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Josh Dech - CHN (01:10.671)
Dr. David Perlmutter, welcome to the show.

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David (01:20.354)
Yeah.

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David (01:29.336)
Great to see you again, Josh, and I appreciate you having me. Thank you.

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Josh Dech - CHN (01:32.751)
it's always a pleasure when we get a chance to connect. You know, we had met last at eudaemonia and it was part of that short series we had filmed, but it just wasn't long enough. I know because we only had a limited amount of time. We had to really cut that down, but I'm looking forward to expanding on all these things today. Now, last time we spoke, David, we got into the primary factors that lead to disease. talked about sleep, food, exercise. We even got into the body and its ability to really heal itself.

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and really into the brain-gut connection. But we talk about gut-brain, I think so much of the time we say, okay, well, it's connected. We understand that, because we hear the word gut-brain connection. We don't really know what it means. Now, we touched into that last time, but for those who may not have heard the episode or if it's been a few months, can you give them just a quick refresher on the gut-brain connection and how it actually works?

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David (02:28.824)
Sure, I think that a lot of people talk about the gut-brain connection. It's certainly part of our parlance these days. Just the notion that we are having this conversation, to me, I think is a little bit strange. In the context of the fact that we all grew up understanding that the gut is over there and the brain is in another area and gastroenterologists and neurologists have nothing to talk about because they're totally different disciplines.

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And it's a bit of a Cartesian way of looking at the human body, and it just isn't going to serve us any longer to consider these disparate parts. So the gut is highly influential in terms of what the brain is doing at any given moment. And beyond that, what's going on in the gut clearly is deeply involved in charting the brain's destiny as it relates to cognitive preservation.

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or putting an individual at risk for cognitive decline or motor decline as it relates, for example, to Parkinson's or any number of other issues, even mood disorders, for example. So, you know, across the realm of motor issues, cognitive issues, neuropsychological issues, et cetera, this intimacy between gut and brain, I think, is vast and...

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beginning to be well understood and understood in a way that it is very empowering for, I think, healthcare providers and patients alike in that this understanding is paving the way to really meaningful interventions, taking full advantage of this connection between things going on the gut and the issues that I just mentioned, to bring about healing, to bring about improvement, and to bring about

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you know the ability for people to better experience the the gift that they've been given you know this wonderful life

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Josh Dech - CHN (04:20.867)
Hmm, that's a beautiful way of saying it. I think it's something we take for granted, that the body kind of just works. know, so many of us spend so much time just, we wake up in the morning, we breathe without thinking, our heart beats without thinking, we go about our day, we eat when we're hungry, we drink water when we're thirsty, and our body just does things on autopilot without much of a consideration. But the problem we run into is in a modern industrialized world, where we're also putting things into our body without the same consideration.

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and it leads to these degenerations, these disease processes. And I mean, we know what 90 % of our neurotransmitters come from the gut. So your brain and your gut are connected that way. There's a bi-directional vagus nerve that we talked about on our last chat as well, where there's communication both ways. And we had a chance to even speak to your son Austin, and he was talking about how food and nutrition, these nutrients actually work as almost programming, like software in a computer.

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for your gut and your brain and your microbiome. And these all happen without our consideration. But we're at a stage now in the modern world with this, since the industrial revolution, you could argue, we have to make these considerations and be more aware than ever before about our body working on its own because it's no longer working the way it should. So what are the biggest factors right now that you see? I we know sleep, exercise, diet. Those are some of the ones that we need to be doing.

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Do we want to elaborate on those a little bit deeper or do you want to scratch the surface on the big factors?

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David (05:49.688)
Well, I think we could spend hours and hours on any one of those, that's for sure. But I want to go back to something you said just a moment ago, because I think it's awe-inspiring. And that is that this whole system works. mean, when you deconstruct so much of what we're involved in as scientists and look at these very finite pathways,

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and that they're always operative and they're always in balance and being affected by external stimuli and yet coming back to balance gene pathways, gene expression, changing from moment to moment, how refined things are that allow us to be healthy at any given moment, it's mind boggling that it works at all. I just can't get my arms around the fact that it's...

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Josh Dech - CHN (06:37.443)
Shit.

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David (06:42.306)
You know, that if you cut your nail, it's gonna grow again and you cut your skin, it's gonna heal. It's mind boggling. You know, there's so many considerations. I don't know where to begin. But I think that the issues that you mentioned are all important because these are issues over which we have control. Our sleeper exercise, our food, our connectivity, our socialization, our exposure to nature. All of these things are issues that are...

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Josh Dech - CHN (06:45.539)
Hmm.

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David (07:07.554)
highly influential in terms of our health destiny and importantly our issues over which we have dramatic control, i.e. we have, we're holding the reins of controlling where we're going to go. We are the architects of our health destiny, of our brains destiny. For me as a neurologist, to be having a conversation about the fact that we are controlling our brains destiny is a bit further in terms of a stretch in

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for people who don't even get the fact that you know these issues that you mentioned these lifestyle choices are charting your physical destiny well you know for 25 years we've heard of a heart smart diet people have kind of gotten that memo that okay whatever I eat it's going to affect my heart or weight-bearing exercise going to affect my bone density in the case of women men and women of course so I think those are the inroads to understanding the effects of your lifestyle choices on

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health and as it relates to bad choices, cigarette smoking, not wearing a helmet when you're bike riding, all the things and not being an unrestrained passenger, et cetera, and how that threatens your health. think people get that. But when we start talking about lifestyle choices affecting the brain, it takes people to ice that's perhaps a little thinner. It's getting thicker by the year, but it's still an area where I think.

