EPISODE 230

[INTRODUCTION]

[0:00:01] ANNOUNCER: Welcome to the BetterHealthGuy Podcast, where we take a deep dive into complex chronic conditions and explore ways to build resilience, improve vitality, and achieve better health.

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And now, here's Scott, your BetterHealthGuy.

[INTERVIEW]

[0:00:57] SCOTT: Welcome to episode 230 of the BetterHealthGuy Podcast. If you're seeking new ways to create better health, you are in the right place. Today we explore Lipid Biology, Plasmalogens, and Neurodegenerative Prodromes with my guest, Dr. Dayan Goodenowe.

He is a neuroscientist, biochemist, inventor, and clinical research expert who, in 1999, invented and patented Ion Cyclotron Resonance Mass Spectrometry Technology, enabling comprehensive monitoring of human biochemistry for the first time.

Using this technology, he analyzed blood samples from tens of thousands of individuals of all ages and races from multiple countries. The biochemistry of healthy individuals was compared with that of individuals experiencing a wide range of diseases. Over 20 conditions were studied, including autism, dementia, colon cancer, heart disease, and others. Differences between the biochemistry of younger and older populations, as well as associations with all-cause mortality were also examined.

This body of research identified early biochemical patterns associated with disease and mortality risk, thereby contributing to the development of an extensive patent portfolio. These patents cover diagnostic tests for early detection and screening across numerous conditions including specific cancers, neurological disorders, psychiatric conditions, and cardiovascular disease. He is also the author of Breaking Alzheimer's, which documents his research journey and examines the biochemical findings that informed his work in neurodegeneration and lipid biology.

In part one of our discussion here in episode 230, we talk about lipid biology and plasmalogens. And then in part two of our discussion in episode 231, we will dive deep into neurodegenerative prodromes. This conversation was so full of light-bulb moments that we had to make it two parts. I hope you enjoy it as much as I did.

And now, part one of my interview with Dr. Dayan Goodenowe.

[INTERVIEW]

[0:03:11] SCOTT: I am super excited today to have one of the brightest minds in medicine back on the podcast, Dr. Dayan Goodenowe. I'm also honored to have him as the first guest on the relaunch podcast, which is now the BetterHealthGuy Podcast. He and I talked back in episode 186, almost 3 years ago. And I do urge you to go back and listen to that discussion. We're not going to cover everything that we covered then in our conversation today.

I have found the solutions that he's created to be very powerful tools in the realm of healing and really want to learn more through the lens that he looks at chronic illness through and try to understand more about those conditions that we're all facing today. Dr. Goodenowe, welcome to the show.

[0:03:53] DR. GOODENOWE: Well, thank you, Scott. Very happy to be back again.

[0:03:56] SCOTT: Talk to us a little bit about the lipids that make up our cells and drive our biology. How much of our cell membranes are plasmalogens versus other lipids like phosphatidylcholine, or serine, or ethanolamine, or inositol? Does that differ by the type of cell? Is it similar for our mitochondrial membranes? And why are lipids so important for cellular health, which then in turn means for systemic health? How important is having healthy, non-damaged lipids in our cells in support of overall health?

[0:04:33] DR. GOODENOWE: Sure. Well, that's a great question. It's a very deep question. Of course, the body contains about 30 trillion cells, okay? From structural cells even in your bones. And there's different types of cells across the body, as you can imagine, as well as all of the gut microbiome, which is about another 30 trillion-plus cells in the body.

The cellular membrane is what provides the biological structure, which is why we're not a bowl of soup, for example. And so, each cell of the body has a three-dimensional sphere or cube-like structure, like an apartment complex would be. And the walls of that cell are made up of lipids, because the body is not made up of wooden plaster. It's made up of actually biological material.

And so how the body makes a biological wall is with phospholipids. And these phospholipids create what's called a phospholipid bilayer, where phospholipid are kind of like a soap-type molecule where they have a polar head group that's soluble in water. We call it hydrophilic. It has a non-polar fatty acid side chain that likes to be in fat. So, we call it hydrophobic or lipophilic.

And so, the hydrophobic chains like to self-organize together, and the polar chains like to stay apart from each other. And so by doing that, you create this biological wall. And so, this biological wall is what separates one cell from another cell. But of course, things have to go in and out of these cells, right? We have to feed the cells. They have to do material. They have to do activity inside the cells. So things have to go in and out of the cells.

Then inside the cells we get further compartmentalization. That's a large compartmentalization. Your liver is compartmentalized, versus your kidneys, versus your brain. And so, that physical compartmentalization is done via by the structural integrity of the body. And a great component of that is those lipids, membrane lipids.

And so, inside the cell then, just like your apartment or your house, your outside walls are a little more structurally rigid. They're a little more careful to deal with external insults and damages. And so, they're more rigid. So, once you get inside the cell, just like you get inside your house, the walls separating your kitchen from your bedroom and your bathroom is not quite the same structural integrity as your outside walls. The same thing happens inside your cell.

Inside your cell, you have all these subcellular organelles, if you will. People talk about the mitochondria, or we talk about peroxisomes, Golgi apparatus, your nucleus, ribosomes that make your proteins. All these little activities that go inside the cell, these are all compartmentalized again by this lipid structure. And so, the lipid membrane matrix is really the fundamental basis of vitality in life.

And so then, deeper into your question. People think they're not homogeneous. Even within a cell, it's not homogeneous. You'll have parts of the cell that have a much more thick structural requirement, and those parts will have more, say, sphingomyelin and saturated or monounsaturated phosphatidylcholines. And then you have other parts of the cell that have more dynamic activity where things are going on, and those are going to have more polyunsaturates in them and more plasmalogens in them, for example. Okay?

And so, within a given cell, there's going to be variance across the membrane because it comprises it. And when we shift, we change the variance. We change the amount of one type of region. We change the proteins that embed themselves in those membranes. The membrane lipid is really the environment that your body is living in.

And then each cell of your body has a purpose, has a job to do. And so, they'll have slight differences in them. We talk about the myelin, for example. The protective coating that goes around your axons. That's a very unique type of membrane structure, very impervious to virtually all insults. And it's a wrapping, right? Versus the synapse, which is a very – like a neuron itself in different areas. One neuron cell will have an axon level, it'll have a cell body, it'll have a dendrite, it'll have a synapse. All those different regions in the same cell will be dramatically different in their physiological structure.

When it comes to the composition, those compositions will change based upon the purpose. The composition of the membrane changes on its intended purpose. And what happens then is if that composition gets disrupted either by nutritional deficiencies, or by excessive oxidative stress, or damage, and whatnot. Then it no longer performs a function. It's supposed to perform – or it doesn't perform that function as well. Ion channels don't open properly, internal signaling. That's one part of this whole membrane structure.

The second part is that this is where the body stores all your fatty acids, for example, and all your lipid mediators. And what happens, it releases molecules based upon stimulation. We talk about inositol, like the inositol trisphosphate system turns on protein kinase C. And so, it's a whole list of things that are involved in that which we get in detail.

Fundamentally, the outer membrane. Back to this whole thing. The core structural molecules are cholesterol, which is a big thing. And it's not the same cholesterol that's in your blood. It's called free cholesterol. Your blood is in your – it's in your protein, like your LDL and HDL proteins. It's an esterified cholesterol.

This free cholesterol, it's about 50% of the membranes cholesterol on the outside. But on the inside – and that's what gives it strong structural rigidity. Okay? And then on the inside, the mitochondria, peroxisomes, they'll only have like 10% cholesterol in them. They're much lower levels because they don't need that kind of protection.

And then phosphocholine and then ethanolamines are the two big components. And those two components, the phosphocholine and the phosphoethanolamine are broken into two types. The phosphatidyl version and the plasmalogen versions. And then those things will modify. And then sphingomyelins are critical structural element. Then you have smaller versions like phosphatidylserine, inositol. Those are relatively smaller components of the membrane.

It's a very long answer to this kind of feeling of – and think about your house, even the walls in your house. The windows don't look like the other part – windows, and doors, and different parts will have different areas. In fact, you'll have some parts of your house that you're not even using a big wall at all. You're just having a curtain, for example. Right? And that's kind of what your body does as well.

[0:11:49] SCOTT: I'm of the opinion that many of our complex chronic illnesses are the result of environmental toxicant exposure. And so I'm wondering when we are bringing in these healthy lipids, whether it's the phosphatidylcholine, or the plasmalogen precursors, can we think of that as essentially a cellular oil change? Do we have the potential to detoxify or remove environmental toxicants, or other toxins, or damage that could be in those membranes through the exogenous supplementation? And essentially then think of that as an indirect method of detoxifying the body and improving our health in our toxic environment.

[0:12:33] DR. GOODENOWE: Yeah. I don't know if you're really doing an oil change, per se, but you're kind of you're filling it up. And you might be switching your oil from – for example, I'm a Canadian. In the winter time, we run 5W30 oil in our cars because you need a thinner oil for the cold temperature, and for tractors and things like that. In the summertime, we switch out the oil to like a 20W40, whatever it is, right? Or straight 40. So, a thicker oil. That is changing the oil composition based upon the environment.

Now as the oil gets old, you replace it to get fresh oil. That's for sure. Okay. Now, however, the cells themselves are alive. It doesn't keep a lot of toxicity in the membranes. When a membrane gets oxidized, it induces an inflammatory immune response. And then what happens is the composition changes, and the oxidation preferentially takes away your polyunsaturates.

And so the composition of your membranes become less polyunsaturated, more saturated or monounsaturated. And they become thicker and they become less pliable. So then the cells start shutting down because it becomes less active. And so when you're replacing lipids or you're providing the materials for the cell to restore its natural healthy lipid composition, then it comes back to life again. And so then you're restoring that structure.

Because anytime a molecule gets oxidized in the membrane, it's not going to stick around in the membrane because there's enzymes called phospholipases that will knock off the oxidized phospholipid. For example, we often measure that for blood work. You look at PLA2. And so that's what the body uses to – when a protein, like a LP(a) or LDL gets oxidized, the LDL particle doesn't get oxidized. What happens is the arachidonic acid typically, which is an omega-6 fatty acid, that is part of the lipid.

If you ever get a picture online, look at what an LDL particle looks like, an LP(a) looks like, it's a sphere. Okay? It's a phospholipid sphere. And the protein, whether it's a HDL protein or an LDL protein, the protein is just a scaffold that holds that lipid particle together. And so, when you get oxidized LDL, it's not the LDL that gets oxidized. What happens is the phospholipids in that sphere get oxidized.

