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Brain Wash: The Rise of Neuroinflammation

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Brain Wash: The Rise of Neuroinflammation with Dr David Perlmutter

We know that modern lifestyle and dietary choices, including lack of sleep, stress and the Western diet, all contribute to chronic inflammation. It can be a real struggle to make healthy choices for ourselves. 

But did you know that chronic inflammation literally disconnects our rational “adult” brain from the impulsive, reactive “child” brain, perpetuating the cycle of poor decision making over our lifestyle and dietary choices?

Dr David Perlmutter returns to FX Medicine to share the details of his new book, Brain Wash, diving into how inflammation influences our mood and actions, how to leverage the gut-brain connection, why having a sweet tooth isn’t so bad from an evolutionary perspective, and how all this translates into learning how to make better decisions about our health. 

Covered in this episode

[01:05] Welcoming Dr David Perlmutter
[02:02] Evolution of humanity and drivers of inflammation
[05:57] How inflammation affects decision making and aggression
[13:05] Measuring inflammation
[16:36] How do we make better choices with our diet?
[21:48] Your brain is being manipulated 
[25:52] Transgenerational changes in the brain
[27:12] The evolutionary advantage of having a sweet tooth
[31:12] Personalising supplementation
[35:12] Leveraging the gut-brain connection
[40:45] Phosphatidylserine as a delivery tool
[43:02] Why it’s important to balance both building up and breaking down cells 
[47:53] Discussing David’s book Brain Wash
[53:31] Closing remarks


Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook. Joining us on the line today is Dr David Perlmutter, who's a board-certified neurologist and five-time New York Times best-selling author. 

He serves on the board of directors and is a fellow of the American College of Nutrition. He received his medical degree from the University of Miami School of Medicine where he was awarded the Leonard G. Rowntree Research Award. 

He serves as a member of the editorial board for the Journal of Alzheimer's Disease and is published extensively in peer-reviewed scientific journals including archives of neurology, neurosurgery, and the Journal of Applied Nutrition

There's so much to Dr David Perlmutter's bio, I'll leave you to read it later. So, welcome to FX Medicine, David. How are you?

David: Well, I am delighted to be with you and I miss everybody down in Australia. This is a great opportunity to reconnect.

Andrew: We had a lot of fun when you were here for the BioCeuticals Symposium. 

David, now we're sitting on the precipice of an avalanche of issues, which affect the brain, including Alzheimer's but also things like stroke for metabolic disease. What went wrong with our lifestyles and diets? And when did this happen?

David: Andrew, I think the answer to the question "what went wrong" is what we call an evolutionary mismatch. In other words, our genome has been refined and cultivated in response to an environment that has been relatively static for tens of thousands of years. Suddenly we have challenged our genome with signalling that is manifesting as ill-health. According to The Lancet in 2019, we now know that 1 in 5 deaths in the world is a result of an unhealthy diet. That's just one part of our lifestyle consideration. 

The foods that we eat are albeit a big player, but our genome wants us to survive, wants us to be healthy, and continue our ability to reproduce and carry on. But it evolved at a time when our world was different. So I think that, to answer your question quite specifically, I think the fundamental mechanism here that explains why the most common cause of death on our planet are the chronic degenerative i.e. lifestyle diseases as a manifestation of the evolutionary mismatch between environment and genome.

Andrew: And then inflammation flows from that, and it's becoming accepted as a major driver of chronic disease, but we need this vital process as well. When is that tipping point when it turns into a driver rather than a protector?

David: Another good question. I think you bring up a very good point. Everybody is pointing fingers saying “inflammation is bad” and “insulin in high levels is bad.” I think that we have learned that basically the U-shaped curve, or the inverted U-shaped curve either way, is really applicable to any of these metrics.

Andrew: Right.

David: Certainly, without inflammation we would probably perish within a couple of days. It's a powerful mechanism within our bodies to deal with infection, to deal with wound-healing, to deal with limiting the viability of organisms that may have gained ingress into our bodies. It's a very powerful and incredibly conserved - from an evolutionary perspective - mechanism. The problem is when we get outside of the curve, when we have inflammation that's either way too high a level at one time, or chronically at a less high level in over a longer period of time.

