#38–Francisco Gonzalez-Lima, Ph.D.: Alzheimer’s disease & the vascular hypothesis

1. 0:00 – 0:04

   Intro

   1. PAPeter Attia0:00

      [upbeat music]

2. 0:04 – 10:09

   Francisco's Background and Functional Brain Mapping

   1. PAPeter Attia0:04

      Hey, everyone. Welcome to The Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterattiamd.com. [upbeat music] Hey, everybody. Welcome to this week's episode of The Drive. I'd like to take a couple of minutes to talk about why we don't run ads on this podcast and why instead we've chosen to rely entirely on listener support. If you're listening to this, you probably already know, but the two things I care most about professionally are how to live longer and how to live better. I have a complete fascination and obsession with this topic. I practice it professionally, and I've seen firsthand how access to information is basically all people need to make better decisions and improve the quality of their lives. Curating and sharing this knowledge is not easy, and even before starting the podcast, that became clear to me. The sheer volume of material published in this space is overwhelming. I'm fortunate to have a great team that helps me continue learning and sharing this information with you. To take one example, our show notes are in a league of their own. In fact, we now have a full-time person that is dedicated to producing those, and the feedback has mirrored this. So all of this raises a natural question. How will we continue to fund the work necessary to support this? As you probably know, the tried and true way to do this is to sell ads. But after a lot of contemplation, that model just doesn't feel right to me for a few reasons. Now, the first and most important of these is trust. I'm not sure how you can trust me if I'm telling you about something when you know I'm being paid by the company that makes it to tell you about it. Another reason selling ads doesn't feel right to me is because I, I, I just know myself. I have a really hard time advocating for something that I'm not absolutely nuts for. So if I don't feel that way about something, I don't know how I can talk about it enthusiastically. So instead of selling ads, I've chosen to do what a handful of others have proved can work over time, and that is to create a subscriber support model for my audience. This keeps my relationship with you both simple and honest. If you value what I'm doing, you can become a member and support us at whatever level works for you. In exchange, you'll get the benefits above and beyond what's available for free. It's that simple. It's my goal to ensure that no matter what level you choose to support us at, you will get back more than you give. So for example, members will receive full access to the exclusive show notes, including other things that we plan to build upon, such as the downloadable transcripts for each episode. These are useful beyond just the podcast, especially given the technical nature of many of our shows. Members also get exclusive access to listen to and participate in the regular Ask Me Anything episodes. That means asking questions directly into the AMA portal and also getting to hear these podcasts when they come out. Lastly, and this is something I'm really excited about, I want my supporters to get the best deals possible on the products that I love. And as I said, we're not taking ad dollars from anyone. But instead, what I'd like to do is work with companies who make the products that I already love and would already talk about for free and have them pass savings on to you. Again, the podcast will remain free to all. But my hope is that many of you will find enough value in, one, the podcast itself, and two, the additional content exclusive for members to support us at a level that makes sense for you. I want to thank you for taking a moment to listen to this. If you learn from and find value in the content I produce, please consider supporting us directly by signing up for a monthly subscription. My guest this week is Francisco Gonzalez-Lima, a Professor of Neuroscience and Pharmacology & Toxicology at the University of Texas, Austin. In this episode, we talk about Alzheimer's disease. In particular, Francisco explains the vascular hypothesis of Alzheimer's disease, a hypothesis that his colleague and collaborator at UT Austin, Jack de la Torre, introduced to the field about 25 years ago. He makes the case that the central problem in late-onset Alzheimer's disease is a progressive neuronal energy crisis, meaning impaired blood flow to the brain and impaired mitochondrial respiration. If the problem is an energetic crisis, Francisco argues, then we can improve the supply of energy and blood to the brain. We could probably make progress in the prevention of Alzheimer's disease. We, of course, get into great detail at about all of this stuff. And to paraphrase my friend and my colleague, Richard Isaacson, who I've already spoken with on the podcast a while back, as you may remember, and who directs the Alzheimer's Prevention Clinic at Cornell, if you have a brain, you don't want to miss this episode. So without further delay, here is my conversation with Francisco Gonzalez-Lima. [upbeat music] Francisco, how are you?

   2. FGFrancisco Gonzalez-Lima5:22

      Fine, thank you.

   3. PAPeter Attia5:23

      Thank you so much for making time to see me on a Friday afternoon.

   4. FGFrancisco Gonzalez-Lima5:27

      My pleasure.

   5. PAPeter Attia5:28

      [chuckles] This is actually my first time to the university. I've been to Austin many times, but I never seem to be north of downtown, so it was beautiful to drive by the medical center on the way here.

   6. FGFrancisco Gonzalez-Lima5:39

      Mm.

   7. PAPeter Attia5:39

      It's kind of amazing. I haven't even been to a football game, which I hope to one day do at some point. [chuckles] So how long have you been in Austin?

   8. FGFrancisco Gonzalez-Lima5:46

      I've been here as a tenured professor for 27 years.

   9. PAPeter Attia5:51

      Wow.

   10. FGFrancisco Gonzalez-Lima5:52

       Yes. And during that time, I started out in, uh, pharmacology and toxicology, and moved to psychology, just added that. Then the recruiting institution was the Institute for Neuroscience And now I'm a faculty also at the Department of Psychiatry at the new medical school.

   11. PAPeter Attia6:12

       And we were talking a little bit earlier, y- you describe yourself as a behavioral neuroscientist.

   12. FGFrancisco Gonzalez-Lima6:18

       Yes.

   13. PAPeter Attia6:19

       Tell me a little bit about what that title means. Why behavioral?

   14. FGFrancisco Gonzalez-Lima6:22

       My original training as a PhD was in anatomy and neurobiology, and then as a postdoctoral fellow, I tried to understand how the brain related to behavior, and I did that work as a Humboldt Fellow in Germany, and that was my introduction to the study of functional brain mapping and how we could see behavioral functions reflected in brain activity. This was a time where we developed the fluorodeoxyglucose autoradiographic method in that German group in Darmstadt that later became the key to develop FDG PET, the first functional imaging technique in humans.

   15. PAPeter Attia7:10

       It's interesting you say that because I noticed that a number of patients when I talk to them don't understand sometimes the difference because I don't think physicians explain the difference between functional studies and imaging studies, and I remember feeling very fortunate in medical school during a radiology rotation where one of the residents sat me down and explained the difference. And the PET, of course, the FDG positron emission tomography being a great example of a functional study. It's not giving you anatomic resolution. It's giving you functional resolution with respect to glucose uptake. And similarly, you have-- you now have functional MRI which is doing the same sort of thing. And so yeah, that's a, a very important distinction and-

   16. FGFrancisco Gonzalez-Lima7:50

       Especially important if you want to be able to determine a disease in a very early stage in which there are no structural changes in the brain that can be seen at least at the microscopic level. And having functional techniques, you are able to identify these functional changes even before you have any other signs of the disease.

   17. PAPeter Attia8:15

       So I know you, you're a gentleman who has spent time all over the place. You, you were born in Cuba. You left Cuba when you were quite young. You spent time in Costa Rica, Venezuela. I mean, where did, where did you-

   18. FGFrancisco Gonzalez-Lima8:27

       Puerto Rico.

   19. PAPeter Attia8:28

       And Puerto Rico, of course. All of those things, at, at what point did it become clear to you that you were interested in the brain?

   20. FGFrancisco Gonzalez-Lima8:35

       I think my father was a veterinary doctor, and originally my interests had to do with working with animals. But soon I realized the nervous system was so important for the entire health of the animal and the behavior of the animal, so I started to move away from just a more general interest to something that had to do more with the brain. But I would say my key influence happened as an undergraduate at Tulane University in New Orleans when one of my professors, Dr. Joan King, dissected a brain in one of our classes, and this was an undergraduate honors class. And it was fascinating to me, and I joined her lab to do an honors thesis working on the relationship between the brain, hormones, and behavior in animal models.

   21. PAPeter Attia9:33

       It's r- so interesting. I think back to my own time in medical school. There were clearly a subset of my colleagues who were so captivated by the brain, which in gross anatomy really doesn't depict a fraction of its brilliance, right? Unlike the heart where certainly microscopically there are things about the heart that are relevant. You can't see the Purkinje fibers. You can't see the AV node or the SA node. There's so much that is invisible to the naked eye. But for the most part, you can appreciate the brilliance of the heart at the macroscopic level. But then there are other organs that, you know, on the other end of the spectrum get no attention like the liver. I mean-

   22. FGFrancisco Gonzalez-Lima10:09

       Mm-hmm

3. 10:09 – 24:36

   Brain Circuitry, Redundancy and Parallel Processing

   1. PAPeter Attia10:09

      ... microscopically it's just a lump of whatever. But of course, what's happening inside the liver to me makes it one of the most remarkable organs. But the brain is an organ that has such a unique look, right? Grossly it looks so distinct. The tissue looks so distinct from all of the other tissue outside of the central nervous system. And also to this day, I would say our knowledge of the brain must be far, far behind that of any other organ at the sort of physiologic signaling level. I mean, is that-- I mean, is that a fair assumption?

   2. FGFrancisco Gonzalez-Lima10:41

      Oh, yes, I agree completely. And I would say using the same analogies that you have, the heart, you can think of it as a mechanical engineer or a pump, a hydraulic pump. Whereas the brain is more of an electrical engineer where you have lots of circuits. And the liver, for that matter, will be a chemical engineer [chuckles] where we break down all of these substances that the body consumes.

   3. PAPeter Attia11:07

      I actually love that. I've never thought of what you just said, and that is a great way to explain the different types of engineering. The kidney would be some sort of sanitation filtering engineer.

   4. FGFrancisco Gonzalez-Lima11:17

      [chuckles]

   5. PAPeter Attia11:17

      I mean, we could really-

   6. FGFrancisco Gonzalez-Lima11:18

      Environmental.

   7. PAPeter Attia11:18

      Yeah. Yeah.

   8. FGFrancisco Gonzalez-Lima11:18

      Environmental. [chuckles]

   9. PAPeter Attia11:19

      Yeah. And, and so in many ways the brain is probably not only electrical engineering, but it's computer science engineering.

   10. FGFrancisco Gonzalez-Lima11:26

       Correct.

   11. PAPeter Attia11:26

       It's, it's-- There's so much going on there.

   12. FGFrancisco Gonzalez-Lima11:28

       Right. You hit in a very important point. One cannot simply look at the brain the same way that you look at other organs. Because of that circuit property, it allows the developing of computational power. So the brain uses the circuits not just for communication, which is the most obvious function, but to determine and compute outcomes that then are used to guide the other tissues in the body. For example, the musculoskeletal system cannot do anything on its own without the commands that are the result of computations from the nervous system. So all of our behavior results from how the nervous system process our experiences and our current situations. And this become, uh, not in the same way as a computer works that is a serial device. The brain is a very redundant parallel system where there have to be a lot of convergency between different regions that are computing for that to be acknowledged as the way to go in, in a behavioral point of view.

   13. PAPeter Attia12:46

       So for a person listening to this who might not have the, the luxury of knowing some of the, the nuances about the brain that you do, when you're talking to an audience that is presumably most people are interested in the brain because of brain pathology. It's, you know, once, once a disease strikes the brain, everybody becomes well aware of how much it's doing because the absence of that function leads to such an obvious downside. How do you describe for people this notion of convergence and redundancy and overlap? I mean, obviously there's a very strong evolutionary reason. What are some examples of those and, and how those things are-- these processes are preserved in terms of-- 'cause you use, I like the use of-- I'm an engineer, so I do like the use of talking about serial versus parallel processing. Maybe expand on that a little bit.

