Dr. Norm Salem – Part 2: Is DHA Essential?

OmegaMatters: Episode 12, Part 2

Hosts: Drs. Bill Harris & Kristina Harris Jackson

Guest: Dr. Norman Salem

Background and Key Takeaways: Dr. Norman Salem is a prolific omega-3 researcher whose career has focused primarily on omega-3 DHA and the brain. Dr. Salem obtained his PhD from the University of Rochester School of Medicine and Neurobiology. For 30 years, Dr. Salem worked at the National Institutes of Health (NIH) where he led the Laboratory of Membrane Biochemistry and Biophysics. And after retiring from NIH, he worked at Martek, the first algal DHA company, and then for DSM when they acquired Martek. In this episode, Dr. Salem gets very deep on DHA’s mechanism of action and specifically how it influences the brain and nerves. He also talks about how crucial DHA is for pregnant women and why it should be considered an essential nutrient, much like a vitamin. Last but not least, he ponders why a dietary reference intake has yet to be established for DHA and that the time has come to get this underway.

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Dr. Kristina Harris Jackson: All right. Welcome to round two of OmegaMatters with Dr. Norman Salem.

Dr. Kristina Harris Jackson: We finished our conversation about building the brain, and we had more to talk about. So we decided to keep him around for a few more minutes. Again, Dr. Salem is prolific omega-3 researcher in the world of DHA and the brain. He had a very long, industrious career publishing. So you can find Norman Salem’s work all over PubMed and find out what he was into.

Dr. Kristina Harris Jackson: But today we’re going to go to the bigger question of what is DHA doing in the brain and in the nerves? What are the mechanisms of action? So we wanted to just allow him to guide us through all of his thoughts, and what he knows about it.

Dr. Norman Salem: Some time ago I approached this question about, is the DHA molecule, that precise molecule, essential for proper brain function? The brain accumulates large amounts of it. Is that necessary? There were early suggestions in omega-3 deficient diets where the DHA fell in the brain, typically these studies were done through two generations. So you deprive a female rat and look at her offspring, maintaining a deficient diet, deficient only in the omega-3 fatty acids, not in omega-6 fatty acids. And you can see the behavioral deficits.

Dr. Norman Salem: But these were done by lipid chemists and the behavior was done rather poorly. The number of subjects was too small, the statistics weren’t done, or weren’t good. So we decided we were going to try to do this again. We were lipid chemists too, but we were going try to do good behavior, good quality behavior. And we tried a variety of behavioral experiments with, what we would think were some proper controls. We worked with 2-3 generations of omega-3 deficient rats. We got the brain level of DHA down about 80%. And almost all of that decrease was reciprocally replaced by docosapentaenoic acid, DPA, omega-6.

Dr. Norman Salem: We found a fairly profound deficit of things like spatial tasks. Morris water maze, Barnes maze, these are mice or rats, mostly rats. There was not a deficit in motor function and there was not a deficit in the sensory function. They were able to receive the stimuli perfectly well. They were able to swim perfectly well in the Morris water maze. So, we ruled out those simple explanations for the behavioral deficit. And we were trying to make the case that there was a higher level executive function deficit with a DHA loss.

Dr. Norman Salem: This really came to fruition when we came upon the olfactory modality for learning-based experiments. Because rats are really good at olfaction and they actually are macrosmactic. That means they navigate the world using olfaction. Not like us primates, we use vision. And so we always frame behavioral experiments in terms of vision, visual stimuli. But that’s a primate bias.

Dr. Norman Salem: You know, if you’re a rat, it makes more sense to use an olfactory cue. And so we designed our study using these olfactometers, where we could introduce smell A, or smell B, and tell teach them to press a bar with smell A and not smell B, and so on. And then we were able to teach them to do this, they would get very proficient at it, 95% correct responses. And then as soon as they learned it, we would reverse it, and make the other one correct. And then they had to relearn it to respond to the other smell. And then when they would learn that, we would reverse it again.

Dr. Norman Salem: And we were looking for set learning. So the number of mistakes that you make, every time it’s reversed, your capability of set learning will decrease. So, the first time you make 10 mistakes, and the next time you make seven, next time you make five… and the best you could ever do, if you’re a human being, is make one mistake. As soon as, the very first time it was reversed, you would say, “Ah, I got it — it’s the other one that’s correct, and I’m not going to make any more mistakes.”

Dr. Norman Salem: So, we found that rats were capable in the olfactory modality of set learning. And this is considered a high-level function that only primates can do. That’s because the rats were always asked to do these things in the visual modality. And so, what we found was, in the n-3 deficient rats who had low DHA, they were not capable of set learning. And of course the n-3 adequate rats sailed away, and did the set learning perfectly well.

