Our guest on this episode, Dr. Michael Ash, is a researcher who discusses lipid replacement therapy. The applications for this treatment include all fatigue related illnesses, including but not limited to environmental toxin exposure, Lyme disease and long COVID. Oxidative damage, which this therapy addresses, occurs in aging and all chronic and acute illness.

When the immune system is activated (e.g., after an infection), mitochondria can be damaged. The defective mitochondria become swollen and leak electrons, which results in the oxidation of membranes. Oral lipid replacement therapy is used to remove and replace damaged membranes.

Highlights include:

  • Mechanisms of actions of inflammasomes
  • What causes danger signals in cells
  • Supplement dosing and sources of this nutrient through diet
  • Symptoms and consequences of poor membrane health
  • And so much more!

Resources mentioned in this episode:

Lipid Replacement Therapy for Any Fatigue-Related Illness | Ep 275

James Maskell:
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Hello, and welcome to the podcast. This week we have Dr. Michael Ash from the UK talking about lipid replacement therapy, one of the hottest supplementation trends in functional medicine. And this is really important for all of us to get on board with because in this year of growth, we’ve been talking about the potential for the functional medicine community to really own long COVID because so many of the resources and tools that are at our disposal are necessary for helping the huge number of people that are having downstream consequences of their COVID infection.

So what we’re going to talk about here today is the sort of fundamental basis of lipid replacement therapy. We’re going to talk about the physiology of the cells. Mike shared an awesome story about Dr. Chatterjee’s TV show, Doctor in the House, from 2015 and 17, where they actually use lipid replacement therapy, although they didn’t show that on the BBC, to help someone with significant fatigue. This is a critical episode to anyone who’s in clinical care and is dealing with fatigue, which I know is just about everyone. So, enjoy. So a warm welcome to the podcast, Dr. Michael Ash. Welcome, Mike.

Dr. Michael Ash:
Thank you, James. Thank you for inviting me.

James Maskell:
I’m really excited to have you on here. We’ve spent a lot of time together over the last few years at different events and all the trailblazing that you’ve done in the UK to bring functional medicine there and educate the physicians, and just really excited to actually dive into a clinical topic with you and a topic that I know that you’ve had a lot of experience with. And I think we’re going to talk about lipid replacement therapy here today, but I guess maybe we’ll just start at sort of the level of the physiology of the cell. And this lipid replacement therapy has sort of become quite en vogue recently, but I want to just maybe start with the physiology of why this is important and what’s happening in the cell that means that we need to replace these lipids.

Dr. Michael Ash:
Sure. Well, I think… Let’s just contextualize this a little bit… Came into this world of therapeutic intervention through a clinical need, but much of my initial work hinges on some very significant papers that were published in the early 1970s, of which my co-author on virtually all the papers that we’ve written about the subject, Garth Nicolson. Professor Nicolson wrote the fluid mosaic of the membrane and described that the membrane wasn’t simply two walls with something squished in between the middle, that there was a matrix, a fluid movement of proteins, lipids and other messenger molecules that could be influenced, ultimately, by exposure to either adverse events or beneficial intakes of lipids. It got refined a couple of years later, and what’s remarkable is that most scientific models do evolve over time. But here we are just over 40 years since that paper was published, and the vast majority at the nano scale that Garth and his co-author, Singer, wrote about at the time is still very valid.

And I listened to Garth give of a presentation, I think in about 2012, even earlier than that probably, looking at the way that lipids were involved in treating people with persistent fatigue. And my work for many, many years was involved in the aberration of energy production due to immune insult, leading to a cascade of consequences that led to mitochondrial membrane oxidation. And so he and I sat down and had lunch together afterwards, and we started to explore the idea of doing a lipid replacement therapy utilizing an oral supplement, rather than an intravenous phosphatidylserine or phosphatidylcholine process, which had been explored for a number of years and had been written about many times. So very simply, the membranes around all of our cells have a degree of capacity to flex and bend, which allows those cells to become curved. They have an inner membrane and an outer membrane. And inside those membranes are embedded various molecules, proteins, lipids, fats. And then inside there, there are rafts or congregations of lipids, and all of these agents flex and bend.