   14. FGFrancisco Gonzalez-Lima13:34

       In reality, all of the anatomy is redundant and parallel. At least, for example, we have bilateral symmetry. You know, everybody knows we have two hands, two legs, two eyes. We probably could have done it with one eye, but the way the system works is that it creates redundancy. And in, for example, the circulatory system is the same. You have parallel blood vessels where you can get the blood from one point to another in more than one way. And of course, when you sit, when you put your elbow down, you can compress a blood vessel, but there's still another route that can be used. It's like coming from the university to the downtown area. You have many options to get from one point to the other. So in the brain, this is maximized to its extreme. It's an organ specialized for this large amount of communications. In other words, having so many highways and avenues where information can go through. So in that sense differs from other organs where you have a pattern that repeats itself and the redundancy is only on that pattern. Here in the brain, the redundancy is combined with the acquisition of new networks or circuit options that are not possible if you only have one design. So you have multiple designs. If you want an analogy, for example, when NASA was sending the man to the moon, they have like 100 computers doing the same computation, and then they look at the output and they see which is the output that is repeated more often, and that's the one that those coordinates are the ones that they're gonna pass on. The brain uses that strategy, and that's what I mean by convergency. In other words, you have all of these multiple parallel system and they are doing these computations, but only the ones that converge on the same solutions are the ones that are acknowledged and move on for the next stage.

   15. PAPeter Attia15:41

       And when you look at other species beyond humans, how much of that redundancy do you see as you go down the evolutionary chain or down the food chain maybe is an easier way to think about it? I mean, at what presumably, you know, chimps and cats and dogs are very similar, but is there a point at which it very suddenly stops or does it simply diminish to the point where, you know, when you're looking at a simpler organism like a worm, for example? I don't even know what the nervous system of C elegans looks like.

   16. FGFrancisco Gonzalez-Lima16:12

       Well, definitely mammals and primates in particular where basic plan is the same and most of the differences have to do where which of the networks are more developed than others. So in primates we have the cerebral cortex becoming the dominant component in the brain. This is to a certain degree the same thing in all the mammals, but then other regions of the brain have more similar contribution. When you go down to, for example, reptiles or amphibians, the midbrain, the mesencephalon is the largest part of the brain, not the portion where we have the cerebral cortex. And what that means basically is in addition to this parallel processing that we have, information goes through several hierarchical stages and at every one of these stages similar processing is done and you add an additional piece of information when you move it on. For example, you can respond at the level of the spinal cord. That will be the lowest level of response.

   17. PAPeter Attia17:24

       That would be, for example, a reflex. Like if you tap somebody's knee, you transiently lengthen the patellar tendon, the knee kicks out to straighten it-

   18. FGFrancisco Gonzalez-Lima17:32

       Yes

   19. PAPeter Attia17:32

       ... or reduce the length, and that is happening outside of the brain.

   20. FGFrancisco Gonzalez-Lima17:35

       Yes. However, when you tap the knee, the information also goes to all the levels of the nervous system. In that case, you saw the spinal reflex being manifested.

   21. PAPeter Attia17:48

       But the person still knows.

   22. FGFrancisco Gonzalez-Lima17:50

       Yes.

   23. PAPeter Attia17:50

       They felt the sensation and they know what happened.

   24. FGFrancisco Gonzalez-Lima17:53

       So the same was happening at different hierarchical level of processing. So behaviorally speaking, when we respond to a stimuli at very basic level, like what you indicated, like the spinal level, we call it a reflex. So that would be the, the most basic behavioral response. But that means that you are not seeing what is happening at the other levels. But for example, in a frog that is following an insect, a worm as it's moving, the frog would orient to the movement as long as the worm is moving in the same direction as the long axis of the body. You have the same worm that is a fake worm where it's moving in a direction perpendicular to the long axis.

   25. PAPeter Attia18:41

       Its long axis, yeah.

   26. FGFrancisco Gonzalez-Lima18:42

       The, the frog will not follow.

   27. PAPeter Attia18:44

       So the pattern isn't recognized. So if a frog sees a worm moving in the normal direction a worm moves, it knows that pattern. If it sees the exact same food source standing up and walking on the side, it's not going to pursue it.

   28. FGFrancisco Gonzalez-Lima18:58

       It's not pursuing it. So but in order to do that new computation, then you needed the level of the midbrain. So the midbrain becomes now the point at where decision is made and whether to follow and then, uh, eventually snap and capture the worm. So the sub-mammalian species primarily operate at that level, and they have well-defined instead of being called a reflex, we would call this like release stimulus. Release stimulus creates or generates a pattern. There is a pattern generator that recognizes it. But then in, in mammals, we have to move information to the level of the thalamus that is in the middle of the brain, but higher than the midbrain. And then from there, the majority of the mass of the brain is in primates and humans in particular is in the cerebral cortex. So we have to pass that information to the cerebral cortex and then feed that back down to the output systems.

   29. PAPeter Attia20:05

       So it might be a way of oversimplifying, but one could think of it as the brain stem and spinal cord are responsible for these reflexes. For example, we breathe without thinking because our brain stem allows us to. We recoil from pain without thought because of these things. The midbrain took it up a notch by basically allowing for that stimulus response, but the thalamus then becomes the gateway to the cortex where we can do this higher processing. That's probably an oversimplification, but-

   30. FGFrancisco Gonzalez-Lima20:31

       And the main contribution of this thalamocortical system is to allow us to inhibit behavior. In other words, not to respond in a more immediate short-term manner. So the ability to delay a response and to try to compute what are the consequences if we were to make that response, this is what really is brought up by our more elaborate cerebral cortex. So the majority of the influence of the cerebral cortex on subcortical levels-
4. 24:36 – 41:36

   Why the Amyloid Hypothesis Fails: Early vs. Late Onset Disease

   1. PAPeter Attia24:36

      What is the typical explanation for what causes Alzheimer's disease and therefore by extension what the path should be to prevent it or treat it?

   2. FGFrancisco Gonzalez-Lima24:46

      You're completely right. We have not made any significant progress in Alzheimer's disease research. This is the largest failure of the biomedical research enterprise in the world during my lifetime. And the main reason is we have remained faithful to an initial observation that was done or published at least in 1907 by Alois Alzheimer that indicated that he saw these abnormal depositions in the brains of an individual after that individual died. This individual was 51 years old when he died, but Alzheimer's was actually a psychiatrist, not a neuropathologist like it's pointed out in books. He worked in a psychiatric hospital. He was part of the original group led by Kraepelin in Munich, and they were studying mental illness. And in those days, it was believed that what we call nowadays dementia was a form of mental illness. And he was surprised by this young patient that was showing these early signs of dementia, you know, in his 50s. And already by the time he died, that person had been suffering for many years. So what Alzheimer's describe has in the brain of that individual has Alzheimer's disease is not the same disease that is happening in older people. It's not the same disease that is the most common type of dementia, and this has been the most basic misunderstanding from the beginning. Historically, there was a competition between two groups, one in Prague, in Czech Republic, at that time was under German rule. And Oskar Fischer published studies where, for example, he looked at 16 brains from patients that had what was called senile dementia. That is the type of dementia that was showing up in people after they were 60, 70, 80 years of age, not these younger individuals. And he described some of these same abnormalities that later that Alzheimer's published, but for that single case. However, Kraepelin was a rival of that group, especially about Fischer, who was Jewish. And so he published in the first book that talk about Alzheimer's, the first textbook of psychiatry that was published by Kraepelin, and then he say, "Oh, what we're seeing in these old people, this type of dementia, is what Alzheimer's described in that younger individual." And from there on, there was a movement away from factors that were related to aging and to say this is a disease that is invading somehow, and it's not something that is building up over the years. Of course, this is actually not the case. So nowadays they try to have a compromise and say Alzheimer's disease, there is early onset or familial, which is primarily familial. There is some evidence for inheritance, but nine out of 10 cases of what is referred to as Alzheimer's disease, there is absolutely no inheritance or familial component, which is one of the greatest fears of people when they have patients with dementia in their family. And not only that, it's aging related, and because it develops very slowly over the decades, it provides an opportunity to intervene to determine what are the risk factors that are behind and to do an intervention. If you take the other approach that this is a disease of these abnormal proteins and it can happen early on, then you have a very different strategy. So the whole field has been dominated primarily by what is called the amyloid beta hypothesis. This hypothesis is completely, absolutely false. It has no relationship whatsoever with what we see in the older people that develop dementia. It has a relationship with some of these early cases that like the one that Alzheimer's describe and that have a familial component and that there is a somatic genetic component.

   3. PAPeter Attia29:30

      Let me just interrupt for a second to make sure I'm understanding. This is obviously such an important point that I want to make sure I'm, I'm clear and that the listener is clear. Now, the case that Alzheimer's found in 1907, I have to assume that was a PSEN one or two mutation. That was what we now see accounting for less than 1% of Alzheimer's disease, but it is probably the closest to a fully penetrant gene that results in Alzheimer's disease. Has that ever been confirmed? Are there any biologic specimens remaining from that particular individual who was so young?

   4. FGFrancisco Gonzalez-Lima30:02

      There are slides available, but it has never been confirmed. And the patient died in 1906 after many years with this chronic dementia in that hospital in Munich, and he was deteriorated in every other respect by that time, unable to move and carry on on activities of daily living. So he'd been suffering from this for many years.

   5. PAPeter Attia30:26

      Which is not unlike what we can see in the rare patients that do have the PSEN one or two gene, which is it can easily take hold in the 40s. I, I unfortunately have a patient whose mother is, you know, debilitated in her mid-50s. Now, it turns out she doesn't have the gene, which was a surprise to a lot of us, we assumed because it had taken hold so early. But the autopsy, the pathology that they could see, which at the time was limited to very gross things relative to today. Gross for the listener, I don't mean gross as in disgusting, I mean gross as in visible through a microscope. Was this the first time that amyloid beta was observed?

   6. FGFrancisco Gonzalez-Lima31:02

      No. The first time was done by Oskar Fischer in the senile dementia.

   7. PAPeter Attia31:08

      So Alzheimer's was basically describing a phenotype, but without a pathologic explanation or characteristic.

   8. FGFrancisco Gonzalez-Lima31:15

      Yes. But because it was happening so early, then it moved the people away from the idea that this has something to do with senility, with the older deterioration that happens as a function of aging. So they say, "Oh no, this can happen early on, so aging cannot be a primary contributor." So even though a very small percentage of people that are described as having Alzheimer's belongs to this early onset, over 90% of the research is focused on that group. And the, the reasoning is because it's the same disease, which is a false premise, if we find out what's happening in the early onset and we model that in animals by doing this genetic manipulation, then we can fix the more common senile older age late onset dementia. And that false premise is what has been driving all of these failures because, yes, they have been able to detect genetic changes. They can manipulate this. I was able to work examining the brain of the first amyloid precursor mouse model that was developed, and one of the first things that I noticed in the brains even before there was any amyloid deposition in that model that they had inserted, they had-- It was a transgenic mouse model. They had taken away the native gene from the mouse and replaced that gene with one that was abnormal from a patient with early onset Alzheimer's. But even before that gene could start any s- any observable deposition of amyloid, these brains, by that very manipulation, were abnormal. They had severe atrophy in, for example, the corpus callosum, the bundle that communicates the two hemispheres, and the region of the hippocampal formation had lost one third of its volume.

   9. PAPeter Attia33:20

      So the intervention itself may have altered the resilience, if nothing else, of the brain.

   10. FGFrancisco Gonzalez-Lima33:26

       Yes. And of course then these animals show all kinds of behavioral abnormalities, but these things were happening even before there was any amyloid deposition. So it was clear that having a gene with these abnormalities, even before you can see that product building up, is enough to distort how the brain develops. So this has been the main problem, and because biology, just like when I started studying biology, my major was called cell and molecular biology, and that became the dominant orientation in biology. So people who do this research oftentimes don't have a very good understanding of the brain as a whole, and they just focus at that molecular level. And in a way, they're trying to find the answer where the light is, that is the light that they can use, and trying to ignore that this is really a disease of all age that involves a long development, and that there is absolutely no correlation, no relationship between the amount of, for example, amyloid beta deposition and the onset of memory deficits or cognitive impairment or the progression of the disease. There are brains of individuals that I have the fortune to examine here in Austin as I'm primarily a neuroanatomist, a functional neuroanatomist. I collaborated with the neuropathologist here, and the brains of these people who were cognitively normal after they die, they couldn't differentiate them from the ones that were diagnosed as Alzheimer's based on amyloid and neurofibrillary tangle depositions.