And once they get oxidized, they can't hold that spherical structure anymore because the spherical structure is dependent upon the physical nature of the lipids. And so once the lipid becomes oxidized, it can't hold that. So, it pops his head out. All of a sudden, you get this oxidized fatty acid sticking its head out of the lipid, and it disrupts the structure. And then the phospholipase A2 will come in and cleave it off. And that's where, ultimately, we get malondialdehyde downstream. And so, when you have PLA2 elevated, that means that there's lots of oxidized that your body is redacting to. That's why it's a good biomarker for atherosclerotic risk, for example.

Anyways, back to this whole story. What happens then is it's not so much that you're accumulating a whole bunch of toxic peroxides in the membrane. What you're really doing is you're disrupting the actual phospholipid distribution. The membrane no longer is functioning properly.

Take a look at your paint on your house, for example, right? When it gets oxidized, it changes color, but it also changes its structure, right? It no longer becomes a nice, smooth, pliable thing. It can shrink and become cracked, right? It's not just that it's becoming oxidized. The actual physical composition is changing because you're actually destroying a certain – you're selectively destroying a certain subclass of molecules. And the subclass of molecules that you're destroying are polyunsaturates and plasmalogens. All that happens then is that now, instead of having 30% plasmalogen in the membrane, you now have 25 or 20. Okay? Then that changes the whole structure of an activity. Sorry for the long answer.

[0:17:15] SCOTT: How does the fluidity, or stiffness, or rigidity of the cell membrane correlate to the health of the cell in terms of what can move in and out of the cell? If we think about Bob Naviaux's Cell Danger Response, we have this concept of cell membranes becoming more stiff, or rigid, or inflexible when someone's in that CDR1 or defense stage of the Cell Danger Response.

If we're thinking about lipid replenishment with plasmalogen precursors or other lipids, does that impact the rigidity of the cell? Do we need to remove the insults that are driving the Cell Danger Response to benefit from those exogenous lipids? Or are they part of the solution to moving out of that Cell Danger Response in that they're helping the body to remove or better mitigate or respond to whatever those insults might be?

[0:18:09] DR. GOODENOWE: Yeah. The Cell Danger Response is really a two-part process. And it starts typically – well, it can start from more than one way. But, really, when you have a mitochondrial deficiency. And so if you get oxidative stress or any kind of inflammatory stress to a cell, puts stress on the mitochondria.

And exercising, for example, is a positive stress, but still creates stress on the mitochondria. And the body has to be able to adapt to that stress. And so the mitochondria's fundamental purpose is to convert hydrocarbons and oxygen into water. Okay? And carbon dioxide. And generate energy in the form of ATP.

And so what has to happen is either a fat in the form of a fatty acid or hydrocarbon in the form of a sugar molecule goes into – well, goes into pyruvate, then goes into the mitochondria. And then it gets this simple little molecule called acetyl-CoA, and the body burns it. Just like your furnace burns methane, for example. And it creates carbon dioxide and water.

The energy released from that burning process is used to charge a battery, called the electron transport chain. And that battery drives what's called an ATP pump, and that creates ATP. But the point is it's very oxidatively demanding. And when the cell gets overwhelmed, the mitochondria stop working, and we get what's called an anaerobic-type reaction, where it starts creating – when the mitochondria shuts down, it starts creating ATP outside the mitochondria. And this is the classic cancer activity process. And it creates an anaerobic, and it's less efficient, but it allows the cell to survive. It's a survival pathway.

Typically, what can happen, insulin and plasmalogen deficiencies, for example, the membrane structure gets modified. And one of them is the lack of cholesterol regulation, for example. This is where HDL and low cholesterol becomes an issue. Then it opens up the gates so more glucose comes into the cell and can cause more oxidative stress in the system.

Back to your answer. There's two parts. One is strengthening the mitochondria. Okay? And two is restoring the membrane. They need to go hand-in-hand, right? The membrane dysfunction, the plasmalogen depletion, peroxidation of the membrane, those induce an immune response. Those disrupt the normal movement of energy molecules in and out of the cell.

And then that leads to the mitochondria being shut down, and it's switching to a cell danger phenotype or a cancer phenotype. And then that becomes a self-perpetuating loop. To turn back that loop, okay, it starts with making sure – first things first is making sure that the mitochondria have all the materials it need, which is a good old-fashioned niacin. Okay? Riboflavin, which is vitamin B2. Okay? Thiamine. B1, B2, and 3. They're 1, 2, and 3 for a reason, okay? And they're important, okay?

N-acetylcysteine to make sure your glutathione levels are important. Alpha-lipoic acid is important to help the pyruvate dehydrogenase complex work properly. Proper minerals. Make sure you have magnesium, selenium, zinc. Those things need to be part of your – you get mineral deficient. People don't take enough appreciation to their ionic requirements quite often. And so if you get that – and then carnitine is another big one, CoQ10.

It's a big long list, but these are all the key components of that mitochondria. You need all of that. You need all of that support. Okay? And people say, "Oh, can I get all this from nutrition and whatnot? No. If you actually need to get pharmacokinetics. Wo we do biochemical engineering in a sense. These are core molecules that the mitochondria need to perform. And it needs all of it. If it's missing one of those things, it won't perform properly.

First thing is making sure the mitochondria can do the job. At least it's not deficient in some critical element of doing its job. That doesn't mean it's going to be done. It just means that it's not – you're eliminating the fact that you might have some deficiency. And there's no way to measure every single one of those things. And even when we measure them in the blood, we're never going to know exactly what's happening in a cell someplace in your body. You just have to kind of take those things.

And then the membrane composition changes and reducing the oxidative stress. Because the big issue of oxidative stress is the peroxidation of membranes. When a membrane becomes peroxidated, it stimulates macrophages, or microglia in the brain, or immune response. Because that's what the body uses to recognize if a cell is damaged. That's the whole point of multiple sclerosis. Okay? Everyone with multiple sclerosis, they call it an autoimmune. Or anyone with any kind of autoimmune. Okay?

What happens in an autoimmune disease scenario? Someone has been under some chronic oxidative stress scenario. Okay? And the cells get oxidized, and they create a unique immune signal. And that individual person's B cells. Okay? Their B cells will then create their own personal epitopes to your own personal inflammatory signal. Then you have this memory cells. And your B cells become memory cells. And it's your B cells that stimulate your T cells, which then create your immune response.

And so, what happens then? You go into dormancy for a while, right? So, you're in remission. Then sometime later on you get another flare up. Well, your body's already recognizing this is my flare up. And so this is why when a flare up happens, the immune system reacts directly.

In the past, they try to get T cell replacement therapy, right? Or T cell depletion. They never worked because everyone's T cells is unique. They would never find a way to do it. They finally came up with this idea, which I don't personally agree with, but it does reduce relapses, is the B cell depletion. So what they did is they deplete everyone's B cells. And so it depletes all of your immune response. So you can't respond to anything immune related. You still have your old historic B cells that are in your bone marrow, but you don't have any ability to make new responses. Anyway, that's how they treat MS.

Long story short, this process is it still starts with this damaged cell that ends up with peroxided membranes, and then the peroxidated membranes stimulate immune response. That's the only way that the body recognizes that there is something going on at the cellular level. You can have oxidative stress markers in your cytosol or in your blood system. Those are actually positive.

For example, when people take hyperbaric oxygen, okay? You're inducing oxidative stress. The whole point of hyperbaric oxygen is to create oxidized phospholipids. And the oxidized phospholipids creates a flushing response to the body. The body recognizes it as energy. And then you react to it and you get this positive reaction to it. And that causes vasodilation, and it wakes your body up. And your reaction to it is what gives you the benefit. And that's why it's careful to do it in a properly titrated way.

[0:25:56] SCOTT: You just touched on one of the Prodromes that we're going to talk about later, which is MS. But I want to come back now to the plasmalogen precursor products that you created. I was even surprised. Back in 2006, as I understand, I think many of us think these are new tools. But they've been tools that you've been working on for more than two decades. You've offered the ProdromeNEURO product, which is now PlasmalogenN3, and then ProdromeGLIA, which is now PlasmalogenN9. Wondering if you want to share a little bit about that kind of evolution just in terms of the product naming.

[0:26:31] DR. GOODENOWE: Sure. So, these are plasmalogen precursors. They're alkylglycerols, or alkyl-acylglycerols that are absorbed in the gut and intestines into the bloodstream. And then they go into the cells and they get converted into plasmalogens. Okay, these are called plasmalogen precursors. And I invented them back in 2006 for plasmalogen replacement therapy.

They're are dietary supplements. Okay? They're naturally occurring molecules. And we manufacture them. We can talk about those a little more in detail in a minute. They're naturally part of the food supply. For example, the omega-9 is quite prevalent in human breast milk, for example, the alkylglycerol there. And the omega-3 can be found in certain shark liver oils, for example, right? In relatively small amounts. They're dietary supplements, first and foremost. Okay?

We provide them as dietary supplements. But because of the DSHEA regulations in the United States and around the world, dietary supplement cannot make disease claims. When you're talking about a dietary supplement, you cannot talk about – you can only talk about the function and structure claims. And it's about restoring health, helping support this function, and so on and so forth.

And so in order to actually do claim language where you say, "Okay, this molecule can be used for the treatment of dementia, or this molecule can be used for the treatment of autism," for example, the distinction between what is a dietary supplement and what is a drug is entirely dependent upon the intended use of it.

For example, one of the most popular drugs or one of the most famous drugs of all time is a drug called L-DOPA, which is used for Parkinson's. Okay, L-DOPA is not a drug. It's a dietary supplement. L-DOPA is just a precursor to dopamine. It's a naturally occurring molecule that's present, especially the substantia nigra parts of your cell. So, it's a dietary supplement. It's a precursor. But it's been developed as a drug for the treatment of Parkinson's. And so in order for a diet – the dietary supplement version of L-DOPA, it needs to go through an IND process and become an actual drug.

ProdromeNEURO is being moved out of the dietary supplement space into an FDA IND pathway for the actual full drug-related clinical development path, so that we can actually get to the point we're doing full claim language. And this is why I created a company just called Dr. Goodenow Dietary Therapeutics for that purpose. We have a lot of nutritional supplements that have very clear unambiguous health benefits in disease. And they're published peer-review publications, but they're not available to people with that claim language. I think it's is a big problem. Okay? Because there's still legitimacy.

We're here in an advanced podcast with you, Scott. And our viewers, your viewers are going to look into things. Okay? But as much as our advanced work and our advanced network of like-minded people are, we're still a relatively small percentage of the overall population. Okay? The overall population still does trust the FDA, trust the institutions. Okay?

And for the most part, those institutions, the structures within them, there's nothing really wrong with them. They're designed for a purpose. And the problem is we don't use them. Or the public health doesn't use them. That's the point. So N3 and N9. GLIA will eventually move into a drug path as well. And I think the naming just makes it easier for people to understand. PlasmalogenN3 stands for the omega-3. N9 stands for the omega-9.

