About the guest: Richard Bazinet, PhD is neurochemist and nutritional scientist at the University of Toronto. His lab studies brain lipid metabolism in health and disease.
Episode summary: Nick and Dr. Bazinet discuss: lipid metabolism in the liver and brain; dietary fatty acids (saturated, monounsaturated, polyunsaturated); fatty acids in brain health & disease; endocannabinoids; omega-3 PUFAs, seed oils & diet; and more.
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Episode transcript below.
Full AI-generated transcript below. Beware of typos & mistranslations!
Richard Bazinet 3:47
Sure. So I'm a professor at the University of Toronto. And I'm in the department of nutritional sciences, which I'm sure we'll get to the significance of that a little later on. And I'm a neuroscientist, maybe an old breed of neuroscientists, which you might call a neuro chemist. And we're really interested in in brain neural chemistry with a focus on the lipids, you know, you might know this, but if you exclude water, your brains pretty much half fat. And that's almost as fat as your body fat. So we're interested in, you know, how does the brain get to be like that, that comes back to the part to nutrition? And then the ultimate question is, why is it like that, and that's, you know, are brighter. So we use a variety of, of model systems, including human clinical studies, to try and get at the answers to some of the questions we have.
Nick Jikomes 4:41
And just just to give us a like a bird's eye view, like what, what components of neurons and the brain generally is is fat used to build and how does that compare to the rest of the cells in our body or do neurons have more fat than other cells or less fat and is it Just the cell membrane, or is there are there other components there that are made out of fat?
Richard Bazinet 5:04
Yes, so there's a few things there. You know, from from a lipid chemistry perspective, if you stand out far enough and you look at a cell, they're they're quite similar in that the phospholipid membrane is phospholipids, which is a lipid. And then there are fatty acids in there. They vary from tissue to tissue, the brains a little unique, and we can get into that. But the brain is also a little unique in that lots of our tissues would also have a fair amount of trace of glyceride, or triglycerides, kind of a storage fat that people would think of. Either that they're using it for energy when they're exercising, or it's a thing that's, you know, putting on a few too many pounds, our brain doesn't have that. The other thing with fats, though, is they they're in this membrane, but they also can come out of the membrane. And in that respect there, they're involved in a lot of signal transduction. So we, we study them, kind of both of those levels, because there actually are some big questions on how the the composition of the membrane affects the amount of fat that's released for signaling afterwards.
Nick Jikomes 6:11
Okay, so they're not they're not just structural things. No,
Richard Bazinet 6:16
no. If you picked up a textbook in biochemistry from about 1975, the year I was born, Len injure would say, they they keep you warm in the winter. They have structure. You know, they're used for energy, something I'm probably forgetting, because I'm trying to count to four on the spot right now. But they have no unlike nucleic acids and proteins at the time, they have no ability to share information. And that's not true. Right in. In 1982, the Nobel Prize was given out for the discovery of a molecule called prostaglandin E to backstep, a little bit prostaglandin e two is made from cyclooxygenase. That's the enzyme that aspirin inhibits. And if you step back a step further, that comes from arachidonic acid, which is a fatty acid derived from essential fatty acids. And that, you know, classically was thought to relay information about inflammation. arachidonic acid is one of the fatty acids, it's, you know, in the neuronal membranes, and the micro glial membranes and all of the different type of membranes. And, you know, that has a fluidity in a structural function, but it also gets released in response to signals and relays further signals. So there, they have a very important role structurally, that's been, you know, probably the focus of 4050 years of research. But more recently, we're getting into these nuances of their derivative, sometimes called bioactive lipids, and their role in signal transduction. Yeah,
Nick Jikomes 7:52
definitely want to get into a bunch of that stuff at some point, stepping back a little bit. So when we when we think about fatty acids, generally, people maybe are most familiar with, you know, seeing some of these things on nutrition labels and things like that. There's different types based on their chemical structure, you've got saturated, monounsaturated and polyunsaturated fatty acids. Can you give people just a general sense for what the major differences between those types of fatty acids are?
Richard Bazinet 8:17
Yeah, so you now that there, we've got saturated fatty acids, which which the, if you can picture a structure in your head, right, now you've got a series of carbons connected to each other, and carboxylic acid at the end, when they're in a phospholipid, they're no longer an acid, because there's, there's an ester linkage there. And saturated, you know, at least when I visualize a fatty acid, I don't do this innately I just see the carbons, but there's hydrogens all there, right. And so saturated, will often be referred to as there's no double bonds. True, but not quite accurate. What it means is saturated saturated with hydrogen, so therefore, there are no double bonds. And if you had a double bond in, you've removed hydrogen, so it's now unsaturated, or mono unsaturated. And then if you remove multiple, you get these polyunsaturated ones, and the brains are a little unique in this respect, and that there's one of these polyunsaturated fatty acids, called docosahexaenoic acid. dokolo means 22. hexa means six. And so it's 22 carbons long and it's got six double bonds oncology DHA. And that one's you know, really unique in the sense that it's highly abundant in neuronal membranes. And we find it that the level of the signups quite enriched in some specific phospholipids, you know, it can reach 40 to 50% of the composition of that phospholipid. So there's spots in the brain where this molecule just just lives, so to speak, and that's unique composition. So we don't see that and in the Liver and the muscle, you know, there's DHEA in those tissues, but not quite at that level. And it begs the question, you know, why is that how to get there? And why is that?
Nick Jikomes 10:08
And so in terms of the saturation, you know, we're talking about how many double bonds exist between the carbons in sort of geometric terms, what is the level of saturation mean, in terms of the overall shape of the fatty acid, whether it's sort of straight or bent or highly curved? And what significance does that have. So
Richard Bazinet 10:28
two things so the in, you know, in a simple model system, it's easier to pack saturated fatty acids on top of each other, you can make them more tight, tight. So we talked about the membrane being more rigid or less fluid. And the implication of that is that proteins or receptors, or anything in the cell, will have different patterns of movement, maybe slower patterns of movement, in a more rigid membrane. But there's also something and then you add increasing unsaturation, the membrane becomes more fluid, and things can move around a little easier, so to speak, in a very simple model system. But it's also very important for signaling, because a lot of these molecules like prostaglandin E to essentially require oxygenation or hydroxyl groups to be added to them. And those are typically added at the sites of unsaturation. So you can't make a prostaglandin e two from a saturated fat like Paul metate, Monetate 16 carbons, but even if it was 22 carbons, recall, or 20 carbons, we call it a shidduch acid. Similar to arachidonic keep, but you probably heard that even with my little French Canadian accent, typically that the difference, you can't you can't add hydroxyl groups to ever shidduch acid, but you can add add them to arachidonic acid, because it's got the double bonds there. And that becomes very important in the in the signal transduction afterwards. So membrane fluidity, and signal transduction are reflected in this saturation, or unsaturation. And the various indices around those
Nick Jikomes 12:08
I see so so the amount, so if we, if we mentioned a cell, we have the cell membrane, there are proteins in the cell membrane, like, like receptors and different things, and they don't stay in one spot, they're kind of moving around in this membrane and the membrane, I don't know, if we think of an analogy or something I can, you know, I could imagine wading through a pool of water maybe, or a pool of molasses. And that would maybe, you know, the blast is gonna be harder to wade through, I'm gonna move around a little bit more slowly. That would be that would be akin to saying the membrane has, you know, a higher lower saturated fatty acid content, and it's more or less fluid.
Richard Bazinet 12:41
Yeah, so I like that, and I'm gonna steal that from you. Because it's better than how I teach it is, it's perfect. The one thing I'll say, though, is that, you know, it's a little more complicated than that, because if you, it depends on the fatty acid that's beside it a little bit. And then things can get really complicated because the membrane is made up of phospholipids. And there's specific types of these phospholipids, predominantly phosphatidylcholine, there's an endo and Ethan Olamide. And there's subtypes of those. And then there's inositol, and serine. And for whatever reason, they have their own biases, or affinity. So, so you, you, you, you kind of can't put two politics in a phosphor title searing in reality, right, it's usually got one of these DJs in one position, and something else in another position. So in and you know, I can't really explain all the biophysics of this, but sometimes you'd say, if I put a palmitate, I'm trying to do this in my head with something with with one double bind, would be might be much more rigid than something with to double, you know, it doesn't add up one to one to one for every he can't count the number of double bonds and say this is the fluidity of the membrane, because it depends on some interactions, I guess, is what I'm trying to say.
