The Alzheimer's Drug With a 25% Brain Bleed Risk - Dr. David Perlmutter | TUH #306

Alzheimer's is an almost uniformly fatal condition, the 3rd leading cause of death in adults in America.

You know, there's a lot of theories around Alzheimer's and accelerated brain aging, but many of them point to insulin resistance and high blood sugar as one of the hallmarks of accelerated neurocognitive decline.

90% of America's pre-diabetic patients don't know it, 'cause you get your annual blood work, you get a pat on the back. Well, you're not diabetic yet. Go home and hope for the best.

I really reject that in the face of 7.6 million Americans I think there are a lot of people that my age that are dealing with aging parents, and I'm hell-bent on turning this around for my mother, and to the extent that I can prevent it for other folks like my kids, that's a service that I think is well met.

I'm hell-bent on getting this message out that you could rewrite your destiny as it relates to your brain, and you absolutely can do it, and you just need the tools.

In these conditions like Alzheimer's, patients are not losing their memory per se, they're losing access to their memory. What do we do now? Now to try to restore that access.

You know, ultimately, I think well beyond what I describe here is—

Hey guys, welcome back to the Ultimate Human Podcast. I'm your host, human biologist Gary Brecka, where we go down the road of everything anti-aging, biohacking, Longevity and everything in between. And today's podcast guest is a very, very, very special guest to me. He doesn't even realize this, but in the 300+ episodes that we've done on The Ultimate Human, only one other time have I used this next phrase, that I am sitting down with someone that I consider one of my early mentors in this space. The first time I used that was with Mark Hyman because I had read most of his New York Times bestselling books. And in 2014, I read a book that this gentleman authored called Grain Brain, and it entirely and permanently changed the trajectory of my career. So, Dr. David Perlmutter, welcome to the podcast.

Well, I'm delighted to be here today. It's very special to be here too. I love this area of the world. Very, has a lot of meaning for me.

Yeah, you know, we, I learned something very special before the podcast today. I walked into my kitchen and he was FaceTiming with my father-in-law, and it turns out that My wife's father built your dock 40 years ago.

That's right.

That's a wild connection that we have, but working years have been a neighbor for a while. Yeah, it's true.

It's a small world though. I mean, who knew?

It's a small world. But I read Grain Brain. I wanna say you wrote it in 2013, but I read it in 2014.

So yeah, it was published in 2013, wrote it in 2012, obviously. And, you know, that book focused, I think, on something that's now pretty well understood and embraced, that eating a diet that features a lot of highly processed carbohydrates is a bad thing for the brain. That was my contention back then. And, you know, it was a great success. The book was a great success, but I got a lot of heat from my colleagues that, I mean, what do carbs have to do with the brain? How could you make such a statement? We didn't have the term back then of ultra-processed foods.

Right.

Now, of course, that's what we're talking about. And then ultra-processed carbohydrates being Under that umbrella. And now we see really great data coming out that higher consumption of these foods that are modified such that they're gonna raise your blood sugar, threaten the functionality of your insulin, and at the same time are devoid of things that you need, like dietary fiber to nurture your microbiome, that these happen to be really threatening for your metabolism.

Mm-hmm.

And guess what? The brain is intimately involved with metabolism, either being supportive or being destructive.

And, you know, I'm going through this right now. I've been very public about this on my platform with my own mother. And, you know, I'm upset with myself in a lot of ways because as I really peel back the layers of the onion, she was hyperglycemic or high glycemic, you know, insulin resistant and pre-diabetic for almost 20 years. That we can go back and find. And there's a lot of theories around Alzheimer's and accelerated brain aging, but many of them point to insulin resistance and high blood sugar as one of the hallmarks of accelerated neurocognitive decline.

I want to stop you right there, and I want your audience to remember what you just said, because you said something I think that is fundamental. You said, for 20 years. Long before her cognitive impairment was noticeable.

Yeah, but she didn't have diabetes, which is why they didn't treat it.

Doesn't matter. Yeah, that's why we're here today. That's the discussion I think that we are going to have today. And that is that when you begin to have these cognitive issues, forgetting why you walked into the room, the Wi-Fi code, the grandchildren's names, whatever it may be, that situation has been brewing for decades. So that's what our target then needs to be. It's the people in their 30s and 40s who are watching us right now. thinking, well, they've got time because, well, Alzheimer's begins in your 70s. It does not. That's when the clinical manifestations begin. And that's when modern mainstream Western medicine begins to think, oh, there's something we need to do.

Right.

I want to tell you a quote from an 81-year-old man who was the oldest person to sign the Constitution of the United States of America and actually signed not only the Constitution, but the Declaration of Independence, Benjamin Franklin.

Wow.

One of his famous quotes is, an ounce of prevention is worth a pound of cure.

Oh, yeah.

We are focused in America, to be fair, on the pound of cure. We're focused on the development of drugs to take care of people, to cure their illnesses, when just giving them the tools to prevent them 20, 30, 40 years prior to their onset or to the manifestation really makes sense from an economic perspective. It makes sense from a health and longevity perspective, and it absolutely makes sense from an emotional perspective too, knowing fully what you are experiencing right now, because I've been there.

Yeah. And we're now trying to backtrack and catch up for the last 2-plus decades, and it may have been even longer. We, we just have data from 20 years ago, um, and knew that she was pre-diabetic, um, but never really tripped into the full diabetes range, so never really got care for it. I mean, maybe in some ways, had she done that, there would've been a lot more teaching.

Well, you're talking about a third of American adults are pre-diabetic. And here's the gripping part of that statement, and it fits perfectly with what you're describing. 90% of America's pre-diabetic patients don't know it.

Right.

'Cause you get your annual blood work, you get a pat on the back. Well, you're not diabetic yet. Go home and hope for the best.

Right.

And do whatever it is you're doing. I really reject that. I really reject that in the face of 7.6 million Americans now diagnosed with Alzheimer's, with being pre-diabetic being a huge entrée to that event. We've got to pay attention. We owe it to people to call this out and to really just sort of challenge this notion that annual blood work is enough. And the idea of being in the normal range is something we should be thinking is a good thing.

Yeah, or just not having disease. Right.

I want everyone I relate to to be in the optimal range. I want to optimize health, and therefore, ounce of prevention worth a pound of cure. Keep these people healthy and recognize that, again, the seeds are sown metabolically for developing Alzheimer's in your 30s and 40s and 50s. It doesn't just happen. There's something called a heart attack. You are perfectly fine. You're walking down the street one day, and all of a sudden, this thing out of the blue comes and attacks you. narrows, shuts down your LAD, and down you go. That's not how it worked.

Right.

It didn't just attack you out of the blue. You've been dealing with that for an awful long time that narrowed your coronaries. So, you know, this is the mission. And I think our time together today is to really raise up the sense of empowerment that here's the knowledge and here's what you need to do. Here's how you can keep your brain healthy. If you live to be age 85, and I'm sure that's your plan, and I'm sure that's the plan of everybody watching us right now.

I'm between 82 and 81. Right.

Your risk is 40% to 50%. That's basically a flip of a coin of becoming an Alzheimer's-diagnosed individual or not. And the purpose of our time together right now is that you can influence that risk dramatically in the time, as John Kennedy said, the time to fix the roof is when the sun is shining.

Right, wow. You know, do you subscribe to the fact, I mean, some folks will say that Alzheimer's is type 3 diabetes, insulin resistance in the brain. And I don't think Alzheimer's is one thing. There are genetic predispositions. There are lots of, I guess, multifactorial—

We've got a lot to talk about today. Gee whiz. You know, that's a term. And it's a term I think that's a bit myopic. And because it's more than just, insulin resistance in the brain that plays an important role. But insulin isn't really having a huge effect on a lot of the brain.

Mm-hmm.

There are 4 major areas: the hypothalamus, the hippocampus, the prefrontal cortex, and the olfactory bulb. Why is that important? It is important because those areas are involved in Alzheimer's. The olfactory bulb— why do Alzheimer's patients often lose sense of smell early on, even before their cognitive dysfunction becomes manifest. The hippocampus, their memory center, of course, central player as it relates to Alzheimer's. The hypothalamus, yes, Alzheimer's patients become metabolically dysfunctional. Being metabolically challenged with insulin resistance sets the stage for it. But at the same time, the brain becomes— Dysregulates metabolism from the hypothalamus. worsening the problem. And finally, the prefrontal cortex. I'm pointing to my forehead because that's where it lives, allowing us to carry out purposeful executive— what we call executive function. Planned activities, planning for the future, thinking about outcome, relating to other people, recognizing what I do to myself today might affect me tomorrow. Those are fairly sophisticated human attributes that begin to decay as Alzheimer's manifests. So Those areas of the brain basically require insulin for their functionality. Other areas of the brain, not so much. But beyond that, insulin is more important than just helping regulate blood sugar and drive blood sugar into a cell for metabolism. Insulin in the brain is what we call a trophic hormone. You and I had a talk over lunch about BDNF.

Mm-hmm.

Brain-derived neurotrophic factor. a trophic hormone. And in a very real way, insulin acts in the same way, nurturing neurons, nurturing synapses. And, you know, in that regard, we need functional insulin in the brain. So the idea is then, if this insulin lack of function gains the moniker type 3 diabetes for these reasons, I can live with it.

Right.