[0:30:31] SCOTT: If we think about PlasmalogenN3 as the omega-3, that DHA plasmalogen precursor, which may help people dealing with brain volume issues, cellular fluidity and resilience with cognitions. More of that gray matter of our brains, our neurons. And then we have the PlasmalogenN9, which is the omega-9 plasmalogen precursor. Can think about structural support, like the myelin, for example.

I think of it for inflammation, neuroinflammation, maybe microglia inflammation. I also think of it as kind of those people that have a real hypervigilant or autoimmune type response, more supportive of our white matter. I also think of that, maybe in this listener community, as the place to start to kind of calm down the system, reduce that neuroinflammation, maybe help improve sleep. And then potentially bringing in the N3 plasmalogen precursor later if they really need more cognitive support. Tell us a little bit about how you, kind of through your lens, how do you differentiate them. And what are some of the benefits that you see clinically?

[0:31:40] DR. GOODENOWE: Yeah. The omega-9, for sure. The PlasmalogenN9 product is really focused – it's your core product. Okay? Because heart membranes, myelination. From an anti-inflammatory perspective, it starts first at restoring the core structures of your cells. Before we get into the active vitality parts of your cells, we need to work on the core protective mechanisms of your cells.

When we talk about the Cell Danger Response, okay? Polyunsaturated. But, really, the omega-9 component of our heart membranes, myelin sheath, all that stuff, when it's messed up, everything is kind of on fire. And even when the myelination is disrupted and is inflamed, then all the neurological signals that are going through them become noisy, and staticky.

And so, the simplest way to think about these two plasmalogen precursors is like an old radio. Okay? The N9 is essentially tuning the station and you're trying to find the sound. And remember an old radio, you hear that crackling sound. You're not tuning in the radio station. And once you tune it, the signal is clear. And then once the signal is clear, you crank the volume up and you got great sound as long as you want.

But what happens when you're in a Cell Danger Response or you're in chronic inflammatory situation is that the signal is noisy. And if anything happens in your life to crank up the volume, then it just goes crazy. All you hear is static, and it drives you crazy, right? And if anyone's been driving across the country with an old radio, you'll know when the signal is staticky, if you keep the volume down low, you can often hear the music through the static. But if you turn the volume up, all you hear is static. And the body is like that.

The first thing we need to do is focus on cleaning up the static noise. And that is the mitochondrial support and the omega-9 plasmalogens. That's why it's such a powerful anti-inflammatory. And people feel their improvement in sleep. because it's cleaning up the neurological signals. The neurological noise comes down. Okay? And that's the big deal.

And, certainly, for the heart, the membranes of the heart, and core membranes. Say, for example, in your lungs and others. It's a real core – there's one molecule, if you got stranded on an island for help support, it's the omega-9. In case of emergency, take this type molecule. Okay?

The omega-3 now, it is for all activity functions. And there's lots of activity functions that we don't even think are active. Reverse cholesterol transport, atherosclerosis, ability of your epithelial layer, your endothelial layer of your vascular system to maintain tight junctions and have the ability to flex. The vasodilation. And so your whole parasympathetic system is dependent upon vascular flexibility. And so that's all done with the omega-3 plasmalogens and other lipids. And that could create that pliable process. That's at a physical level.

And at a transport level, it just moves more things. It's like the body opens up, and things are moving, right? And so once things are moving, you want more fluid to make them more moving. And when you're in a stress response, you're actually shutting things down. You stop moving, right? You want to reduce the movements as much as you possibly can.

The omega-3s then, they enhance the cellular function of all of these transport mechanisms. They improve just the mobility of actions through all of your ion channels and all these other little things that we don't talk about. The big ones though are synapses, is the release of neurotransmitters. And that's how one cell communicates to another is the release of these neurotransmitters at the synaptic cleft. The presynaptic neuron releases these neurotransmitters into the synaptic cleft, and they react to the postsynaptic neuron. And that's all handled by very, very fluid membrane structure. Your neuromuscular junction as well as your brain really function that.

When you increase that, that's when people see, "Wow. The lights get brighter. My brain is sharper." Also, depression. Okay? What happens? Especially with people with long-COVID, for example. The first phase is to try to restore the mitochondrial function, get their membrane structure and function back. So, they won't feel better, but they still they still feel kind of brain fogged. Or they haven't really jumped out of the rut yet. And the omega 3s are like booster cables, okay? The PlasmalogenN3, it increases your cognitive function. It reduces depression. That was interesting.

One of our biggest study, one of the biggest issues was – because we do a lot of work with Parkinson's. I mean, a lot of patients in Japan. One of my doctors, he's noticing that one of the biggest feedbacks from his Parkinson's patients was that they were less depressed.

[0:37:18] SCOTT: Building on the topic of inflammation, we know that that PlasmalogenN9 can be helpful for those with inflamed, or activated, or primed microglia. How is the activation of microglia tied to the peroxidation that you talked about earlier? Can these plasmalogen precursors shift the microglia from their pro-inflammatory M1 state to an anti-inflammatory M2 state? Do we have ways to measure that?

And then extending on microglia, mast cells are another immune cell that often contribute to chronic inflammation, through the release of histamine and other mediators. Is there any potential role of plasmalogens in terms of stabilizing mast cells?

[0:38:06] DR. GOODENOWE: Clearly, the microglia part. First part on the microglia. Absolutely. The whole induction of microglial activation is from peroxidated membranes in the brain, fundamentally. Okay? And we can measure that now with advanced MRI. With our advanced MRI technology, we can look at – there's a sequence that we run on the MRI called NODDI. Neurite Orientation Dispersion and Density Index.

And this allows us to actually measure cellular water and differentiate water that's in axons and water that's in cell bodies. And so, when you have an inflamed brain, there's lots of microglia. And those microglia show in a specific format. We can actually measure now brain inflammation using advanced MRI. And we can see how that inflammation decreases once we have reduced the inflammation of the brain. That's one of the most clear examples.

And especially, even from a clearly indirect perspective, we know animal models that are clearly microglial mediated inflammatory models, like cuprizone. Those are completely prevented and resolved using plasmalogen precursors, especially the omega-9. It's working at that core level, at the foundational level of reducing the membrane oxidation, which then there's nothing for the microglia to react to. Okay? And so, we remove the microglia activating system.

Now mast cells are going to be a little more different because there's a little more stimulation with those. Of course, the histamine response is a critical component. You're still going to want to work on that antihistamine response as well. But these cells all contain – all their membranes do contain plasmalogens. And they typically have a component to it. It's supportive on that.

On the mast cell activation situation, definitely, you want omega-9. Anything that you can do to add to the system that reduces the inflammation cascade is good. But you're still going to want to make sure your mitochondrial and histamine strategy is working for you.

[0:40:12] SCOTT: When people are starting to incorporate the N3 and the N9, what's kind of the range of dosing? Is it best to do the N3 in the morning and the N9 at night? Are they more effective taken standalone versus maybe put into a smoothie? Does that not matter? And can we do too much too soon and potentially have an exacerbation of any symptoms?

[0:40:36] DR. GOODENOWE: Depends on the sensitivity of the individual. So each person's experience is going to be that person's experience. Okay? If you are in a hyper-sensitized space, start slow sometimes just one capsule for a day, for a couple days, for a few days, and see how it reacts. And then move up to two, and three, and four, and keep going up.

And then if you do see a little bit of a sensitizing reaction, then go off it for a couple days. Okay? Because what you're doing is – a lot of people talk about the dormancy of cells, or cells get into the senescence state of a cell, right? And there's two components. One, can we can we go in there, and can we kill those cells with increased autophagy? But a lot of these cells can come back to life again, because we don't want to go around killing all these neurons because it's hard to make a new neuron. Can we preserve the neurons that we have? Can we just restore them to help?

What happens when you start restoring membrane structure, cells start coming back to life again. And so they will start releasing some of this intracellular toxic soup, if you will, because they haven't been active. Right? And so you can get some flushing that occurs in individuals that are in this really hyper-sensitized shutdown state. Each person has to handle that themselves. Go slow. Start low and go slow. Build yourself up if you're in that hyper-sensitized space. And don't be afraid to take a couple days off if you have to.

And then what we found, especially in our autism community. Okay? And then, again, the community of people really are helpful in guiding their own actions. Autism is a good example. For the longest period of time, I was really against giving any child or adult with autism an omega-3 plasmalogen because I would want to activate – or ADHD, for example. Right? Omega-9, omega-9, omega-9. And that was all working. And we have dramatic results.

In fact, we have over about 200 families now on our neuro support program. And the response rates and the positive outcomes is just enormously positive. Seriously, we're talking 95% of the parents are reporting back within a few weeks to a month that they're seeing positive change in their children. Really, really amazing stuff. And we'll be reporting on more of that later.

But they had some families, and said, "Well, I'm going to go ahead and try the omega-3." Okay? They're going to do what they're going to do. And they got some really amazing results. It really kind of jumped their children into a much faster learning curve. And what they did say a lot is it gets worse before it gets better.

A lot of these parents say, "Okay, you're going to get some activation. Okay? But it's going to get way better afterwards." And so, this is feedback that I think this is really important that people realize that they're really in control of this, right? Nobody knows their own body, their own symptoms better than themselves. The goal is to get good quality educational information, okay? So that you can make informed decisions, because it is a big complex world out there. It's the hardest part is knowing where to start. Okay? But find a place to start. Go slow. Go back and forth, and then move forward.

Now, for normal people that aren't in an active danger response, you can go to pretty high doses. And we really want to reduce and reverse the brain aging. For example, for me, and I've tracked my brain and my plasmalogen levels, and trying to reverse the aging of my brain, which I've been very successful at doing. I'm taking roughly 20 to 30 ml. I'll go through a bottle of Neuro in 3 days. Roughly, 10 ml of the NEURO, which would be equivalent to 20 gel caps. Okay? And then with the same level of GLIA.

And at these higher levels, what I'm trying to do is I'm trying to make sure I'm just kind of washing these cells with plasmalogen so that they can then – and, of course, I'm doing other things, not just plasmalogens. My mitochondrial support, methyltransferase support, muscle support, structures. Okay? Because your body is an integrated system. You can go to high doses.

And for people with serious diseases, basically they'll go through a bottle of each every two days. They go through a half a bottle a day. So, you can go to very high doses. But most people find the usefulness at the lower, moderate doses.

[0:45:24] SCOTT: And is it better to do the N3 in the morning, N9 at night? And is there any increase in effectiveness taking them standalone versus in a smoothie?

[0:45:33] DR. GOODENOWE: No, you can take them either way, but definitely the N3 in the morning, the N9 at night. Yeah, taking N3 at night will probably keep you up all night. It's pretty activating. But you can make it in a smoothie, as long as you're getting it in a relatively short period of time.

