be, happens in men and women. It's the exact same process. But we have to go a little bit upstream and unpack a term called immunometabolism. These are immune cells. That's the immuno part. The brain's immune cells called microchleal cells. But let's talk about metabolism. So this is when we begin to find some areas of explanation in terms of why women are twice as likely to develop Alzheimer's in relationship in relation to men in comparison to men.

Yet there are hormone relationships and we're going to unpack those, that's for sure. But I think fundamentally for both genders, we've got to understand that upstream of this accumulation of beta amyloid that seems to get all the attention, which is not warranted, are the fundamental issues related to changes in the metabolism of the brain that plays out as changes in the brain's immune system becoming threatening. That's the fundamental that underpins our entire time together today. So women are at higher risk. We know that these immune cells seem to be more primed when suddenly in women,

estradiol levels fall. And that happens in perimenopausal time that hormone changes are pretty dramatic. Estradial E2, a type of estrogen, when it falls, precipitously as it does during menopause somehow labels the synapses one brain cell connected to the next brain cell and that is a signal for these brain immune cells to destroy the synapses that's pretty fascinating like an autoimmune condition it is you know it's not a classic autoimmune condition but is it an autoimmunity 100 it's the body's immune system turning on itself it's exactly what's going on You know, it's not lupus.

It's not rheumid arthritis, the classic celiac disease, type 1 diabetes that we discuss. But you hit the nail on the head. It is absolutely an immune issue of the human body. But importantly here, now we know why. It's because fundamentally, the metabolism of those immune cells has changed, and that's what causes them to change from being friend to being foe. What is so important, again, for our time together, today, this is one of the bullet points, if you had bullet points, is that the metabolism of

these brain immune cells that determines whether you're going to have a brain that's going to be playing the game with you for the rest of your life or that's going to turn us back on you, the metabolism of those cells mirrors your body metabolism. Wow. Think about that. So everything you do to remain metabolically intact. And I want to say that in the context of the figure that demonstrates that about 94% of American adults is not metabolically intact, has at least one marker of the metabolic syndrome.

So we've got work to do. And this explains now why rates of Alzheimer's and Parkinson's and the whole panorama of neurodegenerative conditions is expanding. It's because we're becoming more and more menaceans. metabolically compromised. That changes the conversation in a very dramatic way, away from hoping for a cure, for example, for Alzheimer's. We are not anywhere near there yet, to the idea of preventing Alzheimer's in the first place, keeping our metabolism on track. I mean, to be fair, the most powerful risk factor for the development of Alzheimer's happens to be our

chronological age. We know that women live longer than men, and therefore that's at least a partial explanation as to why they are at greater risk. But menopause in and of itself is associated with obviously these dramatic hormonal changes, but also very dramatic metabolic changes in the brain and through what I'm now describing, the relationship between metabolism and immunity called immunometabolism, it affects these brain immune cells to virtually, again, become our brain destroyers and gobble up the synapses and leads to loss of connectivity. That's what defines these neurodegenerative connection diseases, is loss of connectivity of one brain cell to the next. So the networks just decline. We know that women in the perimenopausal period

have a greater risk of issues with their glucose metabolism. Right, yep. That affects the brain and ultimately challenges their synapses. So there's a lot going on. All of this kind of converges, more so in the woman's brain, in comparison to the man's brain, in producing excessive inflammation. And that is a powerful activator of these brain immune cells. So would it be fair to say that the woman who's going through perimenopause

and all of a sudden got all this belly fat, that there tends to be, and I mean this with complete compassion, frustration around the vanity aspect of that extra weight around the belly. But is that extra weight a sign that the brain is going to follow because there's a metabolic disruption happening through this hormonal change? Mindy, when I'm asked, well, what is the one of the best tests? Here's my response. One of the best things you can do to determine your risk for Alzheimer's is to go out and buy a very, very expensive, highly technical instrument called a measuring tape. You put that measuring tape around your belly and you put it around your hips.

And you determine, based on those measurements, a waist to hip ratio. And when that number is elevates, that is a powerful risk factor for the development of Alzheimer's disease. That's a metabolic issue. That's one of the five cardinal findings, elevated waist hip ratio of metabolic syndrome. And it works the same in men. So you are exactly right. Why so? Because when we have a higher waist hip ratio, our bellies are getting bigger, that is pro-inflammatory and is also associated with elevating.

elevated blood glucose and reduction in how insulin works in the human body and, dare I say, in the brain. We should put that on the bulletin board here because we look back to that. But the idea that this increase in belly fat is pro-inflammatory is so fundamental. Why? Because the chemicals of inflammation that are called inflammatory cytokines that are produced by this excessive belly fat make their way to the brain. And in the the brain, these microglial brain immune cells see those inflammatory cytokines and that causes them to shift immediately from being brain defenders to being brain destroyers. It's that straightforward.

So interesting. Yeah, it's why to be more sophisticated, yes, we can measure markers of inflammation like C reactive protein that correlates with Alzheimer's risk. We can certainly look at blood glucose measurements and correlate that with Alzheimer's risk and even hemoglobin A1C and fasting insulin. for that matter. We know that type two diabetics may have as much as a three-fold increased risk for Alzheimer's, a disease for which there is no meaningful pharmaceutical treatment.