And the healthier we are, in very simple terms, the more flexible and the greater ability we have to renew those lipids than when we are unhealthy. And there are many explanations that you can follow through for almost every disease, whether it’s a chronic or an acute disease, that leads to changes in membrane fluidity. And so what we began to explore was the idea that you could take an oral supplement that would be transported across the small intestinal barrier, and then disperse in different forms throughout the body so that cells that were in need of renewal could take those lipids into the membranes and return the fluidity and flexibility. So very simple, biochemical terms, the concept is to improve both the cell membrane and then ultimately as we’ll get into a bit more detail, the inner mitochondrial membrane as well.

James Maskell:
So why do some cells become in need?

Dr. Michael Ash:
Well, the simplest one of all is, as we age, we are less efficient at replacing both the primary cell membrane molecules, the fats and lipids, and secondly, that the inner workings of the cell, which are the mitochondria that we’re going to refer to, rely on a large part of both regeneration and recycling, which requires us to provide a certain form of different fractions of lipids. So you can have infection, you can have insult, you can have stress, you can have aging, you can have environmental triggers. Everything that we, in the functional medicine community, we regard within the matrix has, as a consequence, an event at the lipid barrier. And if we’re very healthy, it’s a short term transition in which the lipids might become stiffer or more permeable or less permeable, and they can be corrected through lifestyle and dietary interventions, all of which are relevant to what we’re going to be talking about. Because although we’re talking about an oral replacement therapy, it has its limitations operating in isolation. It has to be combined with all the other strategies that we’re familiar with in the functional medicine model.

James Maskell:
Interesting. So in a sort of a normal, healthy environment, would these be being replaced by dietary fat?

Dr. Michael Ash:
Yeah. So essentially, you can take in whether it be animal fat or plant fats. As long as they’re broken down into their constituent components, they will be utilized by cell membranes. And I think we’re all familiar with the idea of an oxidized fat cell generally seems to be therapeutically disadvantageous, whereas unoxidized fats, which are flexible and can be bound into membranes, confer an advantage. The concept that we simply have a more flexible membrane underestimates the importance in terms of human functionality. So in order for your brain, your liver, your kidneys, any tissue in your body to be able to operate, to be able to transfer messages, to be able to move proteins or fats in and out, to flex, they require some capacity to renew those lipids on a regular basis. And what we began to see 20 odd years ago was that people with persistent fatigue seem to have an immune response. It’s often very difficult to quantify, but it’s possible to look for certain cytokine markers in patients who have…

Initially, I was exploring predominantly people with persistent unrelenting fatigue. We could find that certain cytokine profiles were raised, in particular is IL-1 and TNF-alpha, which suggested either that there was an infection or some form of insult was taking place. And the consequence of that was a raised level of defense mechanisms, which are very tiring. If you want to defend yourself, everyone knows that feeling. We get a tickle in the throat. It’s very hard to maintain that same level of energy when your body is effectively distributing energy towards the production of either white blood cells or other types of mechanisms to defend you. And whilst in the early days, it was difficult to quantify what that might be, I began to piece together, and Garth’s work really helped to pull this into some form of clinical strategy, that there may be what we call a sterile inflammatory event.

And this has been looked at now for the last 10 or 15 years, where particulates from these cell membranes, and also from the inner membranes of the mitochondria, are oxidized because of an insult to their structural flexibility, and they then distribute themselves around the body and are recognized by pattern recognition receptors as being problematic. The attempt to eliminate them is a normal process of clearance from the body, either back into the stools, to the urine, to the liver, to the kidneys and so on. But if they continue to be produced on a regular basis, the energy necessary to do that becomes depleting, and it’s very difficult in order for that person to recover from either the original insult where they get post-viral fatigue, for example, long COVID. Garth recently been writing about the fact that long COVID is a classic example where we see persistent, sterile inflammatory consequences of the original insult.

So looking at the very delicate membranes inside mitochondria, where they rely on cardiolipin, or the membranes of the cell where there’s a wide range of glycerin, phospholipids that make up those areas, an opportunity to replace them with undamaged, unoxidized lipids therapeutically suggested that there should be a benefit.

