Plasmalogen Deficiency And Dementia with Dr. Dayan Goodenowe

ranscript of the episode

Dr. Adam Rinde: Dr. Goodenowe, welcome to The ONE Thing podcast. I'm delighted to speak with you today.

Dr. Dayan Goodenowe: Well, thank you very much for inviting me, Dr. Rinde. I'm very excited to talk about plasmalogens and answer any questions you may have.

Dr. Adam Rinde: You're welcome. Same here, I am very excited to learn more about this very interesting topic. I think a great place for us to start is just to kind of hear a little bit about your background about how you've got involved with plasmalogens. I think it goes back to probably before 1999, doesn't it?

Dr. Dayan Goodenowe: Yes. The plasmalogens came afterwards. So, technically speaking, my background is in synthetic organic chemistry and then my PhD is actually in the biochemical mechanisms of psychiatric disease. And so, my background is in the pharmaceutical industry in medicinal chemistry looking at drugs, structure activity, relationships and so on. And, what happened in the late 80s, early 90s was that this whole genomics revolution took off with this concept of being able to sequence the whole human genome and our ability to kind of look at health in a more global sense. But my background in biochemistry and chemistry, there was no really technology that was analogous to whole genome technology for small molecules and for the biochemistry of life. And so, I had to take a little bit of a pause and my first real invention was this invention of complex sample analysis using high field mass spectrometry and really allowed us to do comprehensive, non-targeted analysis of the biochemistry of systems.

And the real cool thing about it was that we could measure in large numbers of individuals because we could do clinical trial work as well as cell culture or animal model studies and we applied this technology to human health and clinical trials. We're looking at case control studies, people with cancer, without cancer, people with dementia, without dementia and so on. And when we did the dementia studies, we found that this class of molecules was reproducibly lower in individuals with dementia and the more severe the dementia was in these individuals, the more severe the depletion in these molecules were.

And, when we did structure elucidation of what these actually were in the blood of these individuals, it turns out that their plasmalogens, so that's how I really discovered plasmalogens. It really wasn't something that I was pre-thinking about. It was totally organically discovered using human epidemiological research.

Dr. Adam Rinde: Sort of an unexpected finding.

Dr. Dayan Goodenowe: Absolutely.

Dr. Adam Rinde: It wasn't something you were looking for.

Dr. Dayan Goodenowe: Yeah. It's both exciting and annoying at the same time because when we figured out what these things were, it's not some trace level molecule. It's 20% of your entire brain, 60% of the ethanolamines or even 80% in your synaptic cleft and then the glial white matter are comprised of these plasmalogens. But yet, they're not really in your normal everyday lexicon of human biochemistry.

And so, that's where the story keeps getting more and more interesting, so that's where the plasmalogen story came in. And then, my background in synthetic chemistry and in biochemical mechanisms of disease really started taking it one step at a time and from there, we looked at much more detailed studies as to the biochemical mechanisms of plasmalogens, we synthesized precursors, the structure activity relationships to understand which plasmalogens did which things then it just became one of those really obvious situations where these depletion in plasmalogens was preceding this neurological decline.

And in terms of cognition and dementia, these were the systems of the brain that were the most susceptible and the most sensitive to plasmalogen depletion situation. So, that's kind of where it all came in and now we can restore them.

Dr. Adam Rinde: That's really interesting. I'm curious like this is 2020 and since you came across plasmalogens when you've published a lot of papers about them, you've done a really thorough scientific investigation. How did you go about that? It seems like it would be almost something that you would want to get out into the world fast with growing incidence of dementia.

Dr. Dayan Goodenowe: When we first discovered these plasmalogens and I patented them and I patented their associations, it was really this cognition and Alzheimer's focus. But the more we studied them… and of course plasmalogens are natural, so at that time I had my pharmaceutical hat on and I was designing non-natural plasmalogen precursors that I could get accomplished in a matter of patents on.

So, I patented a whole bunch of plasmalogen precursors. But that restricts you to this FDA drug program where you have a very narrowly defined indication for a particular product. And, as this research got more and more involved and we saw the association with Parkinson's and association with stroke and our ability to restore white matter in multiple sclerosis and on and on and on, it became very clear that we're dealing with not just a specific Alzheimer's drug model but really a generalized neurological deficiency and it really looks at a concept of neuro degeneration of which cognition is the canary in a coal mine.