And I say it like that because it's so important that we challenge the current paradigm of live your life however you want, you know, be sedentary, eat whatever crap you want because you like it, and then know or think you know that there's a, uh, a, uh, a, uh, a, an Alzheimer's medication that's going to help you. That is not where we are as we have this conversation right now. There is no meaningful treatment for that disease whatsoever. I get phone calls and emails every single day. You know, my wife, my friend, someone, so-and-so, recently been diagnosed.

And now they're on IV therapy that's targeting the beta amyloid in their brain as a treatment for Alzheimer's. It doesn't work. It's not that your guest on your podcast today is telling you about two months ago a Cochrane analysis. Cochrane analysis are created to answer really challenging questions in medicine. And this question was asked, how effective are the FDA-approved anti-emoloid Alzheimer's drugs? Are they safe? And did they work? Right?

We'd want to know that about any truth. Yeah. Are they safe? No, they're not. 25% or so of people getting these drugs. experience brain hemorrhages and or swelling or even died. Crazy. They're not safe, but how about effective?

No, they're not. In fact, the changes in the rate of decline, not even stabilization, were, according to the Cochrane analysis, their word, trivial. So the drugs don't work. They're dangerous, and they are FDA approved. And, you know, when I talk to individuals who are more supportive of the use of these drugs, the response is, and it's painful from me to repeat it is, well, we've got to do something. Okay. Here's what I propose we do.

Let's prevent the disease in the first place. Then we won't be in this predicament. We were not painting ourselves into a corner. Right. But, you know, there's nothing heroic about preventing a disease. You don't get the glory. No, you don't know you prevented it. Right.

And like that's, I always think you don't even know that you, the disease you would have gotten. But it's the right thing to do. It's a hundred. I know. It's an interesting moment. And it's not remunerative. Nobody's making, uh, making money off of it, you know, of you not getting sick. People healthy.

Yeah. Who knew? Um, okay. Uh, you know, it's better to light the candle than curse the darkness. I get that. And, and therefore you and I have this conversation today. For anyone who's listening, uh, who wants to learn what's going on and to really, really, you know, begin a program for protecting their brains, becoming the architect of their

brain's destiny, then you and I are all in. Yeah. You know what's interesting is that in the menopause space right now, the message that women are getting is that your brain, your symptoms, they, they are occurring because you didn't get access to hormone replacement therapy. We read that study wrong. And one of the things I've done in all my research and in everything I've seen with women is you change their metabolic health and you change all of those menopausal symptoms. So where does HRT fit into this equation? Is this as simple as put a patch on and you're not going to get Alzheimer's? Let me, I will answer that question. Let me go back to the part about the the metabolic issues. So we know that women are certainly at higher risk for cardiometabolic issues.

And I don't, what about that term, cardio metabolic? Why not neurometabolic? Why not osteo-metabolic? You know, so everything's affected by its metabolism. Why did, how did the heart end up getting all the glory here? But the issue is that these metabolic changes that are more common in women, affect the metabolism of the microgleal cells and shifts them to being destructive as opposed to being supportive. You know, the number one cause of death in America in women is cardiovascular disease because they are cardiometabolically compromised. Yeah, well said.

And your point is well taken. And the idea that you would say to your audience, not just today, but in multiple times on your podcast and in your outreach, that when we get the metabolism right, hormones fall into place. Who knew? Right. Who knew? And it's so forward thinking and it's it's so dialed in because when metabolism it has gone awry, blood sugar is elevated, waist hip ratio changes, blood lipids are compromised, blood pressure is elevated. It increases inflammation and inflammation threatens the functionality of the hormones and their production as well. Their production is dependent on good metabolism, good mitochondrial function, which declines in women as they become metabolically compromised by definition. So is it as simple as putting on a hormone replacement patch? No, it is not. So the idea, and I came out in brain defenders as being supportive, by the way, of HRT, but I think timing is really important.

We can talk about that in an end of it. But is that going, could that be effective? I think it's a very important piece of the puzzle. As you well know, Dr. Lisa Moscone right now, have engaged a trial, a blinded trial, to determine what is the risk reduction of dementia in women who do receive appropriate. When I say appropriate, I mean not conjugated estrogens, et cetera, but appropriate hormone replacement therapy with natural progesterone, et cetera. What is there risk reduction? Is there a risk reduction in comparison to those who do not or receive placebo? That's going to be a big study. I think I know the results. But again, timing is really important. But getting back to the fundamental of your question, it's a piece of the puzzle. When we improve metabolism by paying attention to lifestyle choices, then by default, hormones are going to improve.

sensitivity of those hormones, their receptors will improve. And, you know, I'm not going to say problem solved, but this goes a long way. And it's so important to recognize that these metabolic issues that ultimately play out as reduction in cognitive function and other neurodegenerative issues, the metabolic issues begin in our 30s and 40s. It's not like wait till you're cognitively impaired that we should begin thinking about what to do for you. Oh, we'll give you this IV therapy that doesn't work. It's time to really think about the idea of prevention, keeping the brain healthy through the continuum. The seeds for Alzheimer's are sown in our 30s and 40s in the form of the metabolic issues that are becoming pretty evident at that point. I want to invite you to something that I am crazy excited about. This October 3rd,

and forth, I'll be joining an incredible group of speakers at Empower Your Life, a live event at the Alex Theater in Glendale, California. We'll spend two days exploring health, personal growth, mindset, and practical tools to help you create meaningful change in your life. I'll be there alongside speakers like Susie Orman, Jim Quick, Jamie Kern-Lima, Brandon Bouchard, Nancy Levin and many more. It's going to be an amazing weekend filled with learning, connection, and inspiration. I'd love to see you there. I'd also love to give you a big hug, and you can grab your VIP or general admission ticket

by visiting hayhouse.com forward slash Dr. Mindy. That's hayhouse.com forward slash Dr. Mindy. I can't wait to see you. It's interesting. I always tell my audience that when you hit 40, the one number you should look at, the one piece of your blood work is hemoglobin A1C. If you can get hemoglobin A1C as close to five as possible, that will tell you your menopausal symptoms. Would you say the same thing is for Alzheimer's? I think the amount of literature around blood sugar measurements in general, and in particular A1A1, are very compelling. I mean, we've seen the A1C literature for at least the past 22 years.