But that has prompted research into the administration of intranasal insulin. to help correct the problem or override the problem. And I have mixed feelings about that. It's the reason that— one reason I sort of reject it is because why do we now give insulin for type 2 diabetics? I don't fully understand it. They already have very high insulin levels.

Mm-hmm.

But the insulin isn't working because their blood sugars have been elevated for so long. One of the earliest markers that we want to look at is fasting insulin level, because that predicts that your blood sugar is going to raise, or rise, I guess would be more appropriate. But the idea of giving insulin, well, it'll bring the blood sugar down, no question, but we've got to do better than that. I mean, we've now seen over the past decade how dramatically effective in a type 2 diabetic a ketogenic diet can be.

Yes.

To reestablish insulin functionality, not insulin a quantity, but the function of the insulin that we already have.

The sensitivity of the insulin itself.

The function of that insulin. Go ahead.

Well, I was going to say, what is a good fasting insulin level? I mean, because when people get a blood panel and they've got fasted glucose, hemoglobin A1c, 3-month average of the blood sugar, and then insulin.

Between 3 and 5.

Between 3 and 5.

And that is—

Really low single digits.

Yeah, it is. It is. And you and I are talking optimization here today.

Yeah.

We're talking pre-Alzheimer's.

Right. You know, we—

what the heck is that term? Pre— well, we know pre-diabetic because the blood sugar is starting to rise. Well, we have a pre-Alzheimer's when you are metabolically compromised. How do you know? You know because your blood sugar is elevating, your fasting insulin is coming up, your A1C is elevated, your waist-to-hip ratio is increasing, your belly is getting bigger, your blood pressure is going up. These are metabolic issues That are changing the function of your brain's immune cells and creating a brain environment that is threatening to your synapses. Maybe I want to unpack that a little bit more.

Yeah, no, I definitely— this is the route that I want to go because I have a very selfish reason for having you on the podcast today. But also, I think there are a lot of people my age that are dealing with this, with aging parents, and I'm hell-bent on turning this around for my mother, and to the extent that I can prevent it for other folks, um, you know, like my kids and, and their kids, you know, that's, that, that, that's a service that I think is, is well met.

And it's, it's certainly for you, but can you imagine putting your kids through your cognitive decline, what that would be like for them?

Yeah.

You're getting, you're, you, you're getting a sense of that right now, what you're going through, and you don't want your kids to go through that.

That's exactly it.

You know, I Watch my brilliant brain surgeon father die of this disease.

Really?

While I am a practicing neurologist, and I had nothing to offer him. Wow! And it's it's challenging. It really is challenging. What do you do with that?

Right.

And then you just use a term hellbent. So I'm hellbent on getting this message out that you could rewrite your destiny as it relates to your brain. Yeah. You absolutely can do it, and. You just need the tools. And your audience already knows what these tools are to some degree. We'll talk about some leading-edge kind of stuff in a minute, but your very first podcast dealt with metabolism.

Yes. Think about that.

And we now have a term called immunometabolism, the relationship of the immune system to metabolism. Holy Toledo, how does that work? We know intimately that your brain's immune system is responsive to your body's metabolism. Your brain's immune system, made up of what we talk about in this book, the microglial cells, allows those microglial cells to nurture your synapses, to love your neurons, to shore up the blood-brain barrier, or those microglial cells, when your metabolism is threatening, will shift to becoming the evil twin.

Wow.

And when those microglial cells become the evil twin, they destroy synapses. They cause lack of connection in the brain, loss of connectivity. They threaten the neurons and they destabilize the blood-brain barrier. That shift of those immune cells from being what we call M2 supportive brain defenders to being destructive is dictated by their metabolism. And their metabolism mirrors your body's metabolism.

Wow.

Home run.

Wow. So, you know, like the, the notion that all cancer, regardless of its form or origin, was at one time a healthy cell. Um, and what happened to that cell? It shifted its metabolism. And that shift in metabolism now produces a cell that takes as many lives, only second only to cardiovascular disease.

And third on the list? Alzheimer's.

Yeah, Alzheimer's.

Think about that.

Wow.

Who— Alzheimer's is an almost uniformly fatal condition.

Yeah.

The 3rd leading cause of death in adults in America.

Wow. I didn't know that.

So let's contextualize this a bit, that we're spending, you know, $360 billion with a B on caring for Alzheimer's patients for a disease that I will tell you today is largely preventable.

Now, there's a genetic predisposition. So are you talking about in the non-predisposed population?

Nope, I'm talking about those individuals more specifically than you can imagine. So we do know that if you carry 1 or 2 ApoE4 alleles, as many of your audience I'm sure understands, 'cause they've had their blood work done, that you have a, as you characterize it, predisposition. Great word, not destiny. Predisposition is not destiny. So we see the studies now that indicate that dramatic lifestyle changes can absolutely offset That genetic predisposition. I mean, these people get back their genetic stuff with the printout that says, basically, put your wagons in a circle 'cause you're in deep trouble. And I'm here to say to all of your audience, that is just not true. And I'm talking to 25% of your audience right now who got their genetics back, saw the APOE4 and said, I'm basically screwed. It's just misinformation. So there's so much that can be done.

People ask me health questions Every single day about their labs, their sleep, their supplements, their genetics. I wanna help every single one of them, and that's why I built Just Ask Gary. It's an AI trained on everything I know, including my protocols, my research, and my methodology. You ask the question, you get my answer any time of the day. Go to theultimatehuman.com/ai and check it out. Now let's get back to the Ultimate Human Podcast. So I, I wanna get very specific with you and, and really get deep into the book, but, um, what does that lifestyle look like? 30s, 40s, I'm in my 50s. I believe that I'm living it now, but the previous 2 centuries, not so much. So I've got to overcorrect. Yeah, I know.

I know that feeling very well. We were talking real— yeah, I mean, even the head trauma part. Yeah. And I remember lying on the mat, being counted out by the ref.

One.

Because I couldn't get up after I got kicked in the head in a Match of some sort back in the day.

Like a karate tournament?

Yeah, it was before they had MMA. They had— it was full-contact karate. You know, nothing can harm me, right?

Sounds like a great idea.

It was a great plan, you know, and no headgear.

It's a great plan.

No headgear at all. And there were several other events that I had to experience. But anyway, and my lifestyle choices back in the day when you were just like in impervious to these events. They accumulate over time. They manifest in the changes in your metabolism. You can watch it happen if you're looking. So that's a point I want to make. You really want to be metricizing. You want to wear your Oura Ring or Apple Watch or Whoop, whatever it may be, and find out what is the duration and quality of your sleep. Very important. What is your blood sugar doing? Wear a CGM, continuous glucose monitor, from time to time.

Mm-hmm.

Get your blood work done. You can do that without a doctor now and get that information. Then you challenge yourself with the question, well, what do I do with this information?

Mm-hmm.

We'll talk about what that— and I put parameters in the book about what things should look like. But ultimately, I think well beyond what I describe here is availing yourself of a more personalized medicine approach in a clinical situation that's using AI to determine What's best for Gary Brecka that would be different than David Perlmutter? You want to know that.

Right. Very specific, personalized medicine.

And that's state of the art right now.

And it's widely available.

Absolutely widely available. So let me give— I didn't answer your question.

Yeah, I want to unpack that.

So the question was then, what are the things that shift these microglial cells? And we mentioned metabolism. So all the metabolic issues will shift microglial cells away from being supportive to being destructive. That is the fundamental now across the entire spectrum of neurodegenerative conditions. Alzheimer's, Parkinson's, MS, multisystem atrophy, progressive supranuclear palsy, long COVID, post-traumatic stress disorder, major depressive disorder. Who knew? These are not considered neurodegenerative conditions. But they shift the microglia and set the stage for brain degeneration. We've got to pay attention to that. So this understanding of immunometabolism, the relationship with the brain's immune system, in fact, your entire body's immune system to the state of health of your metabolism, is profound. It's a bit iconoclastic, and it is certainly empowering.

Yeah, I notice you don't call it autoimmune, like autoimmune microglial.

Well, and I was just asked that question because it's not a classic rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis type of Crohn's disease.

It's not an antibody to a neuron.

Yeah, it is not antibody-directed. It's not a molecular mimicry where there's on a cell surface of any particular tissue that the immune system is then directed to. So that part of the immune system is directed and causes problems. But in a very real sense, it is your innate immune system going awry. So it's auto in that it's contained within you, and it's certainly an immune issue. Importantly, though, and we should open this up later on.

Yeah.

I think in our 3rd hour, maybe in the 4th hour. Yeah.

We'll get there.

You're in for a long trip. We still gotta go back to Brain Brain.

So that was 2013.

Yeah, I would pick it up from there. But it's interesting to me, and then I'll get back to my point, that this explains Grain Brain. 'Cause when I wrote Grain Brain, it was about the correlations between elevated blood sugar, elevated A1C, dietary issues, and risk for Alzheimer's. Got that, but I didn't know how it happened. I didn't know why elevated blood sugar.

Mechanistically, yeah.

Mechanistically, now we get it. Now it all comes together. And I'm grateful at 71, finally the pieces came together. I wrote a book years later, several years later called Brain Maker. And I had the conclusion, strange as it may be, that there's a relationship between, get ready for this, gut health and brain health. I know, the gut-brain connection. So, talked about that.

I read that too, yeah.