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because of the fact that the brain has seen some, or the mind, let's say, is seen to be separate from the body, that people don't get the fact that the brain is made of stuff, and the stuff from which it is made are the stuff, the things that we supply for that to happen. But I think there's always been this dichotomy between brain and body.

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And therefore the idea that body choices are going to be reflected in brain health and brain resistance to degeneration is a little more of a stretch, it's, I wouldn't say it's nonetheless relevant. It's more relevant because it turns out that the choices we make related to the parameters of sleep and diet and exercise and others.

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David (09:21.792)
are more reflected in brain health and functionality than they are acutely and long-term in other body parts. It is an area that's far more sensitive, therefore, to the lifestyle choices that we make, number one. And number two, it's an area that, and part of our anatomy, for which we've not developed those pharmaceutical or other technological interventions to be as helpful as we can with a pump.

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the heart or knee replacement for the knee. We don't really have much technology or pharmaceutical intervention with respect to the brain. And yet it's more sensitive to the lifestyle choices we make. Therefore, there's so much justification in the work that you do and others in this area in terms of trying to get the message out that, hey, there is not a lot out there that

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mainstream is going to offer you to help you with said problem, be it Alzheimer's, Parkinson's, MS, whatever it may be. On the other hand, guess what? Here's the upside is that, gosh, the brain is more sensitive and responsive to interventions based on lifestyle choices than any other part of your body. So pay attention.

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Josh Dech - CHN (10:24.162)
Hmm.

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Josh Dech - CHN (10:41.078)
Hmm, it is remarkable. I wanna back up to the conversation we had before launching into here where you said it is amazing that it kind of just works, almost awe-inspiring. And it does, it really connects, it's like this domino effect. This whole conversation we just had the last few minutes branches off of it's amazing that it just works. Because all these impacts that we're talking about, the food, the imprintation on the brain, its neurodevelopment, how that all connects and how it all works together is like a series of dominoes.

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It almost reminds me, did ever play the game Mouse Trap? We have to, right, you have to set it up and put all the plastic pieces on the board. Milton Bradley. But it was one of those games that I tried to set up when I was little. And if there was one thing mechanically not working, the little contraptions wouldn't work the way they're supposed to. And the body's got this really complex version of Mouse Trap, where everything works. It's like when you tip the domino, one thing rolls to the next and the marble rolls down and the trap falls and it all just works. But...

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David (11:14.102)
Yeah, sure. Milton Bradley.

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Josh Dech - CHN (11:41.738)
We look at disease, you we're talking about things like Alzheimer's, Parkinson's, things we've mentioned here so far. These are diseases that people get and we go, well, it's just genetic. Or well, you are bound to, it's in your family history. There's really no control over it. But realistically, these are diseases we started contributing to 30 years ago that today finally manifested as a symptom that the body was no longer able to keep up with. It's like there was a fire burning. We had these fires in Alberta all the time.

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They're actually like underground fires, but when it gets hot enough, they finally come to the surface. Zombie fires, that's a great term. I've never heard that term and I live here. so that's, sure, we get the idea, but they don't manifest until it's basically too late. And I think that's what's happening with lot of disease. So take me down the path of neurodegeneration, brain diseases that start early on. What are the first factors?

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David (12:14.904)
zombie fires.

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David (12:19.458)
That's what they're called. I guess a colloquialism obviously, it, you know, they're always there. They're, yeah.

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David (12:38.542)
Well, let me use an example of a heart attack. You know, what a heart attack is, is you're walking down the street, minding your own business, whistling a tune, and you turn a corner and you get attacked by this thing. The heart attack strikes you in the chest and down you go. Out of the blue. Well, the reality is, and that's dramatic, and that's what happens, and 50 % of these people don't even survive it.

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Josh Dech - CHN (12:40.618)
Please.

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David (13:07.022)
But the reality is that those coronary arteries have been narrowing for decades, right? That plaque has built up for decades and finally reached this tipping point where it just couldn't pervade that part of the heart muscle and down that person goes. And it's the same thing as it relates to Alzheimer's, although the presentation isn't as dramatic and sudden, that the seeds are sown for that brain degeneration 20, 30, 40 years in advance. And these are metabolic issues that begin to occur in the brain

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that can be described, that can be evaluated, and can be determined that indicate that that individual is going down the path of ultimately having Alzheimer's disease without question long before that person has cognitive or executive function type issues, memory and executive function issues. That's when we're told, we should start taking interest and go to the doctor because now,

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You can't remember your grandchildren's names, you're misplacing things, you don't remember how to do various things around the house. something's wrong with dad. Let's take him or mom to the doctor because something's not right. Well, at that point, that's when you're noticing something's wrong. call that subjective cognitive impairment. When you go to the doctor and she or he examines you and performs a neurocognitive assessment determines whether you do or do not have

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The next step, is mild cognitive impairment or MCI, and that is the harbinger to ultimately having full-blown dementia, most commonly Alzheimer's disease. And that is looked upon as being a continuum, which we should challenge later on in our conversation. But that said, as I mentioned earlier, those seeds are sown metabolically in the brain 30 years prior. And you can evaluate that activity. You can look at brain...

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Josh Dech - CHN (14:38.559)
Hmm.

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David (15:01.034)
utilization of glucose as a substrate and find that long before there are issues related to deficiencies of cognitive function, that brain energetics are starting to decline, that the brain's ability to utilize glucose, doing a fluorodeoxy glucose PET scan, a type of PET scan that measures how much glucose the brain is using. And oddly enough, what you'll find is there are deficiencies in the Alzheimer's of areas of interest in the temporal parietal regions.

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And also that the amount of glucose in the brain is actually higher than in the control. The glucose is there, but it's just not being utilized. It's a metabolic issue, presaging the development of Alzheimer's by 20 to 30 years. In a presentation, actually I gave at the conference where I saw you, I put up a slide that was, I pirated from the Alzheimer's Association, which looked at the continuum.