Same thing could be said about blood sugar or cortisol or many of the other metrics that we deal with. We know for example, that sleep is a great thing. Sleep is good for our brains. It's good for decision-making. Having not enough sleep is associated with a variety of issues including cancer, diabetes, and Alzheimer's and coronary artery disease. But interestingly enough, too much sleep is also associated with those very problems. That said, I hate to use this term knowing how I feel about sugar, but it is about looking at what is the "sweet spot.” What's that ideal Goldilocks zone in any of these matrices that we can really try to approach and make our goals? Beyond that, understanding that the goals in terms of what's ideal will vary from person to person.

Andrew: And then, of course, you've got so many dietary issues causing inflammation. You mentioned sugar. You've also spoken previously about the issues with wheat. 

But then you've got things like psychological stress and we know that we're way more stressed than even 10, 15 years ago. How do you prioritise, diet, lifestyle, and stress, emotional issues in furthering inflammation or chronic inflammation?

David: Well Andrew, let me take a step back if I may, in terms of this sort of broadened approach to understanding inflammation that you've just alluded to or opened the door to. 

Andrew: Yes.

David: I'm certain that you've interviewed people and you've spoken yourself over the years about the role of chronic inflammation in whatever that chronic disease may be, whether it's coronary artery disease, type 2 diabetes, etc. That's well-established. 

I think what is just beginning to be established is the role of chronic inflammation in mood disorders and even in our decision-making ability, that our ability to make good decisions is threatened by the very inflammation that we've been talking about for years and years. 

That raises inflammation to a higher level because, when there's inflammation increased in the body from whatever cause, be it dietary, lack of sleep, lack of exercise, excess body fat, you name it, it threatens decision-making which often manifests itself as poor decision making, as opening the door to yet further lifestyle choices that make that situation worse. 

We know that when we disconnect from the prefrontal cortex part of the brain and lock into our impulsivity centre: the amygdala. This disconnection is brought about by inflammation when it happens, and then we make poor food choices, which does what? It fans the flames of inflammation and the whole process continues on what we call a "feedforward cycle.” It's a terrible pun, but I think it's apropos.

Andrew: Yeah, yeah.

David: What we want to do then, looking forward into the future, is look at what are the various types of “off-ramps” that we can offer people to break that spell to bring the adult back into the room to manifest better decision-making that will ultimately then help reduce inflammation, which will foster even better decision-making moving forward.

Andrew: There's so many areas we can go here. You talk about off-ramps, and what's going through my mind is not just poor decisions with regards to food. We know that sugar hit causes another sugar hit. Even things like domestic violence, even things that we see in our cultures, our communities where emotion or anger, aggression is driven by poor decisions and drives more poor decisions. Is this where we're going?

David: Yes. I want to break this down a little bit for your listeners because this prefrontal cortex, the area of the brain, the cortex of the brain behind the forehead, is involved in a lot of things but I think for the purposes of our time together today, let's just focus on a couple. 

First, this is an area that allows more thoughtful decision-making that looks at for example future consequences of the actions I engaged today. It looks at the future consequences in terms of other people, how they may respond to things I choose to do. It looks at right versus wrong, good versus bad. It is also this area of our brains that is involved in empathy, being able to share in another person's opinion or viewpoint, cognitive empathy, for example.

The other area that we should focus on is a more primitive part of the brain called the amygdala and that is, as you mentioned, the part of the brain that is much more impulsive, makes sudden rash decisions, allows people to experience what's called “us versus them” mentality, fear, and tribalism, narcissism. These are all mediated by this amygdala area, and what we recognise now is that under the best of circumstances, the prefrontal cortex exercises what we call “top-down control” over the amygdala, basically reigning in it. Pretty much acting as the adult in the room. We depend, through a dramatic degree, on the connection then between the prefrontal cortex to the amygdala, being able to remain connected to it and govern our behaviour from a more sophisticated perspective.

When this connection is threatened, then we default to that area of the brain that is more fearful, that is more aggressive, as you were talking about, more impulsive, poor decision making. That connection is key. What we have been talking about lately is what we call “disconnection syndrome.” That is the reduction in the communication between this prefrontal cortex - call it the adult in the room - and the more impulsive child in the room, the amygdala. We need the adult to exercise this top-down control. And guess what? One of the major factors that threatens the connection is inflammation.

What I'm saying then is, if inflammation for example, relates to diet, and you and I know that it does. And if the modern Western diet is so darn pro-inflammatory, which it is. And this modern Western diet is becoming the global norm pro-inflammatory, then across the globe we are locking...people are becoming locked into behaving from the amygdala in a more impulsive, anger-based, aggressive, global view in part due to the pro-inflammatory nature of the very foods that they are now receiving.