Dr. Norman Salem: Again, it was not that there was not a loss of sensory ability. They were perfectly able to sense these smells, much smaller amounts than what we were presenting to them. So it wasn’t a motivational problem, it wasn’t a sensory problem. So we ascribe it to a set learning problem.

Dr. Norman Salem: So this shows that there is a cognitive loss when you have low DHA in your brain. Now there could be another explanation. Like we already said there was a reciprocal replacement of DHA with DPA n-6.

Dr. Bill Harris: Yeah.

Dr. Norman Salem: But forcing that to be metabolized from linoleic acid. So, that will occur, but it could occur fairly slowly. And the reciprocal replacement, actually we showed in the separate work, that that occurs fairly slowly. It didn’t occur in the first three weeks or so — it took little longer.

Dr. Norman Salem: Because you’re forcing it to be accumulated from metabolism. In order to try to rule out the idea that DPA, n-6 was just as good as DHA, we actually got purified DPA, n-6, and fed it directly, versus DHA, in artificial rearing experiments. We did spatial tasks behavior again in the rats, and we found it was the DPA rats were no better than the linoleic acid rats.

Dr. Bill Harris: Oh, really?

Dr. Norman Salem: Yes. They were the same.

Dr. Norman Salem: So it was a highly specific effect for DHA, and you absolutely have to that terminal n-3 double- bond. So this really started bringing the mechanism of action into focus for us. Because we have this wonderful hint that DPA doesn’t work. And DHA does work. So our first thought was that there’s got to be an enzyme function, and it’s probably going to be some bioactive compound. You know about the prostaglandins, leukotrienes, the lipoxins, and the resolvins, and so on. But we didn’t know about the resolvins when we started.

Dr. Bill Harris: No, not then.

Dr. Norman Salem: But we looked for those kinds of products. And we couldn’t find them actually. So we turned to another thesis. Of course, some of these compounds have been found now, and they have interesting biological activities. But I don’t think anybody has shown that those functions are crucial for brain or retinal function.

Dr. Norman Salem: Well, they optimally activate G-protein coupled receptors (GPCR) in the retina and nervous system. And the one which was the best example of that, the one which we can purify and study in vitro, even in liposomes, is rhodopsin. That’s the visual pigment. It’s the protein that absorbs a photon of light, does a volume expansion of its alpha-helical, seven alpha-helical coils, and gets activated, and then couples with G-protein. There’s a lateral search of the protein for the G-protein in the membrane, which involves the fluidity, the degree of motion in the plasma membrane.

Dr. Norman Salem: And there’s the coupling with the phosphodiesterase. So, there’s two steps of lateral search in the membrane… and, where it’s crucial, where the physical properties of the lipid bilayer are crucial. And we believe that the DHA acts in a couple of ways physically. First of all, it sequesters the DHA phospholipids around the rhodopsin protein itself.

Dr. Norman Salem: Secondly, when it needs to volume expand when it’s activated, it allows that to occur more optimally than DPA, and phospholipids.

Dr. Bill Harris: So, the membrane’s more fluid right around the rhodopsin.

Dr. Norman Salem: It’s more disordered, which allows that expansion to occur more readily. You know, it creates spaces. Think of it this way, it creates spaces in the membrane. It’s called free volume. The free volume of the membrane is increased with DHA. However, the DPA, n-6, it doesn’t have that terminal n-3 double bond, and that last six double-bond fragment is rigid. And, it doesn’t allow for the same kind of fluid state and free volume that the DHA does.

Dr. Norman Salem: And the second place where the physical properties of these phospholipids differentiate and affect the GPCRs is in this diffusional search. Once the protein’s activated, it’s got to find the G-protein and it diffuses along the plane of the membrane, and we’ve shown directly that that occurs faster with the DHA membranes.

Dr. Norman Salem: And these were, there were membranes that were made in vivo. We took the n-3-deficient animals and made retinal segment membranes. So they were formed in vivo, tested in vitro. And we could show that the meta-1 to meta-2, that is the activation of the receptor, was faster in the DHA-adequate membranes, that the coupling to the G-protein was faster, and that the activation of the phosphodiesterase was three times higher.

Dr. Bill Harris: Wow.

Dr. Norman Salem: … than the ones which had DPA, n-6. So we feel that this is fairly conclusive evidence that, a), the DHA phospholipid is optimal for the GPCR function, that the rhodopsin, of course, is one the key ones for retinal function. Secondly, it explains the selectivity of DHA phospholipids over DPA, n-6 phospholipids. And finally I want say that this class of GPCRs is a very large class of receptor proteins. I think there’s around 2500 known in nature, which all have this motif of seven membrane alpha-helixes, that have to volume expand when activated. So we have to expect that they will behave in much the same way. And this can help to explain some of the receptor issues in the brain. Not just the retina.

Dr. Bill Harris: Okay. Not just the retina, right, yeah.