[0:45:48] SCOTT: Let's talk a little bit about what these are made from. What are the raw ingredients? Is the omega-3 or N3, is that algae oil? Is the source of the N9 or omega-9 product, is that sunflower or something else? And then is it entirely derived from something in nature? Or when we're talking about the plasmalogen precursor backbone, is there some synthetic part of that process?

[0:46:14] DR. GOODENOWE: Yeah. Both products are 100% vegan, other than, of course, the PC+ plus products, which are made with egg yolk oil. But the actual plasmalogen precursors are 100% vegan. And so the point is each product goal is to get a high purity, high concentration of a specific plasmalogen precursor. The N3 is an extremely high concentration of omega-3, which is DHA.

What we do is we take algae oil. We find the highest purity algae oil that we have. But even that, it only has about 45% to 50% DHA in it. Okay? When you look at a DHA supplement on the shelf, okay, it's going to say, "Oh, I got 500 milligrams of DHA." Well, it's going to have a whole bunch of other stuff. What they report on there is just the DHA. They don't report all the other stuff that's in it. Okay? And it's going to have at least 50% or 60% of other things in there.

We take a high purity algae oil. Then, we saponify it, which means we remove all the fatty acids off the glycerol backbone. An algae, or seed oil, or anything like that, all those oils are called triacylglycerols. Those are just like the kind of the fat that you get in your triglyceride blood test, right? Those are not plasmalogens.

The backbone – and they're not free fatty acids either. So, they're part of a glycerol backbone. So we have to get this purified fatty acid. Then we take this fatty acid mix, which only contains about 40% DHA, because it's going to have a bunch of other stuff, even though this is high purity algae oil. Then we go through a secondary purification process that purifies and removes everything except the omega-3s. And so, we end up with this pure fatty acid mixture, which is like 95% omega-3. It's just amazing, high-value product. That gives us the fatty acid component.

Separately, we make the plasmalogen backbone. And that's synthetic. Okay? We make that from synthetic precursors. That's just synthetic chemistry in order to get that backbone. It's a very simple process, very non-toxic, synthetic chemistry process. The core components are called chimyl alcohol, batyl alcohol. They've been around forever and ever in the world.

And so, once we get the plasmalogen backbone and we get the fatty acid, we have a specialty secret way of combining them and creating this alkyl acylglycerols. And that's a critical component. And that's the biggest invention part of my 2006 patents was the fact that chimyl and batyl alcohol have been known since the 60s. They're well-established molecules, but they're not effective at elevating plasmalogens except in extremely high doses. What I invented was the ability to create these alkyl acylglycerols.

And we do the same thing. That's how the N3 product is made. It's extremely high potency DHA without any other distractions in it. Then the same process is done for the omega-9. And now we use a high oleic acid sunflower oil, which is like 85%+. And from a cooking oil, it's really a high-quality cooking oil with a very strong, very high flash point. It's not your regular soy sunflower oil. It's not your regular omega-6 seed oil. This is very different. There's virtually no omega-6 in it at all. Okay? It's virtually all omega-9.

And so, we do the same thing. We saponify it. You get a purified fatty acid composition. And then we do the same thing to create the N9 product. These are two vegan products that are purified, sterilized. Since it comes from this our cleanup procedure, there's no trace metals. They're really amazing products.

[0:50:12] SCOTT: Plasmalogens are made by peroxisomes, which, as I understand, are inside our cells. The peroxisomes inside the cells take up the materials in these plasmalogen precursor products to make plasmalogens in the cell. And then that plasmalogen that's created inside the cell becomes part of the membranes, part of that cell wall. Does the plasmalogen that's created inside a cell always remain in that cell, or can plasmalogens be created in one cell and essentially donated to another?

[0:50:45] DR. GOODENOWE: Very good question. The plasmalogens are made in two compartments of the cell. The first part creating the alkylglycerol component of it. Okay? The ether bond. That is made exclusively in the peroxisomes. And then the ether lipid leaves the peroxisome. And then the final plasmalogen is made in the endoplasmic reticulum. Okay. These plasmalogen precursors are designed actually to bypass the peroxisomes.

They're designed to be effective in all peroxisomal diseases. That's the whole point. If you have a peroxisomal diseases, these plasmalogen precursors will replace and restore plasmalogens even if your peroxisomes aren't working. That's what the magic is of these molecules.

And so, yeah. So, then the cell makes its own plasmalogens internally. And it normally gets the supply of the plasmalogen precursor from the peroxisome and takes that plasmalogen precursor from the peroxisome. And then it makes the amounts and types of plasmalogens that it wants from there. It does a whole bunch of things, right? And so we're providing that branch point molecule.

But, yeah. So then, fundamentally, you want to make it inside the cell. Cells will share plasmalogens, obviously, but not as much as you think. Okay? Fundamentally, they need to make most of themselves because there's really not an absorption mechanism. For example, for phospholipids to enter another cell, the primary way is through the LDL receptor. Okay? LDL particles. And so, there'll be plasmalogens and phospholipids on that. Okay? But there's flippases, and there's some other things. But there's really not a lot of phospholipid lipid transfer into cells. There's some, but not a lot.

When we're measuring blood samples, we're actually measuring what's coming out of the cells. And so, when you have healthy plasmalogen levels in your blood, it means that your cells are making plasmalogens in a healthy way. And they're nice and full, and they're sharing their plasmalogens. They're going to go through your liver, and they're going to share them and things. But fundamentally, each cell makes its own.

That's why the precursors are so important. Because, every day, when you're taking the precursors, they're going into the cells of the body and providing them food every day. And that's kind of this pulsing effect. That's important. And, especially, when you take a look at the brain, the plasmalogen levels in your blood, plasmalogens don't cross the blood-brain barrier. Only the plasmalogen precursors cross the blood-brain barrier.

[0:53:16] SCOTT: That was a very key piece of information that I just learned that we're bypassing the peroxisomes by using the plasmalogen precursors. But if we're taking these things exogenously and we want to also make more plasmalogens, can we do things to better optimize the function of the peroxisomes? In other words, can we take multiple angles to attack this problem?

And then are there some people that are better able to take the precursors and create plasmalogens than others? Are there some potential factors that might make someone less efficient in the creation of the plasmalogens even if they have those raw precursor materials abundantly available?

[0:53:58] DR. GOODENOWE: Okay. First of all, yeah, there's really nobody – and even children with rare diseases and with peroxisomal diseases, the plasmalogen precursors get converted to plasmalogens virtually in everybody. I've never seen it not happen quite frankly. Okay? You might need more because they might be more deficient. But once the plasmalogen precursor is in, there's multiple ubiquitous systems that converts into plasmalogen. It's virtually impossible for them not to restore plasmalogens for one.

Second thing, how do you maximize your own endogenous plasmalogen production? Well, that is increasing peroxisomal function. And there's a couple things that are – and this is actually really critical for all your viewers, because maintaining peroxisomal function is a critical component of healthy aging. It's one of the weak links of aging.

Now, peroxisomes are typically stimulated by the fasting state and by exercise. Resistance training, particularly. The way to tell if your peroxisomes are working pretty decently is your good old-fashioned blood work. If you have good levels of HDL and you have low triglycerides, that's a big sign that you have functioning peroxisomes. Okay? That's your big clear. And healthy cholesterol levels. Okay?

And so the three things, the three big things that tell you – and they're all highly related to longevity, which is HDL over 50, ideally over 60, triglycerides under 100. Okay? And then cholesterol over 200, okay? In the 220 to 240 range, right? That tells you that things are working pretty good. Okay.

Then you can stimulate peroxisomes. There's been drugs, like fibrates, for example. People are alpha-agonist. The biggest advantage of omega-3s – the reason why people take omega-3s, and they lower triglycerides, is because omega-3s are PPAR agonists. They are peroxisome proliferator agonist receptor molecules. And so those are molecules, they have a PPAR enhancing effect.

When you're in the fasting state, when you're in the fed state, when you eat a meal, your peroxisome shut off, okay? Because peroxisomes process fatty acids. But when you have high levels of sugar and you have high levels of glucose and glycogen energy in your body, your body's not processing fat. What your body is doing is it's storing fat for later. It's taking all the fat you have and putting them on triglycerides and sending them back to your adipose tissue. And that's why your levels of triglycerides will be very, very high.

The whole movement of energy is outward. Okay? And that's called the fed state. In fact, it even takes glucose, converts it into pyruvate, goes into acetyl-CoA. And then acetyl-CoA goes into fatty acid synthase. And so your body actually makes fat from sugar in the fed state. Peroxisomes are fundamentally shut off during the fed state.

Then fast forward 4, 6, 8, 10, 12 hours, and your body has used up all of its short-term energy in glucose, and now it starts going from the gas tank, which is your fat cells. And now the free-fatty acids from your adipose tissue are flowing into your cells. That's when the peroxisomes turn on. And so your peroxisomes turn on during your fasting state. This is why intermittent fasting is important. And having a low glycemic index food diet is important because that'll help maintain – and maintaining this healthy cycle, from a fed to a fasting, fed to a fasting. Your body should be fed, and you should be fasted every day.

If you're constantly in the fed state, if you're constantly snacking, and you're constantly having high levels of glycolytic food, then your peroxisomes are going to get shut down, and then your muscle formation and all that stuff gets down. Those are the biggest thing. So resistance training, maintaining fasting are critical things.

And so the omega-3 plasmalogen precursor, the N3 contains high levels of DHA. But not only does it actually – it does two things simultaneously. It restores plasmalogens and it stimulates peroxisomes. It's a peroxisomal stimulator itself. Okay? It lowers triglycerides in people. We see that all the time.

[0:58:28] SCOTT: When we first start taking plasmalogen precursors, are there certain cells in the body that are more likely to take up those precursors and essentially have priority for them? And those eventually become repleted. And then other maybe less important cells can then benefit and make plasmalogens. Or does every cell get equal access from the onset of the exogenous plasmalogen precursor supplementation? In other words, is repletion of plasmalogens in our cells and in our body more about the amount of precursor that we're taking in or the duration that the precursors have been available to the cells?

[0:59:07] DR. GOODENOWE: It's a little bit of both. First of all, they have to get to the cell from the circulation. There's actual physical because you're going to consume them by mouth, right? Obviously, the first cells to experience the plasmalogen precursor is going to be your gastric mucosa and your upper or your small intestine. Okay? You're going to see a lot of that.

And then they're going to get transported in the blood supply, and it's going to get fundamentally going – the highest levels are going to go through the liver at first because that's where first pass metabolism goes through. Even though they're going to be go through, the chylomicron system is going to still give it to the brain, and muscles, and so on so forth. It's going to have that kind of pharmacokinetic approach, because there's still a physical circulatory delivery system that needs to take place.