Similarly, you know, there was a lot of pushback, but anyway, explains that too, because part 2 of our story away from immunometabolism is the effect of inflammation from anywhere in the body On polarizing these microglial cells away from being brain-defending, supportive, to being the evil twin, to being destructive. Inflammation, the molecules of inflammation called inflammatory cytokines, can come from the lungs when we're breathing PM2.5s from wildfire smoke, can come from a leaky gut because of dysbiosis or changes in our gut bacteria, can absolutely come from the mouth. when we have periodontal disease, a powerful risk factor for Alzheimer's. Why does that happen? Now we understand.

You mean deep dental cavities?

You bet.

Yeah, cavitations.

Not as much the caries as the periodontal disease, the gum disease, caries as well. I mean, it's just another indication of poor dental health. So while we now understand all of these relationships, the empowering part is, okay, we'll talk about what we should be doing for people's dental health and gut health and reducing your exposure to PM2.5s by virtue of the fact that you're breathing 20,000 times in 24 hours, maybe we should pay attention to the quality of that air. We had a long discussion about what you're doing right here earlier, and, you know, hats off to you for doing that. We do the same thing.

Yeah.

It's that important. I mean, you're paying attention to the quality of your water. Air, especially these days, you know as well as I what's going on, certainly in North America.

Oh, you mean the water is scary?

Well, no, in air quality with respect to wildfire smoke and in Europe as well.

Wildfire smoke, I mean, aluminum. I haven't tested the air in quite a while, but I tested the Miami-Dade water and, you know, everybody talks about the fluoride, the chlorine. It was all of the PFAS and the other things that I found in there, heavy metals, pharmaceuticals, that just made me really freak out and start really aggressive water filtration.

I'm not going to say that's a broad stroke, but I'm not going to play it down either. It's really important. You know, the goal for me is if we can get people even a few on-ramps, here's what a better brain diet looks like.

Yeah, this is exactly what I'm talking about.

Here's why you need to get some—

Take out a pen, guys.

Yeah. Get some quality sleep. tonight and moving forward. Here's why you absolutely had 100% sleep score last night. Oh, did you? You showed me that. Yeah, I showed you my HRV. I was proud of that.

Yeah, 70 HRV. That's incredible. To be 70 years old with 70 HRV.

That's one year less than my age.

Yeah, it's great.

You know, they used to say, if you're a golfer, you should golf your age. I'm not a golfer, but I wonder how it relates to HRV. But, you know, the point is that, These are powerful inroads to recharting your brain's destiny. And the idea that exercise— yeah, you want to be pumped up, you want to look good, you want to feel great, you want to sleep better. It's why I exercise. Yeah, all those things. But it's one of the most powerful tonics for brain health. There are hacks left, right, and center, and some of them have great merit. We talk about them in the book. What's the future of— would rapamycin be something that's in a brain-healthy program?

Right.

What about metformin? What about red light therapy? What about hyperbarics? Well, we can talk about those things, but the broad strokes are what we've just mentioned and do them. You've got to do them because—

Exercise.

Yeah.

And in particular, any type of exercise, weight training, longer duration cardio.

I will say that, you know, the most important part is getting started.

Yeah.

But, you know, it's often a question of, well, which is better for my brain? Is it the aerobic part or the resistance training? And there was recently published a meta-analysis of 32 different studies encompassed thousands of patients and evaluated what was the cognitive outcome in individuals based upon if they were dedicated to their aerobics program, whether it involved a dedicated aerobics program or doing aerobic exercise by playing pickleball or whatever it would be, or those who did resistance training, weights, tension bands, machines, Or even those who decided to do both. And by far and away, the winner was both.

Really?

Absolutely. And it makes sense now that, you know, you read their conclusion and why, but you think about it a little bit and we'll unpack that a little bit. But I just wanna say, and we talked about this at lunch, that I wanna add to that. Okay, people are gonna do, well, I do the aerobics, I do whatever, resistance, but flexibility and balance. Why? So you don't get injured.

Those are the two, I would say, probably my weakest points. You know, I'm not very flexible and I never do any balance work, per se.

But your wife has great balance.

She has amazing balance.

I know, but you can train balance. And the reason you wanna train balance is so you don't fall.

Okay.

And you're not thinking about it right now, but at the older category—

My dad's broken an arm and a hip in the last year in my house.

People in my age category, I'll leave it at that, Fall and may not know how to fall, first of all, and fall because they don't have good balance. I don't know that you can train people how to fall. That's something you learn earlier in life. Various things you can do where you learn how to fall. 'Cause I used to fall not frequently, but on occasion when I was running, and there's ways of falling and you can not get hurt.

Rolling over.

Yeah, yeah. I fell once in front of— this is not part of our talk, but anyway, in front of a large crowd in Washington, DC. I was actually invited to speak to the International Monetary Fund about the health implications of Alzheimer's moving forward. And guess what? It's a preventable, largely preventable situation. And I took a dive. There was a huge crowd.

In front of the audience?

No, no. Other audience that I think in front of one of the sites there. And I was really, you know, going fast. I was training for a marathon, I think, at the time, and I took a terrible dive, but I rolled and I got up on my feet. There's a scene in Pee-wee Herman's Great Adventure where he crashes his bike, gets back on. He says, I meant to do that. I didn't say I meant to do that. Yeah, that would have— but I was thinking that.

That would have been like sticking the landing.

Oh, I know.

Threw your hands up.

It's true. When you mess up, if you can pull it off, uh, yeah, yeah, if you think fast enough.

So those are probably— that's probably from your karate days, you know, 'cause you learn that, how to tuck your head and kind of roll onto your shoulder.

Yeah, there's other— I think judo teaches you more how to fall. But yeah, various martial arts will teach you how to fall. I think learning how to fall is a pretty darn good skill to have. And people don't really train that, but you know, when you're a kid, you're always falling down and either getting hurt or you're not. So you learn pretty quickly. Football teaches you how to fall too, tackle football.

Okay, so aside from tackle football, so strength training, Strength training and obviously aerobic training on a consistent basis over a prolonged period of time.

Let me finish that thought, though. Sorry to interrupt you, but in that study, the people who derived the best benefit were those who had already cognitive impairment to some degree, and also the group 65 years and older. So you're just about to ask me, is it ever too late?

Right.

It is absolutely not ever too late.

So starting a strength and resistance training program now, with some flexibility and balance moved in and some cardio component and doing that consistently, minimum 3 days a week.

That's right. And, you know, calling it like it is, losing muscle mass is a very big risk factor for metabolic issues, therefore directly related to Alzheimer's and cardiovascular disease, but also directly related to risk for Alzheimer's, losing muscle mass called sarcopenia.

Wow.

And I'll tell you, N of 1, and not that, But there's not plenty of data that supports this. The older you get, the harder it is to keep muscle mass. You have to work harder. It's more time. It's paying attention to adding creatine to your regimen, testosterone perhaps to your regimen. All of the things that you've talked about on the podcast, you've interviewed the experts, it all makes incredible sense.

So you're a fan of creatine.

I am.

I actually, that was one of the areas I wanted to talk to you about You know, there's some big claims out there around creatine. I was curious what you felt the data supported in terms of cognitive function, crossing the blood-brain barrier, mitigating sleep deprivation, those kinds of things with creatine.

So let's unpack that a little bit. The systemic creatine that you have doesn't really make its way to the brain to any significant degree. It does. But the brain makes its own creatine. The creatine that's manufactured in the liver and the kidneys works for the rest of your body, definitely works for your muscles. And that sort of is this relationship that we're trying to take advantage of. If you can raise your blood level of creatine, though it may not make its way fully to the brain, you're supporting muscle growth. And that's what you want to support your brain. Why? Because your muscles are an endocrine gland. We begin to get our arms around that. What is that all about?

Like a glucose sponge.

Well, not just that, but the definition of the endocrine gland, the thyroid, the pituitary, the adrenals, is that these are organs that make chemicals that go elsewhere and do other things. There are thyroid receptors on all of your tissues. The adrenals stimulate various tissues during times of stress. That's one part of the adrenal. And pituitary certainly has effects throughout the body.

Mm-hmm.

The muscles do exactly the same thing. They create chemicals that have a huge impact on our metabolism, on regulation of our blood sugar, and even irisin, one of those myokines, myo, muscle, kine, moves. Irisin being one of those chemicals makes its way to the brain and stimulates the production of something called brain-derived neurotrophic factor. We talked about it earlier before we went on camera. That is something we want to have as much of as possible because it amplifies the growth of new neurons, amplifies the formation of synapses so our neurons can talk to each other, and is generally just a good player in the brain. So the more of that, the better. We bring that about by exercising. So who wouldn't want to do that? Other things input to BDNF as well. There are some research protocols to increase BDNF with various interventions, but even omega-3s, DHA in particular—

Really?

amps up BDNF production. So this isn't a direct effect of muscle activity to the brain. It's an intermediary effect of this irisin chemical produced by muscles making its way to the brain. Interleukin-6, which we've been saying for years, oh, that's a bad inflammatory cytokine made when muscles are active. And in some ways, it is a bit pro-inflammatory, which is probably a good thing as it relates to exercise. We need a little inflammation—

Sure.

As a hormetic stress to amplify recovery and repair. But that said, this interleukin-6 cytokine is actually the key for how muscle activity stimulates something called AMP kinase. Now, I don't want to be too technical about all of this.