And once that became clearer, it became much more clearer to say, "This drug based approach really isn't the way to go." And so, what I did from that time is design what's completely 100% natural product. It's still scientifically designed that synthesizes a highly pure product but it's 100% natural. And so, now we can deliver it and distribute it worldwide to individuals with the same basically pharmaceutical vigor but in a completely natural model that doesn't require any phase two, phase three clinical trial design models and then it's not restricted to one indication.

Dr. Adam Rinde: Okay, great. I think a good place to start from here would be to just do like a definition of plasmalogens both from a standpoint of more of a basic definition and then more of a detailed definition. If you could just maybe kind of give us a basic overview and then kind of dive in a little bit deeper to the details of it?

Dr. Dayan Goodenowe: It's just such an interesting story. These plasmalogens are just playing intriguing because first of all you have lots of them but it's a non-redundant system, so at the basic level plasmalogens are phospholipids. So, they are part of the phospholipid bilayer of all the cells of the body. So, you have a trillion cells in your body and within those cells, you have mitochondria and peroxisomes organelles. Every cell and every organelle in the body is separated from each other by a phospholipid bilayer, the membranes and this is what the human body allows itself to compartmentalize and so we can have the complex systems that we have in the human body because we get the separation by membranes.

And so, these plasmalogens are critical for that and they're really critical in terms of the transport of materials in and out and they modify the fluidity. So, we studied them in terms of cholesterol regulation, in terms of amyloid precursor processing, in terms of vesicular fusion and release of neurotransmitters for instance. And so, these plasmalogens are really critical for membrane fluidity and membrane structure integrity. Now, the criticalness of plasmalogens is evident because children that are born with genetic mutations that block the human body's manufacturer of plasmalogens, they have extremely reduced lifespans and mortality. Depending upon the severity of the deficiency, they can live as little as a year or so or maybe up to 10 years.

And so, there's quite a human mortality issue with plasmalogens. So the question is, "As something so critical, how are we making it?" and the power of the plasmalogens is also its Achilles heel. So, unlike biomembrane structure, your plasmalogens do not require any essential nutrients. They're manufactured in your peroxisomes or basic molecules like your basic fats will generate plasmalogens. Not like a DHA where you need an omega-3 or arachidonic acid where you need omega-6 precursors from the diet.

There's essentially no dietary requirement for your body to make plasmalogens so your body has a capacity to make lots of plasmalogens and so it makes these things as sacrificial lambs. So, your body makes plasmalogens and the last step in the plasmalogen biosynthesis is a special little bond it has called the vinyl-ether bond which makes it an incredibly potent antioxidant. And so, it's in all your membranes and it's used to protect these other nutrients that you need to get from our diet like our omega-3s. So, your plasmalogens are the sacrificial lamb if you will. It will get oxidized first to protect your DHA and arachidonic acid and your other essential oxidatively stress sensitive molecules and your body can normally make lots of these things for long periods of time.

The strange thing about them is that just because we can make them and there's a significant amount of them in our tissues, the one quality that makes them so special makes them unavailable as a dietary source. So, the vinyl-ether bond that gives the plasmalogens this power can't survive the stomach acids. So when I eat juicy steak, I'm not getting many plasmalogens in my body because the stomach acids digest the plasmalogens before they get in my body. So, even though your body has a good ability to make them, you have to make them. We can't get them from anywhere else.

And so, as we get older and the age related decline in liver function and other situations that at some point in time our ability to manufacture plasmalogens becomes less than our consumption and we have no other way around it. So, either we find lifestyle ways to stimulate plasmalogen biosynthesis which can be done by exercise training and some other things or we need to find some novel supplement route that can bypass this acid degradation issue and that's what we designed these natural plasmalogen precursors.

It basically like L-Dopa for Parkinson's like L-Dopa is a biochemical precursor of dopamine and we've basically developed the equivalent for plasmalogens which is orally bioavailable, bypasses the gut acids, goes into your liver, converts into your final plasmalogen and then can distribute it through rest your body. So, that's kind of the simple story of plasmalogens.

Dr. Adam Rinde: Yeah. You said some interesting things. One of them is how we are not as effective as making plasmalogens as we get older. Where are they made?