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And on the far left of the screen was patient begins to notice some cognitive issues. The next panel was family begins to notice cognitive issues. The next panel was patient presents to his or her family doctor. Next is referred to a neurologist. Next is gets neurocognitive testing. And on the far right of the screen is patient begins intravenous therapy for Alzheimer's disease. And what I did was I said,

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This is what we are, this is our belief system. Live your life come what may, and when you're cognitively impaired, we'll fix it with some intravenous drug. We might have a chance to talk about that at some point, but, and I moved the whole thing over to the right and stuck a new panel in on the left side of a guy running, cartoon character said, I'm cognitively intact, and I plan to keep it that way. Thank you very much. Because that's where we need to be involved.

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We don't need to be reactive. We need to be proactive, preventive. And, you know, people talk about, you know, maintaining your blood sugar and doing things good for your heart, cardiovascular workout, et cetera. But everything I just mentioned is exceedingly impactful as it relates to your brain's destiny as well. So we very much fully identify.

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David (17:25.302)
those issues that set the stage for brain degeneration versus not. Is there a genetic component? As there is with every degenerative condition, the answer is yes, of course there is. But we're now much less involved in thinking about these genetic risk markers for Alzheimer's in comparison to where we used to be. The APOE4 allele, for example, the PreCynilin-1, a genetic marker. We know that these are issues

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related to increased risk. But we're now at a place that we can understand how these genes influence brain health outcome and where we can intervene to offset this genetic predisposition. So we're moved away from genetic determinism, you got the gene, you're going to get the problem, to a sense of genetic predisposition, meaning you're predisposed, but hey, here's what we're going to do and we're just going to chart you a different future.

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Josh Dech - CHN (18:23.452)
It really circles back to the idiom that genetics load the gun, but your lifestyle pulls the trigger. That's going to determine.

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David (18:28.994)
Absolutely, and it relates to the brain. It's so clear that that metaphor is very, applicable because even this morning I was reviewing a study that was just published last night that showed that we now fully get one way, probably one of the most influential ways that the so-called APOE4 allele, I hate to call it the Alzheimer's gene, but that's what it's been called, how

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one of the important ways that it works and that is through changing the activity in the brain of a particular type of immune cell called the microglial cell. This is a cell that exists in your brain in what's called the M2 phenotype. That'll become important in a moment. So when it's in its M2 phenotype, it's nurturing your synapses, it's helping you grow new brain cells, it's nurturing your neurons, it's shoring up the blood brain barrier.

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It's gobbling up misfolded proteins and bacteria and viruses. It's just your best friend. It's doing everything you want to do and paving the way for you to have a healthy brain. However, it has an evil twin and the evil twin, M1 phenotype, when that is active, it's digesting away your vital brain connections, one to the next called the synapse. It's reducing your formation of new brain cells.

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threatening the health and viability of the neurons that you already have. It's setting the stage for damage to the blood-brain barrier and it's deciding it's not going to gobble up these misfolded proteins and bacteria any longer. It's definitely the evil twin. Now the APOE4 gene predisposition for Alzheimer's tends to favor the shift from the good twin to the evil twin. But now we understand

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a whole host of factors that can offset that. How can we take that evil twin and say, uh-uh, this is not going to be how it's, what our future is going to be. You're going to go back and you're going to learn how to be a good, a good microglial cell. And here's what we're going to do. And there are a variety of interventions now that actually reprogram that microglial cell back to being the good twin and set the stage for, for a better brain, for reducing our risk for Alzheimer's, to reducing

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David (20:50.764)
the impact of certain genes that may otherwise manifest as disease.

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Josh Dech - CHN (20:58.306)
I want to come back to this because I think this is a really great opportunity to move backwards where you mentioned the Alzheimer's continuum in this chart that you had at the Unimonia Summit and you showed this continuum as it is where you come in, you get your symptoms, you bring it to the family, to the doctor, you get your neurologist, your treatment, et cetera. But you said something interesting. You said Alzheimer's is not a continuum or you want to challenge that notion and the treatment process

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was also defined as a continuum. So if our treatment process is a continuum, but the disease itself is not, therefore the disease can't, or the treatment can't match the disease. They're not gonna match. It's a puzzle. doesn't fit. So when you say Alzheimer's is not a continuum, or you wanna challenge that notion based on what we know about the good and the bad, the twin cells and what's attacking you, what's not, can you define Alzheimer's as a continuum or not and help us sort of unpack this, what you mean?

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David (21:53.408)
think that by and large in our understanding of Alzheimer's it is a feed forward cycle that does continue as a continuum does continue to lead to further degradation of the brain and decline in functionality. That's typically what we see and typically what I think people expect when a loved one has been given the diagnosis. We know nowadays

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that we were told that there are alternatives to that hypothesis and we'll explore that in just a moment. But I think that when we look at how mainstream explains that continuum, it's explained by focusing on the brain's accumulation of a particular configuration of a protein called beta amyloid and the accumulation of this beta amyloid over time tends to foster further and further

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brain degeneration. turns out that's interesting, but it's not what's going on. And yet, billions of dollars have been spent developing drugs to reduce the formation or even get rid of the beta amyloid in the brain. And these drugs, several have actually received FDA approval and are being used in treating patients with Alzheimer's disease.

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under the flawed notion that this is the cause and will therefore be the cure of this disease. If that were true, then the drugs would work. The drugs do not work at all. There is some mild slowing in the rate of decline, which could be a consequence of other things that these drugs do. But basically in an 18 month trial, the rate of slowing,

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gave people another maybe couple of weeks difference at the end of the trial in the face of 100 % of treatment group having significant shrinkage of their brains, number one. And number two, as much as a 28 % increased risk of bleeding and other changes within the brain called area, amyloid related imaging abnormalities. That said, it violates what we call the risk benefit.