James Maskell:
Great. Yeah, that makes a lot of sense. So what were your first forays into providing this orally? And how did it go? And what did you learn along the way? As far as what was a… Because I’m sure you are sort of like… You’re sort of just going on your understanding of the physiology and what you think might work. And then when you start doing it, I’m sure you learn a lot.

Dr. Michael Ash:
Yeah, of course, and there are… As with all interventions, there’s normally a parameter that allows you to derive some benefit without being too problematic. I mean, there are sort of extremes where it’s even too little, and so the person becomes disaffected and disillusioned, or you give too much. And so over the years of using this, there’s a rough rule of thumb, something between two and six grams per day of lipids, of which from a commercial perspective, there’s a company called Natural Therapeutics that has been producing these lipids under Garth’s instruction now for a number of years. We would use either as a powder or a tablet or a capsule, so we can deliver it either on their own or in conjunction with various antioxidants or other nutrients, which appear to also benefit from a transporter mechanism. So the lipids themselves seem to provide additional capacity for the cell membrane to allow those nutrients, which are sometimes difficult to penetrate fat soluble tissues, to enter into the cell.

So if you give somebody… Say, for example, we take an individual who’s had exposure to some form of environmental toxin. And a lot of work was done by Garth with people from the Gulf War exposure. So much of the work that I first began to read about was people that are being exposed to various noxious chemicals, for which fatigue was a characteristic, but there were many other symptoms, including pain, loss of energy. And I know rather uniquely, Garth is an honorary colonel in the special forces of America because of the work that he spent time doing it. One of only two people, and the other person was his wife before she passed away. But they were given special military promotions because of their work. And what they found was that they could both drive into the cell nutrients necessary for the cellular function to enhance, but they could also excise those, or bring out of the cell, contaminants.

And like all these things, if you try and bring out things that are problematic to render harmless too quickly, the consequences can be that person ends up feeling worse than they began. So dosing for these things, between two and six grams per day… I think I gave you a few examples. We’ve published numerous narrative reviews and also co-authored studies on the use of these interventions in different groups of people, from age of people to people with toxic exposure and also people with persistent fatigue, chemotherapy-induced fatigue. There’s a variety of different ways. It’s terribly easy. I know when we’ve been writing, we’ve written thousands of words on this, so there’s a lot of technical data. Virtually all of these are free to read, so you can search through PubMed.

And we tend to write for fairly dull journals, so they’re not the sort of typical journal that the average clinician’s going to look at, but things like membranes, and I think we did two very long ones for Biochimica et Physica Acta, which is a name in itself which you’re never going to repeat in a public company. But essentially, these are journals that specialize in lipid dynamics and lipid therapeutics, and we wanted to introduce to these scientific groups and try to encourage more research being done through independent institutions to show how it’s possible to basically resuscitate cells, and more importantly, resuscitate mitochondria. And by doing so, you can reverse the age-related changes that occur in all of us. And in doing so, you cannot just simply improve energy, which is a fundamental component of all activities that take place, but you can also rid the body of various problematic agents.

James Maskell:
Awesome. Well, look, I’m really glad we’re talking about this because just last weekend I was at the PLMI conference and the whole topic was sort of functional immunology and functional immunity. And in this year of growth that we have here at the Evolution of Medicine, I think what we’re looking at is, where are the real opportunities for this medicine to grow and grow at a more rapid rate? And obviously, you mentioned there long COVID. And part of the reason why that PLMI conference and why we focus so much content on it is… We’ve looked at Lyme disease because there’s a lot of doctors that have worked with Lyme disease over the last 20 years and have learned a lot that is relevant to that. And then obviously, even things like mold related illness, chronic inflammatory syndromes.

These are all issues that have some similar root causes to them. And so we’ve been building a lot of content around these topics because we believe that if the numbers are correct and 20 to 30% of people who got COVID have some sort of long term sequelae, and if we are correct in thinking that conventional medicine isn’t really going to have anything to support them because they don’t really understand what’s happening, that this could be an area of potential growth. So we were talking at the conference of maybe some of the things that could be used to identify what’s going on in the physiology of the long COVID patient that’s leading them to it. I guess maybe you could just contextualize for us, where do you see lipid replacement therapy fitting in sort of the therapeutic toolkit for the average doctor that is now seeing a lot of COVID patients, and where would you put it sort of in the therapeutic order or the hierarchy of needs for that patient?

