163: How Mitochondrial Decline Drives Brain Aging with Dr. Francisco Gonzalez-Lima

In this episode, we are joined by Dr. Francisco González-Lima to delve into the metabolic mechanisms that drive brain aging and cognitive decline.

He begins by outlining how reductions in cytochrome oxidase activity, disruptions in oxidative phosphorylation, and the accumulation of mitochondrial mutations progressively impair neuronal energy metabolism. These metabolic deficits, he explains, often emerge long before the structural abnormalities associated with Alzheimer’s disease.

Building on this foundation, the conversation examines how reactive oxygen species, mitochondrial inefficiency, and altered cortical oxygen utilization contribute to diminished cognitive resilience over time. Dr. González-Lima highlights why these metabolic disturbances provide a more coherent explanation for geriatric dementia than traditional protein-centric models.

The discussion then shifts to emerging therapeutic strategies. Dr. González-Lima reviews evidence for low-dose methylene blue and 1064 nm transcranial photobiomodulation, both of which appear to enhance mitochondrial respiration and support prefrontal function by directly targeting cytochrome oxidase activity.

He concludes by emphasizing the need for metabolism-focused interventions, improved cerebral perfusion, and more precise energy-based frameworks to guide the future of brain-aging therapeutics.

Learn more about Dr. Francisco González-Lima: https://liberalarts.utexas.edu/psychology/faculty/fg

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Transcript

Disclaimer: This transcript was generated by AI and may not be 100% accurate. If you notice any errors or corrections, please email us at phil@longevityroadmap.com.

     So what happens as we grow older? This, uh, whole machinery starts showing, uh, decrements, in particular cytochrome oxidate. And, uh, the mitochondria as a whole is designed that when the certain level of the metabolic machinery does not operate, uh, for the oxygen consumption and the a TP production is self-destruct.

Welcome everybody. This is Buck Joffrey with the Longevity Roadmap Show and, uh, today very fascinating show. Dr. Francisco, uh, Gonzalez Lima. We are gonna talk about what I, I think it's an incredibly interesting topic, which is, uh, brain metabolism and what happens, uh, to brain metabolism as as we age. In other words, the brain is an incredibly high energy consuming organ.

Uh, at the, if you remember from Bio 1 0 1, or if you've, uh, you know, maybe you're more advanced, uh, as a, uh, science person, but the, um, you know, the power centers of the cells or the mitochondria. And if you also remember from biology, there's the electron transport change. That chain that creates a TP, which is sort of the central, you know, energy fuel.

Um, Dr. Lima's, um, research focuses on that, um, the mitochondria and, uh, these, uh, the electron transport chain, especially, uh, the last part of that chain, which involves, uh, an enzyme called saro oxidase. And, um, this show gets into the weeds. And so if you really like science, you're gonna like it. And we might not understand a hundred percent of it, honestly.

There, there is. Um, we, we do get into detail, but I think the big picture is that essentially you've got this, this paradox of, you know, aging when it comes to, um, mitochondria. Mitochondria. Inherently, when the mitochondria function the way they're supposed to do and the electron transport chain function the way it's supposed to, it releases, uh, uh, reactive oxygen species are free radicals around it.

And you probably know, you probably heard that those can actually, uh, create, uh, tissue damages within the cells, uh, within the DNA of the mitochondria itself. And so. It's in a machine that's somewhat inefficient and that, you know, uh, the byproducts of it are, are actually damaging the mitochondria itself.

So the dilemma then becomes, well, how do you potentially intervene with that? So we talk a, a lot about is research in that space. Uh, and we focus on a couple of different, um, interventions. One of 'em, uh, with Methylene Blue, uh, which, you know, I know some people are using Methylene Blue, uh, as a supplement.

I do not. You know, I, I just think one of the reasons that I don't, you will learn about from the show, because the idea here is methylene Blue potentially can be. Helpful at lower doses, but at, you know, if you don't get that dose right, it could actually be harmful. The other thing that we talk about in the show is the role, I think more interestingly, uh, of, of light, of, uh, specifically of near infrared light, uh, that is delivered, uh, to the brain through the skull.

And, um, the potential promise of that. I've heard quite a bit about that. And, uh, some very promising things about that in terms of cognition and pretty healthy people who just want to feel sharper and that kind of thing. At any rate, this, uh, this is a long show, uh, but if you like science, if you are into getting down in the weeds of, of this kind of stuff, I think you're gonna love it.

We'll have this show right after these messages. Hey, longevity enthusiast. It's time to take it to the next level. I've been fine tuning my longevity regimen for years, and I look better and feel better than I did a decade ago. In fact, my blood work is even better than it was back then, and it's all because of my data-driven regimen, and it's inspired me to create a course in community just for you.

It's called the Longevity Roadmap, and I urge you to check it out. If you're tired of your belly fat, tired of being tired, or just wanna optimize yourself for the next 50 years, visit longevity roadmap.com. That's longevity roadmap.com. Welcome back to the show, everyone. Today my guest on the Longevity Roadmap is Dr.

Francisco Gonzales Lima. He's a, so, uh, George I. Sanchez Centennial Professor at the University of Texas at Austin, uh, internationally recognized for his pioneering work on brain energy metabolism, mitochondrial function, and the role of. Cytochrome oxidase in cognition, memory, and aging. His research has helped, uh, shape how we think about neurodegeneration and the science of maintaining brain health across the lifespan.

Thank you so much for joining us. My pleasure. So, um, Dr. Gonzalez, Liam, and why, why don't we start with this. How did you, uh, start getting interested in the study of brain energy metabolism and its, uh, role in aging? Well, the first steps,

uh, happened, uh, long ago, about more than 40 years ago. Uh, when I realized the relevance of, uh, energy, uh, for brain function.