AMPK.

But AMPK is a powerful target for our mitochondria, allows the mitochondria to be removed if they're defective. It amplifies mitochondrial biogenesis, the growth of new energy producers, the mitochondria, through activation of something called the PGC-1 alpha pathway. But the point is exercise through IL-6, through AMP kinase, PGC-1 alpha, is good for the mitochondria. Let's just say exercise then connects to mitochondria.

That hormetic stress causes the mitochondria to improve its metabolic function and potentially even increases mitochondrial density, right? The proliferation of mitochondria.

It absolutely does. How can we see that? You can actually visualize that. The normal fat gets converted into brown fat, the metabolically favorable kind of fat.

The thermostat.

And it's brown because it has more mitochondria. Oh, that's why it's brown.

I knew it had more mitochondria.

That's why it's brown. 'Cause it's so rich in mitochondria. But let me rein this back to our time together today, which I'm really enjoying.

Yeah, I am too.

I really am. You know, we knew each other kind of peripherally, Anyway, and that is that the shift of these microglial cells from being supportive to being destructive, from being brain defenders to being brain destroyers, is characterized by a shift in their mitochondrial function.

Hmm.

When the shift happens, their mitochondrial function basically evaporates almost fully. Now they're using Glycolysis, another energy-producing pathway, far less effective. Interestingly, what cancer cells use, we talked about that in the hallway.

Glycolic respiration.

They're using a far less efficient way of making these ATP energy molecules. So everything that we have talked about, about exercise and the mitochondria just now, AMP kinase and all of that, and that we will talk about that deals with mitochondria, The play here is that when you improve mitochondrial function, you're protecting the supportive brain defender, microglia, in your brain. Let me tell you how vast this becomes. I mentioned earlier a laundry list of neurodegenerative conditions that are characterized by this shift of the mitochondria away from being supportive to being destructive.

Which is the hallmark shift of these microglial cells going from being reparative to destructive.

Exactly. We can image that in living humans now.

In the brain?

In the brain. We can absolutely do scans.

Is that a qEEG?

No, it's called a TSPO scan. And TSPO is a marker that is much more expressed On the mitochondrial membrane of the M1-damaging microglial cells in comparison to the supportive microglial cells. So when you do a TSPO scan of an individual, if it lights up, it's telling you those microglia have shifted. And in my lectures, I show what a normal brain versus an Alzheimer's brain TSPO scan looks like. Let's look at that image right now.

Yeah. And so walk us through what they're seeing.

You see on the left side of your screen, what you're seeing right now is the normal brain. On the right side of your— of the image, that's the TSPO image in the Alzheimer's brain. It's light up. What you're seeing light up here is evidence of the microglia being activated into their destructive condition. And what you're actually imaging is this TSPO binding to a unique receptor on the surface of the mitochondria of these activated microglial cells. Let's look at this next slide because I think it's really compelling.

Okay.

What we're seeing here is a list of all of the neurodegenerative and other conditions in which TSPO imaging is positive, meaning if you look at this list, these are all diseases and disease states in which the microglia have shifted to becoming Destructive.

Wow.

Microglia shifting to becoming destructive is something that we now have the tools to target. And most importantly, we should be living our lives, choosing lifestyle interventions such that we can keep our microglia away from being this TSPO image type of situation where they're shifted already to being destructive. We have the tools to make that happen right now.

And what are the tools once you are in that situation? Because a lot of what we've talked about is what we do to prevent that situation. Well, exercise, controlling blood sugar, getting, you know, uh, making sure that you don't become insulin resistant, and to the extent that you are, managing insulin resistance. Um, omega-3, high omega-3 fatty acid intake. Uh, I would imagine a diet, uh, low, lower glycemic diet. But now that we find ourselves in a situation like I'm in with my parent, where I haven't done that image, but I assume that it would light up, I've seen the hypoactive areas of the brain on qEEG. And so what do we do now to try to restore that access? Because one of the fascinating things that we talked about before the podcast—

Yeah.

was that even in these conditions like Alzheimer's, patients are not losing their memory per se. They're losing access to their memory. How do we restore access, or can we?

Well, we give you the tools, and I will walk you through it. But far be it from me just to sit here and say, well, this is what I think we should do. Let's talk about a study that was published last year in the Journal of Prevention of Alzheimer's. Actually, no, that's not where it was published, but it was published by— we'll cover that study in just a moment because I think it's really very relevant. This study was carried out by Dr. Rudolph Tanzi at Harvard, along with Dr. Dean Ornish, an interventional trial on 51 patients who were diagnosed with Alzheimer's disease, an intervention that lasted around 20 weeks. What did they do?

Yes.

They changed their diets, they increased their exercise, they managed their stress. And what did they find?

Well, that's it. Changed their diet, increased exercise, managed stress. Right. Okay.

Normally in 20 weeks, Alzheimer's patients decline. In 20 weeks, Alzheimer's patients on the newer beta amyloid drugs Decline. And we're going to talk about that because it's really, uh, it's fundamental, I think, to this whole discussion that these drugs are ineffective. We'll talk about that.

They're focused on the endpoints, like the neurofibrillary tangles.

Exactly, which is the beta amyloid plaques. Unfair. We'll get there. I have a few things to say about that. Yeah, that's true.

I know you do.

Um, but what they found is that in 70% of the individuals that underwent this intervention, their cognitive decline either stopped, which no drug can do, or improved. Their cognitive function improved.

Hmm.

I want that one to stew for a moment because most of your audience has not heard of that study, and they should have. Most of your audience has heard about the idea of, oh, we've got a brand new drug that targets beta amyloid for mom or dad Start to have cognitive impairment, and we'll talk about you know I'm going to talk about that.

Right.

But I think that it was very telling. It was a small study. Granted, it was a small study, but let's wind the clock back a little bit to individuals who are at risk because of their metabolic issues. A much larger study published in the Journal of the American Medical Association, and it was called is called the Pointer Study that was completed last year. This was more than. 20,000 people, a 2-year intervention where they did the diet, the exercise, stress mitigation, and had them doing cognitive training using a particular app, BrainHQ. They had 2 arms. One arm got these recommendations and did this type of training, but had very aggressive interaction with people in the study during the 2-year study, 18 times per year, 36 total. Meetings virtually or in person. How are you doing? What's the diet like? How's the exercise coming along? The other arm had the same program.

I imagine these were older ages, right?

That's an important point.

So a lot were deconditioned.

Well, not just deconditioned, but these were people selected because they were at risk for Alzheimer's because they are metabolically compromised, cardiovascular disease, overweight, age 65 and older. So they're already set up for Alzheimer's. They are. They're well on the continuum. So the other arm didn't get the handholding, if you will, the 36. They got a total of 3 a year. So a total of 6 meetings with people. How's it going? Are you doing the program? So they pretty well got the program and almost do your best and we'll talk to you later. The end of the program, they evaluated these individuals with cognitive assessment. And these people are expected to decline cognitively because of their age, because of their metabolic derangement, if you will. No, they didn't. They didn't even stabilize, but they dramatically improved across various domains.

Wow.

Now, that's what they found in the group that had the handholding, the deep intervention. But here's the part of the POINTER study that I want people to Google it, find it, Pointer Study, JAMA, you'll find it, is that the group that got the program and didn't really get the guidance had a fairly dramatic improvement in cognitive function as well. Not the extent of the other group, but nonetheless, an improvement when they should have declined.

Wow.

That's how I answer your question about, is it too late? Is it reversible? And what can we do? Um, you know, it's about doing these things though earlier, uh, get these things involved earlier in someone's life so it's not as challenging.

You know I'm all about optimizing performance, and lately I've been using the ION Weighted Vest during my workouts, and it's been a game changer. It isn't your average weighted vest. It's designed to fit like a second skin, activating your core, improving blood flow, and even helping you with recovery while you train. What I love most is that the weight is perfectly distributed. It doesn't pull on your shoulders or throw off your alignment. Whether I'm doing strength training or cardio or just taking a walk, I'm burning more calories, building muscle, and pushing my endurance even further. If you're serious about leveling up your training and unlocking your full potential, check out the Aion weighted vest at aiongear.com. That's aiongear.com, and you can use code ULTIMATE for 10% off and start training smarter today. Now let's get back to the Ultimate Human Podcast. So just being more specific, what were the dietary interventions? I assume removing highly processed foods, lowering the glycemic impact of high glycemic sugars.

Yeah, and we'll talk about that in a moment.

Was there a keto reset, something like that?

No, but again, back to Benjamin Franklin, it is a question of well done is better than well said.

Right.

Or well said. I think he said, well said is not as good as well done. You got to do it.

Right.

And again, you know, as Kennedy said, the time to fix a roof is when the sun is shining. And that's what we really want to target. It can be done later on, as I just demonstrated. So the diet in the interventional trial from Rudolph Tanzi and Dean Ornish was very much a plant-forward, plant-centric diet.

Okay.

That's been Dr. Ornish's push for cardiovascular disease or cardiometabolic disease for an awful long time. I use the term cardiometabolic because metabolism affects the heart. Well, metabolism affects everything. So we'll say neurometabolic disease as well. That's what Alzheimer's is. This may be the first time I've ever said that term, neurometabolic disease.

Yeah.

I think it is, but let's make that stick because—

Yeah, let's make that stick.