Nick Jikomes 14:07
I see. But you know, the sort of profile of fatty acids in the phospholipid to the membrane is gonna determine how fluid that membrane is how easily proteins and stuff can move through it. And presumably, this stuff, change the fatty acid composition of membranes in the brain and elsewhere in the body. Presumably, that changes depending on the fatty acid profile of our diet, or is that not true? Yeah,
Richard Bazinet 14:29
yeah. And that's why I'm a nutritional neuroscientists, right. And so we should take a step back and go there's another way to classify these fatty acids. We've got them saturated, monounsaturated, or polyunsaturated. We can also call them essential or non essential from from a biological function. Okay, well separate. I think they're all essential biologically, but dietarily essential. And that brings us into the field of nutrition and so these agitated fats and these mono unsaturated fats we can make okay we can we can eat them in our diet and absorb them directly POM from almost any sort of fat it's going to have palmitate in it oleic acid, one of the mono and saturates sounds like olive oil is famous for all oil butts and all kinds of things, you can eat them. Or you can use glucose and make them do lipo Genesis, and we have some enzymes that can make oleic acid because that double bonds in this specific position and we have an enzyme to do it, then you get into the polyunsaturates. And there's a couple minor exceptions to this that I don't think we need to get into. But there's roughly two types, there's the the Omega sixes, and then there's the Omega threes. And we eat in our diet, essential precursors. So there's two of them, and the naming is awful here, you gotta pay attention. There's little lag, and Lenovo lenok, it's sometimes I tripped up like so little lag comes from the Omega six side and little Lennox, sometimes called alpha linolenic comes from the Omega three side. And they have a double bind and a specific spot one in what's called the Omega six position, one in the Omega three position. And if you're in organic chemistry, right, now, you're going to be confused. Because you start naming the fatty acids from the carboxylic acid end of the molecule. In nutrition, we start on the other end, the methyl end. So if you if you say the bonds in the three position, you gotta tell people if you're a nutritionist or a chemist,
Nick Jikomes 16:36
so if someone's not a chemist, or nutritional chemist, the names, you know, you sort of you sort of said this in multiple ways already, the names these long, complicated names, and the numbers like Omega six versus three, that's just referring to like, how many carbons or the position of the bonds, it's referring to something about the chemical structure.
Richard Bazinet 16:55
Yeah, so typically, that there's the name kind of usually referring to where it was discovered. Or we get into Greek to make it a little more simple kind of thing. But the even some of the Greek names, you know, some of the names like DECOs, our, or, you know, PENTA something, that we have a common name for them, usually based on where they're discovered. But But these, these positions, are telling us, you know, the coza hexanoic acid, their six double bonds, there's nothing in that name that tells us where the double bonds are. And you'd have to know that the first one is in Omega three, because that's an Omega three fat. But anyways, going back, we've got these 18 Carbon precursors that we in our food right, in a variety of food sources, and then we can take them in our diet. Right bring them to our liver, we can make them a bit longer. And we can make in one case that arachidonic acid from the Omega sixes and DHA and some other steps in there, and we can eventually get them into the brain and into the membranes. The other thing to make it just a little more complicated is you can either make DHA or you can eat it directly. And it's famous for being in fish, so So you have a choice. You can either eat it from fish, or you can get the precursors and get it but you have to eat it. Okay, there's no glucose coming in here. There's no amino acids, there's no lipo Genesis, you have to get the the 18 carbon precursors started. And that's why we call them nutritionally essential, which, you know, doesn't necessarily speak to how biologically essential they are.
Nick Jikomes 18:30
Yeah. So all these things are essential. Biologically, our body needs all of them saturated monounsaturated, and the different polyunsaturated fatty acids. But as you said, the saturated and the mono unsaturated fatty acids are not nutritionally essential, so nobody can make them. But these Omega six and three fatty acids, the polyunsaturated ones are nutritionally essential, we have to get them from the diet. Is that sick? Like, does that tell us anything about their significance? Or how they're used? Or what why is it that some of them or body can make and some of them we can?
Richard Bazinet 19:01
Yeah, so it's a good question. And, you know, that reminds me my PhD exam. And I was very interested in DHA in my PhD exam. And so one of the neat things about probably in humans to some extent, but definitely, in animal models, if you if you remove it from the diet, you can lower the levels in the brain. And then we can use that to start to study its biology and its physiology, right. And so we're very, that's really exciting because there's wiggle room with this fatty acid, you can have higher levels or lower levels. And does that matter? Okay, so so we're really excited about that. But the question came to me as as a young PhD student from the examiner palmitate it's almost impossible to change in the brain, okay. And we've done some work on this. We've published some of this recently. It's so rigid, you can remove it from the diet, sprain level stay the same. We make diets that aren't even you know, don't even model what humans really levels basically don't change. in the brain. And so the question the examiner said to me, well, doesn't that mean it's more important? Because there's tight biological regulation on that. So it's a good question. At the time I did my PhD a long time ago, we didn't quite have the tools to answer that. I still think we don't have the answer. But now we've got biological tools with knockouts. And, you know, they tried to knock out the the enzyme fatty acid synthase, a long time ago when I was a grad student, and it was lethal. But now with tissue specific knockouts, I think we're gonna get a get a better idea. And you know, the lipid nerds can sit down and say this molecule is actually more important for that than that one. But the lipids have been really tough to study, largely for this reason, you can't knock out a lipid. There's no gene encoding for commentate. There's, there's genes encoding for its synthesis, but there's a variety of them. And there's no gene encoding for DHA, right? So you can't knock it out. So we've, we've struggled with it compared to some of the other fields not having those tools available to us.
Nick Jikomes 21:04
Interesting. We're gonna spend most of our time I think, talking about brain, brain lipids, and and stuff to do with the brain health and disease. Before we get there, I want to talk about just some basic fatty acid metabolism, and probably just talking about what what the liver is doing here. So you know, I think you mentioned briefly before that, you know, the liver can do so it can metabolize fatty acids, it can make them longer, it can change them in different ways. I believe it can sort of make them from scratch, or process and change some of the ones that we can't make from scratch. But can you give us just sort of a basic Craske Crash Course and fatty acid metabolism? You know, what are these terms desaturate D saturation, elongation and oxidation? And what are those things mean?
Richard Bazinet 21:46
Yeah, maybe maybe we'll start from the mouth, right. Okay. Most most of the fats, we are in the form of triglyceride, I say triglyceride, you know, chemists would say try Aysel glyceride. Sometimes we call them tags, that's usually three fatty acids bound to a glycerol molecule. You eat others, you need some phospholipids use some of the things but you know, triglycerides, 98 99% of your diet. There's some enzymes called lipases that start actually at the Tookie lingual lipase and kind of make your way down. And they essentially break the fatty acids off of usually there's there's three positions, they break it off in the one and three position, typically leaving the two position intact, which which might be important for some things in development, there's that one molecule DHA in human breast milk, is in the two positions, suggesting it's protected, right. And it's important for neurodevelopment, it's just kind of a neat thing, we might go there. And then you take these fatty acids, and you bring them into the intestine. And you basically repackage them off. So you've broken them all down on one side, and you bring them all back in and you repackage them all into a pile of Viagra and you send them out, they drop into the lymphatics, and they go to a variety of places, including the liver, a notable exception, and you have to put them in these chylomicrons, because they're not soluble in your blood. And one of the things these kinds of microns are which are essentially lipoproteins, there's the outcome solubilizing in the blood, so we can transplant them around, transport them around, so we're not transplant them. But there are exceptions. You know, I my bias is I started thinking of fatty acids at about 14 carbons in longer. It's totally not true, they're shorter ones, and there's a lot shorter ones. And as they get shorter, they become more water soluble, even though we'll call them a fatty acid or lipid sometimes, and those ones have different absorption mechanisms through instead of through the lymphatics through the portal and they don't require Kyla micron. So keep that in mind. And then a fatty acid kind of comes into a cell, almost any cell with with some with some differences between tissues in the cell can say, hey, I'm going to take you and store you into triglyceride, something we don't really do in the brain. But you do in the liver, you do it in your muscle and others or I'm going to throw you into the membrane, or I'm hungry, I need some energy and I'm going to oxidize you beta oxidized you and that's I'm going to take you through, you know, a series of steps to break it down to acetate, and we'll put you through the TCA cycle, we're going to eventually make ATP out of this. And it's quite a rich process. If you've got double bonds, and you I can still do that, and there's some minor exceptions to the pathways. But just one thing for your listeners to be aware of, we can also auto oxidize you. And that's when oxygen reacts and makes oxidative products which are which you know, sometimes are considered bad things but they might also be signals for other cells that something's going on here. So don't just like to call them back. And so they get into the liver, and then eventually they get into the blood and to the adipose tissue in a variety ways and then You know, circle paths to the brain. And you know, I think the in the human, the blood brain flow is about two seconds, something like that it's just under a second and a rodent. And they have to cross the blood brain barrier and eventually get into the brain, assuming that's where they're going. And there's a lot of debate in that how that works in our field. Okay, I'm part of the debate, but I'll try and give you two sides of it. The fatty acids in the blood can be in lipoproteins, there's a variety of them, LDL being a famous one people might know about, but there's others. It could be as a free fatty acid, or as what's called a laser phospholipid, which is a phospholipid with a fatty acid missing on it. And so my colleagues a long time ago, could make artificial membranes with no proteins in it. And they could see free fatty acids crosses artificial membranes, so we realized that fatty acids might not need a transporter to cross okay, we came into the field and we started knocking out the candidate lipid protein receptors didn't seem to do much. So they didn't seem to be quantitatively a major role. These laser phosphor lipids can also cross and so now we've been debating whether the crossing just like free, or things, helping them. And this has been a massive area of confusion for our field because we named a whole bunch of proteins, fatty acid transport proteins, pretty clear by the name what they do. You know, you have a membrane of fatty acid on one side, you increase the amount of fatty acid transport proteins satps fatty acids go through it more quickly. Looks like a transporter smells like a transporter. Is it a transporter? No. They're a Sukhoi sensitizes, which are what are molecules that take a fatty acid and when it's in the membrane or other places, and you put a big coenzyme in on it. And coenzyme A is massive, and it's water soluble. And that does two things, it sucks it out of the membrane doesn't let it float back across and makes it kind of water soluble. But the problem is, if you look at this, because it's facilitating the uptake, it looks like a transporter. I like to compare it to glucose and hexokinase, or Glucokinase. glucose goes through a glute glute for a transporter gets six phosphorylated. And essentially disappear. So more can come back in. But if you looked at hexokinase activity or Glucokinase activity, you'd say, oh, that's facilitating the uptake. It's a transporter, until you get really close and you realize it's metabolizing, the glucose, allowing more to come in. And a lot of our proteins that are called fatty acid transport proteins are really involved in the metabolism of fatty acids and papers. And you could Google this right now. And you'd say you're wrong 500 times everybody's calling them transporters. But this is this is an area of debate. And there are some others as well called CD 36. And there's one called the MF s d two way that probably works on the lysophospholipid to help bring them into the brain. And eventually there's a series of enzymes that help them kind of get where they're going. And ours can't remember what the question was now. So
Nick Jikomes 28:16
So Well, it sounds to me like basically, when one important part of what you just said, if I'm hearing you correctly, is that the type of fatty acid, we're talking about terms of its geometry, the number of double bonds, whether it's saturated, unsaturated, as well as its overall length, if it's short, medium, or long, those things are going to dictate how it gets absorbed and transported throughout the body. Yes, yes. And so one of the key steps in fatty acid metabolism and one that you know, certain corners of the internet in the world talk about a lot is oxidation, as you mentioned. So fatty acids can become oxidized, how many double bonds they have, is going to tell us how many places can become oxidized. And you said something that was kind of interesting. You said oxidation can have a negative effect that can produce, you know, my understanding is they can produce things that are toxic oxidative byproducts. But you said they can also produce things that carry information or active signaling molecules. Can you say a little bit more about that and the role of oxidation?