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David (24:15.926)
ratio, it violates what we call above all do no harm. And it's a flawed notion of just focusing on this beta amyloid as being the cause of this disease. We started our conversation with a discussion of the metabolic issues going on within the brain long before there's cognitive decline, long before a patient would ever present to a doctor. That should be our concern that this metabolism

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is threatening the brain and you know metabolic issues are rampant more than ninety percent of american adults has at least one metabolic issue that's out of out of whack if you will meaning that less than ten percent of american adults are metabolically intact elevated blood sugar elevated blood pressure central obesity or increased abdominal girth dyslipidemia elevated triglycerides these are issues that threaten the brain

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certainly the insulin resistant part and the elevated abdominal girth as well. And that said, these are issues for which we should be really rallying the crowd to become aware of long before cognitive decline begins. That's when mainstream medicine is stepping in, when you've already got the problem and it's feed forward, it's making itself worse. Once these...

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healthy, wonderful microglia cells shift to becoming the evil twin and are digesting away the synapses, digesting away the neurons, letting more beta amyloid accumulate. Once that happens, it fosters more and more of these microglia cells joining that side of the war, becoming participants in the destruction. Which is why when you are following an Alzheimer's patient clinically, as we do,

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We see that they stumble along, they're declining month after month, and then suddenly they fall off a cliff with respect to their cognitive function. They just get to a point where things just suddenly gain momentum and they lose cognitive function at a rapid rate. We see that both in the untreated as well as in the patients who are treated with these so-called Alzheimer's drugs. They both fall off the cliff. The cliff is a couple of weeks down the line in the treatment group.

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David (26:41.752)
But so what? mean, that versus the side effect profile. So my point is that we've got to look at brain metabolism as being an inroad to rerouting those bad microglial cells back to being healthy. And we're already seeing research demonstrating that that's certainly able to occur and that cognitive function can be restored, can improve when things like the microglial cells are targeted.

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Josh Dech - CHN (27:13.162)
And that's an interesting question to really bring up is what can be improved, how much can be improved. Alzheimer's, like any disease I'd say within the Western world, we'll say allopathic medicine diseases are inevitable, they're innate to your biology, there's nothing you can do. Once you get them it's genetic and all we can do is slow your decline with drugs. What you're suggesting is taking these microglial cells, shifting them back from bad twin to good twin.

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and sort of reducing the buildup of these beta amyloids, which are continuing, which they say, well, here's your problem, but you're saying it's not. Then the IV drugs don't work. And then it was something interesting I had read a while back that in 2016, they put a whole bunch of money, billions of dollars, was $2.6 billion to research. And there was a doctor who was actually caught defrauding.

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his studies, he published something like over a hundred studies and he manipulated images and all kinds of stuff to show that it was working to get this funding and now it's not. So we have all this research that's now in question. What you're saying is it doesn't really matter anyway because the theories they were running on may not be correct, that it may be a reversible process. So I'd love to ask, go ahead.

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David (28:27.63)
No, I was just gonna say, so he had published many, you're right, hundreds of articles, but the one in question was reviewed and indeed they photoshopped the images that really were kind of foundational to this whole beta amyloid theory of Alzheimer's disease. Other studies certainly have demonstrated that there is a relationship between the accumulation of beta amyloid and risk of.

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brain degeneration. There are countless patients with incredibly high amounts of beta amyloid in their brains who are cognitively intact. And there are countless patients who have been diagnosed with Alzheimer's who don't really have much beta amyloid in their brains as well. But there's clearly a relationship of beta amyloid as a consequence, however, of what's going on in the brain metabolically. So again,

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The degradation of the beta amyloid in the brain normally happens when these microglial cells are in their happy M2 phenotype, gobbling it up. We call it phagocytosing the beta amyloid and getting rid of it and paving the way for a healthy brain versus the M1 angry evil twin who lets that amyloid accumulate. that is upstream of the accumulation of beta amyloid and importantly, and again, we're targeting beta amyloid in these.

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in these drugs that we've talked about. But importantly, the main thing that determines friend or foe with respect to these microglial cells is their metabolism, meaning their mitochondrial function. So at the end of the day, or beginning of the day, the function of the mitochondria, the energy production within these cells is the determinant of their mission.

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of what they do day in and day out and your brain's destiny. It's all about their mitochondria. So, you know, for years, all the interest in the brain has been on the neuron. And, you when we say, the brain uses 25 % of your total energy, although it only weighs three to 5 % of your body weight, all good because neurons are so metabolically active. Well, guess what?

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David (30:45.78)
So are your neuroimmune cells, which 10 % of your brain's volume, your brain cells are made up of these microglial cells. So having said that, when we target brain metabolism as a way of improving brain functionality, we're also targeting the brain's immune system such that we are paving the way downstream for less accumulation of beta amyloid, less inflammation, better brain energetics,

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preservation of the blood-brain barrier, preservation of our precious synapses, and the growth of new brain cells by targeting brain metabolism. And that means body metabolism.

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Josh Dech - CHN (31:27.608)
Well, that actually branches into where my question was going to go is that, you know, we look at gut, for example, there's a lot of really great natural practitioners in the world of gut health who look at this and they say, let's do a stool sample. We'll look at your microbiome and if it's messy, we'll fix it and that'll fix your problem. But upstream, the question we have to ask is why did it get screwed up in the first place? And in the same way with Alzheimer's, like you're talking about these beta amyloids accumulating, that's...