And then in the brain, what we'll notice is it gets concentrated highest in the choroid plexus at first, which is where cerebral spinal fluid is created. That clearly tells us that when it goes in the brain, it goes into the cerebral spinal fluid, and then from the cerebral spinal fluid into the brain cells. But once it's in the brain, the different brain regions seem to get absorbed about the same rate.

And then we look at long-term stuff. We know concentrations in the eye go up. But, fundamentally, pretty much every cell gets it, even down to your bones. There'll be slight differences between cell types, but not dramatic. There's really not a dramatic difference.

[1:00:40] SCOTT: So, let's talk then a little bit about how efficiently we can get plasmalogens from our diet. And I hear a lot of debate in this realm. I recently heard a brilliant doctor talk about consuming squid, octopus, shrimp, scallops, krill. You mentioned shark oil earlier, I believe. That those were good sources of plasmalogens. I know you've said that we don't benefit from plasmalogens consumed in our diet in any significant way. You have also said that a newborn gets plasmalogens from breast milk. So, is there something that happens as we age that limits our ability to benefit from exogenous plasmalogens, not the precursors?

And then building on that, is mom depleting her own plasmalogens to create plasmalogens to support the newborn or infant, or is her ability to create plasmalogens upregulated or enhanced during pregnancy and breastfeeding?

[1:01:37] DR. GOODENOWE: A couple things. On the nutritional sources of plasmalogens, there's two parts. One is the bioavailability of the plasmalogen itself. And the second is the composition of those molecules. What is the purity of the compositions of those molecules? So like anything else, if you take enough of it, you're going to have a benefit.

There's a study I show in some of my presentations on rats. Looking at old rats versus young rats. And then an old rat that was given plasmalogens during their lifetime maintain youthfulness. Okay? And they use 300 milligrams per kilogram. Pretty high dose of an actual natural plasmalogen. That wasn't using a plasmalogen precursor. If you put enough in, you will get some out clearly. Okay? There's benefit there. But you don't really have any control over the composition of it.

And most of them will get broken apart in the stomach. The hydrochloric acid will break down those plasmalogens. Anything with the vinyl-ether bond. But there's going to be some plasmalogens in there that are called ether plasmalogens, rather than vinyl-ether plasmalogens. The ether plasmalogens will get somewhat absorbed.

But, also, there's an enzyme called plasmalogenase. For some reason, our digestive system is designed to prevent us from getting plasmalogens, like the intact ones. Okay? And so that's one of the things that is happening. The fully intact plasmalogens are minimal. And you don't need to go to shark and squid. Your own muscle, like any – it's in our muscles. It's going to be in cow muscle. Any kind of animal food product, every single cell has plasmalogens. There's no there's no uniqueness. Okay?

What happens in these particular products is that they have slight – these marine-based plasmalogen products, they're going to have a higher percentage of DHA and EPA plasmalogens. And so when they take these products and you get a plasmalogen elevation, the question is are you actually elevating plasmalogens from the plasmalogen composition? Or are you elevating plasmalogens from peroxisomal stimulation?

Because all the studies that have looked at radiolabeled and stable isotope labeled fully intact plasmalogens have shown pretty clearly that they don't make it through the gut at all and the intestines. And how much is in those pills is extremely low. The fully intact plasmalogens from a scientific perspective that we can actually track a very, very small percentage of it makes it into the circulation. Okay? First of all.

But more importantly, the plasmalogens that make it in the circulation aren't actually bioavailable to the cells. And so even if I give you an IV injection of a fully intact plasmalogen, that plasmalogen won't get across the blood-brain barrier. Okay? And there's no real mechanism of taking that plasmalogen into cells. There's no real transport mechanism into your cells. Okay? You'll get some. Don't get me wrong. Some always gets in certain ways.

Plasmalogen precursors, which are alkyl acylglycerols, they enter as food. Okay? And they are very non-polar. So, they don't have the phospholipid head group. So, they just dissolve. They diffuse through membranes. And we've shown this extensively with pre-clinical research. So, it's very clear.

So, then you say, "Okay. Alkyl acylglycerols are the preferred dietary source to get into the brain, get out of the places." What are the possibilities? We have breast milk. And breast milk is mostly omega-9. It's actually really good quality omega-9 plasmalogen precursor. It's great. It's designed as it should be. It's made by a human, and it's designed for human myelination.

[1:05:47] SCOTT: And is it a precursor, or is that actual plasmalogen?

[1:05:50] DR. GOODENOWE: It's precursor. Yeah, it's an alkyl acylglycerols with omega-9 in it. Yes, the mom makes this stuff. Whether she gets induced or not, it's a load. It's a metabolic load on the mom. Absolutely unambiguous. And we know that because what happens is, early on at the colostrum stage, colostrum has high levels of plasmalogens. And then the first one to three days, there's still relatively high levels of plasmalogens in breast milk. And then it decreases until – by about day 15, the plasmalogen composition of breast milk is still good. It's still 10 times higher than cow's milk for example. Okay? But less than what it was at the colostrum stage, for example. Okay? We know that for sure.

Clearly, supplementing mothers during pregnancy is a big deal. And we definitely recommend that. And we have a number of people in our company, young mothers, that have – not only while they're pregnant, but while they're breastfeeding, it improves their milk production. And their babies really are happy.

[1:06:59] SCOTT: Did I understand correctly that what we're saying is in the breast milk, it's not the plasmalogens. That it's the plasmalogen precursors that are in the breast milk.

[1:07:08] DR. GOODENOWE: Correct. Plasmalogen precursors.

[1:07:09] SCOTT: It's not so much that the mom is being depleted of plasmalogens because the precursors are different than the plasmalogens themselves.

[1:07:17] DR. GOODENOWE: Oh, she's not getting depleted membrane-wise, but she is alone. Because the plasmalogen precursors are what the body makes to make plasmalogens. If she's removing plasmalogen precursors, she's lowering her own plasmalogen load. For sure. Absolutely. For sure.

[1:07:39] SCOTT: You just gave me a new idea for now that the podcast has kind of been relaunched. I need like a sign with a light bulb. Every time a light bulb goes off, I can have a little visual there. You also mentioned that you can get plasmalogens from muscle. But if we're, let's say, getting a piece of steak, for example, is there a problem with the plasmalogens being heated? In other words, if we think of seed oils, some can be good if they're not heated, but they're bad if they're heated. Do we not want to heat our plasmalogen sources before we consume them?

[1:08:13] DR. GOODENOWE: The vinyl-ether plasmalogen, the final plasmalogen, yes, they'll be heat sensitive and acid sensitive. They're easily broken down. They're designed to be highly sensitive to oxidative stress. But it doesn't really matter. You're not going to get them anyways. The ether ones, the plasmalogen precursors are really quite stable, okay? We heat them up to high temperatures before we bottle them. They're quite nice.

Back to the shark liver oil. The second part. We had breast milk. Now, your shark oil roll has also alkyl acylglycerols in them. But the problem is it comes with a whole bunch of other stuff, like squalene and things. There's been really interesting papers where they've isolated plasmalogen, like alkyl acylglycerols, from other materials. And showing that these are anti-cancer. They have positive immune modulation. Really important for endothelial function.

But the biggest challenge is that, again, it's the concentration of what type of plasmalogen. It's got a lot of saturated ones. You don't have any control over your cellular manipulation, if you will. Okay? And so the DHA component of it is going to be very, very small. It's going to have high levels of arachidonic acid and stuff like that in there. It does have a plasmalogen precursor. It's still a valid precursor, but it's just not the purity. You don't have any control of purity and the other issues that you have.

[1:09:38] SCOTT: I was going to ask a little bit about IV, but you already made the comment that there really wouldn't be significant advantage to IV plasmalogens because they're still not going to cross the blood-brain barrier. We do know in the phospholipid realm, Dr. Patricia Kaine made IV phosphatidylcholine therapy. Very popular. And that can be a tremendously helpful intervention. Is there any advantage to doing IV plasmalogen precursors? Would that be any better than taking them orally?

[1:10:06] DR. GOODENOWE: Well, yeah. So, it's going to be creating that product very soon actually. Well, literally in the next little short little while. So, yes. It's all based upon the purpose. IV phosphatidylcholine, excellent product. Okay? Because it increases the lecithin cholesterol acetyltransferase system. It really improves reverse cholesterol transport. Really, really powerful for anti-atherogenic activities. Excellent product in that concept. And all the data has been supporting of that.

The plasmalogen precursors, also very nice. Because it'll go into the blood-brain barrier very quickly. Actually, if we use it, it gives us direct control over other modalities. If we combine it with photobiomodulation, or a focused ultrasound, or other activity. So the IV plasmalogen precursor, obviously, we're going to have to test it. But in theory, it could be very powerful.

[1:11:13] SCOTT: I'm excited about that. When you're working with people with these complex chronic health challenges, how often do you find people being depleted in plasmalogens versus other phospholipids? Is it that the majority of people just need the plasmalogen precursors? Or is it that they need a combination of plasmalogen precursors with the phospholipids, like phosphatidylcholine, which we'll talk about some of the tools you've created in just a moment.

[1:11:41] DR. GOODENOWE: Yeah. They're separate and additive. The plasmalogens themselves, clearly, it's a critical measurement. All these chronic diseases, all cancers have low plasmalogen levels. I published in all this work. Alzheimer's is low plasmalogens. Parkinson's. Okay?

Anytime that we see someone with low plasmalogens is a strong indicator of reduced peroxisomal health. And that there is some stress on the system that is depleting. It's a big deal, okay? And so, the plasmalogen, there's basically three core lipids that we focus on. Plasmalogen levels, phosphatidylcholine levels, another very, very important one. There's only one deficiency that will reproducibly produce cancer every single time, and that's a phosphatidylcholine deficiency. Okay? It's very important. Virtually, all pancreatic, liver cancers, are caused by a phosphatidylcholine deficiency. Okay? Period. Measuring phosphatidylcholine deficiency is always critical to make sure that those are normal.

And they're independent. Phosphatidylcholine deficiency system is typically maintained from diet and the methyltransferase system. And the third one is cholesterol. Okay? Whenever you see someone with low cholesterol, it's a very strong indicator that really poor cellular health is going on. And those are the three core components of lipid. Those are the big ones that you need to get right. And we see a lot of that now. A lot of young people.

What happens is we see these turbo cancers and so on and so forth. This all stems from mitochondrial dysfunction. Okay? When the mitochondria aren't working, we get this extra mitochondrial ATP, and that shuts down peroxisomes. Okay? It creates this pseudo fed state, if you will. Okay? And disrupts a bunch of things. You have a lot of these people with high oxidative stress markers and low plasmalogen. And they're just fatigued. And these are big problems. Yeah, it's a big deal. It's definitely a major canary in the coal mine.