Richard Bazinet 29:13
Yeah, so two things I say about oxidation. One is that it a little bit better model on the periphery is that we think some cells can recognize immune cells, these oxidative products, and then you know, I don't want to overstate it but like chemotaxis, and they go there, and then they do things so they so they gave up a signal. That's not always bad. Clearly, you know, they can destroy memories and not help. One of the mysteries that I'm going to throw out right now is if I were designing a brain, or a body, I would keep these polyunsaturated fatty acids away from the sites with the most oxygen uptake right oxygens what's going to oxidize them. I put them in the opposite places. What do we see the exact opposite, right? There's a positive correlation between oxygen consumption of a tissue or or brain region and the polyunsaturated fatty acids, this DHA with six double bonds that would be most susceptible to auto oxidation, they're in the same place. You can ask me why I'm going to tell you I don't know, right? Nobody knows this. And I'll bring it back a little further, it's really wild because it jumps across animal kingdoms. And that two of the richest non mammalian sources of DHA are the Hemi hummingbird breast muscle, which has massive oxygen consumption. And the little muscle that I can't name on the tip of a rattlesnake tail that beats really quickly. That apparently also has a lot of oxygen consumption, there are rich sources of polyunsaturated fatty acids that are going to be highly susceptible to oxidation. So PhD thesis waiting to happen. I don't know why that is. I've had conversations with people. We have hypotheses, but I nothing other than I'm compelled to tell you right now, like this is the one that that we're betting on.
Nick Jikomes 31:09
Another another way that oxidation gets discussed this. So these things can become oxidized in the body as part of the chain of metabolic events that's happening, they can also become oxidized outside of the body before we consume them. So you know, one place people talk about these are, you know, french fries or something at fast food, it's basically you know, you're boiling these long chain fatty acids, they become oxidized before even put in your body. Does that have an impact in terms of how they're used by the body or their toxicity or anything like that? Yeah.
Richard Bazinet 31:38
So So you know, if you google this in the internet, you'll get the answer. And it's the this is the devil's oil. And this is the root of all evil, why everybody's dying. I don't think that's the case. But we're starting to do research. Now. There's somebody named Amir Taha, at the University of California Davis and others are really interested in this question, because they're studying, you know, the first question, these oxidized lipids, for a variety of reasons, we would have a hard time getting absorbed, okay, turns out are absorbed just in small quantities. We don't know the details of how they're absorbed. Like, I can't draw you that you can open a physiology textbook and find that you really can't even find a paper and find that, we assume it's similar, but we might not quite be right. But they're absorbed, they seem to be absorbed in relatively small quantities. So the body clearly has some mechanisms to try and keep them out or get rid of them, which might relate to the tox illogical properties. But yeah, you're absolutely right there, they can be found in foods, especially foods that had been exposed to oxygen or, you know, left that would their levels accumulate. Sometimes fats, and there's some little details here, I don't want to put my neck out too far, but smell bad. And it's not exactly clear to me, at the most minut level of it's just oxidized fats, or we need a mines in that mixture to make things smell bad fish being a great example. And that these are also cues for us not to eat these foods, that something's wrong with them. And then the debate we have there in the field, are they? Are they the toxin? Are they the canary in the coal mine? For something else? Or are they both right? And so we're working on that a lot of people are working on that. But there's clearly, you know, evolutionary programs signals where we tend not to like oxidized lipids from a nutritional perspective, with oxidized lipids in them. So
Nick Jikomes 33:45
based on how we prepare foods, you know, with a lot of the vegetables and stuff, they get heated, there's a lot of oxidized lipids out there that we put into our bodies. It sounds like you're saying most of those oxidized fatty acids don't get absorbed, and that it's probably a good thing that we only absorb a tiny little bit. One place my mind goes there is I assume it's under sort of baseline conditions. A healthy gut doesn't absorb a lot of those. What if there is some kind of a gut dysbiosis? And there's like a leaky gut, does that mean that some of those things could get in more than you'd want them to get in? Yeah, so
Richard Bazinet 34:18
great question. We don't know yet. Nobody's done that yet. Yep. At least to the best of my knowledge. I know a couple of people working on this. And and, you know, when you start these studies, you start simple, right? You don't, you know, go with a more complex pathophysiology. Very reasonable hypothesis. My guess is probably, but I don't know that. Interestingly, the, the, the infant, which would be another cause for concern with if I can call the easier term leaky gut, you know, usually is drinking human milk. And that would not be a major problem in human milk, right? Under normal circumstances, so it's It's a great question. I don't know the answer to that one. I think so. Sure.
Nick Jikomes 35:04
And before we dive into the brain more, one more question with the liver I want to explore is, does the fatty acid composition of our diet have an influence on things like fatty liver disease? And how much fat actually accumulates in the liver based on, you know, the based on which fatty acids we're actually giving to the liver? Yeah,
Richard Bazinet 35:26
yeah. So it does. And it's not always clear if the dietary fat is regulating that. So I think I think excess calories, in general can contribute to a fatty liver, and then, you know, disease states as well. But when we look at fatty livers, they tend to be more saturated, and maybe mono unsaturated. So if you if you took a fatty liver sample, and you ran it on an instrument, maybe I'll just recovered, you know, whatever Mass Spectrometer, or what we call the GC, you'd see that it's it's bias, and it's palmitate. And it's only eight. But it's not 100%, clear to me if those were the dietary fats in the liver that accumulated there, because those are the two you can also make from lipogenesis. And maybe somebody knows that answer, and I'm just, you know, unaware of those studies, but it seems to me, it could be either those two, or a combination of those two, nobody's reporting fatty livers up with omega three fats, right? Like we don't, we don't see that in the literature. If anything, there's a small literature that some of the dietary omega three fats Could, could maybe you know, mitigate or attenuate the effects of the fatty liver or shrink it just a little bit, not a not a sledgehammer, but a little little effect there. And
Nick Jikomes 36:47
then, you know, when we start to think about the brain, and we think about the fatty acids in the brain, how are they getting there? Are some of them made inside of the brain? Are they primarily made elsewhere, then they go through the bloodstream across the blood brain barrier into the brain out of the fatty acids in the brain? Get there?