So, you're right that these changes are happening. We're seeing it. We're seeing this incredible isolationism and tribalism. Fear and aggression virtually permeate the entire planet. Based upon this model that I've just described, it may well be that this Westernization of the global diet through the process of inflammation may in part be responsible for exactly what you described, this aggression and fear that is so pervasive.

Andrew: I've read of the research of Felice Jacka in Australia looking at mood with even basic dietary changes, which decries just how poor some people's diets are. We know of Julia Rucklidge's work from Massey University in New Zealand looking at basic supplementation, changing the mood of ADHD kids and things like that, replacing certain nutrients in their diet. 

How simple is it to change certain things when people are in that grind? They're in the sugar hit. They're already obese. They've got the hunger drivers. There's a second part to this question: how can we measure it?

David: Let me get to the second part of the question first, and that is how can we measure it? The most sophisticated thing that we can do is, of course, do functional MRI scans on people. It's obviously not repproachable and not to scale. But again I think that there is a direct correlation between imaging of brain connectivity and C-reactive proteins, with higher levels of CRP being associated with decreased imaging of brain connectivity. You can see disconnection syndrome on a brain scan and you can correlate that with C-reactive proteins.

I would say that our old-school of markers of inflammation...I mean real old-school, if you wanted, like fibrinogen and von Willebrand factor but more recent things, like interleukin-6 and tumour necrosis factor-alpha and of course C-reactive protein, can be surrogate markers for what is going on. We know that inflammation is at play here. 

We know that as such...you bring up Professor Jacka and her work at the Food & Mood Centre is really standing at the forefront of really trying to raise the awareness that, you bet, food matters. It matters directly in terms of micro and macronutrients. They matter somewhat indirectly through the lens of how food affects our gut bacteria and their role, for example, in the creation of so-called neurotransmitters. 

And, as mentioned through the process of inflammation, also very important not only in terms of the connection we talked about a while ago between the prefrontal cortex and the amygdala and the top-down control but also through another interesting pathway. This is the kynurenic acid pathway whereby inflammation inhibits, if you will, the transformation of tryptophan into serotonin, favouring some more neurotoxic metabolites.

Inflammation turns out to be operant at many levels. Ultimately it becomes a feedforward process whereby inflammation is related to mood disorders, increasing cortisol levels. What does cortisol do? It changes the array, the diversity of gut bacteria, and also increases gut permeability which then, of course, amplifies inflammation yet again. There are many surrogate markers here that can give you a sense of what's going on. Not only markers of inflammation, but certainly markers of bowel inflammation and specifically bowel permeability all relate back to these fundamental mechanisms.

Now, I'm going to ask you to remind me what question number one was because we jumped on number two.

Andrew: When we're in that melting pot, we're already there in the grind of these very powerful drivers of hunger, of poor food choices. How do you get out? How do you teach people to make a better choice?

David: It's really a very good question, I would say. At this stage of my career, that's a question I might get three or four times a day because it's what people struggle with. There's no question. They struggle with that first step, and our goal is to offer up any way we can to get a crack in the door to regain even a modicum of better decision-making; in other words, better connection to the prefrontal cortex.

It might mean that, when a patient visits a healthcare practitioner to lose weight, that's the goal. That at week 1, the discussion has absolutely nothing to do with diet. There's no diet given, which will raise that patient's eyebrows, no question. But, at week 1, we only work on decision-making ability and that might mean in that first week that we're going to really give it our best shot this week to improve the quality and quantity of your sleep. 

Now, what in the world does that have to do with my food consumption and my dietary choices? Weight loss might be of course almost a confrontation with the patient but what we're trying to do here is begin the process of first rebuilding the brain through neuroplasticity to allow better decision-making that will then serve us moving forward and will build on itself moving forward to really fully realise not just the dietary changes, but changes across multiple lifestyle platforms. 

We're actually building this out right now with The Institute for Functional Medicine, their Physician Wellness program, that this should be job one. Because you take a step back and you realise that today we don't suffer from a lack of great information. I mean there are so many good books and programs and podcasts. There's tons of good stuff out there. But I would submit that it's worthless. All of that information, even my books, for you or anyone, are going to be worthless until you implement the information. What we need to do is bridge information over to action. Then, we're talking about something.