Yeah. Indicating that Alzheimer's risk actually begins well below the diabetes range of A1C. People think, well, I got my A1C below seven. I'm going to continue taking whatever the drug is. Getting your hemoglobin A1C below seven is fairly meaningless in the scope of trying to be as healthy as possible. We want to optimize everybody's markers so that they are at the lowest risk possible. So A1C, around 5 is really great. 5.2 I can live with. But Alzheimer's risk really begins at around 5.8.

There are a lot of people who are told, God, your hemoglobin A1C is 5.8, you're good to go. That's in the normal range. It's not good enough. I certainly don't. I want it lower as to you. That's your favorite test? I think it's a very important test. Mine might be fasting insulin level, actually.

Because I think it's predictive of where that A1C is going to go in the future. So what would you want fasting insulin to be at? Three. Three. Yeah. Agreed. Yeah. Where do you think the GLP1 drugs are going to fit into this equation?

It's a fascinating story. And, you know, this is certainly the topic de jour. And if we take a step back and, and sort of revisit our conversation that what is so central in what makes a good brain go bad is the shift in the brain's immune cells. And what causes the shift in those brain immune cells is a shift in their metabolism. Right. And their metabolism mirrors body metabolism. It's an interesting segue to the conversation about GLP1s, isn't it? Because we know that the GLP1 drugs are powerfully influential more than anything that we've ever seen in terms of metabolism.

Therefore, one might assume that maybe there's a role for GLB1 agonist drugs in neurodegenerative conditions. Do I think there is or will be soon? And did I write that in my new book? I did. I absolutely did. And that may surprise people. You know, Dr. Promot is thinking about lifestyle and natural ways of doing this. You bet. You know, Alzheimer's is on. almost uniformly a fatal condition, a lethal condition. By some estimates it's the third largest cause of death in adults in America. So would we consider the use of a GLP1 agonist drug if, in fact, it were demonstrated to be effective in Alzheimer's?

I absolutely would. I think the risk profile is acceptable in the face of a fatal condition. You know, we would give, you know, Danexiety. dangerous chemotherapy to cancer patients because otherwise they would die. So that's the comparison. Well, let's look at what the data shows, first of all. So in 2024, I think in April, the New England Journal of Medicine was a fascinating interventional trial.

It means it was a double-blind placebo trial where they gave a, they had a group of 151 Parkinson's patients. Half of them got a GLP-1 agonist drug, and the other half received a placebo injection every single day. And they followed these patients over the course of one year, and they measured their functionality. And what they found was really quite interesting. In the placebo group, as one would expect, their functionality declined on what's called the unified Parkinson's disease rating scale, UPDRS. And that's what you see in Parkinson's. In the group receiving the GLP1 agonist drug that targets metabolism, that targets the microbial cells, their situation did

not demonstrate any decline whatsoever. And as a matter of fact like, there was a tiny improvement. Wow. Bart Simpson would say, Kawabunga. I mean, it's breathtaking. Because look, we have drugs to treat Parkinson's tremor and rigidity and all those things that worked very well. But that's only treating the symptoms. It's not treating the underlying issue. This was the first intervention that target the metabolism of the brain and the brain's microchleal cells. And what was the response? It was phenomenal and it was breathtaking. To be fair, about 48% of the individuals who received the medication had gastrointestinal

side effects. Some of them were in fact, you know, fairly compromised to the extent that they would have to stop the medication. But it opens the door, doesn't it? It's a glimmer of hope. That said, what do we know in Alice? Alzheimer's. Well, in looking at diabetes patients for which the GLP1 drugs were first developed, who are taking a GLP1 versus another type of diabetes drug, and there are several other types, including things like metformin, et cetera, what was discovered is that when you follow these

individuals, those getting the GLP1 agonous drugs had a 40% risk reduction for the development of Alzheimer's, and recall these are individuals who are at great risk because they're having metabolic issues in comparison to taking the other drugs. That we cannot ignore. So let's then design an interventional trial, or we give half the people placebo pill who are not diabetic, and half the people, a GLP-1 agonist drug, in this case semaglutide, who actually already have Alzheimer's and we will follow them over a period of time to determine is there any effect in terms of cognitive function. Cognitive function. Well, this was done in multiple countries around the world, a very large study called the Evoke and the Evoke Plus study. What did they find?