Richard Bazinet 37:04
Yeah, so this is, you know, I started off simple. And then I'm going to church and you know, confuse everybody because I'm a bit confused. And we just published a study on this, and the results were wild. So. So these these omega threes like DHA, and to the brain, through one of those kinds of mechanisms we spoke about a little bit, then it's really wild, because there's, there's another fish oil, if I can call it omega three called EPA Eicosapentaenoic acid, we haven't talked about it. It's barely detectable in the brain. So if I showed you like a readout of one of these Chromatographs, there'd be a little something that that you might call noise, and I might call a peak and we probably agree to disagree on so it's so low in the brain, you can barely detect it compared to the things are really clear. What we found, though, that was wild is it gets into the brain, at about the same rate as that one DHA roughly the same, but you almost can't find it in the brain. So it's metabolized, maybe I should use the word cat categorized very rapidly. How fast I'm not exactly sure, but probably within a minute, most of it is either destroyed or turned into something else. So so they get into the brain. But my point here is that the brain itself can help regulate its own composition, okay? It's, it's things are getting in there. And you'd predict to see them in there, but you don't find them in there. So the brain is doing something with them, okay. And then we've got this, this molecule, let me back up a step. So if you look at the brain, usually the most abundant peak, and I use the word peak interchangeably, unfortunately, with a mount is only eight. And then you've got one got late because there's 18, carbonyl, one double bond, and you've got one called stearic. Family and steers, it's 18 carbons, no double bonds. Paul imitates rate in the running, they're sometimes second, sometimes third. And then you get the DHA probably about fourth and this one arachidonic fifth and then things with the exception really dropped off a lot, right? So so they're there, but they're an order of magnitude lower. You know, what we've just discussed probably covers more than 80% of what's in what's in the ranges this few. And so some of them get into the brain, some get. We see them there. Some of them get into the brain, and we can't find them there. And then there's this molecule called palmitate, that I told is very hard to change in the brain, okay. And it turns out that the brain has these enzymes that can do lipo Genesis, so the brain can make palmitate okay. There's a lot of palmitate in the blood. And it turns out that it also comes in from the blood and enters the brain so the brain doesn't say I'm making use Stop coming in. It lets you come in as well. What we did that was a little wild and a little surprising is we gave rodents diets essentially palmitate, free, not quite, or very high palmitate and in the middle. And what we found was that even if we get these animals on these diets for a long period of time, we couldn't change brain palmitate levels, I hinted that never changes, right. So it's quite stable. And it what we found is that the the, using isotopes, if I can call it that, that there was more, when we remove palmitate from the diet, the parliament in the brain was more synthesized right from from the carbohydrates, the glucose makes sense. What doesn't make sense is we did a lot of work on this. And we found that it was actually the liver that was synthesizing and sending it to the brain. And so the brain MRI has the machinery to make it, okay. It can take it up from the blood. But when there's none in the diet, the liver up regulates its ability to synthesize it, not the brain, the brain is going to, I don't want to overstate it, but it really looks like a static level of palmitate synthesis, or lipogenesis going on. And if you give it more, it doesn't downregulate if you give it less, it doesn't operate late, it relies on the liver to do that. And I'm not sure why that is. But cancer cells do something very similar. They have a very critical level of lipid Genesis. And if you block that with a drug that inhibits it, you kill them. And then the textbook experiment is well, I'm going to stop it from making palmitate with this drug. So if I had palmitate, back, I'll rescue it right. You can't rescue it, cell still dies. And then the wild thing is there's there's tons of you know, I don't know why it's making the palmitate because there's tons in the blood and the vasculature could just take and what it makes its creats back out into the blood. So it's kind of useless, like, we're missing something. Yeah. And the brain looks a little bit like breast cancer and are the studies were MCF seven cells, which are breast cancer cells that I'm thinking of. But the brain looks a little similar to that, like it has to make palmitate for some reason, and it doesn't change that right. So we're missing a little something going on there. And it doesn't seem to change its regulation.
Nick Jikomes 42:24
Interesting. So the brain has this sort of constant level of palmitate unsaturated fatty acid synthesis, it never really changes. But the amount of palmitate made in the liver will change based on your diet. And that's going to influence how much it gets into the brain from the outside. But but somehow through all of those changes, the brain is sort of like holding the poverty levels constant.
Richard Bazinet 42:44
Exactly. Exactly. And so I don't mind hypothesizing too much. But I think sometimes we you know, we can measure palmitate. And that becomes the that's, that's the point of Label Genesis. That's why we call it lipo Genesis lipogenesis. But there's a lot of little reactions in there that balance things like NAD pH and NAD ratios. And without data, speculating that that might be also very important. And maybe we should recall that, you know, NAD regulation agenesis.
Nick Jikomes 43:20
So maybe it's sort of a byproduct of something else is going on. Yeah, it
Richard Bazinet 43:26
looks like it looks like a good hypothesis and the cancer cell that secretes it back out in the brain, I have to add on another layer to say and the brains evolved the mechanism to store it in the membranes, right? Why waste it will put it in the membrane? I gotta add that little pardon? Yeah.
Nick Jikomes 43:43
And so I would imagine that in the brain, from a structural perspective, obviously, you've got your phospholipid bilayer of the neurons themselves, it's gonna be made and other cells is gonna be made out of Bette acids. Presumably, it's also a component of the myelin. And I would guess that maybe there's some differences there in terms of which fats get used for cell membrane versus mileagelands.
Richard Bazinet 44:06
Yeah, a big difference actually great for bringing this up. The myelin is really enriched in all metate and another one got all the aid so it's so it's relative to the you know, if I can say the rest of the brain, it's quite rigid or would not be a very fluid membrane. very biased in that respect,
Nick Jikomes 44:31
because it's got mostly saturated monounsaturated and very little polyunsaturated. Yeah,
Richard Bazinet 44:35
yeah, not none, but very little. So So, roughly speaking, you know, if you look across the whole brain, a molecule like DHA would be 10 to 15%. It would drop down to about 1% in the myelin. So someone people say the brain composition and this is this it does vary a lot by cell type and architecture of the cell. Now, with the palmitate, and the all the eight jumping up even higher in the myelin the myelination?
Nick Jikomes 45:08
Yeah, and as you mentioned before, these fatty acids, they're not just used for structural reasons. They're not just, you know, building physical structures, they're not going to use as an energy substrate to, you know, used, you know, used to make ATP for the cell, they can actually serve as signaling molecules themselves. And I'm wondering if you could start to tell us a little bit about that. So in the brain, how is some of the signaling happening? How is it affecting synaptic transmission? What are some of the major things we know about how some of these fatty acids are actually used for informational purposes? So
Richard Bazinet 45:41
two things and one I think you've covered nicely earlier is by changing the membrane fluidity, they change, you know, how the receptors whether their spatial orientation or their movement, so they can have those effects. But the other thing we've known for some time now, and I'll use dopamine as an example, dopamine is G protein coupled to D two receptors, G protein coupled to an enzyme called phospho lipase a two okay. phospho lipase, it's like phospholipid lipase, like the digestion lipase, we were talking about earlier. A to is when you look at a phospholipid, there's two positions, there's the one position the two position, and then the three position kind of doesn't count, because that would be a choline or an eternal life and the one in two position that'd be a fatty acid. And usually, or at least a high bias, the two position is a polyunsaturated fatty acid like this DHA or that other one arachidonic acid. And so dopamine binds to the D two receptor. You know, you've had a lot of neuroscientists on here, everybody's interested in what happens after that. One of the things that happens after that is phospho lipase, a two gets activated, and it releases the arachidonic acid, typically, depending on on on a few little things. And that arachidonic acid comes out, some of it gets converted to what we call oxy Lipton's now, which would include this prostaglandin e two, but this is a field that's blown up, and that there are many, many of these molecules. And then it does something. And in some cases, it might be you know, it's relaying the signals of dopamine. But we haven't worked that out systematically yet. So you know, the work that was done on olfaction, how much have they systematically worked that out? We need to do that with these molecules, because there are hundreds of them. And they're being released, and they're doing something and I'm not going to do a very good job right today and telling you what they do, right? I'm going to write that as a grant. But one of the wild things is that arachidonic acid that comes out, about 97% of it just goes right back into the membrane. We call that the land cycle name that there guy, the lands, and we don't know why that is either. So you see, you take a whole bunch out, you lose about 3%. And you bring 97% rate back into the membrane. And we do that with other fatty acids as well. What
Nick Jikomes 48:09
about things like? So I know that certain fatty acids that are ultimately of dietary origin, they connect to endocannabinoid production? So can you just remind listeners, what are endocannabinoids? And what's the connection here between dietary fatty acids and endocannabinoids? And what they're doing to regulate synaptic function? Yeah,
Richard Bazinet 48:32
and what will go back, maybe a little bit to some of these axelent. And so, so we use we've got fatty acids, and then we get fatty acid derivatives. And we use these terms like bioactive fatty acids, and there's a lot of different types. And we haven't touched that. I don't think I've ever had to define endocannabinoids on the spot, but they're essentially, you know, people found the, the CB receptors, the and the cannabinoid receptors, CB one, CB two, which THC binds to, and then it was obvious, hey, they're not made for marijuana. There's something endogenous in there. And you know, the first big hit was a molecule called anandamide. And anandamide is actually derived from arachidonic acids. So it's an ethanol amide attached to arachidonic acid and that's an end of mine, and it binds to the CB receptors. Huge discovery really elegant stuff. And that that really helped us understand its role in appetite regulation and a lot of the things that people would be familiar with. Then it turns around, it gets the story gets a little more complicated because arachidonic acid is an endocannabinoid because it binds to CB receptors. It's to chemists, it's an ethanol amide it's just what you would call it okay. And then we find that I think all of these fatty acids, or everyone we've looked at, can make these Ethan Olamide derivatives. So if you're chemists, you're like, I got this no problem. They all make them, there's these these enzymes, there's a series of enzymes that do this, and you make them, where the biologists maybe gets a little annoyed with this is they're not all endocannabinoids, you know, no meaning endogenous cannabinoid. And that they don't have affinity for the CB receptors. Maybe they bind to paper, maybe they they bind to something else. Some of them we don't even know yet what they do. But they're involved in in a lot of the synaptic transmission as well. They're produced locally on demand, especially in neurons. And they really, you know, seem to be very important for synaptic plasticity and models of memory and learning. And interestingly, some of them you can change a little bit with your diet. And, you know, one thing I think we have to be careful with nutrition with nutrition is if you look at something and it's one is higher than the other, I don't know if the one's higher, or the ones lower, okay? It's just always a problem. We have a nutrition, if I say this one's higher, your listeners would say, Well, how does he know the ones not lower? fairpoint. Okay, we just use the language to get us by so, but we can change the levels of some of these with diet, if you One of them's derived from DHA, and we would call it d H, E, AE, which is terrible if you study hormones, because it's not that one, but it's because the hexanol Ethan Olamide, not not, not the hormone. And, and that is really important for us synaptic plasticity. And at least in animal models, we can change this level and change those functions. So there's a whole cascade of those molecules, my lab doesn't discover molecules, but the only one we've ever discovered is one of these longer chains of DHA can even get bigger. From DHA, it's called T H, E a, it's got a really long name. And we found that during ischemia that when gets released, and if you add it on to neurons, it can affect synaptic plasticity as well. Okay,
Nick Jikomes 52:17
so some of these dietary fatty acids like like, in particular, linoleic acid, Omega six, polyunsaturated fatty acid, you get things like that in the diet, we eat it, those things can be turned into arachidonic acid or any number of other fatty acid derivatives, and some of those acts directly as endocannabinoids. So some of those fatty acids are literally behaving almost like neurotransmitters.