Dr. Dayan Goodenowe: So, they're made in your liver and they're made in organelle of your liver cells called peroxisomes. All the cells in the body have two main organelles for energy generation and synthesis. One is the mitochondria and lots of people know what mitochondria. So, the mitochondria are your internal combustion engines. They take fats and carbohydrates, convert them to a little molecule called acetyl-CoA and then burns that into carbon dioxide and water. So, mitochondria are 100% catabolic.

They're supposed to be pure energy burning engines to generate energy. Mitochondria don’t make things. Mitochondria consume and generate energy. Peroxisomes are the brother or sister of mitochondria and peroxisomes are anabolic, so peroxisomes make things. But they digest fats and lipids into acetyl CoA but this acetyl-CoA is used to make all the cholesterol in your body, used to do fatty acid elongation and they also make your plasmalogens. But peroxisomes are called peroxisomes because they make peroxide and so they're oxidatively demanding cells and that's why you make your plasmalogens in your liver and transport them to your brain.

So, even though the whole body can make plasmalogens technically speaking, it chooses not to do so because of the oxidatively demanding biosynthesis. And so, it made your liver, transported basically via HDL particles in the blood supply and goes into the brain. And so, people with high plasmalogens typically have high HDL levels. So, HDL levels and plasmalogens also affect your reverse cholesterol transport by improving cholesterol clearance from yourselves which we published pretty extensively. So yeah, they're made in the liver and then transported through the blood supply to the cells of the body and the brain.

Dr. Adam Rinde: Got it. Okay. So, fast forwarding a little bit to the disease process in dementia and that progression to Alzheimer's disease and there are several types of dementia of course but the kind of classic model with beta amyloid plaque and tangles and the kind of model we think of just kind of basic model for dementia and Alzheimer's. How are plasmalogens featured in that process?

Dr. Dayan Goodenowe: That's a really good question and it's a really important one because we start changing definitions of words. There's actually two phrases I'd like to draw upon. One is Occam's razor by William of Ockham who says, "Plurality should not be assumed without validation." Basically, if you have a hypothesis, choose the simplest one until a more complex one is proven to be a more accurate. And, the second one is from Einstein which I love which says, "Make things as simple as possible, but no simpler" which means don't oversimplify things to the point that they have no meaning.

And I think, sometimes what we've done is we've conflated the pathological characterization of a disease with the function of a disease. So, Alzheimer's is used to be called senile dementia of the Alzheimer's type and it's a post-mortem diagnosis disease which says, "Hey, here's a person with dementia which is a functional assessment," and let's ask the question, "Can we characterize it? Can we can we give it a library code? Is it Lewy body dementia?" which means here's a person with dementia and they had Lewy bodies. Is it Alzheimer's dementia?

So, here's a person with dementia and they have amyloid and plaque, tangles. Is it vascular dementia? Here's a person with dementia and there's white matter issues and stroke dimension, so on and so forth. So, dementia itself is a functional process which is pretty simple and clearly articulated in terms of cholinergic function in the brain. Dementia is the reduced function of cholinergic neurons and the postsynaptic transmission of acetylcholine. That fundamentally is dementia. And then, we can argue that what are the other causes or what are the other things associated with it but at a pure human neurochemical perspective, that's dementia.

And, that's why the acetylcholinesterase inhibitor drugs work because they work on that and they work transiently. They don't work forever. They work for a short period of time but they do work and they do work because they are cholinergic drugs in the synapse. Sorry for belaboring that point. So, the question is, "Why do plasmalogen deficiencies usually show up as cognitive deficits first?" So, cognition is really canary in the coal mine. So, when you have neurodegeneration especially neuronal degeneration of plasmalogens, the gray matter which is the neuron density typically decreases first and neurologically suck plasmalogens out of your white matter for a period of time.

But you're seeing a generalized decrease in plasmalogens across the entire brain, not just the cholinergic system but the cholinergic neurons are uniquely sensitive and susceptible to a plasmalogen deficiency because they're unique versus other neurons in the brain. So first and foremost, plasmalogens work at the synaptic cleft and they're required for membrane fusion. So all the vesicles that contain neurotransmitters in the presynaptic neuron, when you get an action potential pulse to create neurotransmission event, those presynaptic vesicles have to translocate to the presynaptic neuron membrane and then release their neurotransmitters into the synapse.