And, uh, in the early days, uh, my interests were more in, uh, narrow endocrinology when I was an undergraduate, uh, at Tulane University. And that was a wonderful time because, uh, I had an experience my last, uh, summer there. Working on, uh, under honor thesis that, uh, with, uh, a group, uh, that discovered, uh, some of these, uh, neuropeptides, uh, this hypothalamic hormones.

Uh, they shared the Nobel Prize, uh, only a few months after I left the lab. And, uh, this, uh, was the beginning of my interest of how, uh, neural function and metabolic functions were linked. And, uh, when I was, uh, then, uh, working for my graduate degrees and, uh, as a postdoctoral, uh, humble fellow in Germany, I really, uh, grew, uh, my interest.

And, uh, in that German group, uh, we were the ones that, uh, developed the Fluor Deoxy glucose, uh, method, uh, in animals, uh, that was used as a. The first, uh, functional, uh, narrow imaging mapping technique that I was translated to humans, uh, using, uh, pet positron emission topography. So for the first time, we were able to map metabolic function, not only in animal brains in vivo, but also in humans.

So that was the beginning of, uh, the field of, uh, functional narrow imaging. And it's all based on, uh, metabolic markers nowadays, more so in, uh, hemodynamic or blood

flow related changes. You, uh, you mentioned, uh, the importance of brain metabolism, uh, uh, when it comes to brain function, obviously very important.

So in the big picture, kind of give us a sense for, even in non-disease states, what, what is happening over time as we age, uh, to brain, uh, metabolism? Yes. Uh,

there are, uh, many phenomena that happened, uh, during aging, but, uh, focusing on the energy metabolism

mm-hmm.

Uh, one of the most prominent, uh, changes is, uh, what happens with our mitochondria.

The mitochondria, these, uh, intracellular organelles. They are, uh, in a symbiotic relationship, uh, within our cells. They are there, uh, to provide this energy in the form of, uh, adenosine phosphate or a TP, uh, in exchange. The cells provides, uh, just about all of their needs. Uh, but, uh, they originated, has bacteria.

So for example, their DNA is not a double helix, is a circular, uh, DNA and to maintain the symbiotic relationship, mitochondria only have a very limited amount of DNA. On their own that is devoted for the proteins that they need to survive and produce the energy. And then the rest have to come back from proteins that are, uh, derived from nuclear DNA and chip into the mitochondria.

So the mitochondria is something that we have in every cell, and the more energy demanding as cell is, the more mitochondria we have. What happens as a function of aging is that, uh, some of these, uh, mitochondria starts accumulating, uh, defects. Some of these defects are linked to their, uh, so-called cellular respiration in the process of so-called oxidative phosphorylation, especially when you have excess, uh, oxygen that is not fully reduced into water, that becomes a reactive oxygen species, and there is a key enzyme there.

This is the last enzyme in this so-called electron transport chain that is the one that, uh, converts, uh, or catalyze the reaction of oxygen into water. So when water is fully reduced, it's not reactive, but that reaction is the one that is coupled with the oxidation of an ene to

produce, uh, a TP. And that is a cytochrome oxidase, correct?

Yes. Cytochrome oxidase, or sometimes it's called cytochrome C oxidase or complex four, the terminal complex of the electron transport and the rate limiting enzyme for oxygen consumption. So what happens as we grow older? This, uh, whole machinery starts showing, uh, decrements, in particular cytochrome oxidate and, uh, the mitochondria as a whole.

It's designed that when the certain level of their metabolic machinery does not operate, uh, for the oxygen consumption and the a TP production, this self-destruct, so for example, cytochrome uh, oxidase or cytochrome c oxidate, the name comes because there is a very small protein that is called, uh, an electron carrier cy from C that passes that electron to cytochrome c oxidase and which passes to oxygen.

Oxygen being the ultimate electron sector is the one that is pulling all of these electrons through. Mm-hmm.

So, so in the big picture, just to summarize, so make sure everybody's on the same page that, you know, basically you've got, um, uh, you know, the brain is very, very, uh, energy. You know, it requires a lot of energy, a lot of consumption of energy.

People know in general, the mitochondria, you know, we talk, we talk about it as the, you know, this energy production centers, you learn that from basic biology and the electron transport chain is a big part of that. Electron transport chain has a unique thing in that it's, it, it actually creates, um, free radicals, creates reactive oxygen species, which it needs to do because that's kind of what the reaction is.

But then in the process ends up damaging itself. And in particular, you're looking at damage to, um, the last, uh, the last step basically in, in, in the reaction, which is through this enzyme cytochrome oxidase and cytochrome oxidase itself. Seems to get am am I right? It, it seems to be damaged more in these as we age.

Uh,

yes. Yeah. Uh, that will be the, the simpler way to put it. Yes. Uh, but, uh, since it can no longer take up this, uh, cytochrome c in an efficient way, uh, then the, the membrane of the mitochondria that maintains all of these, uh, organelles and cellular membranes and mitochondrial membranes, they have permeability to certain, uh, compounds on ions.

So this permeability changes and, uh, when the efficiency of the electron transport is compromised, and then the cytochrome c the little, uh, electron carrier protein leaves is able to go out. And this, uh, cytochrome c. Not the big enzyme of the little, the little electron carry becomes a signal for the cell to self-destruct, thereal and apoptotic signal.

So the system is designed that the mitochondria that are defective and the cells harbor more of this, uh, will eventually be eliminated. But what, and, uh, in order to try to compensate for this, when a mitochondria starts having lots of, for example, uh, mutations in their in, uh, circular, DNA is start to try to divide more, divide at a faster pace.

So as time goes by over the years, then what you end up having is what it's referred to as a icic. In other words, some mitochondrial lines. The healthier one, you end up having less. You end up having more of the one that carries some of these point mutation, they're still viable, but, uh, they are, they're reproducing at a faster rate because the only cells with a couple of sections that can reproduce to renew themselves in our body are these, uh, neurons.