Richard Bazinet 52:41
Yes, I want to make I want to make an important distinction here, okay. We've got to get a cell membrane in the brain. It's it's about 10,000 nanomaterials of a molecule like arachidonic acid per gram of tissue. Okay? I'm using 10,000 to keep the math easier. When that phospho laybys releases it into the free form. It's about one animal, per gram. Okay, so there's a 10,000 fold drop, roughly speaking there. And then when we get into these other bioactive mediators, including prostaglandin, e two, or anandamide, which is coming through a slightly different pathway, we drop at least another 10 fold from the one if not 100 fold. Okay, so why am I telling you this? Well, there's we've got a bit of a mystery, in that we think nutritionally speaking, and we have evidence, we can regulate the levels of those mediators, okay. So if I give you a diet very, very low in omega sixes, we will lower some of those molecules in your brain. That makes no sense to me. Because we still have 9999 animals in the membrane. And I've, you know, 10,000, I've taken away 10, I still got a ton left. And yet the brain saying, oh, something's wrong, I can't make these. Okay. And that's, that's a mystery to me why that is? It's like saying, you know, you have a billion dollars in your bank account, I take away 10 million from you, and you're like, I can't buy coffee at Starbucks anymore. It doesn't make sense, right? There's, so we're missing something. And this is a bit of a mystery. Why are there so many of these in the membrane? Why can we change the membrane, but the changes in the membrane are not going from 10,000 to 10. They're going from 10,000 to 9990. And yet, we're still changing the levels of these mediators, and we can show that there are consequences to that.
Nick Jikomes 54:52
So when we think about dietary fat intake and the effects on the brain, you know, we've already started to put some pieces together A lot of these lipids act as signaling molecules they're made from our dietary fatty acids. So now we can get thinking about like how our diet can influence things like endocannabinoid levels, or levels of other fatty acids that are, you know, behaving almost like neurotransmitters in the brain. So if we think about the typical American, the typical American diet is going to be getting way high levels of omega sixes, which are gonna give you you know, arachidonic acid and the endocannabinoids. And, you know, if you're getting sufficient omega threes, maybe you are, but a lot of people might even be deficient in omega threes, can you start to talk about what the typical American diet means in terms of, you know, effects on the brain via endocannabinoids some of these other things.
Richard Bazinet 55:39
So, so, two things we're going to do here, we're going to, I'm going to just give you some numbers, so you can see the perspective and the first theme is going to be slowly and buffered. Okay? So I'm going to use DHA as an example of where I could use arachidonic acid as an example to, but DHA somewhere around the third trimester, it starts to accumulate in the infant brain. You know, postnatally, cumulates, a little bit people are gonna disagree with me on this, but somewhere around two years of age, it plateaus. Okay, what level does it plateau as, and I'm going to use slight rounding just to keep the math a little more simple. Okay, I'm gonna say it plateaus at five grams. So you and your brain you have five grams of DHA. I think you probably have about 3.9. But we're gonna say five, just to keep the math easier. So you've got that in your brain? And everyone's like, oh, five grams. That's a fair amount. Yes, it is. Then what we've been able to do using PET imaging techniques. So with with these carbon elevens, is we've been able to image how much DHA is going into your brain, okay, every day. And the answer is about five milligrams of DHA. And so I picked those two numbers so people can kind of do the the napkin calculation at home. And it roughly means the DHA that's entering your brain is going to last for about 1000 days, about a half life of about 500 days. Okay? So that's one of my first themes, slow. The, the consumption of fatty acids in the brain is at least at least tenfold slower than other tissues. Okay, so So we're, we're talking slow. The other thing is buffer. And we've got we haven't talked about the adipose tissue, right? Because of the EU, let's say you eat a bunch of DHA, I don't think you just send more to your brain, you send some of it to your adipose tissue. And this is actually really neat and important from from a nutrition is the, you know, the term infant has started to accumulate DHA right in the last trimester, and they're born. If you look at a baby, they're pudgy, right? They're the cute pudgy little things, right? There's a gram of DHA stored in that body fat. So so if they don't eat DHA tomorrow, or the next day that DHA gets released, and you know, it's serving as a buffer, I think, for the brain. where this gets really interesting is the preterm infant. Okay, so they've missed out some of the in utero brain DHA accretion into the brain because they came out a little bit too early. The other thing is, if you look at a preterm infant, they don't have that. choppiness, right, they're a lot leaner. So they don't have that gram of DHA. And so we've got a lot of clinical studies with infant formulas that came through kind of the 80s and 90s that didn't have DHA in them and infant formulas that had DHA in them. And they tend to work well in that situation on cognitive scores. Okay, you can show you can have better cognitive scores in a randomized trial like that. So humans
Nick Jikomes 58:54
had omega threes in their formula had better cognitive scores and those who had formula that lacked omega threes,
Richard Bazinet 59:01
generally speaking, yes. Okay. And then there's controversy because you measure those cognitive scores at a fairly early age, do they exist later in life? Sometimes? yes, sometimes no, are the effects big enough? Not clear. My colleagues in Australia just did a study in premature infants, where they gave them DHEA they were actually maybe very premature infants, although I'm not the best with those definitions. They gave them DHA above standard of care and they were able to show probably what we call a meaningful improvement in cognitive scores at five years of life. It was published in the New England Journal of Medicine, which is where you know from a nutritional if I can call it supplements study, that's pretty cool place to publish it it tells you something about what people think the importance of that is. Okay, so that's the infant which is trying to grow a brain and presumably also has what is that turnover which I was alluding to this this five As milligrams per day uptake, and then we get to you and I. And we've got a couple of things going on here, we've got the slow uptake, five milligrams per day, our brains aren't growing anymore, right, we've hit that plateau. So we've lost that. We've got this body fat buffer that can have grams of DHA in it for some, but not for all people. And so we've we've got a situation where, and I don't want any of the people studying appetite regulation to to get upset here. But if you live in my world, I'm not too worried about what I eat tomorrow, right? Because I think I've got a slow uptake rate in the brain. And I think I've got a buffer to get it there. But to your point chronically over a lifespan, that's when we can change things. And in fact, if you take a rodent, we can even do this in a rodent. If you give me an adult Roden and I try and lower its brain DHA levels, it's hard to do, sometimes we don't do it. So the way we do it is we rig the experiment, we start with a low Omega three diet from birth, when it's gonna grow the brain, and we keep it on that for a long period of time. And that's how we change the DHEA levels. And very importantly, we in that case, we lower them right, you know, we don't increase them. And so yes, to your point, can we do this in humans? Right? And and we don't, we don't have great brain data, right? So we don't have a lot of you can't ask people after they died, what they ate,
Nick Jikomes 1:01:27
yeah. What about what about the rodent work? So when you do a study where you are, you know, from birth, basically giving them DHA deficiency, so they're not they don't have enough omega threes. As they go through life? Do we know the effects that has on the brain and the ability for those rodents to do learning and memory tasks?
Richard Bazinet 1:01:47
Hundreds of studies, maybe not hundreds, but 100. And the totality of the evidence suggests a few things, impaired memory, impaired learning, impaired behavioral scores, more susceptible to neuro inflammation, more susceptible to a variety of things, it's a bad position for those animals, a lot of us are working on the molecular details, which involved a lot of the signaling molecules that we're talking about. And even more complicated sometimes crosstalk between the the Omega threes and the Omega sixes, but, but I think the totality of the evidence, you know, maybe there's 50 papers that have looked at brain inflammation. Generally speaking, most of those studies, they they seem more susceptible to it, they seem more susceptible to neuronal death, if you give them a weather in ischemia model or a neuro inflammation model. And, you know, I don't do a lot of behavior work myself. But my colleagues, you do behavior show behavior scores in kind of baseline, especially in response to challenges and those animals, pretty, pretty clear literature there.