We, as healthcare providers, do whatever we can to learn as much as we possibly can. We go to all the conferences and read the journals. And then in the clinical setting, we're meeting with patients and giving them the benefit of our research, of our study, and say, "This is really what makes sense for you. Here's the best diet, 15 minutes of exercise, an hour of exercise..." whatever it may be for this individual. But we recognise that where the situation breaks down is after that, when 50% to 80% of the recommendations made by healthcare providers to their clients or patients are disregarded. You can oftentimes talk to patients on and on, and it's great, but if they don't implement the information, it is completely useless.

We, as healthcare providers, have tended to point fingers at these individuals saying, "Gosh, they must have a problem. I've given them such great information that I learned at an ISM conference, wherever, and I can't believe that they're not going to do what I said. There's got to be something wrong with that person. What's their problem?" 

We've got to stop that blame game because we now have come to understand that these individuals with typically high levels of inflammation, they're type 2 diabetics, they're overweight, etc. Virtually everybody in our modern world has elevated inflammation. They have had their decision-making apparatus in their brains hijacked away from the prefrontal cortex, locking them into a situation where their decision-making is impulsive. They don't have the hardware to make better decisions. It's absolutely time to recognise that and stop the blame game because I'll tell you that these people go home, and look at themselves in the mirror, and ask themselves why they can't follow through with what Dr So-and-So just told them. What do they do? They blame themselves. This is pervasive well beyond the doctor-patient relationship. Everybody wants to get in better shape, maybe lose weight, gain weight, whatever it may be, and yet we blame ourselves constantly for not being able to follow through despite this incredible amount of information that we have.

Andrew: Okay so stopping that guilt particularly as you say in a world of instant gratification, we're bombarded by marketing messages, from teenagers playing exciting games with their friends so there's almost this quasi-social interaction, right through to the guilt that women are placed under and place themselves under from the media that's posted all over the world about how they should look. There are so many things in our whole society, that we really have gone wrong with our society. How do we stop guilt? Is it purely a meditatory-type action that we need to, or an affirmatory-type thing, that we need to do?

David: Well, all those things are important but, for us, job one is to call it out. 

Andrew: Right.

David: Job one is to reveal to everyone the depth at which our brains are being manipulated. I think people have read what goes on in terms of the manipulation of our attention online, away from what we want to be online doing. The constant click-bait and pop-up ads. I think people are aware of that, but not recognising how enticing the internet experience is. Here, in America, the average American adult spends north of 6 hours a day in front of one screen or another. In a lifetime, that's 22 years spent in front of a screen.

Two things are happening. Number one, your attention is being mined, it's being hacked and it's being manipulated. This isn’t a conspiracy theory. We know you can learn this stuff easily enough online as to how aggressive companies are using artificial intelligence to manipulate your online experience, cultivating YouTube videos that happen to interestingly be very similar to the last YouTube video that you might have watched. Why? Because your attention online has value. 

But what we understand as far as our online experience, as an example because I think that's what you're alluding to, that, yes, there's an incredible amount of time that we spend online. A: that's bad for the brain. It does change its wiring. But, B: when you're doing one thing, you're not doing something else. 

Six hours a day in front of a screen, you're not likely to have enough time to get enough exercise, to shop for good food that you would then prepare in your kitchen, to interact with people in real-time, to do all the things that are important: spend a little time in nature, definitely as you spoke about, meditation, mandatory on a daily basis. 

All of these things are really important to cultivate a better relationship with this prefrontal cortex, allowing it to do what it can do, and that is give you a better level of control over your day-to-day lifestyle decisions. And allow you to be a more empathetic individual for other people, for your future self, and even for the planet upon which we live.

There's nothing wrong with the internet in terms of using it with intention. How do I write books? I write books because I have an unlimited access to information via the internet. For me, it's just breathtaking. 

On the other hand, we know what goes on and how our attention can be manipulated. That has value for others, but not so much for us when it's manipulated. Christian Lange, a historian, wrote in 1921 that “technology is a useful servant but a dangerous master.” That was in 1921, right? It's a very, very powerful message for each and every one of us today.

Andrew: What about transgenerational brain changes though? Now we're seeing the stress of the mother and the father being borne by the children. Have you then got a hardwired thing that is irreparable?

David: I think that those two things are… They are not mutually… They don't endow each other, hardwired and irreparable. 

Andrew: Aha.

David: Things can be hardwired, but they can be changed. That is the beauty of neuroplasticity that we can take advantage of. Things are definitely hardwired but you know what? You know that you forget things as you get older in terms of language and skills. So those things can atrophy if we don't continue to pay attention to them. 