That is a biophysical process. There's a physical translocation and a physical fusing of membranes and a physical release of neurotransmitters. Plasmalogens work directly on that process. Your membranes required polyunsaturated plasmalogens to actually do membrane fusion. If we deplete membranes of plasmalogens, they don't fuse so you can get action potential, the vesicles move to the presynaptic neuron membrane and they just stick there. They don't actually release their contents.

And so, that's why we're seeing such dramatic effects with the plasmalogen supplement with ProdromeNeuro are more than we even expected. We see the symptomatic of observations within three to four weeks quite often in individuals and so; it works directly on the synaptic cleft, membrane, fusion and release of neurotransmitters. Now, the reason why cholinergic neurons are sensitive is that they have a unique neurotransmitter reuptake process. All the other neurons like your GABA neurons and your glutamate neurons and your serotonin neurons, your noradrenaline and dopamine and so on.

When a presynaptic neuron releases its neurotransmitters into the synaptic cleft and it sucks it back up; it sucks them back up using these transport proteins that are specifically designed for each of these neurotransmitters. And, most time for all the other neurons in the human body that protein is always present on the presynaptic neuron membrane but cognition uses acetylcholine. And, acetylcholine is really the only neurotransmitter in the brain where the neurotransmitter that is released from the neuron isn't the same thing that's taken back up into the neuron.

So, the neuron releases acetylcholine which acts on the postsynaptic receptor but when it comes off, it gets digested into choline and acetyl-CoA. So, it's actually choline that comes back up into the presynaptic neuron. And, the problem is that all the cells of your body require choline so every single cell in the human body has choline receptors and choline transport proteins. And so, the cholinergic neurons have a special protein called the choline high affinity transporter and that's found on the vesicles.

So, what happens in cholinergic neurons is that the ability to reuptake the choline is also dependent upon membrane fusion which other neurons are not. So, if the vesicles don't fuse and release their contents not only do you have a reduction in acetylcholine being released, you're actually starving the cell of the choline that requires to recharge itself. And so, what happens when you get a plasmalogen deficiency is that these neurons they become starved of choline even though choline is around and initiates what's called an autocannibalism cascade and it starts digesting its own membranes to get choline.

And so, that's why when you see a generalized neurodegeneration or plasmalogen deficiency, it's what I call dementia is canary in a coal mine. It's kind of the first neuron system to reach a critical point that we can see clinical symptomatology from it. But make no mistake; the entire brain is being inhibited with plasmalogen deficiency. We just typically see symptoms of dementia first and that's where link comes up so.

Dr. Adam Rinde: I see. Because some of the studies that I've read that you've done talked about also the beta-secretase enzyme and alpha-secretase enzyme and how you can kind of see the differences in the biochemistry and the pathology in patients who are dealing with dementia and Alzheimer's based on the activity of these enzymes. Can you go into that a little bit? Because that was interesting to me.

Dr. Dayan Goodenowe: Yeah. So, the whole amyloid hypothesis of dementia is a very interesting one. First and foremost, amyloid is real, okay? It's a real molecule and you shouldn't have lots of it in your brain so having lots of amyloid in the brain is a bad thing. No one is going to say it's otherwise. And so, amyloid is a really good biomarker, but it's not a biomarker of dementia. It's a biomarker of membrane deficiencies and I think this is where people get. So, amyloid is really bystander of a bad accident. So amyloid is obviously a natural molecule and it starts from a protein called an amyloid precursor protein and there's two pathways that the amyloid precursor protein (APP) goes through.

One is called the alpha-secretase pathway and one is the beta-secretase pathway. So, the alpha secretase is the healthy… 95% of all your APP gets processed through this healthy process and only 5% typically is being metabolized by beta-secretase. So, what happens though is that these two proteins live in two different parts of the biological membrane. The alpha-secretase likes to be in the phospholipid rich region where it's nice and fluid and the beta-secretase likes to be in what's called the lipid raft region which has high levels of cholesterol and high levels of phosphorylcholine and those are nice rigid membranes.

And so, your biological membranes are not one homogeneous thing. It's a distribution. There's regions that have different levels of fluidity. And so, what happens when you get older this whole concept we've known for 100 years, this whole hardening of the arteries thing, one of the things we know that's a very reproducible observation with aging is that as we get older, the percent of cholesterol in our memories starts to creep upwards and the percent of phospholipids but specifically ethanolamine phospholipids goes down so there's ratio of cholesterol to plasmalogens goes up with age.