They carry this, uh, defective mitochondria that are piling up and becoming a greater proportion of the overall, uh, amount of mitochondria. And this is, uh, often referred to as the mitochondrial of period of aging that is very closely linked to the so-called free radical theory of aging. Because the free radical is the reason that the mitochondria are developing these, uh, mutations and the mitochondria failing and generating this disproportionate, larger.

Amount of defective mitochondria is what is, uh, resulting in this metabolic compromise. The, so this is, uh, really the connection between the mitochondria and this aging related compromise in the ability to produce energy using oxygen. So

is there a reduction in the brain in, in, well certainly you've, you've talked about, you know, a reduction in fully functional, uh, mitochondria because you know these, because of these mutations.

But is there, uh, an actual reduction in total number of mitochondria as well? No, uh, the total number is actually increased.

Okay. And, uh, we

know 'cause it's trying to overcompensate maybe.

Yeah. Trying to overcome. So for example, uh, when this happens in muscle where it's another tissue, there are lots of mitochondria in mitochondria disorders.

Are more pronounced that this slower, uh, change that I uh, mentioned that happens, uh, over the years. Uh, one of things you see in this tissue is, uh, more mitochondria, uh, but more defective mitochondria. So ironically they have more mitochondria, but uh, they have less capacity to produce aerobic, uh, or oxygen

dependent, uh, energy.

The analogy I think of is like in heart failure, you know, you have inefficient pumping and then the heart gets bigger. In that case, it's hypertrophy, not hyper, you know, but, uh, but you're basically trying to make up, you're trying to compensate, um, correct. And comp, yeah. Right.

Phenomenon. Uh, so this happens, uh, uh, during aging and uh, it is something that if we could.

If we could do two things, if we could reduce the amount of these, uh, oxygen free radicals that are the ones that start this cascade of free radicals, uh, but at the same time, uh, maintain our levels of energy production a TP production, this is, uh, what becomes then the ideal situation. For example, some people, uh, that are doing research, they, they will tell you, well, kalo restriction will lower the level of this, uh, oxy oxidated damage.

However, uh, when you do that, yes, you get less oxidated damage or you get less a TP production, less energy production.

Yeah. The paradox in the whole thing is that we need that, we needed to do what it does, and it, it creates the very thing that. That destroys it or that mu, you know, that cause mutation. So that's, I guess, the therapeutic challenge or that's the, you know, that's the challenge in science is how do you thread that needle?

Right. Well, we, we have been able

to, to, uh, to overcome the challenge because the key for this problem is in this, in cytochrome, uh, oxidase itself. Because what is producing the oxygen free radical is when you don't have enough cytochrome oxidase in the active form, the so-called hollow enzyme that is able to reduce, capitalize the reduction of oxygen to water.

That, for example, if you are doing exercise, you accelerate your oxygen consumption. You may reach a point where you go like,

yeah, yeah, yeah. Mm-hmm. There,

there is enough, uh, air and enough oxygen there. But the limiting factor that is not allowing you to produce more a TP is that you already saturated the capacity of the available cytochrome oxidase in your mitochondria.

So that's the rate limit in there. So whe normally when we accelerate, uh, the rate of, uh, oxygen consumption, then some fraction of oxygen would not be fully reduced, and this would, well, for example, superoxide. Uh, and, uh, and then there's a cascade to try to add some hydrogens to make it, uh, from, for, for example, from superoxide to, uh, hydrogen peroxide to hydroxy radicals.

It's trying to make it into water. The body with other enzymes. So this is to call antioxidant enzymes, but in reality, the major and first antioxidant enzyme is cytochrome oxidate itself. So what you need to do is upregulate cytochrome oxidate function to minimize then the, the production of this, uh, reactive oxygen species because you have more enzyme.

So if you increase your breathing rate, your demand for more energy, you will have less of these, uh, reactive oxygen species that are,

uh, being formed. What are some of the interventions that you're looking at, uh, to, to, you know, to tackle this issue? Yes. Uh,

the first intervention that, that we used was following a pharmacological model.

Uh, try to see is there any chemical that can, uh, intervene and act on this process? And this is what led us, uh, to, uh, methyl and blue, but not just methyl and blue in general, but, uh, low dose methyl and blue because only the low dose is, uh, has the capacity When you administer that to an organism like a human, uh, to reach an equilibrium between the oxidized and the reduced forms of, uh, this, uh, chemical dye.

And when it reaches an equilibrium, it just, uh, cycles electrons, uh, between the two forms, the oxidize and the reduce. But these electrons, he takes from the immediate environment that is, uh, surrounding the chemical, and he can also, uh, he can also provide those electrons to the surrounding other chemicals.

So what is the magical about this, and I'm using this term as it was the first w uh, way that it was referred to, uh, when metal and blue was, uh, first injected in a living animal. It was a living rat. Uh, and then, uh, the animal was dissected. The surprise was that the blue, uh, was, uh, concentrated, uh, in the nervous system through, in the brain and other parts of the nervous system throughout the body.

So it had a, it has this, uh, redox cycling low that happens with low concentration as an affinity to get inside. Highly respiring cell. Sure. Cells, where is, is a mo uh, a high opening of electrons to oxygen. And these, uh, in, in, in reality, it not only just gets inside the cell, but it concentrates inside mitochondria where that electron transport and exchange is happening with the oxygen that we are chipping into this, uh, cell respiration.

So it is, even though it's administered systemically, it goes and concentrates, uh, has a mycardial stain and, uh, and which is primarily localized in the nervous system. Of course it goes in any cell that is engaged in cellular respiration, but it's just a large concentration that what leads to that, uh, visible.

Uh, appearance when you look at it. So there you have a chemical that does this. I have not been able to find any other chemical that has this property. It's called auto oxidizing, but an auto oxidizing property that are very low concentration reaches this equilibrium.

Obviously, we know it, it gets to the brain.

