August 26, 2021
Facebook Live: Plasmalogens and Alzheimer’s
Apollo Health’s Chief Science Officer Dr. Dale Bredesen and Chief Health Liaison Julie Gregory were joined by Dr. Dayan Goodenowe to discuss plasmalogens, a subtype of phospholipids (a chemical found in the body) that is correlated with Alzheimer’s disease (AD). Those who develop AD tend to have decreased levels of plasmalogens, which appear to negatively impact cognition and contribute to the severity of the disease.
Dr. Goodenowe’s research has identified the important role that plasmalogens play in the body’s biochemical functions. The recent results from his small proof-of-concept clinical trial have demonstrated that increasing plasmalogens with a precursor supplement may help to prevent and even reverse cognitive decline. In addition to AD, he’s learned that plasmalogens play a role in many disease processes including ALS, Parkinson’s, and autism. Increasing plasmalogen levels also appears to optimize overall health, vitality, and longevity.
We’ve included a complete recording of the session and a full transcript below for your convenience.
Dr. Bredesen: Hi, everybody. I hope everybody is staying safe as Delta moves through the country, just getting better from it myself. And in fact, it’s been interesting. The Apple watch has shown me that my VO2 max dropped fairly dramatically with it, and it’s just slowly inching its way back toward normal. So just tremendously honored today here to have an outstanding biochemist, Dr. Dayan Goodenow, who has done very exciting work, which is why we wanted to talk with him and actually an exciting recent trial on Alzheimer’s disease. So, Dayan, welcome.
Dr. Goodenowe: Thank you very much, Dale and Julie. Pleasure to be with you here.
Dr. Bredesen: And we also have Julie G. here and Julie, welcome. I hope you’re doing well.
Julie Gregory: I’m hanging in there. Happy Thursday.
Dr. Bredesen: Happy Thursday to you as well. So, much interest in all the things we can do to optimize brain health and what we can do to reverse cognitive decline, and to prevent cognitive decline. So incredibly common. And of course, even more that we’ve heard about this because of COVID-19 and the fact that so many people are getting brain fog with COVID-19. And the big concern is will we see more cognitive decline in the future? So Dayan, could you tell us a little bit about how you first got interested in plasmalogens and how you ultimately got to the point of doing a trial on these? What first to put them on your radar?
Dr. Goodenowe: Well, thank you, Dale. So my background is in synthetic organic chemistry. And then my Ph.D. is actually in psychiatric medicine, looking at the biochemical mechanisms of psychiatric disease. And so I’ve been involved in research from the get-go, and in the 1990s, when the genomics revolution was occurring and we were getting to the point where we could sequence entire genomes and then companies were generating cDNA rays that you could sequence, you could understand all the genes of an organism and how that those genes get transcripted and applied. As a biochemist, the small molecules with the metabolites of the world, like the glucoses, which are the common, the glucose in a fly, and glucose in a plant, and glucose in you and I are exactly the same. But this is the biochemical molecules that are used in all the biochemical processes. We never had an ability to measure them comprehensively. So, my first patented invention was on non-targeted metabolomics, being able to measure 1,000s and 1,000s of small molecule simultaneously. And we use that technology extensively in functional genomics, which is interesting with this whole MRNAs thing. Because that’s what we did for many years looking at transcripts. And so as we applied this technology to the study of human disease, we started doing large clinical trial analysis in cancers and neurological disease areas. And we were studying Alzheimer’s disease and cognitive decline. A class of molecules showed up on this technology called plasmalogens. And I didn’t really understand what they were at the time because they have a strange molecular formula and we were measuring 1,000s and 1,000s of molecules. But these plasmalogens popped up and my expertise is in biochemistry. And I really hadn’t heard of these things either. So I seriously, I Googled the structure of these things to find out what they were. And now these things they’re very important. We’ve known them for about a 100 years, so they’re not a new thing. Like we’ve known about plasmalogens, we know how important they are. So children that are born with genetic mutations in the manufacturer plasmalogens don’t survive. Either they have very, very severe dwarfism neurological decline. Like there’s several diseases of proximal biogenesis of children. And this is a very serious diseases. So we know plasmalogens are obligate. We know that all the plasmalogens for the child comes from the mother. The child doesn’t start making their own plasmalogens until several weeks after birth. And so early phase mother’s milk in the colostrum stage has high levels of plasmalogens in them, and then declines afterwards. And so children that are born very prematurely, they can have a disease called bronchial dysplasia, and this is caused by plasmalogen deficiencies. And so we’ve known this all by nature of plasmalogens for human life for a long, long time. And we studied them early in the ’60s for their immune regulators in terms of like radiation therapy and stuff like that. There’s some classes of in shark liver oil, for example. But early stages of trying to modify plasmalogens has been incredibly unsuccessful. Like the base molecules people might look it up called battle-alcohol, and kino-alcohol. These are the simple structures. So as a synthetic chemist, we started looking at designing molecules that could restore plasmalogen levels. This was back in 2000. So I discovered these plasmalogens in 2006. Did a whole bunch of patenting back then, and then developed structures and figured out how, what it takes to elevate plasmalogens. And then we started studying these things in neurological