And so, what we found in cell cultures when we study amyloid processing when we selectively elevate DHA plasmalogen levels in membranes, we can dose dependently increase the alpha-secretase and we decreased amyloid Aβ42 which is the protein that's that goes on to form the amyloid plaques by doing so, so we can completely regulate amyloid Beta-42 processing. And then, when we look at post-mortem brain tissue in humans, the same thing happens. So, humans that have high levels of DHA plasmalogens in their brain have low levels of amyloid in the brain. So, amyloid basically is a biomarker of low plasmalogens in the brain basically.

Dr. Adam Rinde: It's amazing to me because when I read this or came across this first, I was shocked because I've heard how difficult it is to shift this environment and how many drugs have failed at trying to do that.

Dr. Dayan Goodenowe: Anti-amyloid therapies were never ever going to work and we knew that since the '80s. This is not a surprising outcome. If you take a look at post-mortem analysis and if you ask a neuropathologist to try to diagnose dementia in a patient post-mortem based upon pathology, it's almost a flip of a coin accuracy. 100% of cognitively normal people will have pathological amyloid deposits and they will meet the criteria for moderate to severe Alzheimer's on death.

And so, from a pathological perspective these people have full blown Alzheimer's pathology but they have no cognitive impairment. They are completely normal and we've known this for a long, long time. When we do the post mortem analysis, we looked at amyloid levels, we looked at tau levels, we looked at cholesterol and we correct for the plasmalogen levels. If you correct for the plasmalogen levels in the brain, amyloid has no statistically significant association with cognition whatsoever.

And so, it's an interesting biomarker but it's clearly not causative and we've known this for a long time and the whole hope was they did find in some people with certain mutations. Yes, if you have a particular genetic susceptibility to hyper-amyloid then that could be an issue of doing amyloid, but for most of us amyloid is a coincidence. It's still a bad thing. It's a good biomarker, so something's not right with your membranes, but it's not actually causing dementia. Amyloid is not a little Pac-Man chewing your neurons up. It's just not.

Dr. Adam Rinde: Got you. Thanks for clarifying that. That's really helpful; so, going a little bit further into this. I think you mentioned a couple of potential epigenetic moves that people can do to influence their plasmalogens. Obviously, aging or the health of the peroxisome I imagine would be one factor to think about but you said exercise. Can you talk a little bit about that?

Dr. Dayan Goodenowe: Yeah. So, if you take a look at… physical human body is designed to be as lazy as possible. We're very efficient and it will not do anything unless it's forced to do so. So, the whole point is, "Can I drop you in the middle of a desert and can you walk across this desert and survive?" And so, we're balanced. Our arms swing properly. Our legs swing properly and you're going to fundamentally use your liver and your lungs and your circulatory system for 99% of all bodily functions and you only use your other musculatures when needed on a temporary basis.

And so, what happens as we get older we end up having these dormant systems that have been kind of underutilized for our lifetime. And so, in the elderly when you start giving them resistance training regimens where they start working on their biceps and the triceps and the quadriceps in a way that they don't normally use them, we can activate the biochemistry in the cells and they become basically almost like mini-livers working in the circulatory system so it can do a lot of the work that the liver is not doing anymore and that kind of when you stimulate the peroxisomes in your muscles, they start making plasmalogens for you.

So, you can stimulate the production by moderate resistance training. You can also reduce the consumption of plasmalogens by modifying the diet to a low inflammatory diet and making sure you have good levels of anti-inflammatory support molecules like N-acetylcysteine and acetyl-L-carnitine those things that can maintain your mitochondrial function and so it's a balancing act as we get older. Can we reduce the consumption of plasmalogens and can we stimulate the production and to a certain degree can you can do both of those .

Dr. Adam Rinde: Okay, thank you. So, let's take a person that may be at more risk for dementia and Alzheimer's, someone with like an APOE-e4 SNP (single nucleotide polymorphism). So, for the listeners is there a genetic predisposition that puts you at high risk for developing early Alzheimer's disease? If they were to approach as soon as possible like plasmalogen approach, take us through what would be some steps, like what would they do blood draws, what kind of lab markers would they look at and then go from there?