And, and what the, the, the, the, the theoretical purpose or benefit is there, I mean, what, what kind of things have you actually seen in terms of metabolism or, you know, related to the health animal? Well, uh,

two, two things. Uh, first, in order to be able to monitor these things, I have to develop a quantitative, uh, histochemical technique, uh, for looking at the brains of annulus.

Mm-hmm. And, uh, this I did, uh, long ago. It was the first, uh, quantitative histochemical technique, uh, develop. Uh, and is based on enzyme histochemistry. In other words. The more concentration of this working enzyme that is in the tissue, in the nervous tissue, the more oxygen that can be consumed. And one can tie this osis with another chemical that changes its color, uh, the more oxygen consumption that is going on.

And then you set this up in a way that there is a linear relationship between the oxygen consumption, the concentration of the active enzyme, and this, uh, changes in optical density in the tissue. So this allow us to study these changes in animals and, uh, manipulate animals, for example, give them the, uh, metal and blue and low concentrations, see directly the effect on cytochrome oxidase in the tissue.

And then we move from there to humans. The reason I wanted to do this in humans is in healthy people, this should be a benefit to be able to accelerate, uh, mitochondrial respiration. Uh, but also I was motivated by, uh, one of the dissertation works of one of my student, uh, Joan Palla, that in which, uh, we analyze the fresh, uh, frozen brains from Alzheimer's patients in order to do this.

It was a unique, uh, study. Uh, we couldn't get this fresh, uh, postmortem brains, uh, from anywhere in the world, including all these brain banks. It was too late, uh, uh, this postmortal tissues. So we went to a place, uh, in Arizona, it's called Sun City, Arizona, uh, where, uh, retired people live there. They have a healthcare system there where they get the donations of this, uh, brain and they can quickly, uh, freeze them.

And we also were there, uh, when the pathologist, uh, was, uh, informed that there was somebody as, uh, to, to certify death. Uh, we will be there. Uh, we'll, uh, remove, uh, the skull and, uh, take the brain. And, uh, my job was to, uh, dissect the brain in parts, uh, that could be identifiable and labeling everything. And I collaborated them with the scientists there, the sun, uh, city, uh, health Institute.

Uh, and I will give them a, a piece, uh, for this region and I will get another piece. And when I have all of these things, uh, with my, uh, student, uh, we ship everything through Austin. Then we start analyzing how what we found, uh, is what we suspected from the, uh, human functional neuroimaging studies, particularly the PET studies that were telling us that there were this energy deficiency in the brain of these Alzheimer's patients when they were alive.

And, but the major change was a decrease in cyro oxidase activity. And we, histochemical could demonstrate this directly on the tissue. And this was particularly, uh, pronounced in the superficial layers of the cerebral cortex. And, uh, these are the layers where we have the largest, uh, decrement and atrophy of, uh, neurons as we grow old.

And, uh, these, however, the main problems of these brains, uh, were, uh, were not due. We're not correlated with things like the amyloid deposits or the narrow fial tangles. So this was a phenomenon that was happening independently of, of these changes. In other words, they, uh, it, it was the opposite situation.

The reason the convention was being impaired was because of an energy metabolic failure. And this was related to mitochondrial compromise. It was not that there was some abnormal protein that was damaging the cells and then was leading to these. So in other words, uh, we saw this opposite of what is the dogma in the field of Alzheimer's from their home.

Yeah. So

is the suggestion that somehow, um, and I, you know, I've heard this theory in, in the context of, you know, people talk about type three diabetes and all that with, with, with. Brain metabolism of, of glucose. But is, is the thought then, is the, the idea potentially that the decrease in, uh, metabolic capacity and these neurons is causal and that, you know, the other things that we're seeing, the structural changes may be sort of secondary to the initial consequential.

Yeah. You, uh, are right. That's exactly, and uh, we, we got, we like to call this the scientific theories, but, uh, what I can tell you is that, uh, we, uh, have seen that in animal experiments where we can test causality. That that's exactly

what's happened in theory. Doctor, wouldn't you be able to, uh, then induce some of these structural changes in animals by, by hurting, by, by creating problems with cyro oxidase?

Oh, yes. Uh, and this was, uh, uh, long ago, uh, it was, uh, the first, uh. After we did these findings, uh, the first so-called Alzheimer's disease animal model was, uh, inhibition of, uh, cytochrome oxidase activity using, uh, mitochondrial toxin. And, uh, and, and, uh, these animals will start developing. You have to do this, uh, at a very low level because if you stop, uh, if you inhibit more, uh, I will say you could go up to a third of the overall mitochondrial cytochrome oxidase activity inhibition.

But if you go beyond that, you'll die. To give you an example, the most, uh, classic metabolic poison in the world is cyanide. What does cyanide do? Cyanide. Directly inhibits cytochrome oxidase inside the mitochondria. It occupies the binding side where oxygen is normally going to be located in order to be reduced to water.

And by, by producing this so-called allosteric innovation, you quickly die. Uh, and, uh, so you can only reduce this, uh, but not, uh, entirely, uh, inhibit this. Or like, uh, using a genetic approach, uh, mutating the enzyme in such a way that, uh, it, it is not viable. You don't have a viable organism, but, uh, you can reduce it pharmac, uh, pharmacologically, and then demonstrate the animals start showing first the problems, uh, with, uh, memory problems as.

Start out with short-term memory problems, and then the, the problems are moved to more recent memory, to more long-term memory.

Do they result in the, you know, the neurofibrillary tangles and all those things? Well,

that's, that's where the, where the same is different. Uh, we don't see any significant amount.

In other words, uh, we don't see any causal relationship between cognitive impairment and amyloid and, uh, deposits. I would not say neurofibrillary tangles because neurofibrillary tangles, when they are inside a neuron, that neuron is metabolically dead. In other words, uh, that neuron, uh, is a ghost. You may still see it.