I don't even think I put a word—

We'll coin it here today. Yeah, you saw it first.

That's true. Oh, can you guys get me neurometabolicurl.com? No, I'm kidding.

Neurometabolicurl.com.

But, you know, the point is that these are all ultimately metabolic issues, and through the intermediary of immunity, now immunometabolism, disease manifests. Cardiovascular disease is primarily an immune-related issue. What's narrowing the coronary arteries is an immune response. When you take the plaque out of a carotid artery or a coronary artery, it's loaded with immune cells. So it's an immune response, very much so, directed by free radical-mediated stress and inflammation. So to get back to where we were, that these lifestyle interventions are, by mainstream standards, not really embraced and often derogated. But when we look at the peer-reviewed literature, it's incredibly supportive. In the world of neurology, this is our only answer right now. Am I going to keep the door open and welcome an Alzheimer's drug if it does 2 things? It's fairly safe and it does the job. Absolutely. I am so down for that. I will embrace that with open arms. We don't have anything like that right now, despite the TV commercials to the general population and despite the ads that are appearing in my neurology journal as a neurologist that I should be recommending these drugs that target beta amyloid. I went into it in great depth in this book. Again, coming from somebody who would absolutely 100% be so down for these drugs.

Yeah.

I'm all for making the toolkit bigger. But fundamentally, we have to practice under 2 principles. Number one, primum non nocere. Above all, do no harm.

Yes.

And number 2, looking at the risk-benefit ratio. These drugs that are being used have dramatic risk, and the benefit is nil. A Cochrane analysis was published about 3 months ago. The gold standard, you would agree, in looking at trying to answer a question. The question that was asked Are these drugs doing anything?

Right.

And here's the answer. They looked at 20,342 individuals who were in 17 different studies, each study lasting 18 months, of the current round of amyloid-digesting proteins, if you will, or monoclonal antibodies that take beta amyloid out of the brain as a treatment for Alzheimer's. What did they find? Risk. 25% of people getting these IV drugs to rid their brains of beta amyloid had brain hemorrhages, brain swelling, or died.

Wow.

That's what, 25%? 25%. 1 in 4.

Wow.

Number 2, okay, that's the risk. I'm not making this up. I wish I were making this up. Then people could write comments about, oh, Gary Brecka had this case. this guest, whatever. I'm not making it up. I wish I were, because then we could challenge veracity, challenge my veracity. What's the benefit? The conclusion was basically none. The word used in the Cochrane analysis was the benefits were trivial. Now, I say that and present this information in juxtaposition to the study that I quoted to you from Dr. Rudolph Tanzi at Harvard. where they changed the lifestyle and the downsides or the side effects were that people's blood sugars came down, they lost weight, they felt better, and that was the other things that happened.

Right.

And these are existing Alzheimer's patients. Back to the POINTER study, that helps clarify one other point that you asked. These are the metabolically compromised 65-year-olds who had a 2-year intervention of lifestyle plus brain training. I want to make it clear that a significant number of these individuals carried the APOE4 risk marker for Alzheimer's.

Predisposed. And what does that gene— what is the line that predisposes you to Alzheimer's? What does that gene do or not do that predisposes you to it?

I didn't write you that question ahead of time. I should have, though, because it's a great question. Fundamentally, it threatens the microglial cells.

That's what it does.

Fundamentally. And more so in women than in men.

So it leaves you— you are more likely because of this gene SNP to have microglial cells who shift their metabolism and become villainous rather than become helpers.

That's right. And again, to use your words earlier, it's a predisposition. it's not a genetic determinant.

Yeah, it's the epigenetic factors that clearly are a big thing.

Yeah, it's associated with increased risk. Yes, it is. So you need to ratchet it up. If you have been told you carry the APOE4 allele, then by all means, pay heed to what we're saying today because it doesn't have to manifest at all. And, you know, it's interesting because it kind of gets us back to the beta amyloid hypothesis, which is only a hypothesis. which I think made people believe that that is the cause of Alzheimer's. Get rid of the beta amyloid, problem solved. It didn't work. Still isn't working. But to be fair, there are plenty of people who have been demonstrated to have high levels of beta amyloid in their brains and are cognitively intact.

I was just reading that.

And others who have no significant amounts of beta amyloid and are going down the tubes with respect to Alzheimer's as a diagnosis. So that is, by all means, not the story. And we need to move ahead and really abandon this hypothesis. And where the research is now and where it's going in the future is targeting the microglial cells.

Mm-hmm.

I mean, you know, some very high-level work is being done to create monoclonal antibodies that there's a study at Brigham and Women's Brigham and Williams, using a particular monoclonal antibody. This is a very high-level science that's given now intranasally that helps keep the microglia in their M2 supportive configuration. They're exploring that in multiple sclerosis and in brain trauma. I describe it in the book. There are ways of targeting the mitochondria. Think back to our conversation that a major characterization of the shift from being supportive to being destructive is a loss of mitochondrial function. There's a product that's called RNS-60 that definitely targets mitochondria. It's a proprietary way that saline solution is hyperoxygenated, creating these nanobubbles of oxygen that seemingly mitochondria love.

Hmm.

There's a future there. Even the drug metformin has a mitochondrial play.

Not just from its glucophage impact.

It is glucophage, but there's much more than simply the activation of the AMP kinase that it looks like metformin glucophage is doing. So there's a lot of interest. You know, we will watch very closely the arms of the TAME trial once that is completed to look at what people taking metformin are gaining, if they're gaining anything, anything they will. Based upon this way of targeting their mitochondria. But guess what? You've got incredibly powerful tools for targeting your mitochondria right now, and it's more of a ketogenic diet and exercise. That's one of the most powerful ways of targeting your epigenome, targeting your epigenetics, but also targeting mitochondrial function.

So even if they're a little deconditioned, getting them to do You know, like my mother can't go out and get into zone 2 cardio, run in a 5K.

But she can walk to the mailbox.

She can walk, she can definitely walk.

Tomorrow she can do that twice.

Yep, that she could definitely do. And she could do resistance training. She's very strong.

Your mother may surprise you.

Yeah.

You may surprise you. I could imagine in a couple of years as her cognitive function improves, that you might be well surprised at what she's able to do physically.

Wow. So the exercise, obviously the glycemic diet, the omega-3s. Um, I, I think it's also important that we touch on the importance of sleep and the glymphatic system and what's happening with the glymphatic system during deep phases of sleep and how important, um, uh, getting proper sleep and how detrimental sleep deprivation, at least over a prolonged period of time, short bouts, you know.

Yeah.

Travel or what have you.

What can I say? It's huge. It is, it is, it's huge. Sleep, eat, and exercise. Yeah. What was it? Eat, pray, and love?

Yeah, very important as well.

But yeah, and sleep might be clearly the most important of all 3. Diet's not great, exercise not often. You don't sleep well, you're done. You are finished. Even, you know, if you don't sleep for a few days, you won't survive. Yeah, you can fast for, I mean, uh, you know, people fast.

30 days.

Oh yeah.

Yeah.

Uh, so, uh, we have that ability.

Uh, and, uh, sleep deprivation is one of the oldest forms of torture. I mean, that's right.

That's, you know, your brain just degenerates very quickly. Uh, mechanistically, what's happening? You mentioned the glymphatic system. We can unpack that I'd love to. But sleep is hugely influential in terms of inflammation, in terms of insulin functionality, and overall metabolic regulation. Those are the keys to the kingdom in terms of regulating your microglial cells, keeping them supportive or allowing them to become destructive. That's the keys to the kingdom right there. Even one night's non-restorative sleep dramatically affects insulin functionality, is manifested by elevation of your blood sugar compared to the baseline, ramps up the production of these inflammatory cytokines that your microglia will see, tend to shift them to the dark side, as it were, and generally is to be avoided. It happens even cognitively. That very next day, you're having issues.

Yes, we all know so.

Interestingly, a study came out this year that show that to some degree, some of the cognitive dysfunction that you have after one night of not sleeping or not sleeping enough or well enough is offset by caffeine. I mean, we all inherently knew that. Best practice here. But this actually looked at what's going on on cognitive testing, and I think it involved fMRI evaluation as well. Underrated. You spend 8 hours, you should, or thereabouts sleeping. That's a third of your life.

Yeah.

Though you were spending more as an infant and a toddler. But a third of your adult life should be spent doing this. You're not going to sleep. You're not going to eat for 8 hours or exercise for 8 hours. I guess some people might, but a third of your life, allowing your brain to contextualize your experience, to build new memories, And to, via activation of the glymphatic system, help offload the debris that is accumulated, the misfolding of the proteins, the glycated proteins, the proteins that are bound inappropriately to blood sugar, and the bacterial breakdown products that your brain does in fact accumulate.

And where do you fall on creatine supplementation in older adults, or specifically those with cognitive decline? Because we touched on it briefly, but Do you have any opinions on the form of creatine, monohydrate versus hydrochloride? Have you read the studies where it can mitigate the effects of sleep deprivation? And certainly in some cases, some wild claims about, I don't want to say reversing Alzheimer's, but treating Alzheimer's.

Well, let me just start with that. The study was extremely small and it was an interventional trial.

Like an N of 2 or something.

Yeah, I think it was 5.

5, okay.