Dr. Dayan Goodenowe: Perfect. Okay, so APOE-e4 is a great story. And it's a poster child of saying, "Can I biochemically overcome my genetic risk factors?" and the answer is clearly yes. We just published a major research project on that last year basically showing that people APOE-e4 carriers with high plasmalogens had no increased risk of dementia so you can override and you can neutralize your genetic risk. You need to understand what your genetic risk is doing though; so, in APOE that the three alleles, the e2, e3 and e4, their fundamental biochemical activity is cholesterol transport.

These three proteins have the ability to transport cholesterol with different levels of efficiency and it's all related to your reverse cholesterol transport capability. So, APOE-e4 carriers have a reduced ability to clear cholesterol from cells. So, when your cell makes cholesterol, you make cholesterol internal of your cell and then the free cholesterol goes into the plasma membrane and that plasma membrane in the free-cholesterol form will esterify the cholesterol and then either will get recycled internally by LDL particles or it will be taken up the HDL particles externally and circulated back to liver.

That's called your reverse cholesterol transport system. And so, people with an e4 carrier that e4 protein is very inefficient at clearing cholesterol from the membrane. And so, people with an e4 allele end up having higher levels of membrane cholesterol in their systems in this whole concept of amyloid. So, e4 carriers have high levels of amyloid in their brain fundamentally, but the amyloid is a biomarker of membrane problems. If you have high levels of cholesterol in your membranes, beta-secretase likes the cholesterol rich region so they have overactive beta-secretase which means they have overactive Aβeta42 formation.

So, people with the e4 carrier on brain scans will have on average higher levels of amyloid but not all e4 carriers will have high amyloid. It's just a statistical averaging thing. So, for an e4 carrier that's your predisposition is a poor cholesterol transport. If you're an e2 carrier, you've got extra good cholesterol transport. If your and E4 carrier, then you need to be able to counterbalance this cholesterol transport problem and that's where plasmalogens come in, so plasmalogens work on the opposite direction. So, if your e4, your HDL molecules they're the ones that come and pick the esterified cholesterol from the plasma membrane and take it back to liver and you have an e3 or e4 or e2 and those will have different levels. Plasmalogens, they push the cholesterol out of the cell.

So, if you have high levels of plasmalogens, the esterification process is ramped up and it is pushing plasmalogens out of the cell. So, it can counteract and support the e4 so an e4 carrier with high plasmalogens has normal cholesterol transport so the genetic risk associated with the e4 is eliminated because you have restored that biochemical mechanism. And then, with large group of people over 1200 people we showed and we looked at the genotype and the plasmalogen levels and clearly showed that your plasmalogen levels can neutralize your e4 genetic risk. It's based upon the mechanism of that process.

Dr. Adam Rinde: So, if they're working with your company there's sort of a blood panel that they can look just to measure the plasmalogen content.

Dr. Dayan Goodenowe: Yeah. So, for an e4 carrier it's even more dangerous to have low plasmalogens because then they have a double whammy. They have poor export of cholesterol and they have poor pushing of cholesterol out of the cells. If you're an e4 carrier, you definitely don't want to have low plasmalogens. So, we can measure the plasmalogen levels and the HDL levels and your HDL to LDL ratios which you want to ramp up. And so, for an e4 carrier really getting good peroxisome function, fasting, proper diet and then obviously the plasmalogen supplementation, we can take it over the top now and completely restore that cholesterol regulation in e4 carriers.

Dr. Adam Rinde: Yeah, okay. So then, how long after taking supplementation would you expect the levels to normalize? Is it a yearlong process or is it three months? What's the general timeframe if someone's coming from a low standpoint?

Dr. Dayan Goodenowe: Well, it depends on how much dose you take. Personally, we've tested them ourselves and I took 100-milligram per kilogram dose and I doubled my plasmalogen levels in 24 hours so the next day my levels were up. That's 10 times what we recommend as a normal dose. All of our studies in animals at 10-milligram per kilogram dose about two weeks your plasmalogen levels are doubled.

And so, basically we offer a bottle of plasmalogen oil which is 30 mL and it contains 900 milligrams of plasmalogens per dose so it's extremely highly concentrated. By the end of your first bottle, people should have normal plasmalogen levels if not slightly higher than normal plasmalogen levels and then from there on, you can maintain them indefinitely.