Well, the study did not reach its clinical endpoints in terms of showing any slowing in the decline of cognitive function. And that's what made all the headlines. Let's talk about what that means. but first let me mention one thing that they did find that really didn't get much attention. A marker of inflammation called C-reactive protein was reduced by 30% in the treatment group in comparison to the non-treatment or placebo group. That's important because inflammation is reduced. Maybe we need to do a longer study. That said, this is an oral preparation of semi-glutide, a large molecule, meaning two things.

could it because it's oral not have made its way to the blood brain through the blood room barrier into the brain possibly is it because it is a large molecule in comparison to the one used in the Parkinson's study be another reason so you can be sure that and I'm telling you this is what's going on there are multiple glp1 agonist trials being done on that to intervene to treat Alzheimer's disease right now there are multiple ways that really high-tech is really looking at what we can do to the microglial cells to shift them back to being supportive. We can do it right now by putting you on a dietary change, increasing your physical activity, making sure you get a good night's sleep, increasing your social

interaction, taking very specific supplements, some fairly novel ideas like flashing a light in your eyes at 40 times per second. Some really cool things we talk about the book. that are right on the edge right now. They're actually being studied in humans by the top institutions like MIT. So, you know, the point I'm making, though, is that we should be preventing and not waiting for the disease. So maybe I won't go there. Let's concentrate on keeping everyone's brain healthy. And as a side effect of helping reduce our Alzheimer's risk, for example, your brain day by day is going to work better.

So yeah. In your book, you quote a study, the Tansy study, I'm not sure if I'm saying this right. And I found it really interesting because they map out a lifestyle plan that can be very helpful for prevention. Can you dive into that study? Tell us what it taught us and map out a plan for us for the person listening that wants to do it differently. And who wouldn't want to do it differently? Right. What Dr. Tansy and Dr. Dean Ornish did was they studied 51 individuals with existing Alzheimer's disease. These are patients with Alzheimer's who may have been told, hey, you know, you take the IV drug or that's the best we can do. But Dr. Tansy, Rudolph Tansy, and Dr. Dean Ornish created an intervention that had, believe it or not, multiple inroads.

It wasn't just one monotherapy, one type of... Yeah, it was really extensive. Yeah, but approachable. They changed... Agreed. They changed their patients' diets. They increased their daily exercise. They did stress modification.

And their study of 51 patients over a 20-week period of time demonstrated findings that were fairly breathtaking. We would have expected these patients with Alzheimer's disease to decrease. on the tests of their cognitive function. No, that's not what happened. In 70% of these individuals, they either stabilized or they got improvement. That's amazing. There's never, ever been a drug that has even targeted improvement, much less brought it about. And who's heard of that study? I dove into the study because I love research. And what shocked me is that it was largely plant-based.

Yes. Can you talk about that? Because we talk on this channel all the time. Carnivore, vegan, like everybody's arguing over high-protein, low-protein. And when I saw that, I was like, huh, okay. What does that tell us? What does it tell us? It tells us a lot of things.

It tells us the power of the polyphenol. We'll talk about that in a moment. But it also tells us the power of dietary fiber. And it really begins to open. the door to the so-called gut-brain connection and the brain-gut connection for that matter. The idea that I wrote a book about this many, many years ago called Brain Maker, the idea that, who knew, Hippocrates knew, the idea that what is going on in the gut can influence the entire body. And here's the news flash. The brain is part of the body who knew.

So the idea that things going on in the gut are so influential in terms of brain health. A fundamental issue that connects the brain to the gut, I think more than anything else, is the process of inflammation. When our gut bacteria, in terms of their diversity and functionality, is threatened, then we increase the permeability, the leakiness, if you will, of the gut lining, bad things get out into the systemic circulation and even locally in the gut, right in the gut, target certain receptors that increase ultimately inflammation. Those chemicals of inflammation that are called inflammatory cytokines, cytosal kind means they move around, make their way to the brain,

easily get across the blood brain barrier, and signal the brain's immune cells, the topic of our discussion, the microglueal cells, that there's trouble. And what do they do when they get that signal, they shift away from being M2 supportive to being M1 destructive. And here's an interesting thought. When the microcliose cells are shifted away from being supportive to being destructive by these inflammatory chemicals, what do they do? They themselves begin to produce these inflammatory cytokines. Uh-oh.

So you're not just getting it from inside the body. Now it's coming from inside the brain. Exactly. Inflammation from anywhere in the body influences the brain and causes more inflammation. We call this a feed-forward cycle. Now we have these little cells in the brain that are creating more and more inflammation in their immediate neighborhoods and are targeting the healthy, supportive M2 microglia to shift over to the dark side. They're like zombies that are converting these other cells to being on their side. And this is a very powerful explanation for us because haven't we all wondered, why is it that the football players, for example, that have had head trauma multiple times, they quit playing football, but they've been diagnosed with this thing called chronic traumatic encephalopathy that is a progressive problem. They're not banging their heads anymore, but yet they continue to decline and die from this series of events, even though the inciting. event the head trauma is no longer occurring. Why does it happen? It happens because once this engine gets started, it's a self-perpetuating process. The inflammation produced by these now damaging, we call them M1 microgleal cells, send signals to the neighboring good microgleel cells

and converge them to the dark side. So our mission is to revert these microgleo cells back to being supportive, and that is something we absolutely can do. The fundamental issue that is gone awry is their metabolism. And I've mentioned that before. When their metabolism shifts, that is what characterizes them becoming destructive. And the key player in their metabolism is the function of their energy producers called the mitochondria. So in a very real sense, what is upstream of all of these issues, of all the neurone degenerative conditions, of lack of hormone functionality in menopause, of cardiometabolic conditions, cardiovascular disease, all chronic degenerative conditions of the body that the World Health