Nick Jikomes 1:02:50
Okay. So in rodents, you guys can give them chronic Omega three deficiency. And basically, bad stuff happens, there's more brain inflammation, there's learning and memory deficits. And, you know, there's no benefit that comes from being Omega three deficient, related to that I want to ask you about. So you've got omega sixes, which we generally think of as being pro inflammatory, because they're used to make stuff that that is used for inflammation in the body. And the Omega threes are typically associated with, you know, anti inflammatory effects, because they're associated with molecules that that resolve inflammation, if you, but then I'm interested in their metabolism, because from my understanding, they, they are often processed by some of the same enzymes. So this gives rise to the notion that the Omega threes and sixes are sort of competing with each other. And so based on what you just told us about Omega three deficiency, which, you know, scientists can induce experimentally in rodents, I'm wondering if you could have, is it possible to have an effective Omega three deficiency, even the presence of some dietary omega threes? If that omega six, Omega three ratio is just highly skewed in favor of the mega sixes? And is that something that we could think about? So
Richard Bazinet 1:03:57
huge debate, and and it's a challenge for us to study? Because when when in nutrition in membranes, when you lower something, something else compensates. Right, so So a fair criticism of the interpretation of our studies that especially the ones that haven't died, delve into the mechanism is we lower Omega sixes in the brain, and we get threes in the brain and we raise Omega sixes. And we kind of ignore that. And we say, Oh, this is a DHA effect, right? And in some cases, I think we have other you know, you can get into cell culture models and you can so the DHA can recapitulate some of those effects you see, or lack of it, you can, but there clearly is a side of this cascade, as you mentioned to the to the Omega sixes in some of those mediators start to become more abundant. And again, I think I told you, this doesn't make a lot of sense to me, right, because we still have enough of the Omega threes in that membrane, but they've lowered they've dropped 20 30% But not 99%. Right. So they're still there. but we still see these shifts from the Omega three mediators to the Omega six mediators. And you get kind of a summary of them there that explain some of these results we're seeing. And some people, although in the brain, I don't think we, you know, the brains neat, from a homeostatic perspective, I can change an animal's blood levels of omega threes, oh, probably in a couple of days, day, liver a few more days, but the brain eroding, we're talking months, right at least. And that's why we do it premature so. So a lot of my colleagues, I think, slip up a little bit and look at a study and they see these massive effects of the balance and these kinds of things in the liver and the blood and some of the weight cells. But we don't quite see that in the brain, because it's got this added level of homeostasis, probably because the uptake rates are low, the consumption rates are low, and we've got a few buffers to get in there. So I think you're right, it's just a slower process than then people might think it is sometimes in
Nick Jikomes 1:06:11
terms of sort of, if omega six fatty acids tend to be pro inflammatory. What do we know about the consequences of chronically high dietary intake of omega six fatty acids? And in terms of what the brain is doing, you know, effects on learning and memory effects on inflammation and things like that?
Richard Bazinet 1:06:29
Yeah, so not as many studies okay. And I know there are people who think they know the answer to this this question. But but it actually gets gets pretty tricky, because it was, it was actually hard to make a diet, because that's how we do this, right? We don't use knockouts, at least not until recently. That was low in omega sixes, and not also low in omega threes. So if you go back into the old literature, and somebody saying, Oh, they were doing all this in the 50s 60s 70s, this, this kid, which I would love to be called, doesn't know what he's talking about, right? You read those papers with a little more detail, they were what we would call essential fatty acid deficiency. And so that's a new term. And it means they were deficient in Omega six and omega threes. And if the title of the paper says Omega sixes, it's probably with a couple exceptions in the literature misleading, right? So. So that created a hiccup in our field in that we thought we were studying Omega six metabolism, but we were also studying Omega three at the same time, okay. And people realize this, one of them was my PhD advisor, that there was some nuance there. And we studied this a little bit more detail. We haven't done nearly as much in the brain that, okay, there's, there's, I could probably count on my hand, the amount of animal studies that have been done to, to intentionally lower Omega sixes without lowering omega threes, and measure outcomes related to that, but I think is broadly consistent with your position. I'm saying lower, you're saying higher, we, I think I told you, it doesn't matter which way it's to, you know, it's the same coin, two sides. But if you get the higher omega sixes in the brain, you get increased of those mediators, you get some of these effects. And then consequently, you tend to get lower omega threes in the brain to and you get lower of those Omega three, you know, resolving signals, which, which is a really fascinating area as well. So, so,
Nick Jikomes 1:08:33
work, higher omega six does tend to translate to more inflammation.
Richard Bazinet 1:08:38
Yes, in the brain now. So there, there are exceptions, right? Not every mediator that comes from these Omega sixes is pro inflammatory. In fact, as I understand it, when when they're in the lab that you mentioned, when the Nobel Prize, one called lipoxin, one of the molecules got lipoxin, came out of this arachidonic acid cascade, and they noticed is actually anti inflammatory. And that confused them, I think, at the time because it opened pro inflammatory. And that postdoc, then went on to discover most if not all, of the anti inflammatory, pro resolving molecules that I think you alluded to, and, and I just find that a funny story because he was exposed to a molecule that didn't make sense in the model. And when then was very open to discovering the rest of those molecules, right? Um,
Nick Jikomes 1:09:28
you know, given given that we know that some of these fatty acids have a role in promoting or resolving inflammation, given that we know that some of them serve as precursors or acts themselves as neurotransmitters and then they play into like endocannabinoid signaling and things like that. You know, I would expect that these fatty acids and the composition in our diet, they're going to have effects on things like mood and cognition. What do we know about any sort of mood disorders or psychiatric disorders were either a fatty acid deficiency Your imbalances thought to be important for the cause, or a and or whether, you know, an imbalance is important, say for the progression or the severity of the disease. Okay,
Richard Bazinet 1:10:10
so great question. So, a couple of ways to look at this one of the animal models, works on the animal models, as you'd predict, right? If you take an animal and you remove the Omega threes, which, which is a lot more research done on it, these can be models of depression, aggression, behavioral learning, etc, etc. Okay, so the animal models work, you know, probably better now that the animal animal model depression is a little controversial. Let's just say that right? Yeah. So does that extrapolate to the to the humans? Well, well, let's look at the humans and see what we've got. We've got some of the post mortem studies that have looked at DHA levels in the brains of say, depressed patients. Literature is not clear, somebody can show it, somebody can't show it. They don't all have the same reasons. It's a really, it's a really tricky thing to do. But that's what that is. And then well, what do we do? You know, how do we test this? Well, we give them DHA in their diet to see if we can make their symptoms better. In general, the answer's no, it doesn't work. But there's two buts to this, it's kind of hard to do, because of what I was telling you about that slow uptake, right. So so if you knew that the uptake rate was five milligrams, and that there was five grams, and you thought the depressed patient had for, you could guess how long you should do that study for but if you do a three week study and say it didn't work, it didn't work. There are other nuances in these studies that make them very complicated to do, right. So I'm gonna go, I'm gonna go on a little bit of a tangent, if you don't mind, because I got involved in a clinical trial on epilepsy. Same idea. Let's give them fish off and see if it works. So if somebody comes in with epilepsy, first they go see their neurologist, and they try and treat them with the drug, right? Hopefully, that works. And they can enroll in your study, okay, they're out, because they've been treated. If that drug doesn't work, the neurologist will try them with another drug and then set some point another drug, and eventually, if they don't respond, then they'll come into your study. Okay, so now you've got a special population here, that's not responding to drugs. And ethically, the neurologist keeps treating, okay, while you're trying to do the study. And this, you know, as, as somebody who came into the clinical world as a little bit more of a need naive, basic scientists, and I'm in the Faculty of Medicine. The studies aren't exactly what I'd like them to be for a variety of reasons, right? We're trying to treat people with refractory epilepsy who are being medicated. And the physicians are changing their medications while we're doing the study. So it's, it's not what we thought and depression is not quite the same thing. But it's a little bit like that. But then what we've got is this wild finding in depression, that there's four reasons we can get into view one, but people, you know, one of the problems with fishers is they're not drugs, right? So so why would a big company want to do this study, and then they've been able to patent derivatives officials, especially one with this EPA. And if you do the studies, you kind of don't see anything. But if you go back and do a meta analysis, and do what's called a meta regression analysis, and do it by the composition of the oils, you see that some of the oils that contain EPA, show, show promise, you know, show amelioration of depressive symptoms. Very few studies have looked at prevention, because that's hard to do. Right? You need more people to do that maybe maybe one study has looked at prevention, and it didn't, didn't work. So. So there are little signals in there. But but there's two ways of looking at this. One is if you're a nutritional scientists, or if you're a psychiatrist, you'd say, well, the effects not big here. And if you have to do it, it takes a really long time. So I'm not going to treat my patient with this, because it's going to take 1000 days, and you know, I get to treat them fairpoint if you're a true nutritionist, you say haha, but we should prevent this. And then we haven't done all those studies, right? So one of the advantages of Nutrition has is you're not going to, you're not going to take an anti epilepsy drug or mood drug, just in case, right? You're going to take it when you're diagnosed, but nutrition is something you got to decide to do. And we can do it just in case and and unfortunately, we don't have those studies. So I can't tell you for sure. What I can tell you is correlational studies, they tend to work right so people eat more fish tend to have better outcomes in this and we can talk about Alzheimer's as well going forward with that so and then the biologist and me or the neuro chemistry me says well, sometimes I don't really care but because these molecules are pretty cool. And I think the molecules are doing things that are really important, and they're working in the animal models, and whether you can really regulate them nutritionally or not. And I want to I want to take a pharmacological approach with these and move that field forward. So there's a variety of ways to look at this bottom line, I don't think nutrition or lipid therapy is going to cure depression. There's some room for some signals, and maybe a way to help us understand that prevention is completely understudied. And we should probably do something about that, right?