   11. PAPeter Attia35:14

       That's an enormous statement. It doesn't call into question the causality of amyloid. It just calls into it the necessity and sufficiency of it. In other words, it could be that you have to have, I mean, I'm making this up, but to, to illustrate a, a point within logic, it could be that you need to have amyloid beta deposition to cause dementia, but that is not sufficient. It is only a necessary condition, and that you might need other factors to coalesce around it. The obvious example that comes to my mind is LDL and ApoB, which is necessary for cardiovascular disease, but not alone sufficient. You still need an inflammatory response and an, and an immune response.

   12. FGFrancisco Gonzalez-Lima35:56

       I go beyond that point. What I'm saying is against the dogma.

   13. PAPeter Attia36:00

       You're saying one step further than that. You're saying that not only is the deposition of amyloid not correlated strongly enough, it might not even be causally related.

   14. FGFrancisco Gonzalez-Lima36:13

       Not, not even. It is not-

   15. PAPeter Attia36:14

       [laughs]

   16. FGFrancisco Gonzalez-Lima36:15

       ... causally related to what we call primarily Alzheimer disease, which is this majority of late onsets. That's not true for the early onset. What I'm saying is that they are two different diseases. The early onset, there is a role for this amyloid deposition. You can demonstrate this.

   17. PAPeter Attia36:34

       In other words, if you take autopsies of 50-year-olds that die from heart disease, cancer, or accidental death, and you examine their brains relative to 50-year-olds who die from early onset dementia, the relationship is more clear that the-

   18. FGFrancisco Gonzalez-Lima36:51

       Oh, it is clear

   19. PAPeter Attia36:51

       ... the amyloid beta is playing a causal role.

   20. FGFrancisco Gonzalez-Lima36:54

       Yes, there is no question, and, and you can find the genetic mutations, and you can induce it in the animal. But that's not the case in the late onset, and the neuropathologist will tell you if they don't know what the clinical picture was, they wouldn't be able to say that this was what they refer to as a probable Alzheimer's disease. So when they see exactly the same pathology and then there's no evidence of cognitive deterioration, they just diagnose that brain as possible Alzheimer's disease. So this created a circular definition.

   21. PAPeter Attia37:32

       To be clear, to close the loop on that analogy with heart disease, you would have to know that there are cases where patients have significant dementia that by all other metrics is consistent with Alzheimer's dementia and not Lewy body or something else, and there is absence of amyloid beta deposition.

   22. FGFrancisco Gonzalez-Lima37:52

       Oh, yes. Yes.

   23. PAPeter Attia37:53

       And what percentage approximately, I know it's hard to know these things-

   24. FGFrancisco Gonzalez-Lima37:58

       Yes

   25. PAPeter Attia37:58

       ... because we don't always get autopsies, but in, in your experience, what percentage of patients who die with or from Alzheimer's disease that is late onset do not have the-

   26. FGFrancisco Gonzalez-Lima38:11

       Okay

   27. PAPeter Attia38:11

       ... histopathologic features of amyloid beta?

   28. FGFrancisco Gonzalez-Lima38:14

       The majority of patients that are diagnosed as Alzheimer's disease, probable Alzheimer's disease when they die have the same level. It's not that they don't have because it's an age-related deposition, the same levels of all the patients that are comparable age. And the only reason that they are labeled as Alzheimer's is because they had the dementia. The pathology cannot really tell them apart. If you give these two pathologies blind to the medical diagnosis or clinical examination, they won't be able to tell apart which are the ones that are actually demented and which are not if you do it in a match. There is a large degree of variability, and pathologies are not quantitative. Pathology is an approximation. You look at only a few sections through the cortex, and then you give a certain proportion of the findings that are found that you see as categories. But even when I have done this personally in 2001, we published in the Journal of Neuroscience a study where we use brains from people who die from Alzheimer's. The main difference from my study from what's been done before is that we were able to obtain brains with only a few hours after the individuals had died. We call it a very small postmortem interval. And I was able to do this by collaborating with the institute in Arizona. There is a city called Sun City, Arizona, and they have a Sun City Health Center which actually ascribes to these amyloid and neurofibrillary tangle ideas. But what we did with them was we went, we traveled there, and with my PhD student, we collected these brains, control brains and brains of people who have died, died of Alzheimer's. Some of them we were able to collect them fresh right there.

   29. PAPeter Attia40:20

       And were you and your team also blinded to the circumstances of the death prior to the autopsies being performed?

   30. FGFrancisco Gonzalez-Lima40:29

       No. What we did is we collected all the brains, and they were, I sectioned them into pieces, and these pieces then were frozen, and then one sample would remain there.
5. 41:36 – 47:56

   Hypometabolism and the Posterior Cingulate Memory Circuit

   1. PAPeter Attia41:36

      Is it generally well-regarded, bringing it back to some of your earlier work in PET, I assume it is generally agreed upon that patients who are in the stages of cognitive decline have hypo-functioning metabolism, so their PET scans show less glucose uptake in the brain. Is that generally-

   2. FGFrancisco Gonzalez-Lima41:54

      Yes

   3. PAPeter Attia41:54

      ... acknowledged?

   4. FGFrancisco Gonzalez-Lima41:55

      And not only FDG PET. When you do also cerebral blood flow, you find the same. When you do fMRI arterial spin labeling to look at blood flow, every technique that have been used has demonstrated that first it was with mild Alzheimer's cases, but more recently also with the so-called mild cognitive impairment that nowadays they're also referring to as, uh, mild neurocognitive disorder. And in those cases, there is hypometabolism, and the hypometabolism is primarily not in the regions that become atrophic Later on in the disease, like in the temporal lobe, it's primarily in the posterior cingulate cortex, one region of the brain that is in the medial part in the center of the brain. This area is the one that you can see having earliest sign of hypometabolism.

   5. PAPeter Attia42:54

      And from a phenotypic standpoint, what does it control in the normal brain?

   6. FGFrancisco Gonzalez-Lima42:59

      This region provides the major input to what is called the entorhinal cortex, which is the part of the temporal lobe that then feeds into the hippocampal formation. So what essentially is happening is you have a functional disconnection between the main input to the entorhinal cortex. The entorhinal cortex is the primary source of inputs to the hippocampal formation. So when you functionally denervate a region in the brain, eventually that leads to atrophy from that region that-

   7. PAPeter Attia43:41

      That is receiving the stimulus

   8. FGFrancisco Gonzalez-Lima43:43

      ... is receiving that. Just like happens when you denervate a muscle in the periphery, there is atrophic action, an action that that region survives because it's being stimulated by the other one. So people have missed-- When you study pathology, you don't study these functional changes, and you don't look at the system as a network of pathways or influence functionality. You're seeing the end result, what has happened after all of these processes have taken place over the years. So by doing that, you cannot infer these other phenomena.

   9. PAPeter Attia44:22

      If you take an animal like a mouse and you just take out the, it's the posterior cingulate?

   10. FGFrancisco Gonzalez-Lima44:27

       The posterior cingulate.

   11. PAPeter Attia44:28

       Yeah. If you lesion that in a rat or a mouse acutely, which is not the same as what's presumably happening in this disease state, what is the immediate phenotype of that animal or behavior?

   12. FGFrancisco Gonzalez-Lima44:40

       Well, you don't have to lesion it. You can functionally deactivate it, which is more similar to what is actually happening in Alzheimer's. It's not that this region is damaged structurally.

   13. PAPeter Attia44:52

       Right. It's just functionally not allowing the conduit.

   14. FGFrancisco Gonzalez-Lima44:55

       Yeah. It's, uh-

   15. PAPeter Attia44:55

       The signaling conduit

   16. FGFrancisco Gonzalez-Lima44:56

       ... affecting that network that is providing the main input to the hippocampal formation. You get the same kind of memory deficits that are characteristic of the initial stages of dementia.

   17. PAPeter Attia45:08

       And is that because of the role the hippocampus plays in the consolidation of memory, or is it to do more with this, the target in the temporal lobe?

   18. FGFrancisco Gonzalez-Lima45:17

       It is because it's a network, not a single region. In other words, for example, long time ago in the 1930s, there was a circuit that was defined by an American neuroanatomist called James Papez, also pronounced Papez, and he describes the connections between the cingulate cortex, this parahippocampal cortex that we now primarily refer to as the entorhinal cortex, and then from there to the hippocampal formation. From the hippocampal formation, the main output goes to a region called the mammillary bodies, and then from the mammillary bodies, it goes to the anterior part of the thalamus. And then from the thalamus, it fans out the projections back into the cingulate cortex, so it creates a circle. And this is often being referred to as the limbic circuit of Papez, and we know it has to do with emotional memory formation because events that have a large emotional signature are the ones we store for longer term.

   19. PAPeter Attia46:28

       We create the greatest memories from them.

   20. FGFrancisco Gonzalez-Lima46:29

       Yes. So if you affect this system anywhere in this system, you get a memory disease, and they just have different names. So for example, people that have chronic alcohol, they develop sometimes referred to as a Wernicke-Korsakoff dementia.

   21. PAPeter Attia46:49

       Mm-hmm.

   22. FGFrancisco Gonzalez-Lima46:50

       Also known as Korsakoff psychosis. Um-

   23. PAPeter Attia46:53

       You can get this from B vitamin deficiencies as well.

   24. FGFrancisco Gonzalez-Lima46:56

       B1 deficiency, thiamine deficiency in particular. You look at the pathology of the brain, where is the damage? The damage is primarily in the mammillary bodies. Well, the mammillary body is the main output from the hippocampal formation, so whatever the hippocampal formation is contributing, if you're knocking down its main output target, you get the same thing. Then the, in a second place is the hippocampal formation itself, then the entorhinal cortex, and so on. All you have damage in any part of the circuit system. There's also something called diencephalic retrograde amnesia that happens with thalamic lesions. Well, this is when these lesions interfere with these anterior thalamic areas. So really, in order for us to see the memory problems that we have linked usually with Alzheimer's dementia, you have to engage the system because that system is part of the brain regions in which this is operating.

6. 47:56 – 54:11

   Working Memory, Early Decline and Where to Intervene

   1. PAPeter Attia47:56

      You used the term retrograde there. For the listener, we should explain the difference between retrograde and anterograde amnesia.

   2. FGFrancisco Gonzalez-Lima48:02

      Correct.

   3. PAPeter Attia48:02

      I'll let you do that quickly, but of course, my follow-up question will be, in the earliest stages of dementia, is the bigger issue the inability to form new short-term memories, which would be a form of anterograde amnesia? That, that would happen before the, the retrograde amnesia, which is later.

   4. FGFrancisco Gonzalez-Lima48:17

      Yes. Let me explain. In the early Alzheimer's disease, the main problem is not in this limbic circuit. When that happens is when I, when you can see the hypometabolism first.

   5. PAPeter Attia48:30

      That's when you can see the behavioral changes in the individual as well, right?

   6. FGFrancisco Gonzalez-Lima48:33

      But before that In the prefrontal cortex, especially the lateral, we call dorsolateral prefrontal cortex, you have a functional deficit that is interfering with what we call working memory. So you can think of memories as having three modes or temporal stages. An immediate memory mode where you can remember things for only a few seconds.

   7. PAPeter Attia49:02

      Tell me your phone number and I have to write it down.

   8. FGFrancisco Gonzalez-Lima49:05

      Correct.

   9. PAPeter Attia49:05

      That's where that's short. Yeah.