Uh, but inside it has this, uh, Tao fibrillary proteins that do not allow the neuron to, uh, operate. And eventually it would just, uh, be, uh. Remove, uh, but the so-called extracellular concentrations of this, uh, amyloid, like the petta amyloid, it is a phenomenon that start happening as a compensation for this, uh, decline in this, uh, energy metabolism uhhuh and that we see.

And in fact, uh, you use

t amyloid, you do see amyloids. Yeah, yeah. You see

amyloid. But this happens as a consequence, right, of this, and it doesn't happen at the beginning. It happens, uh, later on. Uh, for example, if you look at the, uh, embryonic brain in which, uh, there is a lot of, uh, neurons that are dividing, but there is a lot of, also of ne of neurons that are being TriMed down that, that are dying.

So there you see the largest amount of beta amyloids, uh, in our brains is when the brains are developing. So we know, uh, beta amyloid is. A reaction, a consequence to this, uh, neuronal losses that are happening. And it's not a part of the council events that are leading to the dementia. And this is a major difference between, uh, the individuals like me and others are, uh, sponsored the so-called vascular, uh, hypothesis of, uh, dementia.

And I have defended, uh, along with them, uh, that these are the most important things that are leading to the common type of dementia that within all age, what I refer to as geriatric dementia, which is not Alzheimer's disease, like originally, uh, defined by a Lois Alzheimer's, uh, in a younger, uh, patient.

Uh, it's, uh, it is a confusion. Uh, that has, uh, set back Alzheimer's research for over 50 years.

Um, going back to your, your, um, you know, your, your discussion on methylene blue in, in, in this model, um, you would think that there might be some promise for methylene blue to slow down the advancement of Alzheimer's disease.

Well, only if it's done properly that that is using a low dose that leads to this, uh, out oxidizing cycling equilibrium. The problem is that in vitro, if you use metal and blue, you can, for example, you can reduce the aggregation of tau in the, in the test tube. And it is a, is a linear function. The more metal and blue you have, uh, the less tau aggregation that happen.

That was the finding. Uh, discovered by, uh, British scientists, but then they led to their idea that methyl and blue could be an anti-tau aggregation agent. And then they started doing, uh, clinical trials with high levels of methyl and blue. That yes, they have this anti-tau aggregation property, but at those levels they're toxic and they do not have any of these metabolic, uh, properties that I told you.

That is the properties of being able to donate electrons to the electron transport and to reduce oxidated damage and increase, uh, a TP production. So by using methyl and blue, but instead of using low dose methyl and blue, uh, they are are not achieving. So. Ironically then in their clinical trials, they were using very low dose methyl and blue as a control for the ones where they're given the pharmacological levels that in vitro would produce more, uh, reduction in aggregation.

And the patients who benefit, uh, were the ones getting the control low dose methyl and blue. And they were ones getting the higher ones, uh, were not benefiting. And also there was a confound in some of those trials, uh, were methyl and blue was not used as a monotherapy, but it was used in combination with the so-called Alzheimer's drugs, like cholinesterase inhibitors and mementine, which in fact do harm to the brain more than benefit brain function.

In geriatric dementia patients. So in those studies, this, uh, confound and what they found in those studies was when VIR was, uh, used at a low dose and as a monotherapy, then there was a benefit, the cognitive benefit. But if they combined it with these other drugs that are working against energy metabolism and have metal and blue, uh, higher doses that are creating toxicity and are not benefiting energy metabolism, then uh, so this was probably, in my opinion, the worst thing that could have happened to methyl and blue.

Yeah. They looked at it maybe the, through the wrong lens. Right. So,

yeah. And, and that's why I always say methyl and blue is a hormetic, uh, drug that is. Low concentrations and high concentration. It has opposite effects. Yeah. Completely opposite even for the most common use that is in the emergency room,

right?

For carbon monoxide poisoning. Right. So

yeah, carbon monoxide poisoning, cyanide poisoning, any of these metabolic poisoning, uh, that interfere with either oxygen transport or oxygen utilization. Uh, if they give a low dose methyl and blue, they can prevent what is called met hemoglobinemia, which is maybe caused by this carbon monoxide.

Uh, by displacing the, that run the heme part of the hemoglobin, uh, the hemoglobin carries the oxygen. So if we imagine this is the oxygen, the hemoglobin carries the oxygen. The other heme protein that rec receives. The oxygen is cytochrome oxidase. It also has the he group, uh, same area. So this is what happening through our blood hemoglobin caries, and then inside the mitochondria, this gets it, and then it converts it to water the poison.

These portions that I'm referring to are affecting that, uh, pocket, that heme pocket. So, but if you give a high amount of methyl and blue, you induce meth hemoglobinemia. In other words, uh, there is so much, uh, methyl and blue that it actually competes with oxygen instead of just displacing it, uh, from the hem, uh, component of the protein.

So this is something that needs to be understood and that group, uh, that led to these studies and created a company be, uh, around it, never understood this even though they had all the scientific, uh. Research available to them. And not only that, I think one of the consultants was one of our former trainees who explained this to them and who told them, uh, you cannot do this.

Uh, and they did, uh, some, uh, monkey uh, experiments where they were using these larger doses and large doses. She explained to them, this is just gonna be toxic and, and damage the, the, the monkeys and kill them. Sure enough, uh, it was a disaster. Uh, and uh, so they, what they did is that they use as high as they could get away with, uh, with the toxicity.

Thinking always that the more, the better. Or like, just like I I told you with Met Hemoglobinemia, no. The more, the more is not the better. If you get more, instead of saving somebody, you are promoting Met Hemoglobinemia.

Uh. Even in acute conditions. Another type of intervention that you've looked at is photobiomodulation.

Tell everybody what that is and exactly what the, the, how it works and

the type of, uh, photo biomodulation that I, uh, started, uh, investigating. Thanks to one of my, uh, trainees, uh, uh, Julio Ro has this, his, uh, dissertation is an mt. PhD now, professor of neurology, uh, uc, San Francisco. And, uh, he was the one who, uh, indicated to me look, uh, one of, uh, leading, uh, researchers in Cytochrome Oxidates.