Organization ranks as the number one cause of death on the planet are fundamentally issues with how the mitochondria are producing. energy. When the energy production of the mitochondria is compromised, that signals the cell, the microglue cell to become threatening. Now, that's the understanding that allows us then to target the mitochondrial function. Bring them back to being supportive. That's where things like hyperbaric oxygen and a ketogenic diet is just, I'm just going to ketones. I'm like, where does ketones fit into this? Olenzyme Q10. All of the things. All of the things, things that nurture and support mitochondrial function are the players that are so valuable for brain

health and keeping these brain immune cells of microglia in their supportive phenotype and even shifting the ones that are not supportive anymore back to being supportive. That explains why Dr. Tanzi and Dr. Ornish's study was so powerful. What did they do? They put people on a lifestyle program that ultimately improved energy production. Mytochemical and brain. And we've hearded their microglia back to being supportive. Yeah. Now you get it.

It all makes sense. It's just a target. You know, the mission for me is challenging because it's a little complicated. It's not like, okay, go to the doctor now that you're cognitively impaired, sit in a chair and get an IV. I would do that. I'd recommend that if it worked. It doesn't work.

So, you know, it takes a little bit of doing to unpack everything we've opened up so far. We've got a lot more, I think, to flesh out because it's up to us to make those changes. Is it work? Yeah, it's a little bit of work. Is it worth it? You bet it's worth it because you don't want to be that person. You don't want to be in that situation where I just had my cognitive analysis and, hey, it wasn't right. It didn't come out great.

It's too late. I kind of knew it wouldn't because I noticed I can't remember my grandchildren. names, the Wi-Fi Code, I go into rooms, I don't know why, all of these things. You know, by the time those things are starting to happen, you know, we're already deeply down the continuum. That's not where it starts. It starts with your metabolic challenges in your 30s and 40s. For the past two years, I have been in a stuck nervous system. A lot of you have heard me talk about it here on this podcast. And I've been experiencing. many with all kinds of ways to balance my nervous system. And I got to tell you something that's going to

sound incredibly backwards. Because what I've learned is that sometimes the fastest way out of a stuck nervous system or out of fight or flight isn't more calm. It's not sit your butt down on the couch. It's actually a little bit of heat and light. Now stay with me because I discovered something that I'm really excited to share with you. There has been something that my sunlight and infrared sauna has done to my nervous system that no other tool has been able to accomplish. At the end of a crazy long day, a few minutes in a gentle heat with some warm red light on me, and all of a sudden I feel myself coming down from the chaos of the day.

and let's be really honest we could all use a way a quick way to get out of fight or flight not only so we can feel better but so that we can be our best and we can show up in a very balanced way for the people that we love for me this is the rare kind of self-care that's actually doing something and what i love about infrared sauna is that the heat is gentle and comfortable. It's like sitting in the sun and you instantly feel relaxed, but you're in your own home. There's no schedule.

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Sunlighten, thank you. I am so grateful for this tool. So one of the guests I've had on here over the, I've actually brought her on twice, is Dr. Georgia Eadie. Do you know her? I do very well. Yeah. Yeah, so she just came out with an expert consensus talking about sustained ketogenic diet

for chronic depression, anxiety, and schizophrenia, I think, was one of the things they looked at. And she's really trying to infiltrate the idea that ketones, especially continuous ketones throughout the body and brain, can reverse some of these conditions. Can you talk a little bit about, because my audience, we get ketones through fasting. That is the way that so many people access the ketogenic system.

So where do ketones fit into this? And is it all internal ketones? can we use exogenous ketones to help this kind of condition? So first let me say that, you know, the issue here and what she's talking about, the neuropsychiatric issues that are targeted by this type of intervention or becoming or going into ketosis is all about energy. It's all about energy production from the mitochondria. A wonderful book called Brain Energy, Dealing with mitochondrial function, written by Dr. Christopher Palmer.

explores this in great depth. So the idea of being on a ketogenic diet to give those mitochondria better fuel such that they can produce energy much more efficiently I think is absolutely fundamental to the idea of reverting the microglia back to being supportive. So what are the interventional trials looking like?

Well, there are several interventional trials now done with patients who have existing Alzheimer's and also existing, not the same patient, Parkinson's known by Dr. Matthew Phillips. I've had him on my podcast a couple of times. The results are profound. I mean, when you provide energy to the brain in the form of ketones by dietary restriction, by caloric restriction, by time restricted eating, certainly by restriction of carbohydrates

and increasing dietary good fat, it has powerful effects in terms of the energetics of the brain. But all of the discussion until now has focused on the fact that neurons, the brain's cells, need a lot of energy. Well, neurons are only 50% of the brain cells. We've got a lot of other cells in the brain. As a matter of fact, these microglyle cells, brain immune cells, represent 10% of the brain cells. And who knew? They use energy too and a lot of it. If they can't make energy from their mitochondria, they can't make energy from their mitochondria,

they become threatening and they destroy the brain. This now lets us understand finally why the diabetics have increased risk of Alzheimer's disease. Yeah. Why anything that threatens availability of energy is associated with an increased risk for the development of Alzheimer's disease. You know, the risk is increased with elevated, you mentioned at waist to hip ratio, a metabolic issue. Certainly with head trauma, with stress. that is increasing inflammation in the brain. We talked about how these cells see that inflammation and then say, oh, danger, I'm going to shift to being the evil, you know, call out the firemen because we've got trouble.