diseases. So neurodegenerative diseases like Parkinson’s, multiple sclerosis, cancers. And so plasmalogens were critically important to the pathophysiology of these diseases. And like anything, when you find a biomarker you want to find out, is this just a symptomatic? Is this smoke indicating some other fire, or is it actually part of the biochemical process? And typically, you do that by trying to eliminate other causes of plasmalogen deficiencies. Is the plasmalogen deficiency really linked to Alzheimer’s and cognitive decline, or it’s something else and it’s just a biomarker? And reality is you can’t remove it from the equation. Like when we do post-mortem studies, large longitudinal studies. Rush University in Chicago measured just under 9,000 blood samples from 1,000s of people over 16 years of their lives. And it shows up that these plasmalogens are really part of the causation pathway. And they’re biochemically linked to the cholinergic neuron system, which is so when people may hear Aricept for Alzheimer’s. So we knew about the cholinergic system back in the ’70s. And studied a lot of work on that. And basically maintaining cholinergic function is the most proximate to cognition. And then plasmalogens are part of that. So that’s how this all came to be. And then as you learn, what I really discovered was this decline and plasmalogens later on in life. We’ve known about these plasmalogen deficiencies in children, but we kind of ignore people as they get older. And so this kind of different this plasmalogen deficiency and aging really came to be. And so now it’s taken me 15 years to get this in fully into humans. So now for the first time in human history in a 100 years, this chart, the data that we presented at Denver in the Alzheimer’s conference, it’s the first time in a 100 years that we’ve been able to actually evaluate plasmalogens. Is ridiculous because it’s not a small number — 20 to 30% of your tire brain, of lipids of your neuromuscular junction, your heart, your lungs, your kidney, the retina of your eye. We’re not dealing with a small trace level metabolite. We’re talking about a core composition. Your body has literally grams, pounds of plasmalogen in your body. And the weird thing about them is when your body makes them the last step in their manufacturer creates this activity bond called the vinyl ether bond, which makes them unavailable from a dietary source. So you think, oh, wow, there’s so many plasmalogens, I just need eat meat products because if I have them, cows and chickens will have them. And so, but the point is that when you eat plasmalogens from a dietary source, very, very few of it gets into your blood supply. And so the trick was designing a precursor kind of how like L-DOPA works for Parkinson’s. But this works for plasmalogens, and we can restore them. And we can target the different types of them. And so now that we do that, we can now prove all the research that we’ve done in animal studies, and in cell culture and everything else turns out to be true. And we’re getting dramatic results in the doctors and not just Alzheimer’s, A lot of work in Parkinson’s. I have Parkinson’s patients have gone from complete immobility to shoveling snow. Women with multiple sclerosis with optic neuritis, their complete vision been restored. We’re getting some pretty crazy results coming back. And even in depression and anxiety, one of my great collaborators in Japan, he has a number of patients with ALS and he’s got Duchenne muscular dystrophy patient that he’s treating. But he’s got two women that were with Alzheimer’s and Parkinson’s and they reported back to him that it was the mood, their depression and anxiety disappeared. And so they have mood changes. So the thing that plasmalogens are they have three main biochemical functions. So, and it’s not that complicated. They’re membrane molecules, the human body works with lipid membranes. Like you’re not a bowl of soup, basically it help people like you have separation, and compartmentalization, and that’s how your body does it. And your neuro …
Dr. Bredesen: Water in there.
Dr. Goodenowe: Exactly, exactly. The neurons communicate through synapses. It’s like the light switches on your wall. So you have a light switch that connects one wire to another, you light switch then you have a long wire that goes in between the walls that’s covered with your coding. That’s your axons, basically. And so at the switching part that requires plasmalogens and not a small amount of them. It’s about 86% of the mole, like of the amount of ethanol means in the synapse are plasmalogens. And if it gets below 75% neuron transmission goes down. And so that’s why we have this, and that’s also in the neuromuscular junction. When you increase your plasmalogens, you improve neuromuscular function, as well as not just cholinergic function. The cognition in the brain as we get older, it’s the Canary in the coal mine. If you take a common stressor on a large group of people, the largest amount will show cognitive decline with aging. But cognitive decline really is just a biomarker of poor brain health with aging. You get other issues. One person might first experience cognitive decline, where someone else might experience neuromuscular issues or someone else might see that their depression and anxiety is worse with age that they had before. When you take a common environmental stressor and you apply it to the complexity of humans, each of us have our own life history. And each of us have our own genetic predispositions to a particular disorder. And so one stress applied to a 1,000 people will end up with multiple different clinical outcomes. And so what we’re seeing when we restore our plasmalogen levels is that clearly the cognition and the mobility are the number one factors. But there are other issues of neurological health there that are getting improved.
Dr. Bredesen: So, Dayan, could you comment, are there some people who have cognitive decline with normal plasmalogens and some with low plasmalogens, and do they respond differently or is your sense that pretty much everybody who has cognitive decline has low plasmalogens?