Nick Jikomes 1:15:32
I see. So is there very much known about neurodegenerative, neurodegenerative diseases and whether or not adequate, you know, having adequate fatty acid in the diet or having deficiencies in omega threes or something else can make disease progression happen faster, even in animal models? Yeah, so
Richard Bazinet 1:15:49
animals again, works pretty well. And there was a study published in neuron Gs, and maybe about 20 years ago by Frederic claw and Greg Cole, were the first Greg Cole was working on some of the earlier animal models. And for the clone was a little interest in nutrition. And they put the two together, and it worked really nice. So these animals are higher DHA were protected. And a lot of people I assume, even myself, I've replicated those studies, the animal models works pretty well. But you know, as well, there's somebody sitting there saying, so do a lot of the drugs work in animal models that don't work in the humans, right? We're not supposed to document that sometimes. But that's a big one, right? And then so what do we have in the humans? Well, in the neurodegenerative diseases, there are a handful of studies, not all that can post mortem show lower levels of some of these lipids in the brain, great. But they're neurodegenerative diseases. And if you have neurons dying, you might expect a bias in the lipid composition. So we got a chicken and egg issue, right, to some extent. We've got clinical trials, pretty good ones in pretty large studies in Alzheimer's disease. Yeah, I'm gonna say doesn't work. If someone wants to disagree with me on that they can go ahead, then we get into the like more the MCI phenotype. And this and, and my take is a generally doesn't work. People do subgroup analysis, post hoc subgroup analysis, and they can show you some signals and maybe a subset of people who had the most mild forms of it. And that's a little controversial. Some people are going to say, I worked in those people, we should do that. Some people say no, no, that just tells us we got to do a new study with them a primary. And then sometimes the nutritionist come and say these aren't drugs, people, your standards are too high. It's diet, the the heart healthy, the brain healthy diet is also heart healthy. So let's let's do this as a present preventative measure and see what happens. And lastly, if you look at the epidemiology, like the fish eaters have lower incidences of some of the neurodegenerative diseases of the Alzheimer's type thing. So there's some evidence there.
Nick Jikomes 1:17:57
Yeah. Given what you've told us about, about a lot of the stuff, the slow turnover rate in the brain of some of these things, the buffering, what's your opinion on like fish oil supplements, and whether or not those are very effective, or, you know, as effective as just eating? You know, a whole food diet, like the contains fish and things like that? Is there like for? I don't know, for the average adult in America, is there actually much risk for true Omega three deficiency? Can the supplements really help? What do you think about that general world?
Richard Bazinet 1:18:32
Yeah, so the last case of true Omega three deficiency I know of was published in the 80s, a young female had a gunshot wound in her stomach area. And they put her on an intravenous feed, for whatever reason didn't have any omega threes, and she developed neurological symptoms. They added soybean I think, to the to the intravenous feeding, her symptoms disappeared. So we don't have that omega three Deficiency Syndrome around much in the population. My colleagues would be screaming at me right now, because they say nobody cares about that. What we want to know is, is there a level that would prevent or help with neurodegenerative diseases, not these old case studies from from the 1980s and 1960s. Fair point. Okay. And then so sorry, I've lost my train of thought a little bit right. Now, if you can remind me we're, yeah,
Nick Jikomes 1:19:26
I mean, are there any is someone like truly at risk? Yeah. Do the supplements work? Are we truly at risk for a megaphone deficiency as just normal people walking around today?
Richard Bazinet 1:19:34
Okay, so let's work through these one at a time. We'll go forward and then we'll go back a little bit as they circle back so, so fish, fish intake, and Alzheimer's disease, no studies done right? No, randomized that he's done this ditch to try it, at least not to prevent it. But we can use the epidemiology and we can see that people who consume more fish have a lower incidence of Alzheimer's disease. This is a little expensive. What's it? What's it in? Sorry, I can't remember Seattle.
Nick Jikomes 1:20:05
I'm in Seattle. Yeah. So
Richard Bazinet 1:20:06
you get you got fish, but I'm sure you got beautiful fish markets. Yep. It's expensive. It's expensive, though, right? And I'm in Toronto and same thing. And so the problem with that is we worry that it's, there's some sort of confounding that fish eaters have better health care. And so it doesn't show causation. Fine. Should you eat fish? Well, looks good. But the counter argument is, well, what if I'm reading a fish, which at age should eat pork should eat a beef burger? And I think fish comes up pretty high when when you get into those kinds of arguments. Okay. And then, and then you walk along, you say, Well, I, what about a fish oil supplement? Okay, should I take that? And I think the randomized control trials of fish oil supplements aren't overly strong as well in in the neurodegenerative disorders, maybe it's too late. Maybe we can't fix them that bar. The drugs don't work that well, right? In fairness, so why would official work? And then people say, Well, what about prevention? What about, you know, I just don't like fish. I don't eat it. So now we're going to circle back. Okay, so when you eat fish, and this is where nutrition becomes a disaster, it's really fun. But a disaster, you eat a piece of salmon, which has got that that nice level of omega threes or tuna, seared tuna, you've also chosen, if you look at that plate, you may be having a glass of white wine, you may be having some vegetables with it, you might be squeezing a lemon on it, right? And so this is where the fights come in the somebody says, Oh, it's the antioxidants in the lemon that's actually beneficial. And somebody says, No, it's the fruits, the vegetables you're having with the plate, some you know, wine 20 years ago, they would have said it was it. But now that one's a little more controversial. And then somebody says, No, it's not that it's what you're not eating when he who would who would have a fresh tuna steak with french fries and, and potato chips, right? So you're displacing things. So the mechanism of action of food is probably very complicated, right? And then you say, Well, I'm going to take a fish oil supplement to get around that. And I'm going to go to the fast food restaurant tonight, because I had my fish oil supplements. So it becomes a bit of a tricky situation. Fish Oils, the omega threes are similar to that that we find in fish, the absorption is roughly similar, and they'll change your blood levels that are roughly similar. So if you purely argue that omega three is at the sole mechanism of action, you got a reasonable point, okay. But I'm not convinced that the sole mechanism of action because of the complexity of nutrition, which is so complex that now that sometimes we call these dietary patterns, and you see that, you know, they can go to a grocery store in some countries, and based on whether you bought fish, they can predict whether you're going to buy olives, are you going to buy a soft drink, right? And because people eating patterns, so So I kind of didn't answer your question, but hopefully the nuance and, and some of the different sales came through.
Nick Jikomes 1:23:10
Basically, it sounds like an Omega three, a fish supplement, and Omega three supplement will work in the sense that it's going to get into your body, it's gonna be akin to actually eating something like fish. The question is, you know, are the Omega threes? The reason why we see some of these associations in the literature, like lower levels of Alzheimer with fish eaters? We don't know if it's the Omega threes, per se, or just eating a healthier, healthier diet overall, or what have you.
Richard Bazinet 1:23:35
Exactly. I agree with that. Yeah. Okay. And I'll be clear, the association's are strong, and sometimes very consistent, right. So I don't want to I don't want to understate that. And reasonable people will look at that literature and say, I've got to eat something. And this is the best case scenario, right? Like, I don't want to throw foods under the bus, but But eating potato chips does not strongly positively associated with protection from Alzheimer's. Yeah, so you can I get that decision? Well,
Nick Jikomes 1:24:06
I mean, kind of related to that, you know, there's a lot of people who are concerned about seed oils, and the high omega six consumption that we have in the modern world, people will point to things like, you know, if you look at pre modern humans, they were maybe approaching a one to one ratio of omega six to Omega three intake. Biologically, it kind of makes sense that you want those things balanced, because one of them is pro inflammatory. And the other ones for resolving inflammation. Obviously, you don't want too much inflammation, you just want to use it, you know, where you have tissue damage or where you have an infection. So a lot of people make the argument that having a really skewed Omega six to Omega three ratio, which most people do today, 10 to 121, even 30 to one that's generally going to be bad because you're gonna get more inflammation. Are you concerned at all about the level of dietary Omega six intake today and how do you think about that? Yeah,
Richard Bazinet 1:24:54
so yes, and no, you know, there's there's a bit of a problem I'm where I think some people have gone a little too far with the data we currently have. And I think we need to get more data. So one of the things I think people can do is they can use what's called ecological epidemiology, okay. And this is approach where either you can look at different populations or time, right, and you can say, Alzheimer's incidence has increased over the past 600 years. So as seed oils, bingo, okay, got it. Okay, that's some sort of evidence, I don't think it's particularly strong evidence, we can do a better job with what we call prospective epidemiology. And these are studies where we characterize what people eat at an individual level. So not that not at a population level, we're not comparing the incidence of Alzheimer's in Japan to the United States, right? We get individuals all in the same country, and we follow them for a period of time. And we don't have as many of these studies because I think the field of nutrition was largely driven by cardiovascular disease. So these new cohorts were set up to study cardiovascular disease. And that's what they were designed to do. And a few of them are now starting to say, hey, let's let's look at Alzheimer's in these things, right. And so, seed oils do not show up, as far as I can tell, as a massive smoking signal or gun or, you know, issue in those types of studies yet. And in fact, in cardiovascular disease, they show up as a bit beneficial, okay. In those kinds of studies, and then people lose their mind, and they say things like, oh, nutritional epidemiology is not good, blah, blah, blah, fine, if you want to take that perspective, but then you can't argue this ecological stuff with me, right? Because he's because going down the level of evidence, so you want to set a bar here. I'll respect your logic, but let's be above the bar, right? But, but I'm open to the idea that there's biologically plausible mechanisms at play here. Okay. So this pro inflammation, these oxidized lipids, and now that some of my colleagues are saying, Hey, you can absorb some of these things, especially if they're rancid and stuff. So I'm like, you know, I'm not sure what the answer is. I've got a grant submitted that got rejected to study some of this. So I think, you know, that's I never say there's nothing there. But clearly, people go a little bit too far. I think, you know, the neurodegeneration is going to be hard to study, right? It's just a hard thing to study from a nutritional perspective, because of the exposure time. So let's see if we can do what I would call the proof of concept studies, and see if it makes a difference. And pathways, biological pathways that we're concerned about in major depressive and risk or Alzheimer's disease. We haven't really done that yet. And I think we need to be careful, though, just you know, just saying, there's oxidized lipids in the Alzheimer's brain. There's oxidized lipids and seed oils, drive a line. Right. So there's a few steps in that pathway here. So I think it's, it's reasonable that we should we should take a look at this, especially in long exposures, it's going to be difficult to do. I don't get too excited about it, personally, yet.