But it was a very small study. small trial. And frankly, there were some cognitive improvements in these individuals. I mean, we need a big trial of creatine as it relates to Alzheimer's. And what they did demonstrate that I think was really quite remarkable is they were able to image creatine levels in the brains and in fact demonstrate that it increased.

Yeah.

So we've got a way to go, ways to go. But I would say that mechanistically, as we understand what creatine is able to do, It makes sense. I recommend it. It's one of my key supplements in this book. And is it early for me to be bullish on creatine? Yep, it is. And I'm fully happy to admit that. Do I take it every single day? You bet I do. Do I take—

How much do you take?

I take about 7 grams creatine monohydrate. I'm seeing the data on better GI tolerance and absorbability of creatine monohydrate, but I'm not compelled by it.

Hydrochloride.

Hydrochloride, yeah. Yeah, that's correct. And so I'm not compelled by the idea that hydrochloride is necessarily dramatically better. We'll watch.

More water soluble, I think.

Yeah, yeah. And we'll watch that. But creatine monohydrate is widely available. It's really inexpensive. It's tasteless. Yeah, you can have GI upset if you overdo when you first start in, no question. But if it doesn't enhance mitochondrial function in the brain, What we're hoping for, but does allow you to perhaps build a little bit more muscle mass and enhance mitochondrial activity in the muscles, that's good enough for me.

Right.

Based upon our earlier conversation, the relationship between muscle mass and muscle activity and functionality, ultimately on the brain through the formation of these myokines that are good for the brain and good for metabolism, then I am all in. The story is unfolding. I wanted the readers to be— go ahead and start your creatine with disclaimer, your healthcare overseeing all of this.

Right.

Well, hoping that your healthcare provider has heard of creatine. We'll leave it at that. But I don't think we're too early. Risk, I don't see much risk. I mean, there's been a discussion about people with existing kidney disease to check with your healthcare provider on the front end. And I think there's an argument That when you take creatine and you raise your levels, its metabolic downstream manifestation is the formation of something called creatinine. So they're sounding similar, but they're very different.

Right.

So your creatinine level actually may go up as you take creatine. Why is that relevant to this discussion of the kidney issue? Because when your creatinine level climbs, Then your doctor might say, gee, that's an indication of kidney damage and your kidney function is declining. Well, realistically, it's rising because you're taking a supplement that is metabolized into creatinine. So yeah, it's worth looking at to see when—

I've seen that, and if you do blood draws on athletes that have just done a heavy squat workout, they look like they're in kidney failure.

Based on the blood work.

Based on the blood work is what I mean, you know, because their creatinine's off the chart.

Exactly.

8 hours later, it's normalized.

I mean, there are other ways of assessing kidney function. Let's look at the BUN.

EGF-R.

Let's look at the estimated glomerular filtration rate. You're correct. But to suddenly say, no, stop creatine, 'cause look, your creatinine went up. To be fair, I mean, maybe somebody is having renal issues for that reason or other reasons. I'm not saying just 'cause you started creatine that you should ignore Your other blood work, but you know that's what we need to think about. So let me just you know recognize that creatine in and of itself is perhaps not necessarily the mitochondrial tonic that I think it's made out to be. What creatine does is is in the presence of an enzyme phosphocreatine. or rather creatine phosphokinase, that creatine binds to phosphorus, holds onto that, rather binds to, creates a phosphate binding to creatine, forming phosphocreatine that then serves as a reservoir for that phosphate group to then participate in the formation of ATP when it's needed. So there's this right in my next door, neighbor's house is a great source for me to make energy. That's what phosphocreatine is. It's right in the garage in my ATP producer. So, you know, it's a resource for better ATP production. So in that regard, yeah, that's how it works.

Hey guys, let me tell you about one of my favorite new hydration drinks. Now, this is for distance athletes, HIIT cardio exercisers, people that sweat a lot or exercise intensely. And A-Game is a hydration drink. It has 8 essential vitamins. It has all of the electrolytes, the entire suite of B vitamins. Before you freak out and read that it has 21 grams of sugar, which it does, the sugar is coming from natural cane sugar and honey, my preferred mechanisms for getting glucose into the blood during intense exercise. It also has natural flavors, but these natural flavors don't come from bacterial fermentation. They actually come from real citrus fruits, and the color is from vegetable juice. Not artificial dyes. So next time you're looking for a great hydration drink and you're exercising intensely, AG1 is your choice. Now let's get back to the Ultimate Human Podcast. In, in the book, do you talk about any other must-have supplements or supplements that look promising for brain support? I mean, I think this whole wave of nootropics, um, and, you know, brain health supplements, You, you see they're becoming extremely popular. Um, I, I wonder if you have an opinion on any of those, or if you— are there any that are must-haves in your book, or any that you're excited about that are on the horizon for neurocognitive decline of all, of all sorts, and specifically maybe related to the microglial cells?

Yeah, I will, uh, I will put a huge vote in for vitamin D. Who knew?

Great.

I mean, it might be one of the cheapest supplements out there these days.

Cholecalciferol. Yeah.

Yeah. And, uh, why?

It's the only vitamin that human beings make on our own. So you got to think, wow, if we don't need to eat, uh, drink, or breathe to make vitamin D, you know, we just need some cholesterol and some sunlight. Cholesterol— I'm oversimplifying, but no, that, that's, you know, that's basically what you need.

Yeah.

You know, then it has to be pretty important to human function because we don't even need to get it from diet.

There are vitamin D receptors on microglial cells. Let's start there.

That's wild.

And I'll backtrack a little bit because these days people are understanding their genetic profiles and learning that they may have polymorphisms or variations in their vitamin D receptors.

Mm-hmm.

So, for all of you who get your genetic material printouts, look for changes in the VDR information, the vitamin D receptors, and they'll give you whichever program you're on, whether it's 3x4 or whatever genome profiling sequencing company you're working with, they'll tell you you have a VDR polymorphism and you might need to consider a higher dosage of vitamin D. Or as you well said, perhaps get a little bit more sunlight. Sunlight is a pretty effective way, but we wear clothes generally outside. Most of us do, some of us don't, or some people don't. But that said, I don't want to say that everyone should take vitamin D as a supplement out of hand. Get your blood level checked.

Right.

If you're already between 60 and 80, on your levels, then by all means, you're doing great. Whatever you're doing seems to be working. Maybe you're getting your vitamin D from sunlight, from food, from your multivitamin, or wherever. But if it's not, and I'm talking now to most of your, maybe not your audience, but most of the general population.

Yeah, more than 50%.

Yeah, your vitamin D is not, though it may be considered borderline normal range, it's not optimized.

30 is normal.

30 doesn't work for me.

No, me either.

So 60 to 80, closer to 80. Mine is about just under 80, and that's where you want it. So that helps keep your microglial cells on your side. That's what you want. So I've been saying that for a number of years. Let's talk about a couple of interesting studies that just came out. One study that came out this year in the context of a different study, which just floated my boat. I was talking to my best friend, ChatGPT, the other day at the gym. Chat's great.

That's a good friend of mine too.

We unpack this study. I have the best time. Then I want to hold ChatGPT to the mat on going deep on these ideas. So here's what the study talked about, that they took a group of people in their 30s, and it was several thousand people. They followed them for 16 years. At the beginning of that 16-year prospective analysis, they measured their vitamin D levels. At the 16-year point, They brain scanned them for tau protein. Now, your audience may or may not know what tau protein is all about.

Mm-hmm.

I'll back up to the study in just a minute. JAMA just published a study. We've known that this phosphorylated tau 217 is a way we can help diagnose Alzheimer's if we're not sure, predicts how quickly a patient will decline. But the new study in JAMA showed that this p-Tau 217, one of the fundamental blood tests I'd like everyone to get, is predictive of who's going to get it well in advance. Let's get back to the vitamin D study. So the vitamin D levels were looked at in juxtaposition to measuring tau in the brains of people using a special scan. Higher vitamin D, Lower tau in the brain.

Wow.

Now, to be fair, that's a correlation.

Right.

Higher vitamin D, lower tau in the brain. Do I think that's important and therefore supports the idea that we should make sure our vitamin D levels are where they need to be? You bet I think that. Again, that's not what the study allows me to say from a science perspective, but my personal view, which is, I guess, what all of our views are, Yeah. Is that you bet you need to maximize, or optimize rather, your vitamin D level. It's that important. It reduces inflammation. Vitamin D receptors on those microglial cells via— make their way to the nucleus and transcribe genes that are doing good things. They make— it makes their way to the mitochondria and it helps with energy production. So, uh, I'm all in.

Okay, so creatine, vitamin D, vitamin D3. Anything else that is—

Oh, well, there's lots.

Well, we got time. Third hour. We'll do the third hour.

And I'll bring this up because an interesting study published about 2 months ago challenged the wisdom that omega-3 supplements, fish oil in particular, was good for the brain. It was an interesting study that followed, that looked at records of individuals, whether or not they became demented, and cross-referenced that, if you will, with whether they were taking fish oil or not and concluded that fish oil was of no benefit in reducing risk of Alzheimer's and in fact may have actually slightly increased risk.

Oh, wow.

Right. Now, at first blush, a lot of the people watching us right now, your audience, saying, why, that's crazy. I mean, I've known for years that we should be taking DHA, fish oil, omega-3s in general, good for the brain, right?

Right.