Dr. Goodenowe: So, the challenge as we see is the separation of your blood from your brain. And so the blood data that we’ve done on 1,000s and 1,000s of people clearly indicate that low blood plasmalogens is a bad thing. It has a high level of predictability of cognitive climate, but even more so in mortality, this is the scary part. It’s a 30 year difference in lifespan. A 65 year old person with low plasmalogens has the same probability of living to their 70th birthday as a 95 year old with high plasma allergens has of living to their 100th birthday. And that’s actually after correcting for the negative health consequences of being demented. So getting a diagnosis of dementia is a really bad deal. Like the average people think, oh, you live forever with dementia, but you don’t. On average, the time to death from a diagnosis of dementia is five years. Like you’ll live longer with the stage two or three colon cancer diagnosis than you will with a diagnosis of Alzheimer’s disease. And so it’s typically people get to live at home one or two years. Once they get into long-term care, a year and a half to two years, and then they’re gone. And that unfortunately is the reality. Now, of course, people that have lots of good care and lots of good family support they’ll live longer. There’s other ways of getting things, and like what you’re doing in trying to remove the negatives of the situation to give the body the ability to heal and restore itself. These things all become critical aspects of it. But in terms of cognition, plasmalogens, it’s core to the cholinergic neuron itself, and then the weakness of the cholinergic neuron. And this is an interesting thing for people that wonder why it takes scientists so long to figure things out. Because what happens is you get one group of science in the ’70s. It did just an amazing amount of work figuring out this cholinergic hypothesis. It was clear. He turned on, cognition occurs, you turn it off, you get dementia. It was absolutely black and white, but they couldn’t fix it. They couldn’t understand why is it that this damn cholinergic neuron. And they try to everything that we did for L-DOPA for Parkinson’s disease. They said, can you get a cholinergic precursor? Like we gave people such high doses of choline and things like that. And the problem with that is that choline is part of all your cells. In Parkinson’s it’s dopamine. So you only have to hit one cell mass even if you bade the whole body in dopamine, it works type of thing. But we couldn’t get this to working in Alzheimer’s disease back then. And then people figured out what was wrong? What was the Achilles’ heel of these cholinergic neurons? And the Achilles’ heel is this ability to take the neuro-transmitter backup called acetylcholine. But it doesn’t actually take choline up. It takes acetyl it takes up choline there’s a special protein called the choline high affinity transporter that’s only found on cholinergic neurons. And the weird thing about it is it wasn’t it’s on the presynaptic vesicles. It doesn’t actually sit on the membrane of the synapse. Like it’s not sitting there waiting to suck up the neurotransmitter, like dopamine or serotonin thing. And so people couldn’t figure out what was going on. So it wasn’t until like 20 years later in the early 2000s, this group of Ferguson and Blakely showed that this choline high affinity transporter is actually not on the neuron, it’s on the vesicle inside the neuron. And so that means it wasn’t even there, unless you hit the secular fusion. Then a whole different group of people were studying membrane physics. Like this is what happens in science. You get one group of scientists of specialist work in one area, and they don’t talk to anyone else. And they do some really amazing work. And so they figured out that this membrane fusion really required plasmalogens like any disruption in plasmalogen composition in the membrane. These membranes didn’t fuse. These vesicles, these little balloons full of neuro-transmitters would come to the wall and just stick there. They wouldn’t fuse out. And so what happens then if you have a plasmalogen deficiency, is that it’s actually preventing the cholinergic neuron from getting its choline back. And there’s huge amounts of data showing that if that ever happens, the neuron basically eats itself. It takes choline from the membrane structure. And that’s also what gives the brain shrinkage. So plasmalogens not just in proving membrane fusion and neurotransmission. Plasmalogen deficiency actually starves cholinergic neurons from there neurotransmitter. And that’s so when we do post-mortem data, the correlation between plasmalogen levels in the brain and cognition like with the Rush study it’s crazy. It’s for every small change in plasmalogen levels in the brain, dementia goes up five times and it’s much, much more associated with cognitive decline than say amyloid or tau or flotillin which is in lipid rafts, like the cholesterol rich regions. So these membrane structure things are important. So that’s the kind of the key thing in cognition. And then the other big aspect is inflammation. With other part of this clinical trial was we measured a bunch of inflammation biomarkers. Especially, oxidative stress like aldehydes and C-reactive protein. And people have people like remember catalase, and superoxide dismutase people in your group that looks at inflammation. The reason why we lose plasmalogens is that they actually get consumed. People think about antioxidants like they coenzyme Q10. So a lot of the antioxidants that we think of as antioxidants, I call them basically hot potato holders. Like they hold these electrons for a little while. But they don’t actually neutralize them. And they just kind of hold them for a little while, until someone else takes care of them. Plasmalogens actually get broken up in the process. When the plasmalogens actually physically, chemically react with peroxides and they get broken up and consumed, like blowing a fuse, essentially, and the body says no big deal. That’s what they’re there for. They’re there to blow a fuse, and then we’ll make a whole bunch more. So you make a whole bunch of them. And normally you make more than you need, and you have that balance and that’s the issue. And that’s what with the day before that, Julie and I talked about a week or so ago is one of the issues with the April before community is that they’re more dependent than the other genotypes for that plasmalogen counterbalance. And that’s why it reveals itself with an age profile of where the genetic risk factor becomes exposed later in life. And it correlates with that, the decrease in plasmalogen levels in the general population. And that’s why people that have really good health profiles are less likely to have an effect with April before genotype.
Dr. Bredesen: So we hear a lot about good fats and bad fats, especially with respect to things like inflammation and things like cognitive decline. And we hear a lot about omega-3s and omega-6s. And you had said before we came on, that these plasmalogen, you can have some that are omega-3, some that are omega-9s. Could you talk a little bit about where each of those fits in?