   10. FGFrancisco Gonzalez-Lima49:06

       That's the perfect example. A clinician will do this by giving a string of numbers to people, and people will be able to remember approximately seven numbers. So it is usually seven plus or minus two items. And this is the reason why the telephone numbers have seven digits, because most people after reading seven digits, turning around to try to punch those numbers in the phone, if there are more than seven, they drop some of them. This is this immediate memory mode. But for memories to happen, they have to move from this immediate memory mode to a more recent memory mode. So the immediate, that movement from immediate to recent is done by this prefrontal cortex. So the initial deficit that you see in, in Alzheimer's and all of these types of dementia of all age is in this more immediate memory mode. And one way we refer to this is also working memory. So for example, you come out of your house and you lock the door, but after a few seconds you walk into your car, then you ask, "Did I lock the door or is it unlocked?" And then you have to go back and check. So this is the first thing that you're gonna have, and it happens physiologically as a function of aging. And this is the first one, this working memory things are. So the prefrontal one is the initial signal that there is a memory problem. This is before, and this is an anterograde memory. In other words, it's a new memory that you want to form. So this is the first thing that is affected. But once the memory are in the recent memory mode-

   11. PAPeter Attia50:52

       This, for example, would be your phone number.

   12. FGFrancisco Gonzalez-Lima50:55

       Yes.

   13. PAPeter Attia50:55

       Which is one of the easy seven digits to remember because you're so familiar with it that it's now-

   14. FGFrancisco Gonzalez-Lima50:59

       Correct

   15. PAPeter Attia50:59

       ... become, quote-unquote, permanent memory.

   16. FGFrancisco Gonzalez-Lima51:01

       By repetition, by exposure to the same items, this reverberate in that limbic circuit that I just told you, and the hippocampal formation has an inner circuit that is crucial for that. So it is crucial for that forming, and then you being able to retrieve that number again. So when that circuit becomes engaged at any point, then you start having this retrograde memory problem. You cannot remember your number.

   17. PAPeter Attia51:29

       Which is interesting. That's the point at which the family members tend to really notice what's happening-

   18. FGFrancisco Gonzalez-Lima51:35

       Yes

   19. PAPeter Attia51:35

       ... and become concerned.

   20. FGFrancisco Gonzalez-Lima51:36

       Yes.

   21. PAPeter Attia51:36

       But the patients tend to become concerned much sooner. The patients become concerned with the antegrade memory deficits.

   22. FGFrancisco Gonzalez-Lima51:44

       Yes. You are absolutely right.

   23. PAPeter Attia51:45

       How do you distinguish between something you said a moment ago which was this slight deficit of formation of new memory is on some levels not necessarily a pathological finding as we age?

   24. FGFrancisco Gonzalez-Lima51:57

       Mm-hmm.

   25. PAPeter Attia51:58

       But how do we differentiate between the pathologic or the appropriate age-related-

   26. FGFrancisco Gonzalez-Lima52:03

       Mm

   27. PAPeter Attia52:03

       ... versus the potentially, you know, the harbinger-

   28. FGFrancisco Gonzalez-Lima52:06

       Yes

   29. PAPeter Attia52:06

       ... of something pathologic?

   30. FGFrancisco Gonzalez-Lima52:07

       It is difficult to draw the line. This is one of the main reasons that this diagnosis of mild cognitive impairment has been elusive. I have asked this question to all the researchers, and I get very many different opinions. And the main reason is that the only way to know for sure is to compare this to your own history, to compare it to yourself. So in this case, the patient and their immediate partners, they are more knowledgeable whether there being a change. If you just compare to a standardized age population, you may not see any difference, but they, the patient will tell you, "No, I know I am having more difficulty with, for example, this working memory task." So it is a challenge, but the, the beauty of this is you don't have to wait because everybody goes through this cognitive decline. It's just to different extent, and we all start out at a different level of cognitive performance. So it's very difficult to have a standard. So my approach is to try to intervene at that point, and therefore the main target at that point is to intervene in the prefrontal cortex, the region that is just behind your forehead. And that one engages, we call an central executive network that for cognitive processing that is involving working memory, that is involving problem-solving, that is involving sustained attention vigilance. Those are the things that you're gonna be seeing first having a decline as you grow older, just like all kinds of tissues decline as you grow older. This is a reality. But it is possible to intervene then before you get into the limbic system problems, and that's the approach that we have done and in our interventions. And I think this is what's gonna make the biggest difference.

7. 54:11 – 1:08:56

   The Vascular Hypothesis: Chronic Cerebral Hypoperfusion

   1. PAPeter Attia54:11

      So let's go back to now the sort of revised hypothesis. So if I can summarize, the actual nomenclature of Alzheimer's disease might be a bit of an unfortunate artifact in that it was first observed in a subset of what would become this disease that really isn't representative of the epidemic that we're seeing today.

   2. FGFrancisco Gonzalez-Lima54:31

      Absolutely right.

   3. PAPeter Attia54:32

      And so we'll put that aside for a moment because despite how tragic those early onset cases are, and they strike me as among the most tragic things I've ever seen in medicine-

   4. FGFrancisco Gonzalez-Lima54:42

      Yes

   5. PAPeter Attia54:42

      ... by the way. You have more experience with this The thing that's running amok right now is this sort of late onset dementia that it seems to me that we are probably diagnosing it much more than we were before, but it also seems to be increasing out beyond just the rate of diagnosis. And it also seems to be increasing at a rate disproportionate to the increase in our longevity, which is really not that significant. I believe that human longevity is increasing at about 0.4% per year in the United States, and yet the rate of growth of Alzheimer's disease is growing much more than that. So if you discount that somewhat for the rate of, for the diagnostic acumen or urgency with which we seek it, there's still a gap, which means on a real level, not just a perceived level, this disease is becoming more common. In your research, you talk about five areas of study that help you think about this, the epidemiology of the disease, the imaging of the disease, the pharmacologic response to the disease, the pathologic findings in the disease, and then the clinical course of the disease. You and your colleagues have a different hypothesis that pertains to the vascular system.

   6. FGFrancisco Gonzalez-Lima55:55

      Yes. This is actually the original hypothesis that was associated with senile dementia. I don't want to take credit for the people who've gone after that because in the early days it was just an idea, not well formulated. But what seems to be happening is if you compromise circulation to the brain, you're always gonna get a neurological deficit. However, in the case of what we're seeing as late onset dementia that I may refer to as features dementia as opposed to the early onset Alzheimer's dementia, which is what should've been named, there is a chronic hypoperfusion. That is the brain is receiving less blood supply. And for example, it is known that between twenty-two years old to sixty years old, there is a decrease of about twenty percent on your s- supply of blood to the brain. So some people have calculated at approximately half of a percentage per year in statistical terms.

   7. PAPeter Attia57:04

      Do we have a sense of why? How much of that-- I mean, 'cause I think a lay person might understandably but naively assume that is just due to a gradual and gradual narrowing of arteries or something like that. But it, it strikes me that that's very unlikely the case, and that it's much more related to something within capillaries and or other metrics. Because, you know, paradoxically as we age, we're seeing an increase in our blood pressure typically. So when you're twenty versus sixty you're generally running with a higher blood pressure. So if anything, you would think that should increase cerebral perfusion, not decrease it. But of course, we're not seeing that. So what, what do you think at the level of vascular biology-

   8. FGFrancisco Gonzalez-Lima57:44

      Yes

   9. PAPeter Attia57:44

      ... would explain even that observation?

   10. FGFrancisco Gonzalez-Lima57:46

       Yes. Unfortunately, the answer is all of the above. In other words, the vascular changes happen at the macroscopic and microscopic levels. But it is the case if you, for example, only look like we have done at, for example, the carotid artery, the one in the neck that supplies the blood to the head, this is where most of the blood is going to the brain from this, and you can use ultrasound imaging noninvasively and are able to look at the layers.

   11. PAPeter Attia58:18

       So even the intimal thickening of the carotid artery, which-

   12. FGFrancisco Gonzalez-Lima58:21

       Yes

   13. PAPeter Attia58:21

       ... would presumably get a little more and more and more as one ages is, is gonna play a role in this potentially.

   14. FGFrancisco Gonzalez-Lima58:27

       Oh, yes. Uh, there is a linear relationship between what we call the intima-media thickness, the li- the layers of the artery, and the decline in cognitive function.

   15. PAPeter Attia58:40

       Now, why, I mean, this sounds silly, but why a linear relationship given that it sh- it should be nonlinear, shouldn't it? Given that with increase in intimal thickening, you would see exponential change in diameter or in cross-sectional area.

   16. FGFrancisco Gonzalez-Lima58:55

       Mm-hmm.

   17. PAPeter Attia58:56

       Wouldn't that lead to a nonlinear change in perfusion?

   18. FGFrancisco Gonzalez-Lima58:59

       No.

   19. PAPeter Attia59:00

       Which I realize you were talking about cognition-

   20. FGFrancisco Gonzalez-Lima59:01

       Cognition

   21. PAPeter Attia59:01

       ... not perfusion. But yes.

   22. FGFrancisco Gonzalez-Lima59:03

       Not perfusion.

   23. PAPeter Attia59:03

       Yeah.

   24. FGFrancisco Gonzalez-Lima59:04

       The reason there is not a linear change with perfusion is what you alluded to. We have an autoregulatory mechanism. Has-

   25. PAPeter Attia59:12

       I get it, that basically can start to autocorrect, at, at least try to dampen it.

   26. FGFrancisco Gonzalez-Lima59:17

       Tries to. Tries to.

   27. PAPeter Attia59:17

       Yeah, dampens it from an exponential problem to a linear problem. That's a beautiful, beautiful example of biology.

   28. FGFrancisco Gonzalez-Lima59:23

       So as, as the artery becomes stiffer with the thicker walls, it's just like if you imagine somebody having a hose that is releasing water and then you stick your finger in front of the hose, and you can see how the water is coming at a faster place. So this is one aspect that, but this is the autoregulation. The body's trying to achieve that. It does that when the walls becomes stiffer because of the thickening. When you have the systolic pump that they're supposed to comply or arterial compliance, they don't do that. So even though you may see the lumen being the same size, in other words, the hole being the same size, but it's not the same size when you have the pulse, the bolus of blood going through that it has to open up. However, when we increase blood pressure, we have a constant process of trying to increase blood pressure to maintain that same level of perfusion. This now leads to problems with the capillaries because these capillaries, uh-

   29. PAPeter Attia1:00:27

       So the compensation for the macrovascular disease may actually be driving part of the damage at the microvascular disease.

   30. FGFrancisco Gonzalez-Lima1:00:35

       Yeah. You're pushing now with a higher blood pressure through capillaries, and this creates a pathology at this boundary we call the endothelial walls. And these endothelial walls are now subjected to mechanical pressures that they were not designed to do, and you have extravasation, and you have cells that normally are only engaged when we have like a hemorrhage, like the platelets to try to coagulate. Now they start sticking to these endothelial walls and compromising some of the microcirculation as a consequence of. So the, the autoregulation cannot compensate, and it creates additional problems as time goes by. And that's why you are actually better off with less blood pressure by controlling your high blood pressure than with more, even though you're trying to make up for the decreased blood supply.
8. 1:08:56 – 1:18:23

   Mitochondrial Respiration and Cytochrome Oxidase

   1. FGFrancisco Gonzalez-Lima1:08:56

      What would be ideal to me would be what i- the main purpose of that circulation from the point of view of energy is to bring oxygen to the tissue, tissue oxygenation. It is only through this process of reducing oxygen to water that in mitochondrial this process is linked, this cellular respiration is linked to the production of chemical energy. So the more direct measurements would be measurements of oxygen consumption, but also could be the enzyme that is responsible for that oxygen consumption, and that's where it comes to our work and what we found in the brains of those Alzheimer patients. We found that the enzyme called cytochrome oxidase or cytochrome c oxidase-

   2. PAPeter Attia1:09:50

      Which is complex four in the-

   3. FGFrancisco Gonzalez-Lima1:09:52

      Correct

   4. PAPeter Attia1:09:52

      ... electron transport chain.

   5. FGFrancisco Gonzalez-Lima1:09:53

      The electron transport is the, the last rail, the last and the rate limiting enzyme and the one that actually reduces oxygen to water that is linked to oxidative phosphorylation, the creation of ATP.