Uh, Dr. Margaret Warren Riley has done this in vitro study with retinal cells, canon cells in the retina, and she shows that if you have, uh, mitochondrial toxins, uh, light in the red two near-infrared, uh, is able to antagonize this poison. And, uh, we got interested into this and, uh, did some in vitro work.

But then, uh, we used the eye in a living animal. We did mice and rats. Pigmented eyes, uh, in a living animal has our first testing ground, creating a retinal degeneration that simulates the most common type of, uh, blindness in young people. It's called, uh, livers, uh, optic nerve open. So we knew gang cells will die in response to this, uh, mitochondrial toxin.

And then we injected methyl and blue. Uh, in some experiments and in others, we use the photo bowel modulation in the eyes. And what we found in both cases is that we could prevent this, uh, narrow degeneration. And, uh, so once we saw this. I wanted to do it in the eye first because that way I knew that light was gonna get through, through the back of the eye to the retina.

And uh, then we started experimenting. Can this go through transcranial? And sure enough, in animals, even with the red light, you could have it transcranial. And we could demonstrate this. We could, uh, take the brains out. We could measure cytochrome oxidase activity. We could measure oxygen consumption. We could put, uh, a, a probe inside the frontal cortex and in whole measure that the changing oxygen consumption, we were convinced and test the animals.

For example, if it is a visual, uh, function, you can test visual discrimination. You can see that the animal can improve or you can prevent the visual deficit. You can see the changes at the molecular level. You can see the histopathology, you can see the loss of the neurons, uh, when you don't have it. And essentially you can't prevent that.

Uh, so that encouraged us to, to go transcranial. And then, uh, we published, uh, this, uh, for the first time in the general neuroscience in 2008.

Can I ask, what is the mechanism that, that would be working there? Um, you know, we've been talking about the effects, uh, you know, of, of problems with cytochrome, uh, oxidase.

Cytochrome

C oxidase. Yes. Well, that, that, that's the key Cytochrome oxidase, like the name implies cyto cell chrome color cytochrome oxidase. This large enzymatic complex is the main photon sector. Inside cells. In other words, it's what gives cells the color. It absorbs the light at certain wavelengths and it reflects, uh, the other wavelengths.

So, uh, it absorbs light primarily in this red to near infrared range. And when it does that, those photons are absorbing, they operate in the sense of the electron transport in the same way that adding an electron to the enzyme was working. The photon is just like an electron, but an electron has negligible mass, but the photon has no mass.

So when the photon is absorbed by cyro oxidase, the enzyme emits an electron, and that is taken by oxygen. Oxygen is reduced oxidated for circulation, continuous a TP production. Continues. So it is a way to, instead of donating electrons like metal and blue, you are donating photons that when absorbed by the same enzyme, then if they're absorbed by some other photons, can be absorbed by any chemical.

But those chemicals are not coupled in with this process of reducing oxygen to water that is coupled with oxidative ation and a TB production. So that's what make it important and the fact that that enzyme is the major photo, uh, inside the cell. So that's what what we, and we, we not only, uh, studied this phenomenon in animals, we were able to measure this for the first time, uh, in humans, uh, non-invasively.

We did have developed a technology to do this. We can monitor, we can have sensors here and monitor the levels of this. I refer to this process as photo oxidation of cytochrome c oxidase.

How can you tell, um, you know, what's going on in, are you using some sort of, um, imaging to show what's happening in terms of the effects of the light?

Yeah. Transcranial, we,

yeah. We use a type of optical imaging. You, um, uh, likely have heard about the functional, uh, near infrared spectroscopy. Yeah. Uh, that you can measure, uh, oxygenated hemoglobin Yeah. Versus deoxygenated, just like I was telling you in the example. So the oxygenated hemoglobin, the oxygen strap, when it releases the oxygen, it changes confirmation.

So it in the same, uh, hemoglobin, depending on whether it is, uh, oxidized or D or, or, uh, oxygenator or deoxygenated. It, uh, changes colors. Mm-hmm. So that, that what gives you the blue and, and the red, uh, blood, the, the deoxygenated and the oxygenated blood. So this is the same technology that you use or oxygen saturation in your finger.

Uh, but over there you are looking at, uh, one or at most, uh, two wavelengths that are absorbed mainly by oxy or deoxyhemoglobin. But in order for this to work for cytochrome oxidase, we created, uh, what is called broad pan near infrared spectroscopy. In other words, uh, you give, uh, a thousand different wavelengths.

And with all of these wavelengths, you create the signature because every chemical has a signature of what, uh, different photon wavelengths. It absorbs. So by doing this, uh, one can. Determine the concentrations of cytochrome oxidase and how these concentrations are changing in, respond to the extortion of photographs.

Mm-hmm.

What do we know from any kind of human trials right now in terms of photo? My, uh, photobiomodulation in terms of potentially improving cognition in elderly or even neurodegeneration?

Sure. Uh, our first, uh, switching from the animal to the human. The first, uh, report of our study was in the 2013 in, in neuroscience, the flagship journal of the International App Research Organization.

And there we show for the first time in a control study, uh, CHAM control, placebo control, blinded that, uh, shining, uh, infrared light that can penetrate through this, the forehead. We use, uh, an optimal wavelength from our studies. What, what would that be? What's that wavelength? 10 64 nanometer 1010. 64. 64.

So you mean there are devices you can get the, you mean 10 64 wavelength? So, yeah. Yeah.

And that's was one of the reasons we use it because, uh, those lasers have been clear as saved for human use for other applications, and we use them in a very low, uh, power levels. To give you an example for, uh, applications, uh, I mean, not destructive, non able, uh, laser applications, but, uh, we, we use only like three and a half watts, uh, in those devices.