Dr. Adam Rinde: Got you. Okay. Is there any sort of warnings or precautions that people should take if they're going down this road of considering plasmalogen supplementation?

Dr. Dayan Goodenowe: I think regarding the plasmalogen part of the molecule but there's two components that give the plasmalogens their activity. One is the plasmalogen backbone itself which is what you can't get in your diet and that's very much what we have to supply with our precursor. The second is the type of fatty acid that's on it. So, the DHA and DPA, the polyunsaturated omega-3 long chain fatty acid that we put at sn-2, that's what, gives us a neurological activity.

Now, that will have the same issues that you want to monitor if you're on a current omega-3 supplement so people can look at blood pressure or if you're on a blood thinning regimen high doses of omega-3s are indicated for keeping an eye on that but usually it's pretty high levels that you have to watch. But other than what you would normally watch for someone on a DHA supplement which is the only issue you would have with them the plasmalogen supplement because that's where it is.

Dr. Adam Rinde: Okay. So, one of the things I came across is that the way that you manufacture or synthesize your plasmalogens is that they enter into the biochemical pathway in a way that's going to be better absorbed and better bioavailability. Are there certain kind of knockoff products or knockoff kind of attempts to influence this pathway that don't work as well?

Dr. Dayan Goodenowe: Yes. I feel like I'm really bombarding your listeners with biochemistry lessons here and I apologize for getting into the weeds on some of this stuff but yeah, it's really important. There's two aspects. There's the dietary process where you have to ingest it and your lipases will do some metabolism for you before you get in your blood supply and then you can distribute it to the rest of your body so you take extracts of animal products that have plasmalogens in them.

People have looked at those molecules. When you ingest a phospholipid, your pancreatic lipases in your upper GI tract, they take off the sn-2 position and you absorb as lysophospholipids so your lysophosphatidylcholines which don't have the sn-2 position on them which is the critical component of our targeting in membranes. That's one issue for phospholipids. Second issue is plasmalogens in the dietary supply get digested by your acid digestion not an enzymatic than actual chemical digestion in your stomach acids. Like pH of the stomach is between 1.5 and 3 so it's very, very acidic. It's hydrochloric acid, so our stomachs have concentrated hydrochloric acid.

And so, when you put this vinyl-ether bond into your stomach and if you're eating pure plasmalogens that have the vinyl-ether bond, you're just creating a chemical reaction in your stomach creating aldehydes which is not a good thing and so you can't really do that. And so, the molecules that we've done is designed very specifically. They're called alkyl-acylglycerols and when you eat these molecules of ours that the natural gut lipase takes off the sn-3 position so we actually have a very highly bioavailable DHA supplement so it's kind of extra bank for your buck there.

But what's important is that the DHA at the sn-2 position gets absorbed into the bloodstream and goes to liver so we can actually target the actual phospholipid we want. And, that's why with ProdromeNeuro we provide the DHA at the sn-2 which is really important for your neurons. But for younger people, say women with multiple sclerosis or children with autism that do not have DHA problems, they don't technically have a peroxisomal biosynthesis problem which is our problem as we get older. They have a problem caused by inflammation, so they don't need extra DHA.

In fact, extra DHA in the young people can be pro-inflammatory if it's given too much. It's a long-chain fatty acid but we as older people need them. The younger people don't. And so, ProdromeGlia has omega-9 at the sn-2 position. It delivers and so all the white matter like the insulation of your neurons like the white matter tracts, those plasmalogens do not contain DHA. They only contain your short-chain fatty acids. So, ProdromeGlia is designed for people with multiple sclerosis or children with autism to deliver those precursors for remyelination and for white matter restoration; only the alkyl-acylglycerols that allow you to actually target individual plasmalogen species. If you want to do the other way, you have to find sources for injection.

Dr. Adam Rinde: Yeah. I think it's really important that the listeners hear this. Since the dietary supplement industry is not highly regulated, it's really important to understand what you're taking is actually going to work as it's intended because there's just so many chances to jump into.