It's been our messaging. And for me, it's still my messaging. Why was this study, in the face of all of the studies demonstrating correlations between higher levels of DHA in particular and lower risk of becoming demented, dating back to the original work of Martha Clare Morris from Rush, why was this new study, in my opinion, off base? serves as a huge disservice to people. Well, reading the literature or getting informed these days, what's the first thing somebody might reach for if they're developing dementia? Omega-3s.

Right.

Right. I mean, what would you tell somebody? My friends are having— I have a particular friend who's having cognitive decline. What should he or she do? Well, omega-3s should certainly be part of that equation. So you're selecting people out now.

Right.

By putting them— these people are going to gravitate to take— demented people or early dementia, subjective cognitive impairment, are going to gravitate to the omega-3s anyway. That's going to skew these results. You've already selected a group of people who may be experiencing cognitive decline, number one. Number two, to be fair, there's a lot of crap on the shelves in the grocery store.

Mm-hmm.

Being sold as high-quality fish oil in a clear plastic container that's been sitting there, probably shipped in a hot truck or who knows what. How was it refined? All the things that may not have the efficacy we're looking for. Likely it does not.

Right.

So for those reasons, and, you know, our understanding of the chemistry of DHA, mention one thing that DHA does DHA does, earlier in our time together today, enhances the production of brain-derived neurotrophic factor. DHA is a COX-2 inhibitor, i.e., it's an inflammation reducer in the body. Therefore, we need DHA. It's a powerfully important structural component of the neuronal membrane where all the information gets transmitted. It makes up part of the synapse where cells connect to each— neurons connect to each other and share information. So, Don't throw the baby out with the bathwater.

I couldn't agree with you more. I take an olive oil in the morning. I take phosphatidylcholine in the afternoons, and I also take a fish oil.

So, right.

I, yeah, I load up on the EPA, DHA, fish oils.

There are plenty of other things that are not expensive that we should be thinking about, like B complex, a good B complex. Now, might you need a special form of B complex, as I do? Because my homocysteine was slightly elevated. Homocysteine, an important lab study, a powerful risk marker for Alzheimer's. You get a homocysteine level now on the various labs that you're able to get bundled without a doctor's prescription. Homocysteine is included. Why? Because it's a powerful risk marker for cardiovascular disease. And as such, because it's a risk factor for that, You would expect it to be a risk marker for Alzheimer's, and indeed it is. Wow! But here's the good news: you can drive homocysteine levels down with B complex, B complex, and TMG. Yeah, trimethylglycine, trimethylglycine, or dimethylglycine. Yeah, unless you have a genetic quirk, which I have called MTHFR. I don't mean to be too technical, but I will guarantee you. Some of your viewers know exactly what I'm talking about.

All of my viewers do. Right.

MTHFR.

I've been standing on MTHFR for 20 years.

Methylene tetrahydrofolate reductase. Yes. And that is a mouse—

Also called the motherfucker gene.

The mofo gene.

Just say it, Dr. Pompa.

We'll leave it in there.

Just say it, David.

You were going to get me to do that. Now you're going to bleep it out anyway. But so I think that this is fantastic information. #WTF, why, that's fantastic.

Yes.

Right? That's what it stands for. That we now have the ability to not only say, well, your homocysteine is elevated, but here's why. So for these MTHFR people, myself included, we know that we are at risk for elevated homocysteine and other issues by virtue of the fact that we don't methylate. And we can fix that by taking not just B-complex vitamins, But they have to be methylated. Methylfolate, methyl B12, problem solved. My homocysteine went down to 6.8.

Same with mine. Mine was 15, now it's 7.

So if you had a homocysteine of 15, that needed work. And who knows how long in your life you didn't know this.

My whole life until, well, 68 years ago. Yeah. And I've supplemented ever since.

And there are people that we will talk about Perhaps off camera, for whom we need to know their homocysteine levels and vitamin D levels and all the things right now. I mean, we talked about the microbiome and all that, all well and good. These other things are very powerful levers and will allow us to really make headway.

First of all, I agree with everything you're saying. The methylated multivitamins, the methylfolate, methylcobalamin version of B12. Some genetic variants need the hydroxy or the adenosyl.

Yeah, it's not a big deal, Sam.

It's super easy.

You know, I look forward to my sublingual B12 because it's sweet and it's the only, you know, it's my real treat, my sublingual B12. Sometimes I might even have 2 if I'm feeling like I want to reward myself. That's how lame I am.

Eat so little sugar, you mean?

Oh yeah, but I will have dark chocolate. You know, I'll have 85% and that has very little sugar. And fruit I eat and it's got sugar and I'm well aware of that.

But, you know, yeah, fruit, honey, and maple syrup are where I get my sweets from.

And then I use allulose.

Allulose is magic.

Yeah, it's magic. And, uh, yeah, until it isn't. But I think it's, it's, it's, for me, it's—

I would agree with you.

A very important player.

As a— call it artificial sweetener. It's not actually an artificial sweetener.

It's actually natural.

No, I don't want to call it an artificial sweetener.

But it is, it is manufactured.

Alternative, whatever you want. 'Cause I don't want to throw it in there with aspartame and all that other nonsense.

And I think that perhaps monk fruit's innocuous. I'm not a fan of the aftertaste of stevia.

They cut it a lot with erythritol, but the pure monk fruit, I don't know.

Yeah, and I think the data relating higher levels of erythritol consumption to cardiovascular risk is real.

I read that study.

But, you know, if you're chewing erythritol-sweetened gum, I can't think you're getting a huge dosage of erythritol.

Right.

But if this is compared to sugar, then you've made the right choice.

Right.

So, oh, but it's natural. It's cane sugar. It's coconut sugar. Call it what you will, it's sugar. It's sugar. And, oh, but it's organic and somebody, you know, put crystals over it, whatever. I don't care. It's sugar. You gotta stop.

Right.

And gosh, this Dr. Perlmutter is a pain in the ass, isn't he?

Yeah.

I mean, he's making you do— and the reason I am this pain in the ass is so that when you're my age, you'll be able to have hopefully what sounds like an intelligent conversation about intriguing topics, and you'll be able to satisfy your curiosity, remain curious, remain engaged. You're doing your best to keep your children—

And remain independent.

And remain what?

Independent.

Independent.

That's the thing that I, you know, my heart bleeds so much for my parents is they're losing independence.

Losing agency.

Yeah, and losing agency. And, you know, and that to me is, you know, the definition of, you know, your life's decline. I mean, most of us, I think, if we had the choice of lifespan or healthspan, would say, I want the longest lifespan with the longest healthspan. But as my healthspan starts to go off a cliff, you know, there's not a whole lot of joy to derive out of life.

Yeah. And, you know, the worst situation is people who remain kind of physically in fairly good stead, but cognitively decline. And it's just tragic.

Yeah. So first of all, I agree with and love everything you've said so far.

Uh-oh.

Yeah, I do. I mean, I'm in the middle of a podcast. So I got a good score going into the final here. Yeah, you got a good score. I mean, double score.

Double point questions are coming soon.

Great score.

The bonus questions.

Um, so any, any other supplements? And then I want to shift to some modalities. I actually want to get your opinion, uh, right out in the open on, on some of the things I'm doing for my mom, which include, um, transcranial red light, uh, which is saturating her brain with red light, certain wavelengths of red light known to be therapeutic, specifically the ones that dissociate Mitochondrial nitric oxide from cytochrome C oxidase to force oxygen, for lack of better words, into the mitochondria to change this metabolic cycle of the mitochondria.

I wrote about them. You did? Oh, it's red lights in the book.

Okay, great.

But, you know, it may seem hokey. It isn't. We are, you know, we see what it's doing in laboratory animals, that it is able to penetrate into to the brain, that it is powerfully effective in terms of what you just mentioned, in reducing inflammation, which from a microglial perspective is a home run, right? And enhancing mitochondria.

And directly targeting the mitochondria. It's hard to target them, right? You know, to just select the mitochondria, 'cause there's a long distance between, let's say, oral supplementation and getting through the mitochondria and getting into one of those stages of the Krebs cycle electron transport chain. And, and light, uh, can do that. I mean, it ignores the cell wall, ignores the mitochondrial membrane, and, uh, goes into certain complexes and, and actually exerts a measurable effect.

Well, that's what the, uh, the beauty of one of the things I mentioned earlier, this RNS60, instantly just transgresses, makes its way of the mitochondria.

What was the RNS60?

So RNS60 is a nanoparticle change of saline, normal saline, hyperoxygenating normal saline. Clinical trials so far in ALS extending life by 6 months, but dramatically preserving respiratory function and speech. Pretty significant, I'd say. Cutting hospitalization time in half in individuals who've experienced a stroke. Wow!

Yeah. And where do you get this?

Well, this is experimental.

Oh, the company's going through trial.

No. Well, it's being used for developed for scientific research, though that may change.

Can you?

One would hope.

Can you get a hold of it now? No.

No. It I.

You have it though. Ah ha ha ha ha! Oh my God!

Am I true?

Bust. Busted. All right, we'll talk after the podcast.

Um, but, uh, having said that, um, the company is called Revelacio. Revelacio.

Revelacio.

And their, uh, their science is just so forward-thinking. Yeah, very, very exciting.

And, you know, hyperoxygenating saline. So, um, just trying to think of the mechanism there. Interesting.