At the same time, we can strengthen pathways to activities and parts of our brain that allow us to see the world in a better way. To be clear, this transgenerational brain change, really genomic change, at least if we're to believe the laboratory research, is multigenerational. It's not just the children of but it's the grandchildren of, and even the great grandchildren of, at least with respect to these inherited alterations and methylation pathways that we see in the rodent model.

Andrew: You mentioned sugar way back. We’re evolved from hunter-gatherers who lived off a plant-based diet until we finally caught up with that prize of the meat and we gorged on that. But why therefore are our brains seemingly hardwired for the sugar hit? Why have we got that sweet spot?

David: It's a very good question, and I think it's so fortunate that we have this desire for sweet. It may surprise you to hear me say that. It's so fortunate that we have something called insulin resistance. If it weren't for insulin resistance, we would not have survived. 

When we induced insulin resistance by having, for example, high levels of fructose in our diets, meaning lots of fruit at a time when fruit is abundant during the year, it stimulates insulin resistance and has a role to play in lipogenesis, allowing us to make and store body fat that serves as a hedge against times of caloric scarcity.

This is some very interesting genetics, here. We know that the gene modifications that really may have brought about the sweet tooth have to do with changes in our metabolism as it relates to fructose through its mediation of uric acid. It turns out that uric acid, as a downstream product of fructose metabolism, is really at the heart of all five components of metabolic syndrome. 

Again, it has to be looked at through the lens of providing us an evolutionary advantage. If not, then we wouldn't have the genes that allow this pathway to happen, what are called alterations in uricase. We've got downregulation of uricase. It probably happened around 8 million years ago and allowed our great ape ancestors to survive when there were some climatic changes that reduced the number of or the availability of fruit for our ancestors. Primarily in those days, I guess it was figs. 

And that three different mutation site modification of the uricase enzyme allowed us to increase our uric acid and, as such, increase the likelihood that we could develop something that allowed us to survive, and that is insulin resistance. How incredible that you and I are now having a conversation where we are saying “thank you” to insulin resistance because, without it, we probably wouldn't be here.

Andrew: Insulin resistance though, in a hunter-gatherer landscape, I can certainly appreciate that uric acid will help our survival because eventually we'll have a feast after the famine. But the problem is that we never have the famine now, not in our Western society.

David: You are 100% right, Andrew. That gets back to our original question today, and that was: what is it that lies at the cornerstone of the illness that is pervasive around the world? And it is this evolutionary mismatch. You're right. It served us well in times of feast and famine. 

During feast, we would be able to gorge on foods and have access, for example, to fructose, increasing our resistance to insulin, allowing us to make and store body fat, allowed us to survive during famine. That's what those genes were selected for. But today, you are correct. We don't need to be clearly storing excess body fat, but yet we are in light of the fact that we have this downregulation of uricase and this increase in uric acid that is then really playing such a functional role in increasing our ability to make body fat.

Andrew: So what sort of…I’m going to say the word "supplements". What sort of supplements can practitioners use in the naturopathic armamentarium that are effective at changing these or helping people to change these decisions, helping to blunt that next craving for sugar or fat or whatever?

David: You know, I think that...let's look at the word "supplement" first of all. What are you supplementing to? You're supplementing to the diet. I think step one should be the dietary changes prior to really even thinking about supplementation. 

Andrew: Yes. Great message.

David: I think that we have to look at the diet and recognise that some of our positions that we may have taken over the years should be looked at now through the lens of a more personalised approach as opposed to making global recommendations.

But this is what we do know from a global perspective, and this is that simple carbohydrates and sugars are really something to be avoided across all dietary platforms in my opinion. I think that dietary fat is valuable but I think the quality and certainly the type of fat that we are consuming is really fundamental. 

Andrew: Absolutely.

David: I think the type of protein that we are consuming and the type of more complex carbohydrates we're consuming, very important. I think eating along the lines where we recognise that one important leg of the stool is how we nurture our microbiome, I think has taken centre stage these days as well. So I think there are a lot of factors to consider.

Now, in terms of supplementation, it's a very, very good question. I think we can infer from laboratory studies what people may need, but more importantly look at what functional testing as opposed to just laboratory levels of vitamin D or B6, B12, folate, whatever. I think looking at more uniqueness as it relates to those nutrients I think is very valuable. 