[1:14:04] SCOTT: I wish I had thought about having that light bulb thing, because you're giving us a lot of light bulbs already in this conversation. You have your PC+ products, which are a mix of phosphatidylcholine and either the N3 or N9, a few other nutrients in those as well. Those are going to soon be known as PlasmalogenN3PC+ and PlasmalogenN9PC+.

A few questions. Do those also contain any of the phosphatidylserine, ethanolamine, or inositol? Or do we generally not find we need to supplement those? How do you decide when to use the standalone plasmalogen precursors versus the combined plasmalogen precursor-enriched egg yolk oil products? Is that something we need to do some testing on? Or can we kind of get there just academically for a certain person?

And then why do you find the lipids derived from egg yolk potentially better than those derived from soy or sunflower? Have you considered making just an egg yolk oil with phosphatidylcholine without the plasmalogen precursors given that so many people are using phosphatidylcholine from these plant-based phospholipids? But I don't know of an egg yolk oil derived phosphatidylcholine product that's readily available.

[1:15:15] DR. GOODENOWE: The butyrylcholine from eggs versus seed oils, first thing. Especially for the brain-related activity, it has to deal with structure of the phosphatidylcholine. And this is where we kind of get geeky. All these phospholipids have two fatty acids. And they're on two positions. They're called the SN1 and SN2 position.

The SN1 is the conserved. It's kind of the anchor position. And the SN2 position goes off and on, off and on. PLA2 is moving the SN2 position. That two means the two positions being removed. And that's where your arachidonic acid, or DHA, and oleic acids come on.

The SN1 position is highly preserved, especially in the brain. And so when we get phospholipids in the brain, what goes into the brain is called the lysoPC. And a lysoPC is a PC that retains its SN1 position but has nothing at the SN2, just free alcohol. Okay? That's why it's called a lyso. And that's what gets into the brain once it get past the blood-brain barrier. Then once it gets past the blood-brain barrier, then the cells can take it up and use it. Animals only have saturated fat, palmitic, stearic, or oleic at the SN1 position. Okay?

Plants put linoleic acid at the SN1 position. Okay? And the brain cannot use it. The brain recognizes that as a toxic molecule. Okay? And so you need to have a phospholipase A1 molecule. And the brain doesn't contain really high levels of phospholipase A1. The liver does.

Peripherally, you can take a seed-based phosphocholine, and your peripheral system will handle it quite fine. But it's not for the brain. And so for brain health restoration, you need an animal-based phosphatidylcholine. Either get it from eggs or get it from liver. Okay? It needs to be an animal-based source for the brain to handle it. And that's why that product was created.

Looking at when to use them. For most people, we use a neuro – we use the PlasmalogenN3PC+ in the morning. It is the most potent of all things. It has the most powerful brain-enhancing effect. Okay? Just the lipid matrix, it's a very powerful product. Then if you take that in the morning, then you just take pure PlasmalogenN9 at night.

Now, people who are in this more inflamed or in Cell Danger Response, and they're not ready for the N3 products, then they can go with the PlasmalogenN9PC+ product at first. Okay? So, they can start with just pure PlasmalogenN9 first. And then they can upgrade to the PlasmalogenN9PC+, because it's going to be much more activating. It's going to really boost the power, if you will, of the PlasmalogenN9 precursor. And then once they're stabilized, then they can switch from PlasmalogenN9PC+ to PlasmalogenN3PC+. That's kind of how the process goes.

[1:18:46] SCOTT: If we know that many of us are also deficient in phosphatidylcholine, as well as the plasmalogens, why would we not want to just take the PC+ products? How would we decide which person should go just to the plasmalogen precursors versus the combination?

[1:19:04] DR. GOODENOWE: I recommend the PC+ all the time, especially in the morning. I don't recommend it at night. Personally, I like the pure PlasmalogenN9 at night. The N9PC+ and the N3PC+ is just quite activating. Okay? And so, I find just the plain N9 at night is my go-to.

[1:19:26] SCOTT: And is that also something that's highly concentrated? Meaning there are people that have suggested egg yolks being consumed to get healthy lipids. Obviously, I think you would have to take them raw, essentially, or very much not cooked. But is it possible to even get the lipids that you have in your product by eating eggs? Or would we have to eat dozens of eggs a day to get there?

[1:19:50] DR. GOODENOWE: Well, it's actually not about how many eggs you eat. But I still recommend eating lots of eggs. It's still good for you. Okay? There's no question there. The question is the absorption, right? When you eat a regular egg, whether it's a hard-boiled egg or whatever you want to eat, with yolks in it. It doesn't matter. The lipids are pretty stable. Yike you're not losing lipids in that perspective.

And so the problem is it's still got all the protein and everything else that's in the egg. And so that's going to go through your regular digestion process. Your digestion process has to digest and release all those fats from all the cellular material in the egg through your digestive system. Okay? So, it's going to get absorbed kind of in a slow release over the course of an hour or two, right?

And so, when we extract just the lipids, there's no protein, okay? No sugars, no water. It's pure fat, okay? Oil, okay? And then when you take that, then it's just going straight in and you're getting this peak response. Okay? The pharmacokinetics is critical. This is also why it's important for all your other vitamins. You'll say, "Oh, I'm going to modify my diet so I get all these vitamins in my diet." Well, the amount, the total amount is not the same as the peak amount. Because what you want is you take a supplement. If I take like a 100-milligram pill of B2, riboflavin, I'm not going to get this over the course of a whole day. I'm going to get a peak, okay? And it's going to push it into my systems, okay? And then it's going to be go away.

And this is actually why it's healthier for a lot of things when we're talking about just health intolerance. People take things with food because it actually slows that process down. That's why it's designed to really be more pharmacokinetically and pharmacodynamically active.

[1:21:56] SCOTT: I guess what I'm sending out to the universe trying to manifest then is an IV PlasmalogenN9PC+. That sounds like that would be an interesting tool to me personally.

[1:22:08] DR. GOODENOWE: Exactly.

[1:22:09] SCOTT: So, with one of the differences that some discuss potentially being that plant-based lipids are contributing to the inflammatory burden, raising linoleic acid, seed oil conversations has really been a heated or a hot debate recently. Not so much heating your seed oils, but a heated debate with many people suggesting that all seed oils are bad. I personally never resonated with that. I think it has more to do with the type, the processing. Whether or not we're cooking with them or not. I think there's a lot more nuance to that seed oil conversation.

But as a lipid biologist, how bad are seed oils for the human body? Are they all just bad and the internet is right? Or are there some healthy oils? And I'm thinking about black seed oil, or flax seed oil, or maybe macadamia nut oil. Give us your thoughts or your lens on the seed oil debate.

[1:23:06] DR. GOODENOWE: Yeah, I'm generally against all seed oils. Okay? Olive oils, avocado oils, fine. Now, for cooking perspective, these high oleic acids, sunflower, these are different. They're not they're natural seed oils. They're engineered seed oils. And so they're not really even seed oils quite frankly. Okay? And there's some companies making some really interesting oils from yeast products, for example.

The issue is the structure of the molecules. Okay? And plants make a seed, and they make a seed for the next plant. Okay? And so the seed contains the material. An egg contains the materials that a developing chick is going to require to grow. A seed has the materials for a developing plant to grow. And so it is that starter material for a plant.

And the starter – plants have cell walls, not cell membranes. Their membrane structures are extremely different than what we have. Okay? For example, you look at a tree. There's no bones in that tree. The actual cell membranes – the human body, we have this flabbiness. We can have some flabbiness because we got bones and senium. We got other things that hold the structure together. A plant never feels like that. Okay? Plants aren't squishy. They got cell walls. They got waxy cuticles. They're a whole different type of structure on them.

And so the seed contains that type of starting materials. And so it's a structure of the seed oils. It's not the fact that the seed oils are high in omega-6, which is a problem. Corn, soy, canola, these are all really high omega-6 oils, because omega-6 linoleic acid is a critical component of cell wall membranes, okay? Because it creates that type of cell wall membrane.

The human body, omega-6 is also an essential fatty acid for humans, but it's not something that you – there's so much of it around that you don't have to worry about it.

I tell people just focus on making sure you get enough omega-9 and omega-3. Okay? Minimize your omega-6. It'll take care of itself. Okay? It's so ubiquitous. It's impossible to avoid it. Even eggs today will have more omega-6 in it than they used to have. Or you get an animal product. Because animal products, they're fed high rates of corn. What they're fed are going to be in their system. It's not possible in today's universe to be omega-6 deficient, quite frankly.

See, omega-6 – I'm getting in the weeds with you guys here. But omega-3 has one purpose in the human body, okay? The precursors, the alpha-linolenic acids from flax and all that stuff, that doesn't exist in the human body. The body will take alpha-linolenic acid from flax. It only uses it to create omega-3s. Okay? There virtually no alpha-linolenic acid in any of our membranes. Okay? It's not part of human physiology in any way, in any meaningful shape or form.

Linoleic acid is different. Okay? Linoleic acid, which is the omega-6 plant version, our cells actually use that molecule. You will find good levels of omega-6 linoleic acid in our membranes. And why is it? It's a precursor to arachidonic acid. And so, there's two polyunsaturates that the human body uses for membrane fluidity. It uses DHA, which comes from alpha-linolenic acid and precursors. Okay? And it uses arachidonic acid, which comes from linolenic acid. Those are the backup plants.

If you become omega-3 deficient, your arachidonic acids will increase. The body will try to make the total composition of arachidonic acid and DHA this much. Okay? And so, when you're looking at your omega-6 to omega-3 ratios, when you want to bring your omega-3s up, what you're doing is you're trying to change the ratio of omega-3 to omega-6. And that is done by high purity omega-3, maintaining omega-9's and omega-3s.

And so the problem with the seed oils and the omega-6, they create arachidonic acid. Arachidonic acid is the source of malondialdehyde. It's also the source of your leukotrienes and that whole inflammatory intracellular cascade. Yes. As a general, that's just from the omega-6 side. But the biggest problem is the structure of the molecules. But the body will digest that kind of stuff.

[1:27:59] SCOTT: You somewhat answered my next question, because I know there are people that say that the health-focused consumer is often taking omega-3. They have high levels of omega-3 and maybe low or deficient levels of omega-6. I'm hearing you say there really isn't likely to be a deficient omega-6 state.

But two questions. On the omega-3 side, are you of the opinion that fish oil derived omega-3s are ideal? There are people that are suggesting that fish oil is not a good source, and that plant-based or parent essential oils are better. And then on the omega-6 side, even if we get a lot of this in our diet, is the type or source important? Should we be working to minimize those more harmful sources of omega-6 and having maybe some that are considered less harmful? Or does it really not matter?