Yeah. Um, but, but I mean There are protocols now being done in humans to transplant healthy mitochondria into humans. The first studies were in children who have had required heart surgery and couldn't come off what's called the ECMO pump, the oxygenation pump afterwards. By transplanting mitochondria into their hearts, have had a dramatic increased ability to come off of ECMO and survive.

Where do they get the mitochondria from?

Well, they are developed. Taken from the leg muscle, actually.

So you relocate mitochondria from functional areas of the body.

Right, spin them down and then into—

Hypofunctional areas.

Can you imagine?

That's what we're talking about.

The idea of transplanting mitochondria into the brain. I mean, you know, we're scratching our heads right now thinking, oh my gosh, could that ever happen? Look what's happening right now.

Well, it's so small. I mean, right through the cribriform plate or some kind of intranasal?

Through the cribriform perhaps, but I would think first it'll be injected into the brain. into the ventricles, into the spinal fluid itself. But there are— but using the cribriform for this monoclonal antibody, this faralumab that's being developed at Brigham and Williams. Brigham and Williams.

It's small enough to pass through?

Oh, it's a monoclonal antibody. It makes its way right through, yeah. There's a lot of things being delivered via this nasal, even exosomes now. But that said, even microglia, healthy microglia, are being created from stem cells and through CRISPR intervention become microglia, the M2 supportive microglia. And already a human trial has been undertaken for not— it's a different ALS, not the one you're familiar with, called ALS-D, which is almost uniformly a fatal condition and basically has arrested the disease by giving them healthy, good functioning mitochondria.

Hmm.

It has been defined as a A defect of microglial function by giving them healthy microglia. Let me make sure. I think I said mitochondria. Yeah, by giving them healthy microglial cells into their brains, basically saving these people's lives.

Wow.

Pretty astounding.

And again, where are they getting the microglial cells?

So these are created from stem cells, basically. Wow.

That is so fascinating. I'm a big fan of exosomes. Especially because of their particle size, about 1/800th the size of a stem cell.

Yeah. And recently a study was published where exosomes were created from human cells that were like microglial cells, but just a little bit earlier in their development. From these human cells, exosomes created, administered intranasally to the laboratory mouse model of Alzheimer's disease, and having really a profound effect on on reducing beta amyloid load. And we talked about why that may or may not be critical, but also improving their cognitive function, preserving their cognitive function by giving them intranasal exosomes derived from human microglia, like human-like microglial cells.

So your position clearly is Alzheimer's is something that is highly preventable given the right lifestyle factors. And may have some very, very promising treatment alternatives to what's out there right now.

Yeah, and that's right. And I look at what the near horizon looks like and the far horizon, for that matter, in terms of what people are looking at through the lens of these microglial cells to bring about improvement, bring about, I would hope, for a cure of this situation. And again, it's not just that your guest today is saying that lifestyle issues can reduce the risk of this happening. This was published in the journal The Lancet in 2024. The Lancet Commission indicated that if we could pay attention to 14 modifiable factors, that the incidence of dementia could be reduced by as much as 50%.

Wow.

It was an interesting—

I assume that is applicable to Alzheimer's too. I mean—

Oh, yeah. Well, Alzheimer's is the most common cause.

of dementia by far and away.

It was interesting, though, and I've said this before, that they didn't mention diet.

So I wrote—

I, along with a guy, Dr. Robert Lustig, we wrote this letter to the editor of The Lancet and said, hey, here are the multiple studies talking about the various diets, whether it's Mediterranean, Mediterranean Plus, the MIND diet, you name it, and how they play out in terms of dementia risk. So we're sure this was just an oversight. And we got a pat on the back and said, we're not gonna publish your letter to the editor.

Ah, wow.

Okay.

Well, there's a lot of—

Why, you know, why food?

Forces to be out there.

Yeah.

Yeah. Don't want us to think that food is medicine.

Yes. And let me say that—

Exercise is medicine.

We've talked about the broad strokes. I'm happy if that's the only message that lands, 'cause it's huge. Exercise, diet, sleep, being in the presence of other people. Not often talked about as a huge issue, but when you go back to the Blue Zones, those who live the longest and the healthiest— isolation is a major risk for developing Alzheimer's disease. Don't be isolated. And if your elders are isolated, do what you can to make that not happen anymore.

I couldn't agree more.

Even if it's virtual. Even if it's virtual, even if they have a pet. Looking into the eyes of a dog has powerful effects on your microglial cells.

Wow.

Think about it. That's why I was greeted when I walked in here by your dog.

Yeah, yeah.

And I felt, God, you're catering to my microglial cells.

Yeah, that was, I got hosed in that one. I lost that battle. My youngest daughter convinced me that we were sheltering, like we were fostering. That was the term she used. We got it from the shelter. We were going to foster it for like 2 weeks, and then it never works. It's going to go to another home.

That never works at all.

That's been what, 6, 7 months now? 8 months?

No, I'm glad to see that you have a dog. It's great.

He's here now permanently. You know, we've seen him. He's a Staffie. He's a great dog. Oh yeah. Looks like a pit bull, so he looks very scary, but he's just a giant teddy bear.

He jumped up on me.

I thought it was great.

Licked me. Yeah, that's all good.

He's a teddy bear.

How does it work? Well, we could talk about lack of social engagement. Isolation amps up cortisol. Cortisol is immediately and directly threatening to the health and mitochondrial function, I might add, in the hippocampus, the brain's memory center itself.

Fascinating. When we were in the— this is going back years, but in the mortality space, We knew that isolation had a dramatic— there's a lot of data around this, by the way.

Oh, yeah.

A dramatic effect on lifespan. I mean, we know about broken heart syndrome, right? I mean, you show me a couple married 40, 50, 60 years, one passes away, the other one usually goes very quickly. And when we had these second-to-die policies or permanent universal life policies, We had a lot of data on isolation, and it accelerated all-cause mortality. And you know what else? Anecdotally, when you think some of the most horrific crimes, you know, when you read the paper and you're like, who was that committed by? Oh, that was a kid that never talked to anybody. He was the most isolated, never came out of his room.

And he always kept a clean room.

Yeah.

Did you ever notice that?

Yeah.

So they interview somebody, you know? Yeah.

Yeah, so the isolation is a major factor. And you're right, the Blue Zones, community connection, prayer.

Yeah, I mean, that's what Dan Buettner called out. It's not a pill. It's not a specific dietary recommendation. Yes, these people felt engaged in their communities and it's huge.

They also felt a purpose, you know, like, why am I here? When an elderly person is just sitting around alone all day for days on end, my grandmother's sister was like this. They're just alone in their own thoughts, and they got to think, why am I here?

It's hugely distracting. We could talk about mechanistically what may be going on. Well, we know that that's a stressful situation. Cortisol levels go up. As I mentioned a moment ago, threatening directly to the hippocampus. Dr. Robert Sapolsky talked about that 25 years ago in primates who constantly were under threat, looked at their hippocampus after postmortem, and they were shrunken.

Yeah, that's memory.

But beyond that, what's the upside here of engagement? What happens when you're with people and looking them eye to eye, as you are right now? My oxytocin level, my love hormone, is going Right. And oxytocin is bound to the supportive microglial cell and tells them, you better just stay in this M2 configuration and be a brain defender. So you right now are keeping my microglial cells, along with your dog, I might add, in their supportive role because we are in a situation where we're feeling good about each other. We're having feelings of love and because we're doing good things. And so, you know, if you have to break it down to mechanism, okay, there are some mechanisms, but we just inherently know that to be true.

Yeah.

If you ever watch Alone, you watch that TV show Alone? I've seen times when, my gosh, there's a contestant and it's who can last the longest on their own. I mean, these people build musical instruments, a canoe, a house, you know, a hot tub, all these things they're building. This guy's gonna win, home run, he's great, you know? And the next thing you know, he says, look at all this stuff I've built, I can't take it anymore.

Yeah.

He pushes, he calls them the next day and they pick him up.

Yeah.

Because it's just very, very stressful to be alone. And again, it can be virtual, but we've gotta keep people in the loop.

Yeah, love it. Dr. Perlmutter, This is amazing. My VIPs are, are, uh, waiting with a whole list of questions for you because I told them that, uh, told them that you were coming on the podcast. So we're gonna, we're gonna head over there to the VIP group. But before we do, I end all my podcasts by asking my guests the same question, um, and that is, and this can be an interesting answer coming from you, what does it mean to you to be an ultimate human?

To be an ultimate human means to identify Your skill set and exploit it to its fullest.

Wow. That's probably another way of saying fulfill your purpose.

Exactly.

Right? Your skill set.

Identify it and fulfill it.

Identify it and fulfill it. That is one of the most succinct answers I think we've ever gotten.

Well, I think that everybody has something.

Yeah. Well, this has been a great pleasure for me. Uh, really, 2014 was a game changer for me when I read your book. It really had a long-lasting impactful impact on my career and was part of.

I'm very, very honored and happy to hear that.

Yeah, thank you. Yeah, it really did. And I'm looking forward to reading this book because it also is very appropriate for the position that I'm in with with my loved ones, and I'm going to share that on the on my platform. But thank you so much for coming on the Ultimate Human Podcast.

Lots more work to do.

No, no, no. I'm gonna I'm gonna have you back. I mean, especially as I get through this book, I'm gonna have a whole nother podcast full of questions.

Yeah, sure.

And until next time, guys, that's just science.