Nick Jikomes 1:28:28
What? So I mean, just given that you study lipids generally has this impacted you at all in terms of your life in terms of like your your fat diet? Do you eat a high fat diet, a low fat diet? Do you pay attention to the particular fats you're consuming? Are there any general principles there that you think are pretty solid for people? Yeah,
Richard Bazinet 1:28:48
so the so there's a few things with madmen and nutrition department. If I sit down on an airplane at a dinner table table, and people ask me what I do I say, I'm in the Faculty of Medicine, because I don't want to talk about it. Okay? Because nutrition can get a little too exciting with some of these things. So, so some days, I'm a neuro chemist, and my family might look at me and I said, You're a nutritionist, right? And some days, I'm a nutritionist, so, so avoid that. All joking aside, yeah, Ted, it has had a big influence on me. One thing that you wouldn't know about me personally, is I'm a bit of what I would call a foodie. Perhaps I'm into things like that. And I think that drives my dietary pattern a little bit, but, but one of the things I recognize about about diets is that, you know, we don't have the best evidence at hand. We don't have randomized control trials and all these individual things. And we've got mixed data on some things. In general, the the epidemiologic epidemiological data for the brain with some minor exceptions. That looks healthy for the brain looks like it's good for the heart. And I am happy about that because it would be a Real disaster, there are two different diets, right. And so these diets that are high in that are plant based, not necessarily vegetarian or vegan, which we can talk about a little bit if you want, that have a little bit of a lower content of meats, red meats, and have fish, fatty fish and look like they're pretty good for cardiovascular disease, and they correlate with the brain. Sometimes things like blueberries and, you know, show up a little bit more in the brain side than the cardiovascular side. So it's not all that consistent. So,
Nick Jikomes 1:30:35
but you're talking about, you're talking about epidemiological literature. Yeah.
Richard Bazinet 1:30:39
Yeah. Let me take a step back, then we've got a handful of, you know, in some people would say this isn't true. But we've got a handful of randomized control trials on cardiovascular outcomes. Okay. And roughly speaking, these Mediterranean style diets look like they work in those studies in cardiovascular disease, so we get an epidemiology and cardiovascular disease, we get an epidemiology on the brain. they correlate, okay, we've got randomized control trials of diets in cardiovascular disease, we don't really have them in Alzheimer's disease, okay, of diets. We've got supplements for non diet. So as I'm missing that part of the equation, so what do you do? Well, I think it's pretty reasonable to say like, this stuff that we see for the heart looks like it's also pointing in the direct same direction for the brain with some factors missing, and some important factors, right. So you know, some of my colleagues are really interested in ketones, not an area we went, but are a byproduct of fat oxidation. And one of the ideas here, I think that's really important, and we need to study this is that in the Alzheimer's brain, there's a reduction in glucose, glucose uptake. Why is that? Well, you get that neuron, so less glucose is coming in. Okay. Sure. But some people are also saying, Oh, no, no, no, no, there's a little more than that. And if you look at it with a little more nuance, that looks like the glucose impairments, the glucose uptake impairments are early on. And so they're wondering if they can bypass that with other brain energy sources. Proteins are tricky, because the trans proteins pretty much don't cross the blood brain barrier to acids. Amino acids, they're regulated at the transport level, but ketones you can get in and get them through. So they're working on this. And, you know, we spent the whole talk and I avoided that aspect of fats. But can you can you rescue brain energy deficits with ketones good point for the brain. And then that puts us into a little bit of an area where some of that the way to increase your ketones might not be ideal for your heart, or for some other things, right, you don't need to go down there. So there's some little nuances to go through. But But yeah, I happen to live near a fish shop, I pop in once or twice a week. You know, if I'm in a Russia canner, sardines, it makes for a great snack with an apple. Nutritionally, there are a lot of things I think you can do trying to keep your waistline a little, a little tighter than a little bigger, which, which is nutrition and some other things. But but if you looked at my date and say this is this is a guy who eats Mediterranean ish, with a lot of exceptions on the weekends, or when he's traveling or doing things, right, because the foodie side of me, and I like it, right? I enjoy the fresh stuff coming in the seasons. Are
Nick Jikomes 1:33:33
there any, like major misconceptions you feel that are out there about lipid metabolism generally, or brain lipid metabolism particular as it relates to diet? Or things where people seem to be very confused?
Richard Bazinet 1:33:47
Yeah, yeah, tons of them. One is, if you Google, or as AI, I do this in lectures, where the most abundant fatty acid in the brain is it'll say it's DHA, and it's just wrong. Okay? We work through that. But DHA is become this dogma. It's the most abundant fatty acid brain. I love this molecule. I'm fascinated this molecule, I think about this molecule, right? I love it. So I don't want to downplay it, but it's not the most abundant and nobody, what that has done is it's led to maybe a dogma that ergo the dietary requirements of it are quite high. And we didn't get into this there's also a huge debate because the precursors that you can make it from our what we would call plant base, it's not a totally accurate term. So some people say you if you look at the rate of that reaction, it's not that fast. And you got a lot in the brain so they say you can't make enough so therefore you have to eat it but but for me, it's a little different. It has to do with how much is coming into the brain, not how much is into the brain. So so there's there's this this fundamental understanding and DHA is very important for the brain. But how much dietary DHA we need To consume to do that, it's not clear to me. And at one end of the spectrum, some people say it's a really, really high number. Okay, so I think that's one of the darkness. That's, that's there. The other thing is, I think that and it's true from maybe a behavioral perspective. And if you eat fats, it'll determine what you eat, how much you eat at your next meal. And so there are behavioral aspects with this, but, but I really don't think we have any evidence that we can meaningfully change brain fatty acid composition in the short term. Okay. It's hard to do in animals, I suspect it's going to be extremely hard to do in humans. So that's, that's another area. That I think is an issue that the people look at these things in terms of very short timelines, when nutritionally speaking, we're thinking of probably long timelines, which evolutionary is very important, right? Because if you weren't, if you had times where you weren't, you couldn't get access to these things. The last thing you want to do is have your cognitive abilities dropping when you're searching for food. Yeah, that would not be good. Right. So so we've got preservation mechanisms on these things. And then, but then that's not to say that there's not something there that could decrease the incidence of some of these disorders in the long term. It's just it's just these are hard studies to do. Right.
Nick Jikomes 1:36:21
All right, well, we've already covered a lot. This has been fascinating. Is there anything you want to leave people with any final thoughts? Anything you want to reiterate from what we talked about about lipids and the brain in particular?
Richard Bazinet 1:36:33
Yeah, yeah, I would just say, you know, we, we talked about fatty acids. And any lipid chemists coming on here said, we forgot about cholesterol. We forgot about ceremonies, we forgot about these things. Why did we do that? Because we talked about the ones I study. That's, that's what I do. But it's but it's a really fascinating field. And I think I think it's really growing neatly. So we've had advances in people have probably heard of all these ohmic techniques metabolomics, while lipid omics is blown up now. And can I let me just throw one little story at you that can kind of guess, one of the problems with studying lipids signaling molecules in the brain is these phospholipases. Okay, so one of them's called calcium dependent cytosolic, fossil, ABC to the calcium dependent, might give you an idea what goes wrong here. So if you try and take a brain, what I'm going to do with my centers right out of a rodent, almost any way you do that, you're going to cause ischemia, you're going to cause hypoxia, you're going to get this this glutamate signaling, you're going to get calcium release. And you're going to activate these enzymes post mortem, after death, right. And then the fireworks go off. These these mediators show up that don't even exist and weren't there. And they all change so so we have to be very careful to the person who's listening to this saying, you know, I'm going to try this out about how we collect these tissues. Because
Nick Jikomes 1:38:06
the very way that we collect these tissues is going to change the lipid profile that you that you measure
Richard Bazinet 1:38:12
completely, right. And so so we're going to need time right now, where we've got, I think the improvements in molecular biology in the neurosciences have been fascinating. And I think lots of things we were talking about, where we can't knock out a lipid, we can come really close now, because we can knock out the enzyme that synthesizes it or degrades it, right. And so we're we're finally, after decades of struggling with these things where we remove it from the diet or not, and we changed the whole body, not just the brain, right. And then we blame the effects on the brain. We're getting, we're getting these tissue specific cell specific knockouts. And we're starting to make these advances with these with these changes in epidemics. But but every so long, we take a couple of steps forward, and we take a step backwards. And, and some of the methodologies and lipids aren't as intuitive as some of the other fields. So I think it's an exciting time. We're also getting advancements in imaging brain lipids, which are going to take us quite forward. And people are just interested in nutrition. And so hopefully we can we can do more of these studies, you know, part of the neurodegenerative epidemic might be related to the benefits we've seen in cardiovascular disease. So people are just living longer, right? If we didn't, we didn't have Alzheimer's that much in the early 19 1900s 1800s. People are living longer so so we're getting there. And I think we've got a lot of fun tools to study this field.
Nick Jikomes 1:39:43
All right, well, Dr. Richard bassinet. Thank you for your time. And I hope to talk to you again at some point.
Richard Bazinet 1:39:50
Thank you very much. It was an absolute pleasure to be on and talk in such detail and I'm really glad you're doing this
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