   6. PAPeter Attia1:10:08

      Let's pause for a moment to make sure people understand this. It's so important that even though I think I've talked about this before, it's worth reiterating. The mitochondria has an inner and outer membrane, and these have four complexes. Three of them span both the inner and outer membrane. Well, I believe it's one, three, and four. Complex two is only on the inner membrane. These things are about the most essential elements of life. Interrupting their activity for even moments at a time is the end of life.

   7. FGFrancisco Gonzalez-Lima1:10:36

      I would say is the key to aerobic life on the planet.

   8. PAPeter Attia1:10:40

      [chuckles] Yeah. I, I, uh, you can't overstate the importance of the electron transport chain. As you pointed out, it is basically, you know, we can't create energy out of nothing. We simply change its form, and so when we eat food, we're eating stored potential energy that is in a chemical form-

   9. FGFrancisco Gonzalez-Lima1:10:59

      Mm-hmm

   10. PAPeter Attia1:10:59

       ... that is generally between the carbon-carbon, carbon-hydrogen bonds. As these things get reduced to simpler and simpler molecules, this process specifically within the mitochondria takes these units and it, by breaking apart the chemical bonds, creates an electrical gradient by shuttling electrons outside of this membrane as they go from complex one, two, three. And of course, they each come with their own reducing agents.

   11. FGFrancisco Gonzalez-Lima1:11:26

       Mm-hmm.

   12. PAPeter Attia1:11:26

       I spend my most time thinking about complex one-

   13. FGFrancisco Gonzalez-Lima1:11:29

       Sure

   14. PAPeter Attia1:11:29

       ... which is the NADH, NAD shuttle.

   15. FGFrancisco Gonzalez-Lima1:11:30

       Mm-hmm.

   16. PAPeter Attia1:11:31

       But I believe complex four is NADPH, isn't it? Is that what it's using as the electron acceptor donor?

   17. FGFrancisco Gonzalez-Lima1:11:36

       Yes. I, I need to emphasize from what you're saying so people understand, the whole purpose of that chemistry that is done with the foods that we eat is to generate electron donors, electron donors that are gonna donate their electrons to the electron transport, and there are only two of them, the NADH and the FADH. And the NADH primarily it donates to different parts of the electron transport systems, but the other one, the FADH only to complex two, so you have like two entry points, complex one and two, and then you go to three and four.

   18. PAPeter Attia1:12:14

       And that's why complex two doesn't span the full membrane. It's sort of sitting there only on the internal.

   19. FGFrancisco Gonzalez-Lima1:12:18

       And it's much smaller than complex one is the largest one. So this is a key. This is a biochemical key to this phenomenon because what we eat from an energy point of view, it just becoming electron donor. So it's can we donate electrons to the electron transport? If we could do that, we can accelerate respiration because the ultimate electron acceptor in nature is oxygen, and that's what we call oxidation, the process of removing electrons from another chemical.

   20. PAPeter Attia1:12:46

       And so making water out of-

   21. FGFrancisco Gonzalez-Lima1:12:50

       Out of oxygen

   22. PAPeter Attia1:12:50

       ... out of oxygen and these protons that are being donated-

   23. FGFrancisco Gonzalez-Lima1:12:54

       Mm-hmm

   24. PAPeter Attia1:12:54

       ... is the ultimate byproduct of respiration. That's why we breathe out water vapor.

   25. FGFrancisco Gonzalez-Lima1:12:58

       Correct.

   26. PAPeter Attia1:12:59

       And of course, all of this is in service of creating an electron gradient to then fuel the generation of-

   27. FGFrancisco Gonzalez-Lima1:13:06

       Yes

   28. PAPeter Attia1:13:06

       ... adenosine triphosphate, ATP.

   29. FGFrancisco Gonzalez-Lima1:13:08

       Yeah. Yes. What the mitochondria have done is coupling this affinity of oxygen to take these electrons that are coming from the food that we eat into a closed system in which the electrons, when they are moving from one complex to the other, they are releasing what is called a proton that is positively charged. And this is trapped in that intermembrane between the two membranes that you mentioned, the outer and the inner one. And the matrix of the mitochondria, the more innermost portion is primarily negative in electrical charge. Ions are negative. So these protons are trying to move. They are attracted towards this negativity, just like when you have the poles in, in a magnet, the positive and the negative pole. This is what we call electromotive force. There are only very few forces in nature like gravitation, and this one is electromotive force. So the system was designed in such a way that the protons will leak through a hole, and that hole or pore is this complex five. And complex five is designed so that when it... the proton is pushing through to get from the inner... Excuse me. From the-

   30. PAPeter Attia1:14:36

       From the outer
9. 1:18:23 – 1:33:55

   Inducible Cytochrome Oxidase Inhibition in the Alzheimer's Brain

   1. PAPeter Attia1:18:23

      So do you think that this is the first insult then? 'Cause you talked about this-

   2. FGFrancisco Gonzalez-Lima1:18:28

      Correct

   3. PAPeter Attia1:18:28

      ... slightly different type of microvascular disease that is much-

   4. FGFrancisco Gonzalez-Lima1:18:31

      Yes

   5. PAPeter Attia1:18:31

      ... more chronic and insidious and doesn't lead to acute changes like hemorrhage or occlusion.

   6. FGFrancisco Gonzalez-Lima1:18:37

      Yes.

   7. PAPeter Attia1:18:37

      How does that change ultimately impact the ability of the mitochondria to do its job and facilitate electron transfer?

   8. FGFrancisco Gonzalez-Lima1:18:46

      Yes. You put your finger on it. This is what links this phenomena. Regardless of whether the chronic hypoperfusion or the more acute, one of the things that happen is when we have a hypoxia situation, cytochrome oxidase is an inducible enzyme. What that means is that our body only maintains As much as is needed, as much as is demanded. It's a complex of 13 different subunits, three of them mitochondrial DNA derived and the other 10 from nuclear DNA. And y- you can regulate it at many different levels, including both the nucleus or mitochondria. But essentially, within minutes, if, for example, you have an area of ischemia, you occlude the blood vessel, half an hour later, you lost a significant amount of cytochrome oxidase from being functional.

   9. PAPeter Attia1:19:38

      And that's irreversible then?

   10. FGFrancisco Gonzalez-Lima1:19:40

       No, it is not irreversible. That's the, the advantage of the system. The system works on demand. It may not be immediately reversible. It depends on, on the level of regulation. In other words, you can simply inhibit the enzyme and the enzyme is still there. Or you can disassemble the catalytic units of the enzyme, the ones from mitochondrial origin, and then you have a partial enzyme, now the so-called holoenzyme. Or you can eliminate the other components and throughout the mitochondrial inner membrane, you have all of these gradiations of stages that can be used for regulating this. So you can regulate it a more immediate way, or eventually you need, you know, proteins transported from the cytoplasm to be shipped where the mitochondria are and incorporated into this. Why was this done? Because mitochondria have a symbiotic relationship with the cells that they live on, and this was created to develop a dependency. The mitochondria are doing this, but they cannot do it on their own. The cell has to found a way to obtain the energy, but it's conditional on them contributing a component that is necessary for the entire machinery to work. The important portion here is that these phenomena are coupled. As soon as you have hypoxia, ischemia, you reduce, then this machinery goes down regulated.

   11. PAPeter Attia1:21:11

       Is that true of complex one, two, three as well? Are they also inducible the way complex four is?

   12. FGFrancisco Gonzalez-Lima1:21:17

       Not as much as complex four. They are to a certain degree, if you keep taxing the system, it's gonna happen. But the one that has the more flexibility from more immediate to long term because of this role as rate limiting is complex four, and that's the reason it is preferred modulator of the system.

   13. PAPeter Attia1:21:38

       That's why I love doing these podcasts. Every single podcast, I get to learn something new in biology that I didn't know. I had no idea that complex four was inducible to a greater extent than the others.

   14. FGFrancisco Gonzalez-Lima1:21:50

       Oh, yes. As it is, for example, you may have heard for sure during your training about other inducible enzymes-

   15. PAPeter Attia1:21:57

       Yes, of course

   16. FGFrancisco Gonzalez-Lima1:21:58

       ... the cytochrome systems-

   17. PAPeter Attia1:21:59

       Yes

   18. FGFrancisco Gonzalez-Lima1:22:00

       ... in the liver. So the liver is, uh-

   19. PAPeter Attia1:22:02

       P-four-fifty, the most inducible of them all

   20. FGFrancisco Gonzalez-Lima1:22:04

       P-four-fifty. So it's a perfect example. You know, if you have more to- if you drink more alcohol, you're gonna build up more of these cytochrome enzymes. So these are the most inducible enzymatic complexes that we have.

   21. PAPeter Attia1:22:16

       You just never think of it in something so important. Not that the liver's less important, of course, but the ETC is so fundamental for everything [chuckles] that we do. It's so interesting to think of that. And it's also interesting to hear you say that at least in transient periods of ischemia, this is not irreversible.

   22. FGFrancisco Gonzalez-Lima1:22:33

       No, it's not irreversible. It's an inducible system just like you stop, uh-

   23. PAPeter Attia1:22:37

       Just like the liver, as you said

   24. FGFrancisco Gonzalez-Lima1:22:38

       ... drinking alcohol. The, these enzymes are gonna be down-regulated. But if you start challenging the system again, they, they are inducible and they're g- gonna go back. Of course, you're gonna suffer somewhat in between because at the beginning you're not gonna be able to meet the demand. But it... They are inducible and this is the key that I have understood from our investigation of the Alzheimer's brain. In those fresh frozen Alzheimer's brain, the main problem was cytochrome oxidase inhibition. The levels of the protein levels of the enzymes were not compromised, but you could see that the enzyme was not in its catalytic functional state, and you could demonstrate this using enzyme histochemistry.

   25. PAPeter Attia1:23:23

       If you were able to extract at the moment those patients died-

   26. FGFrancisco Gonzalez-Lima1:23:28

       Mm-hmm

   27. PAPeter Attia1:23:28

       ... their cells in culture and now they're perfused, would they have still been hypofunctioning? In other words, would you still have been able to measure a deficit of oxygen utilization?

   28. FGFrancisco Gonzalez-Lima1:23:39

       Yes. Yes. Yes. And, and this has been done. Groups have taken... Actually, what they've taken is mitochondria, and they can then see that these mitochondria are not performing this cellular respiration from Alzheimer's patients.

   29. PAPeter Attia1:23:53

       Give me a sense of what is the magnitude of the deficit to result in the phenotype that we-

   30. FGFrancisco Gonzalez-Lima1:23:59

       Okay. Okay
10. 1:33:55 – 1:38:42

    Risk Factors, Head Trauma and a Common Mitochondrial Denominator

    1. PAPeter Attia1:33:55

       Do we have any insight into how much mitophagy or autophagy, autophagy is going on in the later stages of Alzheimer's disease? In other words, is it possible that so much of this damage is now due to defective cleaning up of the mitochondria? Because the more these mitochondria are damaged-

    2. FGFrancisco Gonzalez-Lima1:34:15

       Yes

    3. PAPeter Attia1:34:15

       ... the more mitochondrial DNA is getting released. The mitochondrial DNA itself is actually looks bacterial, so it elicits an immune response. This probably accelerates the process. It would seem that anything that would increase mitophagy or autophagy would at least be able to curb the progression of the feedforward loop on this damage going and, and accelerating. Wouldn't that-

    4. FGFrancisco Gonzalez-Lima1:34:39

       Yes

    5. PAPeter Attia1:34:39

       ... make sense?

    6. FGFrancisco Gonzalez-Lima1:34:40

       I agree. However, it's too late. If you already compromised the machinery for obtaining the energy, it's too late at that point. So my focus on the focus of Jack DeLaTore and other people is how can we intervene? For example, one way is in the risk factors that have to do with the cardiovascular compromise. Try to intervene with the risk factors.

    7. PAPeter Attia1:35:05

       Besides blood pressure, what do you view as the most important risk factors then?