Dr. Dayan Goodenowe: And also, you can get natural alkyl-acylglycerols like for instance in shark liver oil but they contain lots of squalene and it contains saturated fatty acids so the type of plasmalogen is important; because if I put something like a stearic acid at the sn-2 position, I will actually cause an increase in cholesterol levels. This is why a shark liver oil has the exact opposite effect as a DHA plasmalogen oil. It's important that the right plasmalogen species is provided for the right indication. It is a scientifically mediated process. It's not just a one-size-fits-all. Now of course in the elderly for us as we get older, it's an easy story because the DHA we all need it and this basically replaces your other DHA supplements fundamentally.

Dr. Adam Rinde: Well, we're getting towards the end of our visit and I was hoping that you could leave us with some parting thoughts and then tell us a little bit more about prodrome and just how people can find out about you.

Dr. Dayan Goodenowe: Yeah, sure. Really cool thing about this is that I've been doing this now for about 30 years, my background in biochemical mechanisms of disease so it's been a long time. Most of my work has always been focused on find the disease, kill the disease. You find this disease and you want to find the biochemical process and the prodrome of a disease. And, what we've been really working towards now is the prodrome of health. How do I create what's called biochemical reserve? I can talk about these people with deficient plasmalogens and their increased risk for dementia, but people with the top 10% of plasmalogen levels; they have an 80% reduction in dementia.

A 95-year-old person with high plasmalogens in their blood has the same probability of living to age 100 as a 65-year-old with low plasmalogens has of living to age 70. Like those are really scary numbers, but it indicates that we've got our head scroll on backwards here. We've got this disease focused mindset of saying, "Here's our negative prodromes. These are the biochemical deficiencies that will lead to disease." But we're forgetting the other side of the coin. This is diagnostic.

It's like nuclear technology. You can use it to build a bomb or you can use it to give energy to an entire city. It's how you use it. And so in the biochemistry perspective, we can look at positive prodromes. How do we create biochemical reserve, to create biochemical savings accounts for the body that are there when you need them and you can do it for your plasmalogens, you can do it for your mitochondria. And so, that's what really prodrome science is moving forward is biochemical engineering of individuals using your own health information to get people into this biochemical reserve situation like a biochemical savings account for a rainy day.

And, I think that's kind of where I've really shifted my focus over the last few years especially since I've gone from the pharmaceutical industry into the natural products industry and the availability of targeted biochemical interventions is actually quite large. So, you can look at our website prodromesciences.com and we're available there and obviously, the ProdromeGlia and the ProdromeNeuro products. And then, we look at GTAs and other very large swath of biochemical systems that are critical and it's what triaging. It's about taking care of the big things first and then triaging down your decision tree. As you get down the tree, you'll deal with these smaller issues after you deal with the big issues and these plasmalogens are clearly one of these big issues that need to get dealt with.

Dr. Adam Rinde: That's wonderful. Well, we all know people who are at risk for dementia, people dealing with MS, autism, Parkinson's disease. This is really enlightening topic and I'm excited to bring this to my patients and to my loved ones, so thank you for being on here with us. I'm going to look at it on myself as well and do some level, so thank you for being on here. We really appreciate your time. It would be great to catch up another time and go into some of the other topics that we explored.

Dr. Dayan Goodenowe: Definitely, we will be available and certainly in some of the before and after events that we're seeing with individuals is pretty exciting, so it's really nice to be able to help people and that's what we're doing.

Dr. Adam Rinde: Do you have any case studies that are out there published yet or is that something that's in the future?

Dr. Dayan Goodenowe: Not published, just anecdotal. I'm getting emails and texts from people especially caregivers with dementia patients saying remarkable things. People waking up, carrying in conversations, dancing in their wheelchairs, it's really kind of crazy. It's really, really crazy. Seeing people increasing their sleep is better. They're calmer. Obviously, we do all this preclinical work and we do all these animal studies but the human animal is pretty complex. We have lots of things going on in our bodies and there's lots of neurological issues.

And, I'm personally interested in exercise because in your peripheral neurons there are acetylcholine neurons as well, so it's a long way. We're just scratching the surface. The real exciting thing is that we have a very safe, very effective way of targeting and elevating blood plasmalogen levels and membrane plasmalogen levels. So now, we're going to start seeing really what we can achieve in the human population and individuals are going to be able to take control of their own health and they'll be able to determine what's working, what's not working and whether or not there's additional things that they can add to their regimens so.

Dr. Adam Rinde: Beautiful. Well, thank you for your time and continue to stay well and we'll catch up with you down the road.

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