So for me, before we went on the recording, you asked me a question, you know, what's why this book and why now and what does it mean to me? It explains everything I've done for decades. I wrote grain brain in 2012. And what we talked about in grave brain was, yeah, as a matter of fact, eating a diet in highly processed carbs is associated with a bad outcome for their brain. As a matter of fact, in that book, I actually have a graph, getting back to a question you asked earlier demonstrating, Alzheimer's risk plotted against the A1C. That I wrote that in 2012. And back then, we didn't have the term, which is now in vogue, called it. ultra-processed foods.

That term hadn't even been invented. We called it Western Standard Diet. Yeah, well, first it was standard American diet, then it became a Western diet, and now it's the global diet, call it like it is. Right. People eat globally, unfortunately, which is why global rates of these brain degenerative conditions

are skyrocketing in lockstep with the changes in metabolic health, with rates of diabetes, for example. So again, it explains what we talked about in in grain brain, that when you consume those foods, and now it's validated. Last year, a study came out in the Journal of Prevention of Alzheimer's. The Journal of Prevention of Alzheimer's. Wow, such a journal. I mean, when I used to talk about preventing Alzheimer's, you know, it was people, not everybody was supportive. I'll leave it at that. I certainly won't name names. But anyhow, when you look at these ultra-processed foods, this study came out and followed one thing.

11111 individuals for 12.7 years. Average age, I think, was 69.5 years. And these were individuals who had already some metabolic issues, some insulin resistance, elevated blood sugar, obesity. These people are prime for cognitive decline, if not the development of Alzheimer's. And what they found was in following these individuals, again, over a long period of time, 12.7 years, that averaging one serving per day of ultra-processed foods was associated with an increased risk of developing Alzheimer's of 13%. Wow. If you consume... Just one meal. One meal a day. Not even a meal. I'm talking about a serving, a handful of chips. If you consume 10 or more servings per day, and that is exceedingly common, And when you consider that 60% of the calories that Americans consume adults are from ultra-processed foods, that's sobering, if you get 10 or more servings a day, your risk is tripled for a disease, for which we have no meaningful treatment.

So, gosh. So the food industry has once again destroyed us. Yeah, it's what, again, I don't want to curse the darkness and want to light the candle. So let's talk about what we can do. We can change our diets. I explained it in the book How to Eat. And you're right, vis-a-vis Rudolph, Tansy, Dean Ornish, and others. It's plant forward for the reasons that we've already talked about.

Because the fiber, I just want my audience, because the fiber, I've been really on a fiber kick recently. And because everybody got so into protein. And I really feel like it needs, it should be. called a fiber forward diet is i would agree with that and and by all means i'm not suggesting that everybody needs to be vegetarian right i am not suggesting i am pleading that there's a lot of plants on your plate and they are colorful so that we get a variety of polyphenols that are wonderfully supportive of the gut microbiome that target our gene expression that that have a role to play in the modulation of our epigenetic markers as was recently demonstrated in a study by Dr. Austin Perlmutter, our son.

You know that guy. Yeah, he did an amazing study on one particular intervention using something called Himalayan Tartary Buckwheat, which is really rich in these polyphenols showing a profound effect on epigenetic age markers, in this case, a marker of the rate of aging that's called the Dunedin methylation clock. And Austin has another study coming out very soon with a much larger population doing a lot more in-depth evaluation of this intervention in terms of what this Himalayan tardary buckwheat can actually do. Yeah. And so back to the ketone because in all the research I've done on fasting in the ketone, I got to ask more on this because Lisa Moscone, who I also interviewed,

said that the brain is much more receptive to ketones as opposed to glucose as a woman goes through menopause. We've got Georgia Edie saying, hey, it's a key to some of these psychiatric challenges. Yet the ketogenic diet is not a sustainable diet over time. So what are your thoughts on exogenous ketones? Do we have any research on exogenous ketones? Well, we do know that there are various ways to fairly dramatically increase your levels of an important ketone. Actually, it's not a ketone, but it's lumped in them generally called beta-hydroxybutyrate. Truthfully, not a ketone. Who knew? But that said, you know, there are products out there.

I consume one that's called kinetics. There is the ability you have to raise ketones using medium chain triglyceride supplementation. but I think that being deeply ketogenic in terms of your diet day in and day out is, I wouldn't say it's not sustainable. I think it's difficult to sustain it. And I don't think it's in the preventive stage. I think when we have a period of ketosis, we're reverting those cells back to better metabolism. And we are reestablishing insulin functionality.

And that can be preserved even. then during times when we're not ketotic, when our hunter-gathered forebears finally found food and are no longer restricted and were able to come out of ketosis. So, you know, the system is very flexible. But to never be in ketosis, never have increased levels of this beta-hydroxybutyrate in your blood, that's not a good plan. So you're dialed in. And I have so much respect for Lisa Musconi in Georgia Eats, you know, I, and so many others, Dominic D'Agostino, wonderful researchers that are just Matthew Phillips doing such great work demonstrating that, hey, this is a tool. And it happens to be a very, very powerful tool. From my perspective,

in the new book, this is a tool that reestablishes metabolism in the brain that through the term immunomatabolism targets our microglial cells and can revert them. back to being brain defenders. Yeah. I mean, I watch the tens of thousands of comments, even here on YouTube over and over again, about a woman who starts to learn how to just intermittent fast, just a small fast, and she starts to eat whole foods. And yes, she loses weight, but the second most common thing is that her brain gets back on track. The brain fog goes away and the clarity comes back. Can you help my audience understand when you talk about brain, brain energy. Why is a ketone a more clean source of brain energy than a glucose molecule?