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one of the factors, but we have to go upstream further what caused that to accumulate and then we can keep going to the 30, 40 years prior. So you're talking about the regeneration of brain cells and brain tissue. Now I'd say, I don't want to speak for everyone, but in general, it's one of those things that again has been considered to be an inevitability. Your brain's done, it's done. You've lost what you've lost. But it sounds like you're suggesting that Alzheimer's and Parkinson's and other neurodegenerative conditions

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are in fact reversible when your body is given the tools to begin repairing or reversing that disease process. One, is that accurate? Two, what have you seen in the reversibility of these diseases?

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David (32:32.194)
Yes.

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David (32:35.662)
Well, there's a lot to talk about here. So let's just focus for a moment on the notion of the role of metabolism in brain health and disease. We've unpacked a little bit the role of metabolic issues as it relates to making a good brain go bad in the case of Alzheimer's disease. When we talk about metabolism these days with the general public, we're talking about things like,

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let's say diabetes and obesity. you talk to anybody on the street, what's the news about obesity and diabetes? The first thing they're going to talk about is ozempic, right? That's the hot topic. Or maybe a little bit more broadly, the whole notion of GLP-1 agonist drugs of which ozempic is one. Because these drugs are targeting metabolism in an extremely aggressive and positive, I must admit, way.

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So the question would then be, there any, why would we not want to at least look at improving body-wide, including brain-wide metabolism? Because we have GLP-1 receptors on neurons and microglial cells. What would happen if we were to use GLP-1 drugs in an interventional way in, let's say, Parkinson's disease? Well, this was published in May in the New England Journal of Medicine, a study of just over 106 patients, randomized.

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control study, daily injection of a GLP-1 agonist or not followed for three years. These individuals were followed on what's called the Unified Parkinson's Disease Rating Scale. It's a kind of a standardized scale that looks at mobility, requirement for assistance with activities of daily living, just how's the patient doing on the scale. More higher numbers on the scale means worse.

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You don't want to get a high number on that study. We use it for our intravenous glutathione study, same scale. The people who were not treated declined about three points on the UPDRS scale. That's what you see with Parkinson's. As time goes by, even though the insult may not be there anymore, they continue to go downhill. Look at Muhammad Ali. He wasn't boxing anymore, but he continued to go downhill as it relates to his Parkinson's. We see that.

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David (34:59.18)
people who got Parkinson's from a drug exposure. No more are they exposed to the drug, but they just keep getting worse year after year. So again, it's this feed forward cycle of those microglial cells going from M2 to M1 and the M1s are making every microglial cell into an M1. So if we fix metabolism, what might happen to these people in this study? And remarkably, Parkinson's was arrested, stopped dead in its tracks.

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in the people who got the GLP-1 drug.

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Now, I bring this research to your attention not to be indicative of the idea that, ozempic for one and all, especially for Parkinson's and Alzheimer's, but it tells us importantly that metabolism is really something we should be paying attention to. I've never seen anything do that to Parkinson's. It is the first time I've ever seen something target the fire, not just the smoke. Yes, we have drugs for Parkinson's symptoms for

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for rigidity and the anticholinergics for tremor, levodopa to ostensibly put back the missing chemical, the dopamine that's reduced and get some symptom improvement. But this targeted the actual underlying problem and that's great. I mean, I was very excited to see that, not again to indicate that we should be putting all of our patients on

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GLP-1 agonist, though I'm not saying that's necessarily the worst idea, but the one that they use happened to have better blood brain barrier penetration, the liraglutide. But having said that, we've seen similar compelling results in established Alzheimer's patients, and also one interesting study that came out quite recently looked at...

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David (36:53.186)
looked at over a million individuals, followed their medical records over three years, and found that in individuals who were diabetic, the risk of developing Alzheimer's was between 40 and 70 % reduced in those individuals who were taking a semaglutide, ozempic, versus those who are on other treatment, like insulin or other types of treatments for diabetes. So again,

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You know, this is not, the other drugs like insulin are focused on mostly lowering the blood sugar, but we know that these GLP-1 agonist drugs have wide ranging effects on metabolism. So, and again, I'm telling you this because it really drives home the notion that reining in metabolism is going to be good for the brain. We don't need to load everybody up on Ozempic, but we need to get out the messaging that your metabolism is a consequence of your lifestyle choices.

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i.e. the things that you mentioned earlier.

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Josh Dech - CHN (37:55.625)
Hmm. You know, we very much live in the industrialized world where convenience is above all else. We're going to eat like junk and take Ozempic and that'll lose the weight. We don't have to make hard choices. We don't have to exercise because we got liposuction. We've got, you know, ephedrine and other drugs we can use. But I think a really great question to ask because there's, I'd say, two groups of people and all the gray area in between. The one who are hearing this and going, well, all I need is Ozempic.

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Regardless of the fact that we said that's not the case and then you'll have the other group who goes well if those Zempit can fix me that means I can fix me by making metabolic Corrections, so I want to address both these camps so to speak because no matter how many times you say this can be helpful But don't do it someone's still gonna do it and so when it comes down to Adding things into the body like GLP ones different peptides. These are great signaling for your body to do what it's supposed to do however

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When we ran into each other in the lobby the first time at the conference, you had mentioned it can be a bit like a sledgehammer. And so I'm glad we're having this conversation because my thought would be picture you take a fish and you drop it into water and go, that fish would do better with salt water. So you add some salt into the water. But if you keep adding salt into the water, eventually that fish is going to die because it's too salty. So at what point are we adding too much of what seems to be a good thing? Is that once we're symptomatic, is it once something starts breaking down?

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Is it just when we hit the therapeutic threshold and back off, do we go on for a long time? What does this look like to add therapeutic intervention before it's actually problematic?