Dr. Goodenowe: So people like the whole essential fatty acid community is pretty interesting. I mean if you simplify it down, there’s really only four fatty acids that really matter to human physiology. The rest of them are really bit players on the stage. We have two that we get from regular plant sources, omega-9 like oleic acid from olive oil. And your body uses that virtually unchanged for the most part. And it uses it for the connective tissue and the white matter, like the protective coating of your axons. And then you have your omega-6 that gets a bad name. We get from corn, soy, and canola, for example. And that’s a pro-inflammatory one, but it is really a critical, essential fatty acid. It’s kind of your your Swiss army night fatty acid. Because it can act like an omega-9, but it can also act as an omega-3. Now where people get confused with the omega-3 system is that there’s really only one omega-3 that matters. And that’s DHA. And that’s what’s the predominant omega-3 of your membranes. And that’s what separates us from plants. So what makes animals different from plants is fluidity in their membranes. And that’s called these long chain polyunsaturated fatty acids. And the one that your body wants to use predominantly is DHA. And you make it yourself. Then it has a backup plan because DHA is hard to make, it takes a lot of steps. And then it goes into the proxy zone for its final process. So your body has a backup plan if you don’t get enough DHA. And the backup plan is arachidonic acid. And that comes from the omega-6. So most of us in our current health program, we get bombarded with excess omega-6 and not enough omega-3 in our diet. So the DHA to arachidonic acid ratio is in the wrong direction. And that’s where the inflammation issue happens. And so that’s where so plasmalogen, the omega-3 DHA. That’s the one that controls your reverse cholesterol transport. So say people understand atherosclerosis and you like the foamy macrophages, and you want to get rid of cholesterol. It’s a DHA plasmalogens that are involved there. And in the brain, the biologically active, the synapses is really need DHA plasmalogen, that’s the number one priority. And so they’re very, very dynamic. Omega-9 creates an entirely different biochemical structure. It creates myelin sheath, which is basically plastic coating over a copper wire. It’s there to really be protective. And that’s what happens in autism and multiple sclerosis, concussion, brain injury. So all inflammatory diseases of the brain are fundamentally a white matter omega-9 plasmalogen issue. Two things, mitochondrial function. keep your inositol cystine and carnitine is all inflammation. Fundamentally, all inflammation comes to the mitochondria. 100% of all information, whether it’s a viral infection, whether it’s a bacterial infection, whether it’s, it doesn’t matter what it is. It’s all fundamentally, it’s a mitochondrial insufficiency drives all inflammation. And then you have so plasmalogens they can help the mitochondrial membrane, but really what they do is they reduce that chemoattractant signal. So that’s kind of where, so the omega-9 is for the protective coatings of your axons. And omega-3 is for your, so that’s why we have Prodrome neuro which is for active. I say, neuro is for performance. It improves your neuromuscular junction activity improves sarcopenia. So in this clinical trial, we had a dramatic improvement that can sit stand. This was a really simple test that we use for sarcopenia which is muscle wasting and aging. And it’s a 32nd sit-stand test. Basically, a person sits on a chair and you have a timer stopwatch and say, okay, stand up and sit down as many times you can in 30 seconds. And you count them. And then typically, people can go from 10 to 30, depending upon how active they are. After four bunks on plasmalogens. The clinical trial was an escalating dose. The first month was one bottle. It comes in a bottle with 30 mils in it, which is basically if you have one mil per day, one bottle lasts you one month. And so the first month they went to one bottle a month, and then the second month, and third month they took one bottle every two weeks. They doubled the dose. And in the last month they took one bottle every week. So it’s four mils per day. And then we had a wash-up period, but we had people with increased. They had three to four to five more sit stands within only a four week period. So of the 22 people, we had 12 people that had significant mobility improvements. And it wasn’t even on our radar. Because this was really fundamentally a dose finding study. We were just doing escalating dose biomarkers and so on. And we had a number of people that had complete improvements on their clinical dementia rating the entire score. And we didn’t have just mild Alzheimer’s. We had the mild all the way up to moderate CDR-2 the highest score is a CDR-3. But some of these patients went down to CDRs of 1.5 to zeros in only a four-month period of time. So it was pretty dramatic. And so it was a very encouraging program. So we’re expanding on that. So neuro is for performance, and glia is for protection. So younger people that have say autism, which is a white matter issue. When you want to reduce inflammation of the brain, the glia plus mitochondrial support is the main protocol. But if you want to improve performance, like all of us old people, the three of us sitting here is that we want our brains to work better, and we want our muscles to work better, and we want to and so we need the DHA version. But you can balance them either way.
Dr. Bredesen: And so, in your studies, what sorts of subjective improvements that people notice, were people doing better with navigation, were people doing better with memory, what sorts of things did they or their partners notice?
Dr. Goodenowe: The memory for sure. But the interesting thing is energy. People felt more awake, and aware, and they felt much higher levels of energy. I function people notice that their night vision comes back. Me personally, my biggest personal observation was in my vision at first. I don’t need glasses anymore for four feet. I’ve always been farsighted. So near-site, I’ve always needed glasses for driving, playing hockey, and so on and so forth as a kid. But I can’t wear glasses now for within a four foot radius. I don’t need them anymore. And so that was a major improvement for me. The people mentioned mood. Like they feel better on it. And so that’s probably the GABAergic system being improved upon in some people. Person that doesn’t have a clinical disease like myself. Muscularity like, I’m in my early 50s, I’m actually stronger than I was in my 20s and 30s. And my recovery time from working out, it’s like, it’s anticipated, I wasn’t expecting it. Like I do 50 pushups. I can wait five seconds, 10 seconds, and do 50 more like the first 50. And I go, this is stupid. I couldn’t do this when I was 20 and 30. And there’s no muscle pain anymore. I just don’t have the muscle pain anymore. So it’s working at that neuromuscular junction. So it’s a really simple molecule, and it’s been deficient in us for so many years, even super athletes. Like I did Ben Greenfield’s blood tests before and after, and it’s on our website and he did it on his. Like he’s a super athlete. And sometimes the super athletes they overwork out, they don’t give their body enough time to recover between times. So people always think exercise is good for you. And I tell people, no exercise is not good for you. Exercise is bad for you. Recovering from exercise now that’s what’s good for you. And so, you want to make sure you recover from it because the goal is to create a biochemical reserve capacity or a functional reserve capacity. Like if you go running and whatnot, what you’re doing is you’re increasing your reserve capacity for oxygen utilization in the mitochondria. You don’t do that for the days that you run. You do that for the days that you don’t run. So the days that you’re just walking and doing grocery shopping and whatnot, now you’re just humming. You’re operating far below your capacity because you’ve built reserve capacity on the days that you’re working out for the days that you’re not working out. And so same thing, if you’re lifting weights it’s not for when you’re lifting weights. It’s for when you’re cooking in the kitchen, and you’re getting groceries, and all of a sudden you’ve created this reserve capacity of strength. So, the purpose of exercise and even is for the days that you’re not exercising. And it’s to build a reserve capacity for, and biochemistry is the same way. And so that’s why we were dealing with the plasmalogens, mitochondrial support structure is to create that kind of reserve capacity. People talk about homocysteine and methyltransferase, and your membrane lipids and mitochondrial function. There’s some pretty basic, simple things that we can do to put the body with a savings account. And that’s kind of what we focus on.