Dr. Michael Ash:
Yeah. Well, that’s a great question, James, because it depends on where you start in your thought process. So normally, we have a cascade of differentials that we work our way through. What can we tick off that would make some difference to the way that individual feels as quickly as possible? And so there’s normally a clinical cascade of priorities depending on age, gender, costs, et cetera. What I think lipid replacement or membrane replacement therapy lets you use is, at all times, at least a two point of intervention, so whatever lifestyle recommendations that you’re going to provide for that person. And inevitably, there are going to be some fairly common thematics here. The point is that post-infection, they’re going to have a number of mitochondrial defects that lead to a swelling of those mitochondria. So the mitochondrial inner membrane potential changes that leads to a leak of electrons from the mitochondria, which causes oxidation of mitochondrial lipids, or particularly cardiolipin, and also you get mitochondrial DNA, which starts becoming oxidized, enters the cell, and creates a signal, which is quite a normal signal, which is the sort of thing we should be seeing.

And I’m hypothesizing, to some degree, around long COVID based on work over many years, looking at other types of post infectious events, is that, within the membrane, within the study of the structure, we see a consolation of proteins begin to aggregate and forming what we refer to as the inflammasome. And an NLRP3 is the most common, but there are six inflammasomes. And inflammasomes just mean inflammation throughout the body in simple language. But the reason why this is an important component of all forms of fatiguing-related illnesses, whether it’s caused by exogenous exposure to chemicals or infectious agents or a combination, is that should be a self-limiting or a self-regulatory mechanism that releases the capacity for the body to produce IL-1 and IL-18, which in turn triggers, NF-kB, all of which is a biological cascade to act as a short-term defense mechanism.

Originally, it was set to look for parasites, various types of pathogens and bacteria, particularly at brush borders, which is where the epithelial tissues, predominantly around the gastrointestinal tract, sit. And you may well have seen a recent paper in Nature showing that there appears to be some form of ghost bodies of post-COVID or viral particulates left in epithelial tissues in the gut. So we know that’s the primary interface between both exogenous environment and internal environment. If we see a change in the production of oxidative particulars, a trigger inflammasome response, the activation of this sterile defense mechanism, it leads to a loss of integrity of epithelial tissue barriers. So it leads to increased leakiness of the gastrointestinal tract, which we’re familiar with is a primary mechanism for lipopolysaccharide triggering, cross transfer of partial digestive proteins, all the usual cascade of potential triggers for immune activation, start to migrate.

And in turn, further action changes into the danger cascade around the epithelial tissue, which then migrates those responses into systemic immune activity. So we typically see a series of pattern recognition receptors inside the cell and inside the epithelial tissues, identifying normally occurring particulates but in larger quantities than normal, but are not being repaired rapidly enough, and it drops you into this feed-forward cycle of inflammation-induced changes to further mitochondria damage occurring. And mitochondria are typically either repaired by themselves. So they effectively form a recycled mitochondria where they capture the genetic material and the lipids and reform mitochondria, which is called fusion, or they’re broken up and discharged, which is called fission. And then there’s the creation of new mitochondria, which is called biogenesis, and that takes place all the time. And we have thousands of mitochondria in cells. They can be quite problematic if they become damaged in the face of immune activity. So once mitochondrial DNA becomes oxidized, it releases cardiolipin. And cardiolipin is one of these fats that we replace when we use oral lipid replacement therapy.

So by fractionating lipids, binding them to, in this case fructooligosaccharides, to prevent them from being oxidized during the ingestion and absorption phase, they go through with a… It’s more of a weight bearing transfer of those lipids into the cell membranes. They arrive. And cells are always looking to change and replace damaged lipids. So with the materials available, it’ll pull it into the outer membrane, and then migrate it through to the inner membrane. Then also, the mitochondria will pull that in to repair cardiolipin. And this has been demonstrated in quite sophisticated radioactive assays. So in a study done some time ago in rather older patients, my sort of age group now, a 60 to 65 age group were fed lipid replacement therapy and compared their mitochondrial functionality with a healthy military 30 year old. And they showed that over a period of 12 weeks, that the mitochondrial response to the older patients became equivalent to that of a 30 year old. So effectively you could de-age mitochondrial damage when you were provided oral supplementation.