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David (39:34.99)
The problem is that we don't know the answer to that question. And because we don't know the answer to that question, it directly violates the notion of above all, do no harm. If you don't know, you shouldn't be doing it. The level of GLP, you know, our bodies secrete GLP-1 constantly. It's increased with food consumption. It's part of the whole digestive process.

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allows us to regulate the amount of food that we consume and many other things metabolically. But the drugs are administering to the body and that GLP-1 that we secrete has a half-life of around 10 minutes. When we load the body with these injections, we're giving the body about a thousand fold more GLP-1 at that time and that GLP-1 remains in the body for as long as a week or two. So...

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No one knows the answer to your question, and that's scary. I'd like everything to be okay. I hope everything will be okay. But as James Cameron, the movie director, said, hope is not a strategy. We shouldn't be hoping for this or that outcome. We should know, as best we can know, what to predict in individuals who are on these drugs for 10 or 20 years.

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Josh Dech - CHN (40:32.423)
Yeah.

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David (40:58.772)
And we do not know the answer to that. You know, it's to see the notion that as much as, as many as 4 % of the global population is predicted to be on these drugs for the next couple of years. That's an interesting experiment. That's a large N, you know, and who knows what the outcome will be. But I think your point is well taken, that there are individuals who look at this information and say, therefore, I get the connection with my metabolism and therefore my lifestyle choices.

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And what came to my mind as you were telling me that was I had breakfast at an IHOP of all places in the Keys, because we were going fishing. Well, I'm just, yeah, many, many years ago when I was early on in my career. And I was having breakfast with a friend who for breakfast, this is great, after his short stack with the maple syrup as if it was really maple syrup.

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Josh Dech - CHN (41:37.362)
Speaking of blood sugar, yeah.

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David (41:58.51)
can imagine, had key lime pie, because we were in the Keys, then took his diabetes pill.

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Josh Dech - CHN (42:08.058)
You

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David (42:10.078)
And it just crystallized for me the idea that, hey, do what you want and here's the drug. I don't have to worry because I'm on metformin, so I'm good to go. Doesn't work that way. mean, that's what we're up against, that messaging. And that is a belief that is instilled in individuals. So, you know, people say, well, what is it, Dr. Prometheus? Diet, is it exercise? What is it? And number one, way before any of that is belief.

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Do you have the belief that modern medicine and pharmacotherapeutics has your back and will take care of you? Or is your belief one that says that your choices are really what matters most in terms of your health destiny? That's where we begin.

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Josh Dech - CHN (42:58.065)
So let's talk about that because you know one of the things I love as a researcher, as a scientist, one of my favorite things is talking about the what ifs. Talking about what could be, talking about the problems but one of the things I often neglect to do and this is something I feel I've actually got some great feedback from my listeners, it's so important to also focus on solutions otherwise it's doom and gloom and now the stress stresses your metabolism anyway and we contribute to the issues and here we are. So let's say number one.

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we shift our belief system, the ideology that Western medicine has my back, I can do whatever I want, it's inevitable anyway, let's just take the drugs. We shift that number one and say, I am in charge, my body and mind are working to heal me constantly, they just require the tools to do so, got that. What are the next steps? Maybe let's build a three step or five step program if you will, to say here's how you not only take care of yourself now, but also applicably.

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could begin the reversal of neurodegeneration like Alzheimer's and Parkinson's. What does this step process look like?

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David (44:02.254)
Well, first you have to get your arms around the fact that that is reality. That does happen. We're seeing it happening now with a variety of different interventions, everything from targeting what's called gamma oscillation in the brain with a 40 Hertz light to just some of the work that Dr. Dale Bredesen is doing, hyperbaric oxygen, improving cognitive function, a variety of things that ultimately reestablish brain metabolic health. So that's reality. And I think that

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You know, it's again getting back to people really getting their arms around the idea that that can happen, that that is a possibility, if not a probability, should they engage these choices and these activities. The problem is that who do you trust? And you trust your doctor and you should, but doctor doesn't mean healer. It doesn't mean that's the person who's going to fix your problem. The word doctor means teacher.

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And as such, we should be empowering your knowledge is power, right? So when you're getting information, should be empowering you to go to a better place. That's what the role is. you know, that's what I've, you know, charted to be my destiny as it relates to what I do in my lifetime is to be empowering by giving out knowledge that you can bring in to reality a different

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Josh Dech - CHN (45:07.333)
Mm-hmm.

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David (45:30.936)
via a different belief system bring forth a different reality, a different paradigm where you are making the decisions and watching the outcome. And what is so exciting about the time in which we live is that there are wonderful ways of metricizing these interventions such that you get positive feedback, i.e. dietary change is reflected in my continuous glucose monitor. Wow, look at that, I'm no longer pre-diabetic. Look at my weight.

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A tape measure is an incredibly powerful biometric tool, underrated, right? everyone's got to have all this interface with your iPhone and you're getting constant feedback from your HRV or whatever it may be. A tape measure around your belly, that's very meaningful in terms of your brain's destiny. That's pretty straightforward, as is the bathroom scale. I certainly think that knowing your...

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your CGM results, what your blood sugar is doing throughout the day, not just bursting in the morning once a year, fasting blood sugar. Lots of other laboratory studies that I think are really very helpful as well. But the fact that people can gain access to this information now and then can be given a knowledge base so they know what it means and importantly, how it influences their choices moving forward is a new dawn.

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This is allowing people to be empowered to shift that belief system. As I indicated to me, that's job one.

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Josh Dech - CHN (47:07.117)
Hmm. You know, I think it's, I always get a laugh because we know again, to circle back and beat the dead horse to death, that the industrialized world is the sickest world. And we talk about all this wearable tech and you come back to how simple it can be with a tape measure. Even simpler yet hunter gatherer tribes who don't have obesity, who don't have Alzheimer's and don't have acne and arthritis and all these things that we do, they don't have iPhones and wearable tech. They don't have tape measures. They just...