Uh, instead of, uh, for other applications you can use like 20 watts. And, uh, so the overall power density. That we delivered through the forehead in humans is, uh, a quarter of a watt centimeter square. And this is a very low intensity, but it doesn't, you don't need more than this, uh, uh, because what you do is that you just continue with the exposure to those photons with more time.

So in terms of optics, dosing is, uh, somewhat different than pharmacology. So energy equals the power, the intensity, uh, multiply by the exposure time like watts by seconds. It gives you energy that is measuring JUULs. Uh, so we can, our dosing is the energy dose and we achieve that by radiating for a 10 minutes.

Uh, that, uh, gives enough, uh, energy dose that you move this, uh, remember about the hormetic dose response that happened in methyl and blue? The same thing happened with modulation. Uh, if you, if you give photons to the system to this, uh, cytochrome oxidase and the electron transport you get, you accelerate the system.

You keep moving those electrons to oxygen, more oxygen consumption, more energy production, but you can overwrite the capacity of the system and then again, lead to oxidative stress. So you can have too much light as well. Yes. But in practice, in an animal or in in vitro, you can demonstrate this, uh, hormetic biphasic dose responses.

But in practice, in the human brain, uh, through the forehead. You cannot be.

Yeah. It's hard to get you too much. Yeah, yeah, yeah, yeah.

You cannot get your, because, uh, the skin start absorbing the light and it start hitting up. And, uh, the maximum permissible exposure is something like one wat per centimeter square.

So we remain into the one quarter of a wat. Uh, but, uh, people would not, uh, stand, uh, being irradiated with a level of light ID light that will actually, uh, be counterproductive for this, uh, cyro oxidase energy production mechanism. So, so it is safe inherently in that way.

How about clinical outcomes though?

What have you seen in actual, you know?

Yes. Uh, so at the beginning we did only healthy junk people. Yeah. And, uh, we did years after year, so we started testing, sustain a tantrum, working memory, uh, category learning. Executive function. Each one of these is a dissertation from one of my students. Also, combine that with aic, uh, aerobic exercise that you can use to improve blood flow oxygenated blood.

So how does it compare with it? Uh, we can do better. Eight minutes, somebody sitting getting this on the forehead, that somebody working out for 20 minutes to their 80 to 90% of their maximum, uh, high rate for their so-called Bio max Ma maximum volume of, uh, oxygen consumption. So then I started to look for clinical populations, which clinical populations.

I wanted to look for clinical population where we know there is a hypometabolism in the prefrontal cortex. So because that's where we're targeted. By the way, we're targeting these, not what other people are doing that are using through the hair, because the hair with the, uh, melanin absorbs these, uh, photons and just hits the, the hair and then the dosing is completely, uh, e kevo equi.

You don't know what's going in. But, uh, that doesn't happen here. And the melanin that we have in the skin, even if we have very pigmented skin, it doesn't make much of a difference because we all, in the, uh, deepest layer of the skin, we have this, uh, melanocytes that are fully loaded with melanin. So those are the, the main, uh, the main barrier, uh, everybody has those.

And the wavelength that we use is the one where we can get the lowest melanin exor. This is the extortion of melanin. Uh, other wavelengths. It starts up and then we keep, continue increasing the wavelength until we find the heat. But before we produce extortion into water that the heat tissue. So we use an narrow optical window where there is the least, uh, extortion by the melanin.

So it can penetrate to your cortical tissue, but it will not hit the tissue either. It is not necessarily the optimal one for the cytochrome oxidase enzyme in terms of its peak of exertion. But if the photons do not get to the nervous tissue, it doesn't matter if they are in the exertion peak of the enzyme.

So it is a compromise that, that we use and we use the 10 64 because it was safe to use, uh, in people, but it's around that, uh, 1000.

So were you able to show any, um, benefits to, to co uh, patients with cognitive decline?

Yes. First, uh, population, uh, that we tried, well, we showed two kinds of, uh, benefits. One, if you have a patient, for example, that have depressive symptoms and you apply to that patient, what, what are called with my colleagues here in clinical psychology, uh, cognitive therapy.

Well, for that cognitive therapy to be beneficial, you have to have prefrontal cognitive function optimize. So when we combine there that, uh, cognitive therapy with the photo vial modulation, you can then benefit. Reduce the symptoms of depression. So in my opinion, that's the best way to use this in clinical populations because the main effect of, uh, facilitating prefrontal function will always be cognitive.

However, it also has emotional regulation top down with steeper, uh, subcortical areas. And, uh, so for example, with anxiety populations, we tried a whole range of anxiety disorders. We refer to a topological, uh, fear. And, uh, alone is enough to produce as a monotherapy to reduce the anxiety by acting on this emotional regulation.

In other words, facilitating that, uh, these prefrontal areas, uh, do the top down regulation.

How about actual cognitive declines, though? I, uh, uh, out of psychiatric.

Yes. Uh, we tried, uh, also bipolar patients. Uh, we demonstrated that we could improve, uh, cognitive functions there, especially executive functions.

Uh, uh, a particular one is called cognitive flexibility. It's, uh, improved. We have published all of these, uh, and, uh, the latest one, uh, we did for these bipolar patients. We use people who they are stabilized from the point of view of their mood. In other words, they're remitted. Yeah. Uh, patients, they are, they are monitored every week.

They, uh, to make sure that this is the case. And then we do a weekly treatment and we improve, uh, their cognitive performance in a whole battery of, uh, neuropsychological tests.

How, how about Alzheimer's? Has, have there been any studies in this yet? Not

my group. Uh. What, uh, we have done is older people with subjective memory complaints.

Sure.

And, uh, in, uh, five weeks, uh, five weekly treatments of eight minutes each is enough to see daily, eight minutes daily. We did the only once a week.

Once a week, eight minutes. Okay.

Eight minutes once a week we could see. And, uh, we had a range of people all the way to 90 years old. We also measured, uh, car ultrasound, uh, ways to try to look at other, uh, phenomena.