Dr. Bredesen: So Dayan, we hear a lot about different things that create cognitive decline that contribute. We’ve talked about lack of sleep, and we’ve talked about stress, and processed food. And you’ve mentioned inflammation. So many of these different things, are there certain ones of these that have a larger impact on plasmalogens levels, or do all of these things impact them?
Dr. Goodenowe: I think they all impact them, and they have their own independent issues themselves. The big thing, people methyltransferase is a really a big deal. We typically measure homocysteine. We want to get them under 10, but sometimes we don’t measure them in the right way because we can trick the biomarker test. It’s biomarkers are exactly what they are. They’re biomarkers. They’re there to tell you what’s going on behind the curtain so you can fix them. In the brain, methyltransferase is really critical. It controls the amyloid precursor delivery to the enzymes. It controls the tau formation. So the other classical hallmark of Alzheimer’s is neurofibrillary tangles. And it’s caused by phosphorylation of a cow protein. Most people we hate, we float these words around, but people don’t really know what they mean. Tau is it really critical molecule. It’s what your body uses to accelerate, or organelle transport is like squeezing Tau is what he neurons used to squeeze mitochondria down to two of the axon. And it’s like, if you grab a fist and you squeeze your fist, you squeeze it, you push these organelles. Because these axons are very long distances. Now it’s a problem is it? In order for that hand to relax, you need methyltransferase. Low foliate, low B12, B6 are highly correlated with tau formation. Also they correlate with amyloid. So that’s why tau and amyloids kind of go hand-in-hand in so many ways. Inflammation, like you said, is a big deal. Glucose regulation is and inflammation go hand in hand for the brain. And your vascular issues, like so cerebral vascular disease, stroke, micro infarcts, those types of things. They contribute dramatically. So they all have their own. When you look at that reserve capacity you have to share. So if all your plasmalogens are being used to fight inflammation, there are not enough leftover there for neurological function. And so your body doesn’t, we put them in the body’s a black box but it’s not. It’s still has to follow the basic rules, simple law of thermodynamics. nothing can be created or destroyed. So the human body doesn’t exist on sunlight, water, and carbon dioxide. So everything you see came in. It came into you and it was transformed. And so that’s what your body does. It moves these atoms and electrons around, it make stuff. And if we’re not feeding the right things in the right proportions, we’re not going get the outcomes we want.
Dr. Bredesen: Fantastic. This is great. And maybe Julie, maybe you and Dayan talked a little bit about your own experience with plasmalogens. Measuring them and what the status. What did you find out?
Julie Gregory: So, I’ve been taking the supplement for almost two years now. And unlike other people in our community, I didn’t notice a big difference, but interestingly, Dayan, my near vision is perfect. And I’m only wearing readers now because I have contacts for my distance vision. But when I take my contacts out, my near vision is perfect. And it didn’t use to be. The thing that I’ve noticed with members of our community who are using the supplement is people who are get a really definitive positive reaction are people who are generally not following your protocol. These are people that don’t have insulin sensitivity, they’re not exercising. And people who are following the protocol maybe don’t notice a dramatic difference. That being said, I believe in Dr. Goodenowe’s science. And this is one of the holes in my roof that I planned to patch. And I’ll be taking the supplement for life.
Dr. Goodenowe: And just for the record, like we have a lot of people that are on the Bredesen Protocol that come through our blood testing capabilities here at program. And by and large, they have the healthier programs than normal people. So the protocol is working, and I can tell you why it’s working. Especially the intermittent fasting. And certainly keto, people forget the human body is designed to shift gears from the fed state to the fasting state every day. And it’s normally in days gone by when the sun went down, you stop eating at a certain point in time. And then you’d have a long fasting period of time. It’s the fasting period at nighttime that your body uses to rebuild things. And that’s when your body shifts from a glycolic state to a lipolysis state. And so when you’re in lipolysis that turns on mitochondrial beta-oxidation. It turns on peroxisomal beta-oxidation. And so a good fasting routine gets your triglycerides low, which is very, very healthy. So if you’re in a proper fasting, and you are having a good dietary glucose regulation program, your body is going to be turning on at night for fatty acid beta-oxidation. And that’s where plasmalogens are also made. And that’s also important for your sleep regulation. Methyltransferase makes your melatonin, makes your, so that requires your homocysteine system working properly. And so inflammation counteracts that. Late night snacking is one of the worst unhealthy things that we can do for life because it disrupts that daily fasting routine. People should be fasting. And as we get older, we need to fast longer. So when we’re younger, we use up our energy. So our glycolysis gets done quickly. And so a couple of hours after a meal, we’re already in the fasting state. But when we get older, it takes longer for the body to get into that fasting state. And that’s also what drives cancer. Cancer can’t exist in a fasting cell. Cancer can only exist in a glycolytic cell. And so as we get older fasting becomes far, far more important. And it takes us longer to get into that.
Dr. Bredesen: We’ve got some great questions here. Let’s get into those. Dayan, you have a couple more minutes to go through these questions.