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do because they're living in such a way that just gets their body to heal and to function. So let's say number one, we shift our belief to say, okay, I need to take agency over my own health while being in my future or recovering from the past that I've had the decisions or whatever, what have you. Then we want to go into therapeutic intervention, for example, especially for acute. You mentioned hyperbaric, there's IV therapies, all kinds of things we can do.

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to give our body the tools in excess to hopefully catch up and reverse the damage. The next we can look at is, let's say lifestyle stuff. So what are the top three things? If you were to say to somebody who's actively got Alzheimer's or has a worry about it in the future, what are the first three things you would have them do to ensure success for their disease outcome?

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David (48:26.062)
This gets back to our discussion on what is now looked upon as really playing that central role in the progression, the initial pathogenesis and the progression of Alzheimer's, and that is this unfortunate shift of these brain immune cells to being the evil twin. That's upstream of the inflammation, it's upstream of the beta amyloid accumulation, it's upstream of the what we call apoptosis or pre-programmed cell death of the

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neurons and upstream of the loss of synapses that characterize this disease. So what we've got to focus on is improving the metabolism in these cells. And those cells reflect the metabolism of the brain in general. And the brain's metabolism reflects the metabolism of the body in general. So whatever we can do to target body-wide metabolism is going to play out ultimately through the things I just mentioned, many dots to connect.

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being good for the brain via improving brain metabolism, via improving then microglial metabolism, and then setting the stage for better neuronal or nerve cell metabolism. So all the things that I'm sure that your viewers have heard time and time again that are important for improving metabolism, like getting off the ultra-processed foods, like monitoring your blood sugar, exercising regularly and making sure you're getting restorative sleep, could not be more important.

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Are there other things that are out there that are the next step like supplements? Of course there are. There are things that specifically target mitochondria like urolithin A, coenzyme Q10, spermidine, DHA, various B vitamins, et cetera. Whether NAD is playing a role there or not, a little bit unclear. But there are lots of things that we could be thinking about in the supplement world that are good for the mitochondria.

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And then other things that may not necessarily be as, that may pose threats to mitochondrial function, like pesticides in the environment, pesticides that may come on non-organic food that are very, very common. Stress, for example, is a direct threat to mitochondrial function and health. So that's the next tier. That would be supplements. Are there medications that target mitochondrial function? There are to some degree. There are things like rapamycin metformin.

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David (50:46.19)
and even minocycline, the antibiotic, are all demonstrated, least in animal studies, with some suggestion in humans to be salubrious as it relates to mitochondrial function through multiple mechanisms, like increasing the digestion of mitochondria to allow new mitochondria to grow, for example, mitopogee to allow mitogenesis, or directly increase the function of the mitochondria.

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And then finally, there are some even more technological types of interventions that we are seeing now, demonstrating efficacy, like hyperbaric oxygen therapy. What do the mitochondria do? The mitochondria take oxygen and make ATP through a process called oxidative phosphorylation, i.e. they need O2, they need oxygen. And here's a technique of driving a lot of oxygen into the body.

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It's not exactly how it works with respect to improving the brain, but for our discussion, we'll leave it at that. But I mean, you know, here's research from Dr. Amir Haddani from working in a clinic in central Florida and in Israel, Harvard trained demonstrates improvement in cognitive function, improvement in cognitive function, as well as improvement of people with long COVID, for example, by up regulating or turning on or improving

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their mitochondrial function. When mitochondrial function is improved, it helps to revert that evil twin cell back to being the good helpful cell that nurtures our neurons, that allows beta-amyloid to be digested, that allows synapses to form and to be preserved. It's all about reprogramming these cells based upon reestablishing healthy mitochondrial function.

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Josh Dech - CHN (52:43.408)
So one could go back to getting sunlight, earthing, touching the dirt, sleep, hydration, all those basics. If you don't have access to hyperbaric and other things or even supplementation, you could really do it by being more, we'll say, quote, natural in your life and lifestyle to help that mitochondrial function. Plus, if that's not enough, then you could go to therapeutic grade intervention to help you really take that leap forward. Is that a fair assessment?

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David (53:10.806)
Yeah, and I think, you know, what I covered for you just now were the add-ins, right? The things to add to the program to help mitochondria work. But equally important, I think, is the things to take out. What threatens mitochondrial function? And, you know, we certainly know that there are mitochondrial toxins out there that we should be avoiding. Some have been linked to specific brain degeneration issues like Parkinson's, for example.

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MPTP, classic example, but even certain things that we are told to put on our vegetables that are freely available online or at the store are mitochondrial toxins that are used in experimental laboratory to create Parkinson's in rodents and primates. Something wrong with that. These are direct mitochondrial toxins that work at the first part of electron transfer and yet we're told to put them on our fruits and vegetables.

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I would say that one threat to mitochondrial function that's really important and will help us circle back to our original conversation about the gut, one thing that really threatens mitochondrial function is the process of inflammation as a mechanism. That inflammation anywhere in the body produces these chemical mediators of inflammation that we call cytokines, and particularly damaging our

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things like IL-6, IL-1 beta, tumor necrosis factor alpha, and that these cytokines will shift the metabolism of those microglial cells, change them from being the good twin to being the evil twin, and do so because ultimately they threaten mitochondrial function. When mitochondrial function is threatened in the neuron ultimately, their neurons start to sputter in terms of their ability to produce energy,

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It activates in the neuron a process called apoptosis or pre-programmed cell death. So when we don't have adequate mitochondrial function in the brain cells called the neuron, then these brain cells undergo suicide. We activate a program called apoptosis whereby the cell will die. Now that's a pretty clear...