[1:28:54] DR. GOODENOWE: Two things. On the plant-based side, I can unambiguously say no. The animal-based omega-3, which is DHA, and it's not EPA. Okay? This EPA thing is something else I want to put to rest. The body does not use EPA. EPA is just a metabolic byproduct of DHA. There's extremely low levels of EPA in our membranes.

The human body uses two fundamental molecules, polyunsaturates in its membranes. It uses DHA and arachidonic acid. Important for people to focus on the big ticket items. Okay? And you and your body will have virtually no alpha-linolenic acid in it. Okay? Any alpha-linolenic acid you consume from flax is only used so far as it gets converted. Okay? And it's a relatively heavy load. The fatty acid elongation.

To convert alpha-linoleic acid to DHA is a very detailed process. It goes from three double bonds to six double bonds. It's got to increase from 18 carbons to 24 carbons. And then from 24 carbons, it goes into the peroxisomes. Goes from peroxisomal beta-oxidation to DHA. It's a very detailed process. Creating DHA is a very detailed process.

Creating arachidonic acid is super, super easy. It takes an 18:2, which is linoleic acid. It does one fatty acid elongation state to 20 carbons and two desaturation states. And, boom, you got your arachidonic acid. Your body can make arachidonic acid super, super fast, super, super easy. On demand, anytime. It's almost impossible to become deficient. And does not require any peroxisomal function. Okay? Your body makes arachidonic acid without any peroxisomal function. All your DHA counts for peroxisomes. Unambiguously, yes, animal-based DHA.

And so, of course, in any kind of thing is a source and purity, right? Fish oils, the issue people have is how pure is it? What are these fish eating? Is there mercury in it? Those are all completely valid questions. I would prefer a high DHA algae source that has good quality control testing is probably your safest source of good quality DHA fundamentally. That's what I deal with.

[1:31:18] SCOTT: Do we then care about the source or quality of our omega-6 oils?

[1:31:24] DR. GOODENOWE: I avoid them. I just get them from – omega-6 is ubiquitous. You can't not get it if you're eating anything. Remember, omega-6 is going to be in your avocados. It's going to be in olive oil. Olive oil has omega-6 in it. Omega-6 is kind of the inspector gadget lipid. It's multifunctional. And so that's why it's everywhere.

[1:31:53] SCOTT: Without naming a specific product, I'm curious what your thoughts are on the C15 conversation that's happening now. There are people that are saying that C15 is very helpful for health and longevity. What is your lens on C15?

[1:32:08] DR. GOODENOWE: To be polite, C15 – first of all, C15 and C17. Okay? These are called odd-chain fatty acids. First and foremost, unambiguously, these are not essential fatty acids. The human body does not use these molecules. These are molecules that are made by the microbiome of primarily ruminant animals, like cows. Right? And these odd-chain fatty acids, the human body cannot process and cannot use them. It recognizes them as a toxic molecule.

And so your body has enzymes to deal with toxins. Cytochrome P450s and so on and so forth. Well, there's a specific enzyme that deals with odd-chain fatty acids called alpha-oxidase. Okay? And alpha-oxidase, what it does is it takes an odd-chain fatty acid and converts it into an even-chain fatty acid. And then your body can take that even-chain fatty acid onward.

That particular enzyme is in your peroxisomes. When you have an odd-chain fatty – and if you look at the data, and I did a big lecture on this thing. It's actually C17 that has the benefits that people notice. And when they look at sour cream, and cottage cheese, and those type of usages, and where those molecules have relatively high concentrations in them, it becomes a peroxisomal stimulator.

What they are is they're PPAR agonists. And so the benefit from it is that by taking – normally in your diet, you're going to get a very, very small amount of this stuff, right? And so it has probably the 10 to 100 times higher peroxisomal stimulating effect than DHA does because your body is used to having high levels of DHA.

Since you normally get exposed to low levels of C15 and C17, if you take higher levels of it through supplementation, it's going to have a disproportionately high peroxisomal stimulating effect. Because the peroxisomal will say, "Holy crap. I got to upregulate to deal with this stuff." And then you get this positive outcome. Okay? Does it have a positive outcome? Yeah, absolutely. It's a peroxisomal stimulator.

And so, as we just finished talking, stimulating peroxisomes is a good thing. But your body doesn't use it as – your body doesn't create C15 and C17. If your body doesn't – it's not something we use.

[1:34:43] SCOTT: But the stimulation of the peroxisomes from C15 or C17 could then mean that the body, in addition to the plasmalogen precursors that we're using exogenously in supplement form, could mean that our peroxisomal function now is allowing our own machinery to upregulate the production of plasmalogens.

[1:35:04] DR. GOODENOWE: Yeah. As long as you understand what you're using them for as a PPAR agonist. Okay? And so they're not toxic. They're part of a food chain. You're going to get them in there. There's no fundamental issue with them. But people should understand that's what they're there for.

[1:35:22] SCOTT: When we're talking about taking DHA, phosphatidylcholine, all of these lipids, which I'm a lipid lover. I had my tablespoon of olive oil in my smoothie this morning and all my other fatty nutrients and things. But is there any scenario where consumption of high levels of fat could contribute to the development of fatty liver?

[1:35:45] DR. GOODENOWE: Depends upon how you have other metabolic regulation. Having a pure fat diet. Okay? I think this is why I'm against having a pure keto diet, for example. I fundamentally think that the body should go through its natural cycle. It's got a natural cycle is supposed to be. The biggest issue is intermittent fasting. And we're not talking about going multiple days and stuff, so on and so forth. But just having the natural cycle that your body is supposed to have is important. A good balance of fat and protein, okay?

And I'm a big fan of certain non- glycemic sugars. Trehalose is a big favorite of mine, for example. Okay? It's also a good prebiotic for your gut. If you consume large amounts of fat, then the body will use it as energy, which it's supposed to. But, usually, when you consume it, it is supposed to be going – the body has to process it. When you take fat in your food, that fat doesn't go directly into your body. It has to get digested through lipases. And then the fatty acids get through the gut lumen, and then they get converted into triglycerides, and then chylomicrons. And so that part, there's a short-term cycle there. But then if it's a purely used for fat, you're going to get oxidative stress. Because peroxisomes – when you eat more fat than your mitochondria can consume, then your peroxisomes become energy generators. And peroxisomes are called peroxisomes because what? They make peroxide. Okay, that's why they're called peroxisomes.

Peroxisomes are supposed to be anabolic organelles, not catabolics. So, it's supposed to be designed to make things. And so, if you get too much fat into your systems, then you're going to get more oxidative stress from there. That fatty liver perspective can be a case. Because what has to happen for you to get fatty liver, first and foremost? The fatty liver doesn't come from fat from your blood supply going into your liver. Fatty liver comes from your liver making fat. Okay? And it makes fat through fatty acid synthase. Okay? And the sterile desaturates, which creates linoleic acid in our body, okay?

And so, what's happening is it's got too much fat energy that it can't process, and it's putting it onto fatty acid elongation. And then it's packing that fat around, right? And so it's really about metabolic integrity and the capacity of your cells to process energy. If you have good cellular energy, you should be fine. But you want to have a balanced – you want to have good fat. I don't know if I've answered that question. It's not a simple answer because it's really dependent upon the physiology of the cell.

[1:38:40] SCOTT: Are there certain indicators in the testing that you do that would give us a clue? For example, if someone had a good AST/ALT in terms of liver enzymes, would that be some indication that it's unlikely that they have a fatty liver issue?

[1:38:56] DR. GOODENOWE: Oh, it's super easy to detect fatty liver. What happens with fatty liver disease is that the phosphatidylethanolamine levels in your blood go way up. And so, when you see the phosphatidylethanolamine levels shoot through the roof, you have non-alcoholic fatty liver disease.

[1:39:13] SCOTT: Oxidative stress is a major contributor to inflammation, to chronic disease. We've touched on that some. Wondering how plasmalogens potentially act as antioxidants and how their properties in that realm maybe compare with other antioxidants that we can consume or maybe in our food. Is it the precursors in the supplements themselves that are antioxidant? Is it the end result plasmalogens that the body produces from the ingestion of the precursors that are antioxidant? And then how selective are the antioxidant properties of these plasmalogen precursors or plasmalogens? Are they focused on superoxide or peroxynitrite, for example? Can we see shifts in oxidative stress panels when people are incorporating some of these plasmalogen precursors? Do things like malondialdehyde, for example, reduce with plasmalogen precursors? And does then the incorporation of other antioxidants lead to chewing up less of either our precursors or our created plasmalogens?

[1:40:22] DR. GOODENOWE: Okay. Well, let me unpack all that, Scott. Okay. First and foremost, the plasmalogen precursors are not antioxidants at all. Zero antioxidant capabilities. And so it's the vinyl-ether bond in the final plasmalogen that gives it its antioxidant capabilities. And the vinyl-ether bond is exquisitely sensitive to acid, specifically peroxides. Okay. It's a prime neutralizer of membrane peroxides and hydrogen peroxide itself. Okay. That's its fundamental role.

And why it's so powerful and it's orders of magnitude greater at neutralizing oxidative stress than all other antioxidants in the body is because your body has massive amounts of it, versus vitamin E or other things. And more importantly, a lot of antioxidants, what they do is they're – I would call them hot potato holders. They basically capture an electron. And somewhere later, it neutralizes. Plasmalogens get consumed. They blow up. And when they get consumed, they completely neutralize the peroxide. And so it's in your membranes.

And so why plasmalogens are your main antioxidant in the human body? Fat soluble, if you will. Okay? Is that they're actually present in the membrane. And the way their vinyl-ether bond is structured, it is close to the outer surface of the membrane. It is right there on the outer surface of the membrane. Vitamin E molecule is in the inside of the membrane. It's inside that fossil – it's in that fatty acid bilayer, right?

The vinyl-ether bond is sitting right there. Okay? It's your first foot soldier. It's the first thing that oxidative stress attacks. And then your body – because your body's designed to make more plasmalogens. It can say, "Okay, it's going to blow this stuff up." That's the fundamental role.

And then it can get released through – when the cell feels that it's in an oxidative stress, one of the first things that happens during a Cell Danger Response is phospholipase A2 gets activated. And what happens when phospholipase – and there's different types of phospholipases A2. There's a plasmalogen specific phospholipase A2. And what that does is it releases not just the free fatty acid, which is often DHA or other. But it releases lysoplasmalogen into the soluble interface. And that lysoplasmalogen has that vinyl-ether bond and it gets used as an oxidative stress neutralizer. That's why it's so powerful. Okay?

And so, it doesn't work on the superoxide dismutase system or the peroxynitrate, which happens upstream. All oxidative stress comes from mitochondrial insufficiency. What happens is because oxidative stress comes from the inability to neutralize electrons.