Dr. Goodenow: Absolutely.
Dr. Bredesen: Fantastic. Thank you. And so first one here at Dr. Ram Rao asking, and Ram has worked on neurodegeneration with me for years. He mentions that the protocol and various things that are important detoxification; sleep, exercise, physical, mental activity, et cetera. He’s also an Ayurvedic physician. Now he said, where would plasmalogen fit into this picture? And I think you’ve already mentioned some of this certainly with respect to overall health and resilience and that sort of thing. He says, do you think the above interventions would be improving plasmalogen levels? So it sounds like what you’re saying is people who are already doing the protocol do tend to have a better overall profile than those who are ignoring it.
Dr. Goodenowe: For example, my dad. He’s in his mid 80’s now, he’s an E4 carrier. He functions as a 60 year old man. So he is a highly functional individual. And I didn’t have these supplements available for him when I first started getting plasmalogens up and running. So you can have a diet and exercise program. So fasting, resistance training with proper rest, and then proper supplementation that reduces the plasmalogen consumption load. So if you have a limited amount of plasmalogens that you make, you don’t want to be wasting them. And so you have an anti-inflammatory protocol like N-acetylcysteine and the carnitines, the omega-3 program. And so these things can all contribute to you can reduce your inflammation load. You’re going reduce the depletion of your plasmalogens. But ultimately it comes down to like a vitamin D story. Now, Julie is not a good example because she has superhuman biochemical profile just for the record. And so, because it was quite amazing actually, it was like, I have it on my refrigerator, just joking. But it’s like the vitamin D story. So, if you’re at the right latitude and you spend enough time outside, you can make enough vitamin D, but it’s very, very difficult to maintain enough. And the level. At the end like her attitude is the right attitude. When you look at the data, it’s just not worth the risk, like it is theoretically possible to get enough of these things, but why it’s helpful, period. And so that’s kind of bottom line on the plasmalogens situation. And it frees up other aspects. And so that’s why people took the phospholipid stories. Like you want to take your lecithins and cholines because you need to make them. We don’t take enough creatine in the elderly. It needs to be part of their program because it really also helps their methyltransferase system. So there’s really basic stuff that we can do to help people.
Dr. Bredesen: Absolutely. And then what about Rajia has asked, where do we get plasmalogen since it’s not absorbable from animal meats, obviously you’ve created a precursor, which is fantastic. What is the best way to get these?
Dr. Goodenowe: Basically on our website, Prodrome.com, you can get the plasmalogens on the website there. And you get blood testing if you want to get deeper down the rabbit hole of your biochemical health. And so that’s kind of what we do. And it’s complimentary to other things that you’re doing.
Dr. Bredesen: So Prodrome for everyone, P-R-O-D-R-O-M-E.COM. Take a look at that.
Dr. Goodenowe: And if you want the detailed biochemistry, like I talked some of these things but at Dr. Goodenowe.com, I’ve got educational videos with actual reference data and all the detailed literature reference in epidemiological data. So people can dig as deep as you wish to go.
Dr. Bredesen: Lucy asks what specifically helped improve your night vision? Obviously you were talking about the plasmalogen. She mentioned what about increased DHA? Could you say something about the relationship between, so if people are taking more DHA or taking more fish, does that affect their plasmalogens or not?
Dr. Goodenowe: I think it has in the past, because DHA is also peroxisome alpha greater agonist receptor agonist. So it actually stimulates peroxisomal function. And that’s one of the benefits when people say omega-3 reduces triglyceride levels, how omega-3s reduce triglyceride levels is because they’re actually prefer alpha agonists. And they improve basically like a fibroid. They’re basically a natural fibroid, if you will, in a certain degree. So yeah, so those things are good. And so, people have tried in the absence, if you can stimulate peroxisomal function, you can actually make some plasmalogens. That is a benefit, just not enough. And so the supplement that we have, the neuro it has high levels of DHA. It’s a very, very bioavailable DHA source because DHA in the brain has to come from free DHA in the blood. So you don’t get it through the regular triglyceride structure. And then also fossils share their DHA. So with the ProdromeNeuro you can pretty well subtract out your omega-3 from that, because it provides you highly bioavailable DHA.
Dr. Bredesen: And Melissa asked is this supplement already part of the protocol? So as we’ve always said, we’re agnostic, whatever helps the most. And I think that’s one of the reasons we’re so interested in plasmalogens especially with your recent study. And we’ve had some people like Julie, obviously, who are taking this and others who are not. The question is, should everyone be evaluating it and then going on? And if they are low, do you have a specific cutoff where you say people should definitely be on these if they’re lower than X, or is your sense that basically everyone should be on plasmalogens.
Dr. Goodenowe: So in the clinical trial, we did not segregate people based upon their baseline plasmalogens. So it was a completely random, and we found of the nine people that had a complete improvement of a CDR score rating. Five had low plasmalogens, four had regular to normal plasmalogens. And so we know epidemiologically that the low levels predict future decline. But if you’re experiencing symptoms, the base that the blood levels are not relevant to recover. Because the supplement isn’t a plasmalogen, it’s a precursor. So you get a pulsing, it does two things. When you first take the supplement as a precursor, it goes in every single cell of your body and allows those cells to make plasmalogens. And that phase acts about 12 hours. Maximizes in the two to four hour range. And then it gets converted to the final plasmalogen, which causes your blood levels to elevate. And that allows your cells to collect the plasmalogens from the blood supply or make it themselves. And so every day with the plasmalogen precursor, you’re actually pulsing it into your cells for them to make it on demand. Which is important for your microglia. You’re only going to under sites and mean and new Schwann cells, because those cells don’t have the same type of vascularization, if you will.