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David (55:31.264)
thing to, mechanism to be concerned about as it relates to what makes a good brain go bad. This is brought on by infection in the brain, of course, by hypoxia as one might have when blood surprise is compromised, infection as for example with COVID-19 or other infections. Beta amyloid can make this happen, but infection anywhere in the body can bring this about. Now, or inflammation anywhere in the body. Now,

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where might that inflammation be coming from? It may well be coming from the gut, getting back to this gut-brain connection. The biggest issue for us to be concerned about, the downside of the gut-brain connection, is the permeability of the gut lining such that immune cells lining the gut are activated and increase their production of these chemicals that make their way to the brain and ultimately lead to shifting the good cell immunologically to being the bad cell.

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and that destroys our brain. that is, you know, that's its relationship then between the gut and the brain that probably could not be more profound.

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Josh Dech - CHN (56:43.527)
You know, one of my favorite understandings of the brain and the gut is that they are the same tissues in utero before they split and become their own things. That they actually start from the same place. They're wired together. They communicate chemically, neurologically. They're almost inseparable and there's a reason the gut's called the second brain. Hundreds of millions of neurons that innervate with your spine and the rest of your body. It's just an awe-inspiring system. One of my favorite things...

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almost to a level of obsession so I'll see a therapist about that but what I want to do here David, yeah go ahead or not yeah I mean this is this is what makes science isn't it is obsession but I want to throw the ball back to you here I know we've only got a few minutes left together is there anything that we haven't covered anything we haven't talked about or anything you'd like to make sure to touch on to wrap up here

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David (57:17.314)
Or not.

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David (57:36.366)
I, what can I say? Where do we go with that question? I don't know. I mean, there's so much else that we could talk about. Maybe let's take it to a place where we probably would not have gone otherwise. I think...

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Josh Dech - CHN (57:44.189)
super loaded, you know.

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David (57:56.168)
let's look around about what's going on in our world right now. And, you know, in many ways, some of the changes that we are appreciating and have been appreciating in recent times are not necessarily necessarily boating well for our health, as it were. And I think that, you know, we could tie things all together via, for example, one input into health and brain health, and that would be the foods that

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we are now consuming globally. used to call it SAD, the standard American diet. It became then called the Western diet. And now it's pretty much the global diet, a diet that is highly challenging to metabolic health. And therefore, because of this global change to an ultra-process-based food pervance, we're seeing the manifestations of metabolic changes in rates of diabetes, obesity.

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and hypertension around the world in lockstep with dementia and cognitive decline and, frankly, Alzheimer's disease as well. Being related to this one significant change. But what I want to just touch upon in the last moments we have together is that there are behavioral changes that are happening as a consequence of these foods. Because of the change in global diet,

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It's a much more metabolically threatening diet. Also, it's a much more inflammatory diet for many reasons, not the least of which are the changes to the microbiome and the increase in gut permeability that is now becoming a global issue because that increases inflammation and it wreaks havoc in the brain. But what I want to mention is that in the brain, we have...

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areas that are involved in decision making. have an amygdala which allows us instantaneous decision making to be responsive, but an amygdala that also is very much centered upon what's best for me and makes me the center of the universe and doesn't consider others, doesn't consider the future as relates to me or others, doesn't consider health of other things like my community or my planet.

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David (01:00:18.178)
Those are more appreciated by the prefrontal cortex that's able to look at larger data sets in the brain and amalgamate information to make better decisions and decisions that are better for the individual in the longer term, better for how that individual relates to his or her environment. It's more the adult in the room. And we develop as we pass through adolescence into our teenage years,

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a connection between these two areas such that the prefrontal cortex is able to rein in amygdala based behavior. The adult is in the room. Yeah, I know you want to stay up late and you don't want to eat your dinner. You don't want your vegetables. You want to eat this snack and do these things, but it's really in the long run not good for you. But I want to do it. I'm eight years old. want to, darn it, want to. And the adult in the room, the prefrontal cortex,

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cortex in all of us says, yeah, you know, know you want to eat that Bonomo Turkish taffy in the checkout lane at sunshine hardware that I look at when I go there. But my prefrontal cortex says, a deep breath. I know you want that, but do you really want to challenge your blood sugar and all the things that we know? Here's where I'm going with all this. That inflammation threatens the ability of the prefrontal cortex.

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Josh Dech - CHN (01:01:23.474)
You

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David (01:01:46.36)
to rein in the five-year-old. That inflammation threatens the ability of the adult to stay in the room and exercise control, we call top-down control, over this impulsive narcissistic part of our brains. And that inflammation is being fostered by the global change in our nutrition with the increasing prevalence of

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human consumption of these ultra processed foods. The connection therefore being that decision making on planet earth is being threatened to being more narcissistic, less forward looking by the change in global nutrition. And that's the thought I want to leave you with.

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Josh Dech - CHN (01:02:37.6)
Well, I don't know if I could have picked a better way to end that and I really appreciate the thoughtfulness of that answer. I know it's one that I kind of throw out of the blue and say, here's a big thing, catch and you do, you don't, but I think you nailed it. And it really does come down to making better choices against what seems to be this cultural shift and easy choices, convenience and quickness. So David, I really appreciate you being here. Such a pleasure to connect with you all your time and expertise.

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David (01:03:04.328)
I'm glad, Josh. Thank you. know we barely got started, but it was already last week. We had so much to talk about, but we were, I think we only had a few minutes. So great. I'm glad we got to spend time together.

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Josh Dech - CHN (01:03:15.173)
You and me both. Thanks so much for being here, David.

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David (01:03:17.484)
You bet. Talk to you soon.