Well, I think that the issue has to do both with the molecules, but I think more importantly, deals with the downs, the fact that if you're powering your brain solely with glucose and your diet is one that really amplifies glucose, you're setting yourself up for disaster. Right. And that does not happen on a ketogenic diet or when you're occasionally in ketosis. When you're occasionally in ketosis, you're enhancing insulin functionality, you're reducing inflammation that challenges brain metabolism and allowing all brain energetics to improve. But let me reemphasize an important point. The focus of the brain energetics has always been that the neurons work better when their energy production is rock solid. I get that. I get that.

But it's time that we make a bit of a pivot to include the idea that the brain's immune cells that are pretty much in charge of your brain's destiny really depend on good energetics as well. So, you know, there's a book by Casey and Callie Means called Good Energy. That, you know, really nails this down in terms of mitochondrial function and how it's, when it's compromised, when the function of our brain energy, of our cellular energy, energy produces is compromised, that it has widespread manifestation. So this is well beyond the brain. It really has a powerful effect on the brain because it's so energy dependent.

You're right. But the idea of going into ketosis from time to time isn't just for improving momentarily the brain energetics at that moment, but it's to target these other issues like inflammation, like insulin functionality. you know, we recognize that insulin is a real player in the brain. People know that insulin is really a critical hormone that allows our cells then to utilize glucose appropriately. It's how insulin works. It allows glucose to be brought in the cell where it can then enter into the energy production machinery, problem solved.

And when we become insulin resistant, then that process doesn't occur. But in the brain, insulin acts as what we call a trophic hormone, meaning it nurtures the neurons and the synapses. It's like their guardian. It's like their miracle grow. It helps nurture them into their functionality and into their growth, the enhancement of what's called synaptogenesis, the growth of these synapses. The growth of even new neurons is stimulated in the presence of insulin. If you want to grow neurons in a petri dish, you add insulin. Bingo, they start to grow.

But there are parts of the brain that actually are insulin dependent. And really, there are four major areas. Let me go through them. There's the hippocampus, the hypothalamus, the prefrontal cortex, and the olfactory bulb. The hippocampus, number one. That's the memory center. Right. Mood in memory.

When you become insulin resistant, then your memory center starts to fail. and because it's a metabolic machinery is compromised, then you have more inflammation and you have targeting of these microglyle cells, that sets the stage for Alzheimer's disease. The hypothalamus is involved in metabolism. So you're compromising the rest of your body's metabolism when the hypothalamus can't use glucose appropriately because you are now insulin-resisted. The prefrontal cortex, so important. for executive function, for really the higher human functions that define us as being human beings,

understanding our relationships to ourselves, our relationships to others, the consequences of our actions and decisions, the effects of what we do on others, etc. That's prefrontal cortex. And finally, the olfactory bulb, which is involved in how we are able to smell things. Okay. How does Alzheimer's present? Memory loss, metabolic issues, loss, loss, of executive function and who knew loss of smell yeah so isn't loss of smell one of the first things it may be in many people yeah and so why would that be now we get it we understand that this is a manifestation of this metabolic challenge to the brain that you are absolutely correct in stating can be improved as we utilize this uh type of intervention called getting into ketosis

and we don't have to be full-on ketotic all the time. No, no. And where does exercise fit into this? Because I did a lot of research for my last book, Age Like a Girl, on BDNF and how powerful it can be for neuronal growth. And you can get BDNF through weightlifting by breaking muscles down. It sends a metabolite up into the brain and starts to stimulate that production. So where does strength training fit into this?

Yeah, it's fundamental. I mean, it's critical. So, I mean, here is this BDNF brain-derived neurotrophic factor that you just described, acting just like I mentioned insulin works. It is a trophic hormone. Yeah. This is a chemical that tells neurons to grow. Right. That stimulates the growth of new brain cells.

Who wouldn't want that? That nurtures the synapse where one brain cell through its dendrite connects to the next, neuron and even the growth, the enhancement of the formation of synapse is so critically important for learning. And this was first demonstrated by Dr. Kirk Erickson in the late 1980s where he did a study measuring through MRI analysis the effects of exercise versus simple stretching over a one-year period of time in individuals looking at the size of their hippocampus, their brain's memory center, where the growth of these new neurons actually happens in one other area, but let's talk about the brain's memory center and showed that in the intervention group doing the exercise, their

hippocampus didn't stabilize in terms of declining with age. It increased in its size, as did improvement in memory function. So this has now become something that I think a lot of people are understanding that you are correct, that eryssin, which is a chemical made by muscles, Therefore, when muscles are active, this erycin chemical makes its way through the blood and barrier into the brain and stimulates the brain to make this wonderful miracle grow called B, D, and F. So it means not only do we need to use our muscles to make this erosin happen, but we need more muscle tissue. So we have more of this chemical. We want to double the size of the pharmacy if we possibly can to get more of that chemical. So, you know, one

of the biggest issues that we elderly people, myself included, face is loss of muscle mass. We call that sarcopenia. So we're losing the resource for these and other important chemicals called myokines. Mio from muscle. Kind means they move. So, you know, a critical thing that needs to happen as we age is to maintain our muscle mass. Yeah.