That mechanism has been repeated in people with cancer induced or cancer therapeutically induced oxidative stress. It’s been shown in people with some form of military exposure to exogenous compounds and chemicals. It’s been shown in people who are experiencing a chronic fatigue. So multiple trials has been done across different parameters where the restoration of mitochondrial lipid stability and biogenesis of mitochondria shows responses equivalent to a young person.

James Maskell:
Wow. That’s awesome. Yeah. Well, I can imagine. I mean, now that I hear what you’re saying, I mean, it takes me back to my junior science classes with how turgid is the cell? Am I in the right zone?

Dr. Michael Ash:
Yeah. Look, I think that… What we’ve discussed many times, of course, is because you can track back to mitochondria or cellular world dysfunction, any disease, that you can start becoming a little bit sort of hyperbolic around how lipid replacement therapy is going to be the resolution of all these different conditions. So I think one has to be contextually relevant here, because you are asking the question, where would you start? Where does this fit within the parameter of a therapeutic intervention? Well, in a few cases, and I think most relevantly a healthy aged person is quite straightforward, lipid replacement therapy makes a change to them quite quickly. But where there are other fairly significant clinical disruptions to their biochemistry, biology, and functionality, it’s not going to be enough on its own. But what it does very, very well is it facilitates the absorption of nutrients, it repairs damaged cell membranes steadily, and slowly. It’s not overly dramatic. It takes two to three months, and it works very well at repairing the ability of the human to repair and reuse mitochondria, and also reduce new mitochondria.

And in one of our papers, we’ve tried to do cartoons, because it’s quite complex to pull all this into different things, but an undamaged mitochondria looks relatively evenly balanced in terms of it shape is quite flexible, it moves around. But once it becomes damaged, it swells. And in swelling, it becomes hyperpermeabilized. And we produce a massive amount of energy at the mitochondrial membranes. It’s equivalent to a lightning strike, and we produce a huge quantity of ATP every day, which is roughly the weight of your body. So there’s a huge amount of biological and biochemical activity, which if it gets damaged, spills out messages, initially only at a local cell level, but of course those cells also become distressed and can produce dangerous signals. And so this dangerous signal starts becoming a measurable insult. And that’s when I say the first thing we see is the introduction of a defense mechanism against sterile inflammation, activation and interleukin B1, which leads to pyroptosis or cell damage and death, which in turn leads to further mitochondrial dysfunction, which increases inflammation, and then declines mitophagy.

So you don’t tidy up that damaged mitochondria very efficiently. You become a less efficient waste removal system. And so you get locked into this cycle where people say, “I have no energy. I just can’t do anything.” If you don’t have energy, you can’t maintain immune response, you can’t clear the system. So I’d like to see the use of lipid replacement therapy as a fairly safe, well it’s very safe, I was going to say fairly cheap, safe, therapeutic baseline intervention. Well, let’s just take an example. You will remember that Dr. Chatterjee and I, for the British BVC corporation, did a couple of sort of semi-documentary programs where patients that were chronically unwell were introduced to functional medicine strategies over a period of between four to six weeks. And we demonstrated, in every case, that they either fully or significantly recovered during that time, despite many, many years of unsuccessful standard of care treatment.

James Maskell:
Well, I’ll just say, I don’t think the general public would remember that it was you and Rangan. They just remember Rangan, but I knew that it was you and Rangan.

Dr. Michael Ash:
Yeah, well, of course, I’m not the talent. I was just doing this stuff in the background. But pretty much every single person on that program receive lipid replacement therapy. And one of the most unusual outcomes in one family was where the husband was not our primary therapeutic target, but he was someone who’d had 10 years of persistent fatigue. He wasn’t able to exercise very well. He felt run down. His wife and daughter were the principal targets at the beginning of the program. And I simply said to Rangan, “This chap just needs to have lip replacement therapy and a B complex vitamin. Nothing… Just let’s give him something to get going.” Well, this chap’s health, within that four-week period, transformed from a virtually house bound individual to, as you would see on the TV programs, sprinting with Rangan up and down the beach after four to five weeks.