Dr. Bredesen: Fantastic. Then let’s see, Russ is asking, do you know when your study will be published?
Dr. Goodenowe: We’re working on writing it up right now. I just got crazy schedules. So, we’re putting it together right now.
Dr. Bredesen: We know you’re incredibly busy with all this stuff going on and we really appreciate your time. So let’s see. Omega-3, you just addressed that actually. And let’s see, Melissa is asking, does DHEA cover DHA? Of course, those are quite different. And I don’t know if you want to say something about DHEA versus DHA.
Dr. Goodenowe: No, I see people asking about multiple sclerosis and Parkinson’s, and then comment on those. MS is an interesting disease. It’s almost like girls who don’t get autism, get MS. And they get their symptoms reduced during the pro-estrous cycle. And usually then relapsing remitting until menopause. And then post-menopause typically, we see the transition into secondary progressive. So glia and neuro combination is what doctors have been getting the best results for. And then you can escalate the dose until you see effects. For younger people I like to stick with the glia for the most part. Parkinson’s is an interesting story. I originally thought because there’s a lot of white matter issues with Parkinson’s that we see, the neuro in animal studies reduces L-DOPA induced dyskinesias. But it’s clear that the neuro is the preferred version in Parkinson’s. And we get escalating dose. Like we’ve had some dramatic reversals of people that have had complete restoration of mobility in this. Sometimes you get to a higher dose up to four meals per day, and then you can bring it back down again. Same thing with Alzheimer’s. I’ve got a couple of really late stage Alzheimer’s patients that one of the patients was really bad. He couldn’t function, was going to the bathroom and in the closet, police were called out because he was wandering, the woman, wife, was just at her wit’s end. They’re basically having a life now. He gets up, he dresses himself, has breakfast with her. And so, but he needs the four mils. Four bottles a month. So there is a dose finding effect and everyone is personal. And this is a good point in terms of what Dale does and what we do. People should expect success and you should move in if it’s working, keep doing it. And then look for another solution to it. Because it could be a negative issue. It could be like, you could have all the things in your favor and you might be missing one thing. Like I’ve seen people that are super healthy, and you get a blood test, and they have no choline in their blood for some reason. Like the phosphatidylcholine. They’re on some strange vegetarian diet and they’re getting no choline. And so I say, get some sunflower lecithin or something and start putting it in your salads. And so there are certain things that we want to look for boogeyman under the bed that you otherwise would not notice. And then we can fix those things.
Dr. Bredesen: We always tell people keep optimizing because there are always more things to find. And I know Julie’s been through this with her own situation and they’re asking you here also Julie about what you’re on. Are you taking the neuro or the glia?
Julie Gregory: I’m taking the neuro. I’m doing about not even a full mil, maybe .75.
Dr. Bredesen: And then George is asking Dr. Goodenowe would the Prodrome Glia or Neuro would be most appropriate for a Parkinson’s patient?
Dr. Goodenowe: I’ve stuck with the Neuro. Like I take two mils of Neuro a day. That’s my basic dose. That’s what I have my family on. It seems to be the best in the clinical trial data that we just ran the escalating dose. Two seems to be really optimal. It keeps levels up and then you can mix and match with the glia. Like people that have like, so ulcerative colitis, bowel disease issues, the glia has a much more calming effect on that. And then in combination with certain probiotics it can be very beneficial.
Dr. Bredesen: Then just two last ones here. One asking about cerebral amyloid angiopathy where of course you can get the microbleeds, and of course, lobar macrobleeds as well. Tim is asking, what about whether is this an issue with plasmalogens? I know that obviously when you get these very high omega-6 or omega-3, or omega-6s ratio, so you get down with the six to three of less than 0.5, it is associated with increased cerebral hemorrhage. Do you have any concern about giving plasmalogens to someone who has a history of amyloid angiopathy?
Dr. Goodenowe: Well, I would look at their omega-3 profile if they have really high DHA to begin with, then just give them the Glia. And so now you get the omega-9. Then that’s a really good question because there’s a balance. Autism is a great example and multiple sclerosis. So when you take a blood sample from an autistic or MS patient, you’ll actually see that they’ll have higher than normal plasmalogen levels in their blood. And it’s because of mitochondrial failure and insufficiency. So when the mitochondria fail, it doesn’t do a job. And the fatty acids that are supposed to be processed by the mitochondria, get pushed into the peroxisomes and turns them on. So autistic children actually have higher than normal plasmalogens levels in their terminal fields, like at the synapse level. And that’s why they have a bunch of this neurite outgrowth, but these neurites don’t make good connections. The problem is the white matter tracks and that’s the omega-9 plasmalogens. And so if you see someone with really, really high DHA plasmalogen or DHA levels omega-9. So the Prodrome glia is a 100% omega-9. So in combination, the two of them dilute your omega-6 probably, if you want to. I wouldn’t be so much concerned about low arachidonic acid levels because you really don’t need them that much. I’m being more concerned about not having enough omega-9.
Dr. Bredesen: And Linda is asking about whether you think this may benefit dysautonomia.
Dr. Goodenowe: I don’t even know what that is. What is dysautonomia?
Dr. Bredesen: So people have autonomic it can be an auto-immune issue or it can be a degenerative issue. And then this is like shot. So Shy-Drager is what used to be called. And it’s a Parkinson’s variant where you have some degeneration of the autonomic nervous system. They tend to get things like orthostatic hypotension, things like that.