Yeah, I agree. You know, I was at Equinox gym this morning thinking. Not that easy. No, but thinking about why I'm lifting weights, listening to a podcast about creatine and why, you know, as you age, it's harder and harder to maintain muscle mass. And that's why we've got to do resistance training, i.e. use bands, use your body weight, use weights. It's critically important.

Yeah, the aerobics are important. And in matter of fact, one recent meta-analysis of 36, I think, different studies revealed that it was the combination that was most brain beneficial. It wasn't just aerobics. It wasn't just weight training, but it's both, especially in the 65-plus-year-old category. Yeah. These are the individuals who benefited most. Yeah. Yeah.

So, you know, one of the ways I like to look at books is I think they open up a cultural conversation and they start to change the direction. of the way we think, the way we interact with our doctors, the way we interact with each other. What do you think and what are you hoping this book will do as far as the cultural conversation goes? Well, we're faced with some powerful messaging that tells us otherwise. It's telling us eat whatever the heck you want and sit on the couch, binge watch, doom scroll, and we got this. offload your agency for your health to someone, something else, right? This idea that...

Somebody will save you. You bet. And, you know, the idea of just hope for the cure. Well, James Cameron, the movie director, famously said that hope is not a strategy. And I want people to hear the other side of the story that I would absolutely 100% embrace an Alzheimer's drug if one were safe and effective. you'd hear me singing its praises. You heard what I said about GLP-1s. I keep that door open. We're watching the research and when it looks compelling, I'm going to be singing its praises.

Not for everyone, not as necessarily right now as a preventive, but in the case of diagnosed Alzheimer's, if it's proven to be effective, you bet. I will count me in. And again, that surprises some people right now raising their eyebrows, but my mission is not to be always thinking outside the box. I think the mission is to make the box bigger. We are inclusive, integrative, looking at all inroads to better health and in this case better brain health. So what am I hoping? I'm hoping that people ultimately walk away from reading this book with the firm understanding that they can change their brain's trajectory beginning today. And not to outsource your brain's destiny to somebody who's trying to make you believe they've got an answer.

Yeah. If you were to consult a woman who, let's say a 50-year-old woman who is trying to get her health on track, what would you tell her is the most powerful lifestyle tool she has? It would be belief that you can do it. that's the most powerful because if you don't nothing else matters you're not going to do anything else you're not going to change your activity level diet time you spend in nature the quality of your sleep that you can change the quality of your sleep by doing certain things we talk about them you've talked about them before as well or had guests as well now caffeine curfew what time do you exercise getting off your computer at night getting

light in your eyes and the more all the things right right they matter a whole heck of they do matter yeah am i in favor of metricizing of measuring of biometrics that you can of the wearables as it were absolutely i am how else will you know how else will you know how well you slept last night if you're not able to measure it and gosh we live in a time not only can you determine how long you slept but what is the quality of that sleep as well how much deep sleep did you get that activated your brain's glymphatic system to clear out the debris? How much REM did you get to consolidate your memories? How long did it take you to fall asleep? And did you awaken several times during the night that you may not remember doing? These are really important things. And gosh, whether it's your Apple Watch,

your o'er ring, your whoop, or whatever it may be, these are available to all of us. And, you know, as you're ready to exercise, it's very expensive to go out and buy the equipment. No, you can buy a new pair of what used to be called sneakers and give it a go. That's all I'm asking. You can use your own body weight to exercise. Maybe buy some resistance bands. Right now, as you see, I'm living on a boat. And there is a gym nearby.

That's great. But when we're out, resistance bands, we're wonderful. TRX, another way of using your own body weight. There are ways of making this happen. But you've got to not just want to do it, but understand why you're, doing it and why you're doing it right now today is that 20 years, 30 years from now will be having a different conversation because your brain is doing really, really great. And you did all those things to rein in your metabolism that will help your hormones function

appropriately, help you with menopause. If you're a lot younger, it'll stabilize your menstrual periods. It'll help you lose weight. It'll help your cognitive function now. you're in your 30s and 40s who wouldn't want that when you're in your teens when you're in your adolescence why wouldn't you want that yeah yeah well this was fascinating i really appreciate what you're up to and i want to make sure everybody gets the book so where can where can they find the book and um how can we support you well uh here's the book i just got my hard copy a couple of

days brain defenders i love the uh it's gorgeous graphics anyway so that the the uh the uh website for brain defenders is brain defenders.com. Who knew? There's all kinds of bonuses at that website when people buy the book. Buy the book anywhere you want. I mean, it's been acquired by 16 countries around the world, so it's some attention, which I think is great. For me, I'm at DR, as in Dr. perlmutter.com. That's my website, Dr.perlmutter.com. Just did a whole new website. I'm really excited about it. exciting. Yeah. So again, Brain Defenders.com, and it's all the places that people might buy a book, you'll find it there. Yeah, amazing. Well, Dr. Pearl Motor, what an enjoyable conversation, and I hope this book just permeates the culture and really gets people motivated for prevention.

So thank you for everything. Thank you. I appreciate the opportunity to spend time with you and just to have this platform for getting out this information that I feel is so fundamental. important. So thank you for that. My pleasure. I appreciate you. Thank you so much for joining me in today's episode. I love bringing thoughtful discussions about all things health to you. If you enjoyed it, we'd love to know about it. So please leave us a review, share it with your friends, and let me know what your biggest takeaway is.