And that’s an unusually quick level of recovery, but he was massively depleted in B12, and he couldn’t seem to change B12 levels just by oral supplementation. But when we found that with lipids, B12 was able to be transported into the cell. So as an example, you can use this across a wide range of therapeutic complexities, very safely as a transport of mechanism. And in fact, a paper just out in the Bioactive Compounds in Health and Disease, just came out last month, is looking at the role of lipids in helping transport things like CoQ10 and curcumin and other nutrients into the cell. We saw this clinically years ago, but getting the research then validated takes a bit longer afterwards. So I think it sits a baseline intervention onto which you can then build more strategic or specific nutrient, and if need be, pharmaceutical intervention.

James Maskell:
Awesome. Well, look, you’ve really got me inspired to learn more about this and to share more about this. I’m definitely going to… I think we have some plans later in the year maybe to see if we can unearth Garth onto a Zoom call and see if he’d be interested in sharing. But yeah, Mike, look, I want to just say thank you so much for sharing this. I think this is really critical information. I know that fatigue is just a thing that is in every functional medicine practice, right? Every office, right? Most patients are coming in with a certain level of fatigue, and that can actually drive a lot of visits to a different type of doctor. And so I’m excited that there’s a starting point that can be easy, because a lot of times what you’re looking for with these patients is, can I get a little bit of forward progress early so that I build some momentum into this relationship? And they build trust.

Dr. Michael Ash:

James Maskell:
Because typically, they’ve maybe felt let down by the healthcare that they’ve received up until now because the fatigue hasn’t changed. And so I’m really grateful for you sharing this, and maybe look forward to continue with this conversation in this year of growth, because ultimately, just to come back to it, is that there are a lot of people that need our help. And I am fully convinced, after sitting in another two days of intense functional medicine lectures with the Vojdanis and the Jill Carnahans and the Jeff Blands of the world, that functional medicine is the only operating system that is possible to create the individualized strategies that are needed for long COVID and these other chronic conditions. And so I’m just grateful that there’s so much wisdom out there already, and that doctors who are sort of sniffing around the edges can get started, see the value for themselves, and potentially start on a path towards the kind of education that you’ve brought to the UK and that you continue to provide for many people. So I’m really grateful for you to be part of the podcast.

Dr. Michael Ash:
Well, thanks, James. And also, we can perhaps put a few links to papers, but I think there are about 32 published, either narrative reviews or research related papers on the use of lipid replacement therapy or membrane replacement therapy. So you don’t need to feel uncomfortable with a lot of data. I haven’t covered all the areas in which this has been demonstrated to have consequences, but it’s very safe, it’s relatively cheap, and it has an ongoing persistent benefit for the people that take it.

James Maskell:
Beautiful. What else can you ask for? That’s what we need. All right, so this has been… I’ve been here with Dr. Michael Ash. He’s in the UK. He’s centrally involved in the functional medicine ecosystem there in the UK, as you can hear from the interview, has been involved in a number of interesting research projects, and also projects that have brought these kind of ideas to the front lines with the TV show. And this has been something that we’ve had covered in the evolution of medicine over the years. Mike, thanks so much for being part of the Evolution of Medicine podcast. I’m your host James Maskell. Make sure to check out the June 6th, 2022 Functional Forum on functional immunology, because there’s a lot of great information that will tie into a lot of this. It was a really exceptional conference. Thanks so much for tuning in, and we’ll see you next time.

Thanks for listening to the evolution of medicine podcast. Please share this with colleagues who need to hear it. Thanks so much to our sponsors, the Lifestyle Matrix Resource Center. This podcast is really possible because of them. Please visit goevomed.com/lmrc to find out more about their clinical tools like the group visit toolkit. That’s goevomed.com/lmrc. Thanks so much for listening and we’ll see you next time.


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