    8. FGFrancisco Gonzalez-Lima1:35:11

       I think atherosclerosis is a really important risk factor, and the major blood vessels you indicated, like the carotid, the ascending aorta, and the renal arteries, they are the large blood vessels are the, the main targets of these atherosclerotic processes, especially at the bifurcation points. The other factors that I would consider would be generalized trauma to the brain.

    9. PAPeter Attia1:35:39

       Yeah, I was gonna ask you about this. This seems to bear an uncanny resemblance to chronic traumatic encephalopathy.

    10. FGFrancisco Gonzalez-Lima1:35:47

        Yes. Yeah.

    11. PAPeter Attia1:35:47

        Where the difference is if you're a football player or a boxer, you have repeated short bouts of hypoxia.

    12. FGFrancisco Gonzalez-Lima1:35:55

        Mm-hmm.

    13. PAPeter Attia1:35:55

        It appears from my reading of the literature that every time you're getting hit in the head, you're having a transient interruption of blood flow.

    14. FGFrancisco Gonzalez-Lima1:36:02

        Mm-hmm.

    15. PAPeter Attia1:36:03

        And also it appears based on at least the animal models, we're seeing transient insulin resistance at the level of pyruvate dehydrogenase. So a blow to the head will transiently make it harder for pyruvate to turn into acetyl-CoA, which is the opening substrate in the-

    16. FGFrancisco Gonzalez-Lima1:36:23

        Krebs cycle. Yes

    17. PAPeter Attia1:36:24

        ... the Krebs cycle. And so while the patients we're describing, who presumably let's just make math simple and say they never get a concussion or a hit in the head, they have this chronic, insidious disease process. The athletes who are suffering this type of injury are getting punctuated by spike functions of these, and it doesn't have to be a concussion every time. It could be each play on the, the field or something like that.

    18. FGFrancisco Gonzalez-Lima1:36:46

        Right. Right. Yeah.

    19. PAPeter Attia1:36:46

        Do you think there's an overlap in these processes?

    20. FGFrancisco Gonzalez-Lima1:36:48

        Oh, yes. Completely. This is what's called dementia pugilistica originally, and often nowadays this is confused with Alzheimer's disease and Parkinson's disease. In the case of Parkinson's, it's because when with the blows to the head, there is a rapid twisting of the head when you get a blow to the head, a rapid twisting, bending of the head with respect to the neck, and that, uh-

    21. PAPeter Attia1:37:14

        Yeah, it's an angular momentum that usually causes that injury

    22. FGFrancisco Gonzalez-Lima1:37:18

        ... and this affects the midbrain and the upper brainstem, and actually that's what leads to the knockout.

    23. PAPeter Attia1:37:24

        That would feed more into a Parkinsonian phenotype in the midbrain than you'd see-

    24. FGFrancisco Gonzalez-Lima1:37:29

        Correct

    25. PAPeter Attia1:37:29

        ... substantia nigra. Yeah.

    26. FGFrancisco Gonzalez-Lima1:37:30

        You will be isolate in that region as more vulnerable for this, but it is the same phenomena. All of these forms of dementia will have a common denominator at some point, regardless of the many different ways that you can impact the system The most likely common denominator would be at the level of the mitochondrial respiration. And therefore, another way, for example, the circulation may not be a good target for neurotrauma. But if you find a way to facilitate mitochondrial respiration, even if there's compromised hypoperfusion or some other condition, and this is what I've been working on for many years. And once we discovered that the main problem in the Alzheimer's brain had to do with this inhibition of cytochrome oxidase, we set out to how can we intervene? Is there any way? And-

    27. PAPeter Attia1:38:26

        And you have two interventions that you have now coupled that both work on cytochrome c, but in a slightly different way.

    28. FGFrancisco Gonzalez-Lima1:38:34

        Yes. Cytochrome c oxidase. Cytochrome c is the carrier, and cytochrome c oxidase is the large enzyme.

    29. PAPeter Attia1:38:40

        The, the, the large complex. Yeah. Thank you for clarifying.

11. 1:38:42 – 1:51:11

    Methylene Blue: Ehrlich's Magic Bullet and Its History

    1. FGFrancisco Gonzalez-Lima1:38:42

       So the first one, I use a pharmacological approach because I was more familiar with those approaches, but I couldn't do it with regular. Most of what is called neuropharmacology or psychopharmacology is really aimed at neurotransmission receptors and agonists and antagonists. What's needed here is something that's acting at the level of mitochondrial respiration and reviewing all literature from the 1960s, I found out that methylene blue commonly used compounds in the lab was able to act as a electron donor. And depending on the conditions, but if you make it in a very low concentration, it acts as an electron cycler. It will donate, but it will also get electrons from other compounds, and it will continue to feed into the electron transport as an alternate route. And in fact, if you block, for example, complex one with rotenone that you're interested, still the electron transport can proceed going through methylene blue as a bypass.

    2. PAPeter Attia1:39:50

       Because in a normal organism, complete blocking of complex one would be fatal. You're saying with a high enough concentration of methylene blue, you can still-

    3. FGFrancisco Gonzalez-Lima1:39:59

       Oh, yes

    4. PAPeter Attia1:39:59

       ... get electrons past the bottleneck of complex one.

    5. FGFrancisco Gonzalez-Lima1:40:02

       We, we can prevent in, in animal models degeneration. We've shown this in many preparations. We first did it in, in the retina because it was more accessible, and we could manipulate that locally as a model of the brain, and then we did it in the brain. So...

    6. PAPeter Attia1:40:17

       So this has an interesting history, right? There's a guy named Paul Ehrlich who studied this, right?

    7. FGFrancisco Gonzalez-Lima1:40:21

       Yes. [chuckles]

    8. PAPeter Attia1:40:22

       And the only reason I remember this is I read-

    9. FGFrancisco Gonzalez-Lima1:40:24

       One of my heroes.

    10. PAPeter Attia1:40:26

        Really? Yeah. Well, I read something that, that I love where expressions come from, and so there's an expression, balls to the wall.

    11. FGFrancisco Gonzalez-Lima1:40:33

        Mm-hmm.

    12. PAPeter Attia1:40:33

        Which means like going very, very fast all out. And, and most people don't realize, but it just refers to a governor in a train where the governor, the faster that the train was going, these balls that were hanging on, you know, basically cables would move further and further out as the centrifugal force goes. And once they touch the wall, that's the mechanism that would regulate the speed and slow it down. But there's another expression that comes from Ehrlich's work, which is, uh, is it a magic bullet?

    13. FGFrancisco Gonzalez-Lima1:40:57

        Magic bullet. And he referred to methylene blue as a magic bullet. And Ehrlich, Paul Ehrlich, he worked in Berlin, Berlin, Germany, and he was able to be part of a very progressive group at the time. And-

    14. PAPeter Attia1:41:13

        This was before World War II. This was in the-

    15. FGFrancisco Gonzalez-Lima1:41:15

        Yeah. The, this is-

    16. PAPeter Attia1:41:16

        Actually, this is in the late 1800s, right?

    17. FGFrancisco Gonzalez-Lima1:41:17

        No, no. This is in the late 1800s.

    18. PAPeter Attia1:41:19

        Yeah, yeah, yeah.

    19. FGFrancisco Gonzalez-Lima1:41:20

        Yeah, 1886 he was working on this, and he injected... At that time was the beginning of the Industrial Revolution, and the first thing in the Industrial Revolution that was developed were the textiles, being able to manufacture clothing. And one of the important things was the transition from using natural products for dyes to develop chemists developing synthetic dyes. And actually, Germany led this process, and methylene blue was one of the synthetic dyes, uh, blue dye. And for many decades it was the blue dye used in blue jeans and most of the other blue clothing. So one of the things that intrigued Paul Ehrlich was that he injected methylene blue, one of these new synthetic dyes, into a live, live rat. And then he dissected the animal. After killing the animal, he dissected the animal, and he found out that the methylene blue, this was a large concentration intravenous injection, was primarily staining nervous tissue, the brain and peripheral nervous tissue. So he created the concept there of a magic bullet. This is a chemical that... Remember, this is in the 1880s. This is a chemical that I'm giving systemically, yet it is somehow finding its way to the nervous system, and it's becoming trapped there, as you can see by the stain. Later, this phenomenon was called supravital or vital staining, and it was exploited, for example, by Santiago Ramón y Cajal, one of my other heroes during this time. He referred to this as the Ehrlich reaction.

    20. PAPeter Attia1:43:06

        Mm-hmm.

    21. FGFrancisco Gonzalez-Lima1:43:06

        To be able to stain nervous tissue when the animal was alive. But what does it mean, the animal being alive? The animal respiring, the animal using oxygen. So methylene blue, they didn't know this, but methylene blue has affinity for these redox reactions that are happening in a maximized way inside the mitochondrial in the electron transport chain. And at especially at low concentrations, it becomes trapped for periods of hours inside mitochondria. It can work as a mitochondrial stain.

    22. PAPeter Attia1:43:39

        Does it become toxic at a high... What, what does the toxicity look like at a higher dose?

    23. FGFrancisco Gonzalez-Lima1:43:43

        Yes. Yes. At a higher dose, instead of acting as an electron cycler, it actually replaces oxygen In the... You know, it competes with oxygen. You remember that I told you oxygen was the one that was taking the electrons. So he can be... You want it to have it in a low concentration that is giving electrons and taking electrons at the same rate.

    24. PAPeter Attia1:44:06

        But you're saying at a higher dose it becomes a proton acceptor.

    25. FGFrancisco Gonzalez-Lima1:44:09

        Little. Little, yes, because it competes with oxygen, and it oxidizes the tissues. And actually, that was in part the first application that Ehrlich found for methylene blue.

    26. PAPeter Attia1:44:23

        So that's interesting because the only time obviously that I've ever seen it used is for treating methemoglobinemia-

    27. FGFrancisco Gonzalez-Lima1:44:29

        Yes

    28. PAPeter Attia1:44:29

        ... in the emergency room.

    29. FGFrancisco Gonzalez-Lima1:44:30

        Yes.

    30. PAPeter Attia1:44:31

        So if someone is exposed to carbon monoxide, you know, acutely or even chronically over a long period of time, this basically breaks it apart. So there you actually want it to sort of out-compete oxygen a little bit, right? Is that what's happening there?
12. 1:51:11 – 2:05:58

    Regulatory Status, Purity and the LMTM Trial

    1. FGFrancisco Gonzalez-Lima1:51:11

       Well, yes and no.

    2. PAPeter Attia1:51:11

       I mean, there's clinical trials that are going on to study this in Alzheimer's disease.

    3. FGFrancisco Gonzalez-Lima1:51:15

       Let, let... Yeah, let me clarify that because what happened is that methylene blue was being available for 120 years plus. So methylene blue was grandfathered by the FDA. It preceded the creation of the FDA. So the FDA has not been able to resolve well how they deal with these grandfathered drugs. Being the first synthetic drug available so it was used for many things. I'm not gonna go into all of them, but malaria was probably the, the most important one until some Spanish and French explorers in South America discovered from the bark of the tree quinine, and then that happened and it became the next generation after methylene blue. Nowadays they're bringing back the methylene blue, especially in Africa because there the plasmodium has become resistant to quinines, so they are combining it. So there's a comeback for methylene blue in that, uh, s- respect. So it is used me- medicinally for that. But the FDA never really got to have a say in on it. So what you're referring to is what has survived in the... what is called the US Pharmacopeia, these compendiums of medications with indications. And in the US Pharmacopeia, that indication of methylene blue for methemoglobinemia has survived. Some of the others have been removed, like I told you, for urinary bladder infections when the antibiotics became available. But it's being used to protect the brain. You mentioned cancer early before we started the interview. Many of the drugs that are used for chemotherapy have side effects that affect the brain, in particular mitochondrial respiration. So methylene blue given before or during chemotherapy interventions have been found to be lifesaving. One example is one called ifosfamide. So ifosfamide induced encephalopathy happens in this chemotherapy and, uh, there are many papers on this. However, the problem is the FDA will not acknowledge these uses because there is no pharmaceutical company who is bringing these materials.