For example, what is the status of an individual's vitamin D receptor? Does he or she carry certain polymorphisms as it relates to MTHFR as an example? Might an individual be more susceptible to PPAR-alpha polymorphisms to less tolerance of a higher fat diet as an example?

I think we have the tools now to be far more specific about supplemental recommendations. I would say that there are probably a core that I think are valuable for most people and for myself, and that includes for example vitamin D3. I think that we're not probably going to be in a situation where we're able to make enough vitamin D from cholesterol via sunshine in our modern lives. I think that's a given. I think this is a patch on an evolutionary mismatch. 

I think looking at vitamin D, titrating its levels, but also looking at VDR polymorphisms to consider what might the downstream effect be, or not be more importantly, from compromised activation of that receptor. I think looking at MTHFR and looking at functional assessments...methylmalonic acid, for example, as it relates to B12. Looking at some functional metrics are very helpful in terms of the B vitamin group in general. So I think you have to be pretty adept at utilising laboratory evaluation to really cultivate the best chance of doing right by a patient in terms of her or his needs.

Andrew: Right. I mentioned of Julia Rucklidge's very basic intervention with a multivitamin, and then you have mentioned gut. You've mentioned even the gut microbes, very often practitioners use probiotics there. 

Where do you sort of start? Do you tend to start at the gut level which is the seat of all nutrition? Or do you tend to intervene at the brain level to help people, to maybe help in their neuroplasticity?

David: It's a good question. I think that generally we start at the gut and we then try to leverage this gut-brain connection. But I think it's really important to start at the gut. Who knew? Who knew that food and the gut are important for health? Gee whiz, that's brand new information, isn't it? 

So I think, from there, then we are going to create the scenario that's then good for the brain. We're going to reduce inflammation. We're going to improve what might be increased gut permeability and secondarily blood brain barrier permeability. I think that the brain is going to be a huge beneficiary of enhancing gut health both in terms of mechanistically but also in terms of metabolically, in terms of what the gut bacteria are producing.

Now, having said that, I mean there's plenty of lifestyle things that we can do that are specifically more cerebrocentric. For example, physical exercise is a powerful way of enhancing the production of brain-derived neurotrophic factor. Obviously really important for brain health. Lower levels of BDNF published in the Journal of the American Medical Association strongly correlate with the risk for dementia. We know that BDNF enhances neurogenesis and also neuroplasticity, by the way. Even getting back to our original model of wanting to reconnect to the prefrontal cortex, that can be facilitated by higher levels of BDNF, hence, the inclusion of exercise in the program.

So, you know, beyond that, we know that DHA is a fundamental brain building block. We're learning these days that the type of fish oil we may consume is important, in that now we're seeing some very highly sophisticated extraction methods from cod liver oil that allow higher levels of what are called specialised pro-resolving mediators, resolvins and protectins, which we know have a dramatic role to play in reducing inflammation. We've kind of come full circle. 

Andrew: Yeah.

David: I think that the use of high-quality omega-3s is really very fundamental as it relates to brain health. Overall reduction of inflammation. We know that DHA is a COX-2 inhibitor and, as such, we have pharmaceutical COX-2 inhibitors. This is nature's COX-2 inhibitor that helps also control inflammation.

Again, getting back to our original moments together, there's an upside to inflammation. We need a good robust inflammatory response when we are challenged by, for example, an invading microbe. But then we have to resolve that inflammatory cascade, and we have within our bodies these homeostatic mechanisms. Much as insulin kicks in when blood sugar goes up, pro-resolving mediators help to reduce this inflammation once it kicks up to bring it down to a manageable level. 

So I think those are the key players that are involved in both gut and brain, and really, we say those in the same breath because of their profound, profound bidirectional relationship.

Andrew: I was really interested when I was reading some of the research on these SPMs, and there was a real key to the level of maresins versus the resolvins, that you had to get the right ratios in effect.

David: Yes. I think the issue here is that we are just beginning to get some really good understanding of all of these players and recognising that indeed, we talk about resolvins being derived from DHA and these molecules being derived from EPA. 

Andrew: Yes.

David: We’re now actually seeing similar pro-resolving mediators being derived from the docosapentaenoic acid or DPA, which has been sort of the forgotten child. And recognising the value of EPA moving forward. I think it's an evolving story, and I think that we're going to learn a lot more about it. 