Did some FMRI, it is possible to do daily, but, uh, I wouldn't recommend, uh, with the laser. Mm-hmm.

This device that you're using, uh, is this a commercial, something commercially available, Dr. Lima? Or is this still.

Yes. Uh, the first devices that, that we use after we did all the animal experiments, uh, the, the initial devices we were, we made ourselves, especially my, my, uh, older son, uh, my two sons are engineer.

They help me build, uh, this, uh, device for the lab. And, uh, and, but then, uh, we used, uh, a company that was based in Dallas. Uh, the two, uh, people that ran it, one was an MD and his brother was an engineer, uh, retired from, uh, was a nuclear supermarine engineer. They developed this, uh, uh, laser, uh, they went out of business.

Uh, so those were the initial ones that I used. Uh, but uh, now one of the former trainees that I was his, uh, co-advisor who got his, uh, second PhD in, uh. Uh, electrical and computer engineering, uh, from our university. Very talented, uh, uh, student. As you can tell. Uh, he, uh, created his own, uh, company here in Austin.

And these devices that we use that he makes, are tailored to what we found in, in our experiments to work. Uh,

best. What's, uh, what's the company? Just for people or you are curious? Uh, I think it's called

Cy, like C-Y-T-O-N-S-Y-S-I. I'm not, uh, involved in his company. It's former

trainee. No, it's fine. I just, probably some people at this point are like, boy, maybe I'll give this a try.

Well,

they, they have, uh, uh, developed a, a whole line. Uh, they have like a 3D printed thing that goes into the head, but I really just recommend, uh. The forehead, uh, anything else is questionable. Uh, there is a group, uh, in Toronto that does it in other parts. Uh, they do not use the same, uh, our, uh, the wavelengths that we use is the only one for which there is experimental evidence that it actually upregulates cytochrome oxidate transparently in Bibo.

Uh, none of the others, uh, had, uh, been demonstrated to do that in, and in fact, in the particular wavelengths that they use, not, uh, in my group, but, uh, two different groups, uh, one of them, a Chinese group, uh, had for example, try to, uh, test the working memory, comparing in the same populations, the two, uh, wavelengths.

Only the 10 64 produced the benefits, but the one in the eight hundreds, uh, didn't produce, uh, the benefit. And, and we know from the simulation, uh, so-called Montecarlo simulations, where we can simulate the photon penetration that, uh, this, uh, longer wavelength, uh, can penetrate and, uh, in sufficient amount of photons to be, uh, a sufficient energy dose to make a difference as compared to, uh, shorter wavelengths, which are the most popular that you can find out there because it's cheaper to make those other devices.

And of course, they can work in other parts of the body like the skin. Uh, in the skin. You can, you can do the effects even with red light that is in the six hundreds.

Right? Right. Fascinating stuff. Yeah. I mean, uh, the, you know, I guess the, the thing that comes to mind for me, one, I guess one last point, and we've been going for a while, I don't wanna keep you for long, but the, um, mitochondria, from what I understand, this is something I, I, I learned interviewing somebody else, but there they migrate, they can migrate from one cell to another.

Is it, is that true? Yeah,

it is controversial. There is some evidence for it. Uh, but, uh, mitochondrial are very dynamic. They're all the time. That's why we refer to them in plural instead of mitochondrial. Yeah, we use mitochondria because they are fusing with each other and dividing and, uh, forming these little chains all the time.

So, uh, there is some evidence, I, I wish it will be, uh, better validated, but there is some evidence that they can move from one cell to another. That they can even go into the circulation. Uh, and, and, uh, but, uh, some of this evidence happens in environments that may not be our inbivo environment.

Yeah. The, the reason I was asking is, you know, some people I've, I've heard of the concept of, you know, mitochondrial transfusions, you know, like healthy mitochondrial infusions via like maybe using platelets or something like that.

And I, I'm just curious on your thoughts on that, because if the, if you can bring new mitochondria into the circulation and potentially get these mitochondria into where we need it, like, um, you know, new mitochondria, they're healthy. Um, is, is that something you, you know, that, that you've thought about?

Yeah.

Right now? Uh. I, uh, haven't seen the evidence, uh, that that would make me feel, uh, comfortable. But you're right. You know, platelets, uh, can, uh, help transport, uh, mitochondria and, uh, it is, uh, uh, but you know, they have all the roles. So, so, so you have many, too many platelets, uh, is a problem. Yeah,

no, that's a problem.

Sure. Yeah, of course. And, uh, you, and especially when you mention aging, one of the limitations there is your vascular, cerebral blood flow. Uh, we can improve, uh, this mitochondrial function, and in fact, in the older humans that we have tested, uh, the change in the photo oxidation of, uh, of this, uh, rogram oxidation is, uh, larger than in a healthy jump person.

It's just that we start out, uh, with a lower baseline and we have more room for improvement. The, the, the junk healthy person is closer to, uh, ceiling. Uh, you cannot improve, uh, that much. However, the, there is a, uh, a limitation in oxygen delivery 'cause you can have better mitochondrial function. But if, uh, the delivery is compromised, uh, this is, uh, not gonna be, uh, the full story.

So one of the things I, I, uh, what we, we have to add to the mix is improving, uh, perfusion to the, to the brain. And, uh, because you need that oxygen in order for the mitochondria to provide the energy.

Uh, doctor, I, it's been a really fascinating talk to you, talking to you. Thank you for all your time today.

Uh, really interesting conversation. I think people are gonna learn a lot, uh, and uh, yeah, good luck to you on, on your research. And, uh, thank you again for being on the show. Thank you very much. My pleasure. Thanks for listening. A quick reminder that while I am in fact a surgeon, nothing I say should be construed as medical advice.

Now, make sure to include your physician in any medical decisions you make, and also, if you're enjoying the show, please make sure to show your support with the like, share, or subscribe.