    4. PAPeter Attia1:53:38

       I guess this is sort of an, an impossible situation to understand because the FDA can't really consider the approval for an agent or a use without an investigational new drug filing, an IND.

    5. FGFrancisco Gonzalez-Lima1:53:50

       Oh, yes. Yes.

    6. PAPeter Attia1:53:51

       There's no IND, I assume, for methylene blue because there's no economics in methylene blue.

    7. FGFrancisco Gonzalez-Lima1:53:56

       Yeah. There, there is no company that wants to invest because it's, it's not patentable. They cannot protect their... with a patent. So anybody can manufacture methylene blue and prescribe it or use it. In some countries like Canada, it's freely available. Here in the US it's unclear what its status is, but you can get it through the internet. The problem is there are two problems. One, you have different purities. So you have at least three categories of purities for methylene blue. The one that should be used by in humans like in the, the... for in the emergency room is the so-called pharmaceutical quality or the US we call USP grade. The Europeans have a similar, but the one in the, the USP is actually more restricted than the European methylene blue. Then there is chemical quality that is used in laboratory-

    8. PAPeter Attia1:54:53

       In the lab, yeah

    9. FGFrancisco Gonzalez-Lima1:54:53

       ... for staining. But that can go for, for example, the one produced by Sigma has about 15% impurities. It should not be given to live animals or humans and is readily available. So I always want to warn against that. And in many experiments with animals they use that Sigma product.

    10. PAPeter Attia1:55:14

        So we don't know if we're confounding the results of the experiments with the impurities.

    11. FGFrancisco Gonzalez-Lima1:55:18

        And impurities are very toxic. It has lead, it has mercury, it has cadmium, it has a number of neurotoxic impurities. And then the other one is even less pure is the industrial-

    12. PAPeter Attia1:55:29

        Color the jeans

    13. FGFrancisco Gonzalez-Lima1:55:30

        ... to color the blue jeans and all these things, and that is even more than 15% impurity and nobody knows for sure.

    14. PAPeter Attia1:55:37

        Now, there was a company in Scotland several years ago that ran a compound, LMTM, and the trial Which was announced... Results of this trial were announced about two years ago, and it was a big hoopla because the study, which I went back and skimmed the other day 'cause I knew we would probably... I was hoping we would talk about this. The study basically took patients in early stages of dementia, randomized them to various interventions, but one of them was this agent, this LMTM, which they describe as a methylene blue derivative. I don't know how far a derivative it was. Might have been not much of a derivative.

    15. FGFrancisco Gonzalez-Lima1:56:14

        It's essentially... Do you remember when I told you I added ascorbic acid-

    16. PAPeter Attia1:56:18

        Yeah, yeah

    17. FGFrancisco Gonzalez-Lima1:56:18

        ... and reduced methylene blue? So they've done something like this. They have reduced methylene blue, but they don't use the name methylene blue. They use the name of, uh, methylthioninium chloride, which is a more chemical name, and that's where the MT comes. And then the L is for the leuco.

    18. PAPeter Attia1:56:36

        Because it's clear. It comes in-

    19. FGFrancisco Gonzalez-Lima1:56:38

        Yeah, it's

    20. PAPeter Attia1:56:38

        ... its reduced form.

    21. FGFrancisco Gonzalez-Lima1:56:39

        That's the form that is in the pill.

    22. PAPeter Attia1:56:41

        As soon as it's in the body, it's oxidized.

    23. FGFrancisco Gonzalez-Lima1:56:43

        Yeah. It starts these redox cycles.

    24. PAPeter Attia1:56:45

        And those patients did void blue.

    25. FGFrancisco Gonzalez-Lima1:56:48

        Oh, yes. So it is clear that it's doing the redox cycles.

    26. PAPeter Attia1:56:52

        Now, what was very controversial about this was the primary endpoint of that study-

    27. FGFrancisco Gonzalez-Lima1:56:58

        Mm-hmm

    28. PAPeter Attia1:56:58

        ... was a neuroimaging outcome, and the primary output failed. There was no difference on neuroimaging. There was a secondary outcome on cognitive function, and in a subgroup analysis, which again, the statisticians will say that's... They cry foul, right? And understandable.

    29. FGFrancisco Gonzalez-Lima1:57:20

        Sure.

    30. PAPeter Attia1:57:20

        You can't start parsing the data.
13. 2:05:58 – 2:13:59

    Near-Infrared Light to Boost Cytochrome Oxidase

    1. FGFrancisco Gonzalez-Lima2:05:58

       No. No. I don't have a good point of view. What I can tell you is we found another way to try to intervene with mitochondrial respiration using light, in particular infrared light that can go through the tissues. And the photons in the near infrared light are absorbed by cytochrome oxidase. It turns out that cytochrome oxidase, that's the name cyto cell, but chrome color is because of it absorbs certain wavelengths, and it reflects others. So it's the chemical in the cell that gives color to the cell. And this property of photonic absorption, we have used in conjunction with the laser delivery of near infrared light transcranially through the forehead as a source of photons that actually oxidizes, photo oxidizes cytochrome oxidase. And by doing that, the enzyme has more affinity. That's the confirmation of the enzyme that has more affinity to oxygen for oxygen consumption.

    2. PAPeter Attia2:07:04

       Yeah. I just pulled out a picture that we'll make sure we link to in the show notes that comes from one of your papers actually where it shows in the same figure a close section of the mitochondria, and you can see the effect of methylene blue and also the effect of near infrared light. Now it strikes me as interesting that you can get the wavelength just right because you have to be able to get through not just the tissue but the skull itself.

    3. FGFrancisco Gonzalez-Lima2:07:27

       Actually, the skull is less of a problem. It's easier to go through skull.

    4. PAPeter Attia2:07:30

       Because it's porous because of the bony matrix or...?

    5. FGFrancisco Gonzalez-Lima2:07:33

       Um, because there is less circulation through it. One of the big chromophores that we have is hemoglobin.

    6. PAPeter Attia2:07:39

       I see. So hemoglobin can absorb and reflect much of this light before it actually reaches the neurons.

    7. FGFrancisco Gonzalez-Lima2:07:44

       So what we try to do is we move away from this peak of absorption, so oxy and deoxyhemoglobin to one that is still can be absorbed by cytochrome oxidase.

    8. PAPeter Attia2:07:56

       To how many nanometers then?

    9. FGFrancisco Gonzalez-Lima2:07:57

       We use one thousand sixty four nanometers wavelength, so around a thousand, which is a wavelength that is not very well studied In biochemistry, most of the spectrophotometers in biochemistry, they do not go all the way to one thousand.

    10. PAPeter Attia2:08:13

        Yeah, they're in the hundreds usually.

    11. FGFrancisco Gonzalez-Lima2:08:15

        Yes, they usually end up-

    12. PAPeter Attia2:08:16

        Three hundred to eight hundred or something to that effect.

    13. FGFrancisco Gonzalez-Lima2:08:18

        Yes. But the longer the wavelength, the more it penetrates to the tissues.

    14. PAPeter Attia2:08:24

        How do we know how safe that is? I'm sure somebody listening to this is gonna say, "Wait, that sounds like microwaving my brain." Like how, how...

    15. FGFrancisco Gonzalez-Lima2:08:32

        No, no.

    16. PAPeter Attia2:08:32

        Of course, it's a different wavelength.

    17. FGFrancisco Gonzalez-Lima2:08:33

        Yes.

    18. PAPeter Attia2:08:33

        No, I understand. But as the, as the sort of layperson, this sounds very scary, right?

    19. FGFrancisco Gonzalez-Lima2:08:37

        Yeah. Microwaves move in the other direction, but the longer the wavelength, the, the less energy they carry, so the less they can penetrate. So they cannot really penetrate inside atoms like the ones that have short wavelengths. But they are good enough to penetrate to the tissues, not very deep, and only about one to two percent, if we do it transcranially through the head, actually goes through to the surface of the cerebral cortex. Once in the cerebral cortex, the white matter is also a barrier, so the effect of the photons is primarily in the gray matter layer of the cerebral cortex. And what it does is it... You're donating these photons to the electron transport, so you're bypassing the electron donors by... The photons are not identical to electrons, but they act in the similar way in the electron transport. So the photons and the electrons are very similar. The difference is that the electron ca-carry a very small mass. The photon essentially do not have mass. And by providing photons to the electron transport, you keep the electron transport going because these enzymes engage in the redox changes. And the more photons you send to cytochrome oxidase, the more of the enzyme quickly goes to the oxidized conformation, and that oxidized conformation is the one that has more affinity to bind oxygen.

    20. PAPeter Attia2:10:08

        But I don't understand how is this actually making its way systemically to the brain through a transcranial stimulation?

    21. FGFrancisco Gonzalez-Lima2:10:15

        When you aim through, for example, the forehead, it goes through the tissue and reaches the surface of the cerebral cortex, and that's how it makes its way. It's more localized. It's different from... It's not a systemic administration like methylene blue.

    22. PAPeter Attia2:10:33

        And is it enough to just be able to hit the frontal cortex to create a clinical improvement without impacting the mitochondrial function deeper in the midbrain or lower part of the cortex?

    23. FGFrancisco Gonzalez-Lima2:10:46

        To create a functional improvement. We don't know yet about clinical. Especially, I would not say, uh, that in somebody with the degree of atrophy that many of the Alzheimer's patients have, we're gonna have enough substrate there to be able to stimulate and reverse the disease. So this will have to be tested with clinical population.

    24. PAPeter Attia2:11:12

        Are, are there clinical trials that are going to be looking at this near infrared light-

    25. FGFrancisco Gonzalez-Lima2:11:16

        Yes

    26. PAPeter Attia2:11:16

        ... strategy combined with-

    27. FGFrancisco Gonzalez-Lima2:11:17

        Yes

    28. PAPeter Attia2:11:18

        ... methylene blue?

    29. FGFrancisco Gonzalez-Lima2:11:19

        No, not combined.

    30. PAPeter Attia2:11:20

        You don't think of these as synergistic. You'd consider these separate approaches?
14. 2:13:59 – 2:25:29

    Prevention Through Ketones, Fasting and Metabolic Strategies

    1. PAPeter Attia2:13:59

       In addition to this idea of all the things that matter in the heart, so lower smoking, lower blood pressure, better glycemic control, better management of lipoproteins, et cetera, et cetera, is there anything that you see as unique in the brain specifically that is maybe not unique or maybe not as important in the prevention of cardiovascular disease?

    2. FGFrancisco Gonzalez-Lima2:14:19

       The only one that I would say will have to do with the ketogenic diet. Ketogenic diet will facilitate mitochondrial respiration in a different way, but this will contribute to targeting mitochondrial respiration so that the brain will benefit more than the heart. The heart will benefit, of course. All of these tissues will benefit, but because of the brain reliance on aerobic metabolism. For example, you alluded, for example, on insulin resistance. One of the problems that happens as the brain ages, even in normal people, is that the transport of glucose is affected. So even though we can increase glucose levels in the blood or what we're eating, we cannot get that glucose being transported to the brain as effectively as in the younger individuals.

    3. PAPeter Attia2:15:14

       That's why some of these studies with intranasal insulin administration show transient improvement in symptoms, presumably because they're becoming resistant to glucose.

    4. FGFrancisco Gonzalez-Lima2:15:24

       Yes.

    5. PAPeter Attia2:15:25

       Now, that's obviously not a long-term solution.

    6. FGFrancisco Gonzalez-Lima2:15:27

       No.

    7. PAPeter Attia2:15:27

       But it illustrates a p- a point.