I mean right now, we're sort of early in the game in even being able to measure these products both in humans and certainly as they make up constituents of these omega-3 fatty acids. So that technology is really relatively new. Moving forward, being able to measure them in the omega-3s that we consume and also in humans, I think it's going to open doors for some correlative studies and interventional studies, too.

Andrew: As a neurologist, do you ever employ another forgotten nutrient, phosphatidylserine?

David: Well I think that there's going to be… We used phosphatidylserine years ago. It was kind of one of our membrane kind of "go-to” supplement as it relates to building a more functional cell membrane. But I will say that, in moving forward, where phosphatidylserine is getting a lot of play is as it relates to serine in general as a delivery mechanism for serine.

Andrew: Right.

David: Why that becomes interesting is we're starting to see some really compelling data that certain types of marine algae are producing a neurotoxin called BMAA. And there are now several studies ongoing whereby serine is being used to help offset the damaging effects of BMAA, which is now looked upon as possibly playing a role in things like amyotrophic lateral sclerosis and even Alzheimer's disease. 

So we know that.. Again, as I mentioned, there are several studies underway looking at this and how this then plays out moving forward, we don't know. We don't know how this BMAA is acting in terms of what's called the N-methyl-D-aspartate receptor, how that leads to what is called excitotoxicity, ultimately mitochondrial failure, which then plays a role in apoptosis, pre-programed cell death.

This is an emerging field as well. We are looking at seeing how this exposure at least in vitro of BMAA is involved, for example, in protein misfolding, a central player in Parkinson's and Alzheimer's as well. We're looking at that, and I think that we're probably going to see a bigger role for serine and likely phosphatidylserine as well, as a delivery tool in this realm.

Andrew: Oh, okay. We've gone down back into the cell from the whole organism, but really important biochemical processors, things like...you mentioned apoptosis. What about autophagy and the anabolism or anabolic activity of the cell? How do we balance that? How do we get that right?

David: Well, this is a central question being asked today. Now that we understand that there's clearly a switch that occurs between building tissues like fat and muscles and tearing them down. It reminds me of a song by a group called The Byrds. “To everything, there is a season.” The song is " Turn! Turn! Turn!" A time to build up and a time to breakdown. 

Andrew: Yes.

David: And I think that we have to value breaking down. Everybody's into building up, building muscle, building brain cells, building fat, not so much, but the idea of just continuing to grow is threatening through the lens of cancer, that's for sure. Building and allowing these pathways to be very active, for example in children and in utero, giving things or having children receive breast milk for example that stimulates this activity, the growth activity, I think is really very powerful. But the balance is important.

When we consider that we, in general, think about limiting the activation of insulin-like growth factor 1 (IGF-1) through caloric restriction, fasting, etc. because of its role in regulating something called mTOR, the mechanistic target of rapamycin that really is… This IGF-1 and mTOR pathway really is the switch that regulates, to a significant degree, growth versus autophagy, or breaking down. 

Auto: cell. Phagy: eat. The process by which our cells are able to break down components like misfolded proteins, damaged fats, damaged proteins, even damaged nuclear material, whereby we're able to break that down and recycle that material. This is enhanced during times of stress and certainly enhanced during times of caloric scarcity, allowing our bodies to basically catabolise in order to facilitate our survival. 

At the same time, it is a powerful mechanism whereby we're able to get rid of cells that are damaged and even DNA for example if that's damaged. As we alluded to earlier in our BMAA discussion, misfolded proteins.

So I think it's good to challenge your body in such a way as to enhance this autophagy process and to do it not infrequently. Now that could be done most efficiently, the medicine for it is called fasting. 

How much should a person fast? Some indications indicate that it's a minimum of 36 hours at least until autophagy kicks, in but probably even longer. We don't have a lot of good laboratory metrics to look at this. Yes, there are some leukocyte immunofluorescent techniques that are available to researchers. But that's not something that we can necessarily make available in the clinic. 

So we don't really have a good marker for how well you're enhancing autophagy. Yes, you can look at IGF-1 but it's highly variable. We know the half-life of IGF-1 is about 6 hours, so that's going to decline pretty dramatically early on in the fast. 

Andrew: Yeah.

David: Other things that are looked at are things like metformin which simulates AMP kinase and helps to protect or reduce the stimulation of mTOR. Very big in the anti-aging world, I will say. I serve on an anti-aging research committee, and I'm not surprised that it looked like about 80% of the people at the conference table are taking metformin and they're not diabetic. 