[1:43:35] SCOTT: That was another light bulb for listeners, by the way.

[1:43:38] DR. GOODENOWE: Okay. When you consume energy – when plants take sunlight, and water, and carbon dioxide and combine it into glucose, for example, they're storing sunlight energy in a hydrocarbon. And then the body takes that hydrocarbon and it breaks it apart. And the energy that the sun stored in that molecule gets released. And it gets released in the forms of electron.

And what happens is NAD – people hear about NAD all day long. But NAD is not an active molecule. NAD doesn't contain energy. NADH contains energy. NAD with a plus sign becomes NADH with a neutral sign. So it collects these high energy electrons. Okay? And so, these high energy electrons are then what's used. This energy active molecule is then used to charge this electron transport chain in the mitochondria. And that electron, ultimately, oxygen that you're breathing in, comes in. And that oxygen gets converted to water. Okay?

What happens then is that that NADH cannot be utilized. It's got these extra electrons on it, and it reacts with oxygen. Instead of through electron transport chain, it reacts with natural oxygen. And you get the superoxide anion. O2 with an extra electron. Okay? This superoxide anion becomes this precursor. We have enzymes that normally neutralize superoxide anion, which is called superoxide dismutase. And your body is quite ubiquitous with the superoxide dismutase. And your body can induce it up and down. And that creates a molecule called hydrogen peroxide.

And hydrogen peroxide is a very powerful molecule because it will then create vasodilation. It's important. But it's only supposed to be short-lived. Okay? Supposedly a short little short-lived molecule. And if it sticks around for too long, then you can get peroxynitrate is formation of superoxide plus nitric oxide. Nitric oxide also gets stimulated through this pathway. Anyway, all that said and done. It doesn't work directly with the superoxide anion or directly with peroxynitrate. It works on the step afterwards, which is the hydrogen peroxide molecule.

[1:46:10] SCOTT: What happens to that? I'm thinking of protecting plasmalogens because they sound like it's so important to our cellular health, our systemic health. What happens to that plasmalogen that then gets used as an antioxidant? Can it then continue to still do good things in the body? Is it used up and over?

[1:46:30] DR. GOODENOWE: It's gone.

[1:46:31] SCOTT: Should we be using other antioxidants to try and hold on to our plasmalogens? Is that the best use of a plasmalogen to use it as an antioxidant?

[1:46:42] DR. GOODENOWE: Yeah. In terms of preserving or reducing the antioxidant loss or the oxidation loss of plasmalogens, the biggest one will be glutathione. The other molecule that neutralizes hydrogen peroxide is called glutathione. And then there's peroxidins as well. But glutathione is a big one. Making sure you have good levels of n-acetylcysteine, selenium. You typically don't become deficient in glutamate and glycine, which are the other two fatty acids. But n-acetylcysteine.

Maintaining glutathione levels are big. It's a big issue. And the only real way to maintain long-term glutathione levels is good doses of n-acetylcysteine. Everyone should be on a couple grams of n-acetylcysteine a day. Morning and night. And it'll maintain glutathione in your brain.

Also, it's important. Some people take glutathione supplements. That's fine for your blood supply. But glutathione does not get transported across the mitochondrial membrane. You need n-acetylcysteine. And we call it n-acetylcysteine, but it's really just cysteine. People use n-acetylcysteine as a pro drug to cystine. But quite frankly, the problem is the stuff smells like rotten eggs because it got sulfur in it. And there's no easy way to –

[1:47:59] SCOTT: As we get to our last couple of questions here, NAC question, do you have any concerns about the long-term use of NAC as a biofilm disruptor in that it potentially could disrupt healthy biofilms, including negatively impacting the mucin layer of the gut that houses our microbiome?

And second question, if NAC is so important, which I agree that it is from a perspective of glutathione, do you think that the newer forms, NAC ethyl ester, that can also cross into the blood-brain barrier, do you think that potentially has some advantages over the types that we have been using to date?

[1:48:38] DR. GOODENOWE: I think it's people counting how many angels are on a head of a pen. It's a simple amino acid. It's cysteine. Okay? This is why your protein sources – also, why some of the plant – the biggest problem with plant protein sources is that they're sulfur amino acid deficient. They're typically deficient in cysteine and methionine. Your whey proteins are one of your best proteins to maintain your sulfur balance in your body, for example. Right?

And so, no. It's an amino acid. Okay? You got transport mechanisms. You don't even need to take n-acetylcysteine. You can just take pure cysteine. It's going to do the job you need to do. This is just basic nutrition. And if you take enough of it over time – and so I think people get caught up in this, "Oh, do I need to have this maximally bioavailable thing?" Well, maybe there's a little slight difference. But really, we're just talking food here. The ethyl ester. No, I don't see any reason.

In my data, in my results, we just take n-acetylcysteine. I do magnetic resonance spectroscopy with the brain. And we restore glutathione in the brain. It's the easiest thing in the world to do. And your methyltransferases, take n-acetylcysteine, take your methylfolate, take some methyl B12, and you're going to be fine.

[1:50:01] SCOTT: We talked a little bit about how the plasmalogens become part of the mitochondrial membranes. Do the plasmalogens then improve our ability to produce ATP or produce energy? Do they have any role in the creation of new mitochondria or in mitochondrial biogenesis? And are there any tests from your lens today that are good for assessing mitochondrial health? It doesn't sound like there are a lot of good options in that realm.

[1:50:30] DR. GOODENOWE: Well, two things. Measuring mitochondrial function is a very simple way of doing that. We do that with the ProdromeScan and the BioScan. But in terms of the membranes, it's not going to have any direct effect on that. It's going to have an indirect effect.

What happens in the mitochondria? Mitochondria is an extremely oxidatively demanding cell. Your mitochondria are literally on fire. Okay. They're converting carbon dioxide and oxygen into water. Hydrocarbons and oxygen into carbon dioxide and water. They're literally on fire. And they're very highly energetically demanding system. They're always producing lots of superoxide. They're always making high levels of peroxide.

You want to keep it just nice, and flush, and supple. Maintaining plasmalogen levels is just making sure that the mitochondria are healthy. They're not doing anything directly. They're just making sure the mitochondria are healthy. Whatever its normal inherent capabilities are, because the mitochondria has its own DNA and it has its own transcript processing flow. We're not actually directly influencing. We're indirecting. We're just keeping the mitochondria healthy and happy. And then it can do whatever it wants to do is really where that's at.

[1:51:50] SCOTT: So, my last question then for our conversation today is there is so much focus on genes as drivers of disease. I know you work particularly in some children with true genetic diseases. But a lot of times in the chronic illness space, we're looking at SNPs, or Single Nucleotide Polymorphisms, which are really more potential for a problem. Everyone gets so worked up about these SNPs. Whether or not they represent true issues with function or not is always a big question.

And so, in my mind, if we're taking the true genetic conditions and putting those aside, those are very important, serious. And thank goodness, people like you are working with them. But if we thinking more about kind of the SNPs and genetic function, things like environmental toxicity, or emotional health, or nutrition can epigenetically influence how our genes express. And so my question is, is there anything in the plasmalogen precursor realm or the resulting plasmalogens, that better membrane health of the cells and the components within the cells, that could potentially be optimizing or improving our genetic expression?

[1:53:07] DR. GOODENOWE: Right. Two things. First and foremost, the SNPs that we have for methyltransferase system, for example, like the MTHFR, others. These are all good indicators of where your body has weaknesses. Okay? And they can create problems under certain circumstances.

My philosophy on this process is that there are core biochemical systems that we just need to have working properly. Okay? It shouldn't matter if you have an MTHFR mutation. If you're taking creatine, phosphatidylcholine, and good methyltransferase support molecules. If you're sitting there alive, like your body clearly has function.

If we're just proactively looking at these core systems and making sure that they're healthy and happy, then you can look at these things as potential issues. But they're really for people who haven't been maintaining a proper biochemical restorative health system. Okay? And then once you fix them, then these become irrelevant.

Second part is on the epigenetics. Okay? And this is where people put the cart in front of the horse. Okay? They think epigenetics are driving your function. But no, your function is driving your epigenetics. Your functionality changes your epigenetics. Your epigenetics is a reflection of your health. It is not a driver of your health.

As your health function decreases – as a cell becomes sick, for example, and it can't do its function, its epigenetics will change. Epigenetics are designed to help keep a cell alive for as long as possible, and for you to stay alive as long as possible. If you're consuming 3,000 calories a day because you're a marathon runner, your epigenetics is going to be changing so that your body can adapt that. Then, all of a sudden, you say, "I'm going to take a vacation, and I'm going to go down to 1500 calories a day in diet." Okay. All of a sudden, the body says, "Well, I'm not going to run at this high RPMs all day long." It's going to adjust to your functionality state.

And epigenetics, over time, can get you into a rut. Okay? Because then it gets settled into a certain state. And so when people look at changing their epigenetic clocks, as you restore your health and your functionality, your epigenetic and your methylation clocks will start opening up again because your body is capable of doing more.

And sometimes there's a time lag. That's one of the issues is that how long does it take to modify that epigenetic clocks that we have in the system? That's kind of where people – they get the assumption that the epigenetics are actually driving your – technically speaking, yes. Your epigenetics are modifying your gene expression. That is absolutely true. That's their job, to modify the gene expression. But why? And why are they doing it this way? Who told them to do this? Right? Well, you told them to do this because you basically said, "Okay, I'm sitting on a couch all day long. I don't need all these functions anymore." Your epigenetics says, "Okay, well, since you're not using this stuff, I'm going to turn it off."

And so who's the clock maker here that's telling the epigenetics to go on and off? You're the clock maker. And so, it's your actions and your physiology that drives your epigenetics, not the other way around.

[1:56:47] SCOTT: Can I take that one step further then to say that optimizing our plasmalogen levels increases our function. And our function then optimizes our epigenetics.

[1:56:59] DR. GOODENOWE: Exactly. And they've shown this with increasing vitamin C levels. You improve your health, you can improve your epigenetics.

[1:57:10] SCOTT: That's part one of my interview with Dr. Dayan Goodenowe. Don't miss part two in episode 231, where we discuss neurodegenerative prodromes and understand more about the lens through which Dr. Goodenowe looks at many complex chronic conditions. You won't want to miss it.

[1:57:29] ANNOUNCER: Thank you for listening to today's episode of the BetterHealthGuy Podcast. You can learn more about today's guest, including relevant links and resources in the show notes. This podcast may provide community discounts and occasionally share links from affiliate partners. You can find this and other episodes on YouTube, Spotify, Apple Podcasts, Amazon Music, iHeart, and more. To learn more about Scott's personal journey to better health, visit BetterHealthGuy.com. Join us next time on the BetterHealthGuy Podcast.

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