    8. FGFrancisco Gonzalez-Lima2:15:29

       And unfortunately, insulin primarily facilitates glucose transports in other tissues other than the brain. The brain actually doesn't require insulin. It can boost its transport of glucose, but the reason for that is that when you wake up in the morning that you have been fasting overnight, whatever levels of glucose are circulating in your blood, then the brain tissue will be the only one that will be able to take that up. And it's only when you have large glucose levels that then insulin is released by the pancreas, and then all the tissues then can use it, can feast on it. So the ketogenic diet, so ketone bodies can act as an alternative source for energy in the brain. And the, the important point is that even though glucose is a preferred substrate during aging, this is compromised, this uptake. However, the uptake of ketone bodies is not compromised. Therefore, you could satisfy some of these nutritional requirements by adding the ketone bodies to the diet.

    9. PAPeter Attia2:16:42

       Do you think it matters if a person is on a ketogenic diet or if they're on a non-ketogenic diet but they supplement with exogenous ketones?

    10. FGFrancisco Gonzalez-Lima2:16:51

        I hope it doesn't matter. As long as you have the ketone bodies available, you don't require to have the ketogenic diet itself. But this eventually will have to be resolved empirically. And there is no question that this is gonna promote mitochondrial respiration. And we know, as you know, when we're born as infants, we rely primarily for neural function and, and everything else on, on these ketone bodies produced by, by the liver, but because of the kind of lipids that we get through the mother's milk. So essentially, what we're trying to do is bring in somebody who is in old age to rely more on ketosis. That is a process that we know exists under physiological conditions every day. If we go beyond, you know, 12, 14 hours without eating, we, we start generating this. But it's something that we know in infancy is the primary source for the brain.

    11. PAPeter Attia2:17:51

        I didn't realize that. Is that more a result of their livers not being able to release enough glycogen via glucose and hepatic glucose output? I mean, I, I know they have a very high demand for energy.

    12. FGFrancisco Gonzalez-Lima2:18:02

        Yes.

    13. PAPeter Attia2:18:03

        Can you measure the ketone in their blood?

    14. FGFrancisco Gonzalez-Lima2:18:05

        Yes, but it is because of the source of food that they're taking.

    15. PAPeter Attia2:18:09

        I see. So they're basically getting medium-chain triglycerides through the milk.

    16. FGFrancisco Gonzalez-Lima2:18:12

        Exactly. Yes. The medium-chain triglycerides being the main source there for energy conversion as opposed to some of the other triglycerides that-

    17. PAPeter Attia2:18:20

        So the original Bulletproof Coffee is actually mother's breast milk before it is-

    18. FGFrancisco Gonzalez-Lima2:18:25

        That's right. [laughs]

    19. PAPeter Attia2:18:26

        ... the, the fancy coffees that everybody drinks.

    20. FGFrancisco Gonzalez-Lima2:18:28

        Yes. So I do believe that that's another alternative. So in essence, you could potentially have pharmacological interventions that address mitochondrial respiration, but they will not have to be classic pharmacology like neurotransmitter-based pharmacology. They will be more of a metabolic pharmacology. You can have near infrared light by providing this photonic stimulation. However, that one is targeted. It's not systemic like you pointed out, so one will have to find the target. Luckily, the forehead is more accessible. We don't have hairs, and we can target that prefrontal cortex that shows the initial cognitive difficulties as people become older, and that's what we have been doing. And then the third one will be through the diet, which you facilitate, because as you pointed out, the insulin resistance is because our glucose levels are going up because we cannot transport it into the tissue, especially nervous tissue, which was the primary consumer as effectively, and then we have these high levels of glucose for longer times, so there's more insulin that is being released, and then this desensitizes the receptors. So there is a natural development of metabolic syndrome as we grow old because of this phenomenon. This manifests itself then as less substrate for energy for the brain, and then you have a cognitive decline accelerated associated with obesity and hypertension and this insulin resistance. So it's all part of the same age-related picture. And probably people eat more because they are trying to make up for this lack of energy that the brain is consuming. And if any organ is more liable to influence our eating behavior, it will be the neural tissue.

    21. PAPeter Attia2:20:23

        That's such an interesting thought because I've always believed as, as you've suggested that I think our appetite is driven by fundamentally important physiologic processes, and starvation would be the most important among them. And starvation in the modern world doesn't look like starvation in the prehistoric world. Starvation in the modern world can be in the presence of obesity because we're not talking about the obvious, we're talking about the cellular level. And so if cellular metabolism is deficient, which is often the case in insulin resistance, an individual can be functionally starving and that can drive it. Now I've always thought about it through the lens of the liver, but you're making an argument that says there's also a central starvation-

    22. FGFrancisco Gonzalez-Lima2:21:03

        Yeah

    23. PAPeter Attia2:21:03

        ... that could be also driving these-

    24. FGFrancisco Gonzalez-Lima2:21:05

        Yes

    25. PAPeter Attia2:21:05

        ... repetitive changes.

    26. FGFrancisco Gonzalez-Lima2:21:06

        Yes. But there are also peripheral components, like you say. For example, the case of the obese. An individual that has obesity will, by almost definition, will have downregulated the ketogenesis. The ketogenesis enzyme will not be upregulated unless you're consuming your own fat. And these are trainable enzymes like inducible-

    27. PAPeter Attia2:21:35

        Yes

    28. FGFrancisco Gonzalez-Lima2:21:36

        ... as well. So if you don't go through periods of fasting, you cannot elevate these enzymes. So somebody who is obese and suddenly stops eating is starved because his body cannot... It doesn't have the metabolic-

    29. PAPeter Attia2:21:53

        That's right. Yeah. In, in the presence of hyperinsulinemia, it is a very painful transition into fasting.

    30. FGFrancisco Gonzalez-Lima2:21:59

        You cannot use your body fat to, to feed especially the brain, which is the first one that is gonna give you these signs and symptoms. So the first thing that somebody has to do is start out by having a periodic periods of fasting that in, in my own case, I do it once a week, usually between Friday and Saturday. I fast for at least 14 or 16 hours. You know, it's not difficult to do if you have an early meal and then a late brunch. You will have significant fasting and you can accelerate that process by consuming some of the circulating glucose if you do a workout that morning. So by doing that, I am allowing my body to build up these ketogenic enzymes and therefore then during a regular day in the week, if I don't eat anything between meals, I don't feel hungry because I can consume my own body fat. And people who are obese cannot do that. They don't have the biochemical machinery to do it. So I believe that's probably the third way of approaching this problem. If those three things could be used, and like I say, it may not be possible to combine some of them, like I will have to empirically determine how much methylene blue one can have systemically so that to not produce a photodynamic effect when I do transcranial laser stimulation. We hope in the future we may be able to do this with LEDs. Right now with the LEDs are commercially available, we haven't been able to find the results that we get, but we, we are investing time in trying to, to change this so it will be safer and cheaper to do. So right now the only ones... So my bioengineering colleagues has been able to collaborate with me and develop a device that we can transcranially do imaging with near infrared spectroscopy and actually measure the concentrations of oxidized cytochrome oxidase in vivo in the human brain. And we published that last year. And this allow us to directly have a measurement that we are indeed engaging our target. And this also will allow us to find what is the optimal dose response for that particular brain because like you indicated, different people have different heads and the transmission would not be equivalent. So this is what we're doing. And so we have obtained three major grants for doing this with the bioengineering group in the Dallas area. For example, Professor Hanley Liu, we're doing the development of these devices to monitor the physiological changes, and this is a grant by NIH that is called the Brain Initiative Program. And then here with my colleague Andriana Halley, we're have a grant from the National Institute on Aging to test this transcranial near infrared light in older people and people with mild cognitive impairment. And then the third has been a benefactor who's giving us large amounts of money so that we can pursue this line of work with the transcranial lasers. And I can show you the endorsement from some of the people in the field.

15. 2:25:29 – 2:32:04

    Research Funding, Trauma Applications and the Case for Methylene Blue Trials

    1. PAPeter Attia2:25:29

       Oh yeah. I'll, I'll take a picture of this and we'll, we'll put this on. In fact, it was actually Jack who directed me to speak with you maybe six months ago. This is exciting. You know, I want to add one other thought to this, which is I hope that if somebody's listening to this who's involved in traumatic brain injury, that someone ought to look into a clinical trial of using methylene blue as a rescue agent during periods of traumatic injury because again, mechanistically it's at least plausible that you could salvage and rescue some of the transient insult and the damage that, that goes through that. And again, there's another example of a disease for which we don't seem to have any solution other than the obvious, which is avoidance of the injury, the insult. But there's still a lot of people out there that are being exposed to repetitive head trauma. And you know, as you probably know, there's been some interesting hypotheses around the presence of ketones in the system before ... traumatic injury and potentially as salvage after. But it, but it seems to me that this methylene blue story probably deserves a bit more attention in other areas given these properties you've described.

    2. FGFrancisco Gonzalez-Lima2:26:35

       I actually agree with you, and I would say because it's used in emergency rooms, I believe in every ambulance [chuckles] you should have methylene blue available. And if there is any insult that compromises metabolic supply to the brain, you're gonna be better off infusing methylene blue at a low concentration. We're talking about one milligram per kilogram concentration that is gonna be neuroprotective regardless of the source of the... It could be transient ischemic attack. It could be in a stroke. We have done this in stroke models in animals using the methylene blue, and we've been able to rescue the majority of the, of the damage produced in the infarct in animal models, in animal models where we look at this longitudinally using fMRI. So we know this works in animals. I've just been unable to convince emergency physicians to start doing this to their ischemic patients, and not only for the brain, but ischemia affecting all the other organs is being also tried in animal models of neurotrauma with the similar benefits. So the problem is there's no interest by the pharmaceutical company because they cannot make money on it. And unfortunately, the NIH is also influenced by if you're using an old drug, essentially you're repositioning this old drug for these other applications as a neuroprotective agent or, more generally, metabolic protective agent. They are concerned that their investment is not going to pan out because when it g- goes to commercialization, you're not gonna be able to patent that medication. And believe it or not, even though if it works, if there is no prospect that profits can be made, they don't want to invest.

    3. PAPeter Attia2:28:29

       Yeah, it's a shame because I, I worry that we'll be in this state of limbo where we're not really gonna know the answer, and we can't know the answer without clinical trials. This is about as easy an agent as there is to study given its long history, its relatively well-understood toxicity profile, and in many cases, the speed with which you could see a response, especially if you're studying ischemic events.

    4. FGFrancisco Gonzalez-Lima2:28:51

       And I will tell you that just a couple of years ago, it was published last year, the group that I collaborated with in San Antonio, we were the first to show the effects of methylene blue in the human brain using fMRI and measuring blood flow and measuring bold signals. And also in those subjects, we did memory testing, and we were able to demonstrate a significant improvement in their memory retrieval just after an acute treatment with methylene blue in a blind placebo control study, the first time that that was done. Contrary to these other groups that are doing it as an anti-tau agent in healthy and older people, we can improve memory, and we can demonstrate using imaging that we can do this through methylene blue. So the only problem is the, there's not gonna be any profit because I believe if some company would like to develop this purity pharmaceutical grade methylene blue, there will be a huge market. Other companies may imitate them, but there is enough for everybody. Still, the cosmetic aspect of having urine that is this color is, is a problem. Many people will not accept it because of that.

    5. PAPeter Attia2:30:11

       [laughs] Yeah. Well, Francisco, this has been great. You've been very generous with your time, and I, I really appreciate this discussion. I've learned a lot, and I'm guessing that people listening to this will have also learned a lot. So we will have a great set of show notes to accompany this where all of the papers that we've talked about, a link to Jack's book, and a number of other things will be included so that hopefully it's a reference for anyone else you want to share this with and certainly anyone listening. So thank you very much.

    6. FGFrancisco Gonzalez-Lima2:30:38

       Thank you, Peter.

    7. PAPeter Attia2:30:39

       [upbeat music] You can find all of this information and more at peterattiamd.com/podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog at peterattiamd.com. Maybe the simplest thing to do is to sign up for my subjectively non-lame once-a-week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, et cetera. On social, you can find me on Twitter, Instagram, and Facebook, all with the ID peterattiamd, but usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. And note, no doctor-patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously. For all of my disclosures, the companies I invest in and/or advise, please visit peterattiamd.com/about.

Episode duration: 2:32:08