Dr. Goodenowe: So any kind of autoimmune inflammatory disease is definitely dramatically benefited from this. Because what it does is it reduces the chemoattractant signal of the macrophages and the inflammation cascade. So a lot of these diseases, so all autoimmune diseases are mitochondrial fundamentally. They’re mitochondrial weakness. If I take two seconds on this, I know people are bored people Well, the human body is fundamentally a hybrid electric car. We burn hydrocarbons into carbon dioxide. And we use that energy from burning a hydrocarbon to charge a battery, just like your led battery in your car. But this is called a proton gradient in your mitochondrial-electron transport chain. And that proton gradient is fundamentally a battery, and it runs the ATP pump, and that’s how the body runs. And you have this disconnection between the two of them. And so what happens if the mitochondria can’t and its electrons, it’s a highly electrochemical charged environment. And if you get stressed, if you get glutamate like diabetes, or you get a bacterial infection, or you get an auto-immune disease. The inflammation is designed to kill cells. And so that the inflammatory macrophage is there to clean up the mess. The problem with autoimmune is that the surrounding healthy cells get somewhat slightly damaged. And the inflammation spreads. It becomes like a forest fire and it’ll burn outwards until it uses up all the available fuel. And so by improving mitochondrial. There’s three areas that you can arrest inflammation in the body. One is at the mitochondria level itself. People talk about glutathione and NAC, CoQ10. All those things that we do acetyl-L-carnitine is really important. If you can prevent the electrons from leaking out of the cell, you prevent inflammation, period. Most of autism and MS, these are diseases where a little bit of inflammation spreads from its focal point. The second point that we can reduce inflammation is at the membrane structure. So once these electrons get spit out of the cell, you have enzymes outside of your cell that are used to neutralize them like superoxide dismutase, and catalase and glutathione peroxidase. These are designed to prevent these nasty things from actually making your cells rancid, because that’s fundamentally what you do, is you get rancid oil on the outside of your cells. And this rancid oil on the outside of your cells is a chemo-attractant signal for the macrophages. I tell people the cells of your body is like your neighborhood. Like you really don’t know what’s going on in your neighbor’s home until the chair comes playing out a window and lands on the front lawn. And say, “Oh my God, something’s going on over there.” And then the police come, and they isolate the situation. So it doesn’t spread beyond the one house. That’s what your macrophages do. And so then that’s peroxidation. Plasmalogens block that. So when you have plasmalogens they neutralize all of that peroxidation and so it reduces a chemoattracted signal. So the macrophages don’t even, it cleans up the mess before the macrophages and the microglia come attracting to it. And then you have the third thing, which is most drug activities. With steroids and with biologics, we try to suppress the immune T-cell responses, and so on and so forth. So you have two mechanisms. What your anti-inflammatory mechanisms like your protocols, Dale, like when you talk to him about reducing inflammation, you’re really reducing those two front ends. You’re reducing inflammation from the inside out. And that’s what you want to do.
Dr. Bredesen: And hopefully removing the pathogens and things that are causing the inflammation to begin with. So one final question before we go, I can’t help. But you said something really provocative and interesting, which was to relate MS to autism. So could you just talk for a moment about the relationship? What is the similarity here? What is the common path here in autism and MS?
Dr. Goodenowe: They’re basically the same disease. So what differentiates the gender bias in pre-pubertal boys and girls is the circulating levels of beta-estradiol in boys. But 25% of boys will have girl levels of beta-estradiol. And about 25% of girls have boy levels. And women have much higher levels of neuroprotection than men due to beta-estradiol. And beta-estradiol is a very potent neuroprotectant, and basically allows girls to spit lactic acid out of their cells whereas boys can’t. And it’s monocarboxylic acid transporters what happens. When boys or girls, it’s maternally transmitted, because it’s mitochondrial. if you have a mitochondrial weakness then as the inflammatory environment that we live in gets worse and worse, this exposes more and more mitochondrial insufficiencies. And so that’s why boys get effected. And women also they have much better generally social skills, so they can basically hide their autism better than boys can. Just like we have issues in the elderly, men have a better way of tricking cognition test versus females as a general rule. we have a harder time sometimes getting them, but there’s much better tools now as you know. When you fast forward to MS. MS is a mitochondrial disease. And so now you have this issue where not obviously all women who don’t get an autism, get MS but it’s the same disease. It’s mitochondrial insufficiency. And so when they get a triggering event that triggers inflammation and normal people, you get inflammatory event, it rises your body deals with it, and it goes away. But in autism and MS, inflammation never goes away. A 45 year old autistic man in autopsy will have the same level of neural inflammation as a nine-year-old boy. So their inflammation stays the same virtually their entire life. And what changes is their ability to compensate and adapt to it. And so a lot of their behaviors are adaptive. And so in MS, that’s why women when they get pregnant, their MS symptoms typically go away during pregnancy when they’re proestrus. And that’s also why MS transitions into secondary progressive mostly during menopause. So, that’s obviously broad strokes. There’s all these individualities within them, but as a general rule that’s bottom line. And that’s why carnitines and inositol cysteine, these things have all had benefits in either energy or MS activated issues. So those are basic features of the disease.
Dr. Bredesen: Excellent. Very good. That’s fascinating. Dayan, this was a really a tour de force. Thank you so much for the discussions. Thanks for your biochemical insights, your many years of tremendous research. And I hope that many people are going to benefit from knowing their status on this, and then ultimately for improving it based on what you’ve developed. So thank you so much.
Dr. Goodenowe: You’re very welcome.
Dr. Bredesen: Letting us know about your trial. And we look forward to seeing that when it’s published as well. So thanks so much, Dayan. Thank you, Julie. And everyone, please stay safe.
Julie Gregory: Bye-bye.
Dr. Bredesen: Thank you, everybody.
Dr. Goodenowe: Cheers.