Andrew: Wow.

David: So how compelling is it? I don't know. I'm all for "do no harm.” While the biochemistry is interesting, I think you can accomplish a heck of a lot with fasting and that's available to everybody. You know what? Nothing needed for that. Well, I’m not going to say it's available to everybody. I'm not recommending that everybody fast, that's for sure.

Andrew: No obviously you've published Grain Brain previously. You've got a new book which is called Brain Wash. I get that we've been speaking about some of these things today, about better choices. Is this what Brain Wash will teach us?

David: Yes. Brain Wash again focuses on this model that we described between decision-making based upon the prefrontal cortex versus the amygdala. The value of the connection between the two whereby the prefrontal cortex exercises top-down control. Our decisions from the amygdala being impulsive, narcissistic, fear-based versus composed decision-making, future-looking decision-making, valuing right and wrong decision-making coming from the more advanced, if you will, prefrontal cortex. That's the chemistry of the book, if you will. 

Andrew: Yeah.

David: That’s the model that we build on. And then look at all of the lifestyle factors that are involved in how we can help cultivate our relationship to the prefrontal cortex and enhance its connection to the amygdala, which is so threatened by so much of what you and I have talked about today. 

That's not set in stone. We can absolutely regenerate that pathway and strengthen through neuroplasticity that pathway and bring the adult back into the room, make better decisions for ourselves. That's what it's all about. 

Again, we mentioned this earlier. We don't suffer from a lack of information. We suffer from an inability to implement this great information that you've been getting for years. It's great information but it's useless to people till they decide that it's important and they're going to act on it. Now, we recognise that that ability to act on that good information is what has been so degraded and virtually hacked by so much of our modern society.

Andrew: You know what? I've learnt so much in my time of things like these acute interventions. Let's say with anger or PTSD, where somebody if they're triggered by an anger response and if they have the presence of mind, even simple things like splashing water on their face can help bring them out of that anger. 

David: You bet.

Andrew: The other thing obviously, you know, we've all learnt things like counting to 10. We've all learnt things like don't send that email till tomorrow once you've read it. All of these actions in the now. But until somebody reads your book Brain Wash and brings the adult back into the room by some dietary choices and some lifestyle changes, they're really only actioning or still responding in that “now.” They're not being present.

David: That's right. How interesting it is that meditation, for example, which is totally focused on the here and now. Not what happened yesterday. Not what I'm planning to do this afternoon. Meditation, which is focused on the present, is one of our best tools to allow us to plan for the future. I mean it seems a little bit contradictory but it's true. I always love talking about that. But yes, there are a lot of lifestyle choices that we talked about in the book. I was actually in Australia on your "Today" show just about a week ago. 

Andrew: Right.

David: Very nice that Australia is so dialled in and this book just came out a month ago. It's now being published in 16 counties around the world. My hope is that those who read it will realise that they have a chance at regaining control. Truthfully I think the book is for those who are probably not likely to read it.

Andrew: Yeah, well, that's true. But what I'd urge all of our practitioners is, to get a hold of that book, to read it, and then help implement it with the patients that they see. Perhaps just enlightening them to one page or one paragraph and go, "See? A change can be made."

David: Oh, that's for sure. We covered a lot of information today and I don't want to... We have listeners who think that, because I know we talked about supplementation, there's not a place for supplementation. There sure is. If we had an ideal diet, then we would...

Andrew: We wouldn't eat.

David: ...consider supplements to be what they are; that is supplements. But even as it relates to this whole idea, this discussion we're having with respect to autophagy, I mean there are plenty of well-described supplements, whether it's ashwagandha, turmeric, caffeine, EGCG that we get from drinking green tea, ginger, I3C, melatonin, quercetin, resveratrol. These things are all helping us activate this whole autophagy, cleaning up the body, cleaning up the brain circuitry, so I think there's a role for those. 

Again, I think primarily it's either eating the right foods, or even choosing to fast. It's that low level of stress, that hormesis, that really has incredibly powerful effects across multiple systems in the body that I need we need to take more advantage of.

Andrew: Dr David Perlmutter, every time I speak with you I learn so much. Certainly some lessons for me.

David: Oh, my God. Thank you.

Andrew: I can't thank you enough for joining us on FX Medicine today and teaching us about what's in your new book, Brain Wash.

David: Great. Well, listen, Andrew. Thank you for having me today. It was a great discussion. Thanks.

Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook.

Other podcasts with David include


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