Dr. Kristina Harris Jackson: It’s basically has to do with the speed of the message? Whether it be to the eye to the brain, or your brain connecting is the functional outcome of these — the receptor and how fast it needs to, you know, do its thing? So, at the end of that day you’re just getting that message, and for your eye it has to be almost instantaneous, because that’s what we expect.

Dr. Norman Salem: Yeah. With n-3 deficiency, you don’t go blind.

Dr. Kristina Harris Jackson: Right.

Dr. Norman Salem: Your retina’s still working, but it’s not working as well. So, you can see the difference in A-wave and B-wave electroretinogram. And the effects we saw in this experiment I related to you where they were made n-3-deficient, we saw the differences in G-protein in the rhodopsin signaling. We modeled the magnitude of those effects for the electroretinogram. And we could explain the change in the A-wave. Just based on that alone.

Dr. Norman Salem: And finally I want to say that it’s not just DHA that’s essential for the brain. Arachidonic acid (ARA) is also essential for the brain. And we were able to look at this directly in the delta-6-desaturase knockout mice.

Dr. Norman Salem: So, these animals have no metabolic activity, no desaturase activity at least for the 18-carbon PUFAs, so they’re really dependent upon what we feed them. And, again, we fed them pure fatty acids. And then we fed either ARA, or DHA, or the two together. And what we found was, if you didn’t feed them ARA, even if you did feed them DHA, that there was a decrease in body growth, in brain growth, and in motor coordination tasks. So, adding the ARA could completely negate the growth effects. So, we felt there was pretty strong evidence for the essentiality of ARA as well. So the two together, like the wisdom of human milk, provide the best development for infants.

Dr. Norman Salem: So, our overall conclusion was that DHA must be fed pre-formed in the diet because it is crucial and serves unique functions of the nervous system, and elsewhere. So, eat your fish and take your supplements, and get that Omega-3 Index boosted up real high.

Dr. Kristina Harris Jackson: That’s right.

Dr. Bill Harris: Nice, I like that (laughs).

Dr. Bill Harris: You know, and nutritionists sometimes say that DHA is not essential because it can be made from ALA. So, it’s not one of the classic nutrients like a vitamin C or a vitamin D, because you can provide something else in the diet that can be made into it. Would you argue against that?

Dr. Norman Salem: Absolutely. Because you not only need to have enzymes that can do the conversion, but you also need to do enough of the conversion to supply enough of the product for the function of the DHA.

Dr. Bill Harris: Yeah.

Dr. Norman Salem: We know there’s important neural functions, as well as other functions in the muscle, and heart, and other tissues no doubt. But I would say, especially in early development, yeah, it’s crucial that it be supplied pre-formed and considered essential nutrients themselves.

Dr. Bill Harris: Yeah. But we haven’t been able to get a dietary reference intake, just a defined intake for DHA. For years people have tried this and it’s not gotten the ear of the powers that be. Any idea why?

Dr. Norman Salem: Well, they just aren’t looking at it. I mean, the powers that be haven’t decided to do the analysis. I think now there may be enough of the kind of data they need to make that case. You know, they want dose-response data, physiological response, with dose-response data, and they want to see that basically at all the important ages — infants, and children, and young adults, and the aging adults, and so on. Or, you know, or as many of those as you need to supply many of those examples, and for various functions and then the prevention of disease.

Dr. Kristina Harris Jackson: Right.

Dr. Norman Salem: I think that there’s enough information now that it likely would pass their rigid criteria.

Dr. Bill Harris: What would be your recommendation for a DHA intake, in a pregnant woman and a lactating woman?

Dr. Norman Salem: I think I would say a pregnant woman should take at least a gram a day.

Dr. Kristina Harris Jackson: Of DHA specifically?

Dr. Norman Salem: Of DHA. There’s two levels that are available in various manufacturers, and the higher one is the minimum. And there’s good evidence now that it should be higher than what’s in those formulas. And there’s now a move for infant formula companies to delete arachidonic acid because the European Commission decided it wasn’t essential.

Dr. Bill Harris: Really?

Dr. Norman Salem: You still have to have DHA, but the ARA was optional. And, since that’s the most expensive nutrient in formula, some companies are deleting it. This is a really bad thing, I think. I would argue that women and families make sure their formula had both ARA and DHA, if they’re going to use formula.

Dr. Bill Harris: Yeah.

Dr. Norman Salem: And supplement for mothers, too. If the mothers are going to breastfeed, they need to have the adequate levels of DHA themselves. They probably have adequate levels of ARA.

Dr. Bill Harris: Probably. Right.

Dr. Norman Salem: That’s if they’re Americans or Westerners.

Dr. Bill Harris: Exactly. Wow.

Dr. Kristina Harris Jackson: Is there a worry about getting too high in DHA that you depress your arachidonic levels?

Dr. Norman Salem: Well, for cardiovascular health, that’s thought to be the mechanism of the benefit of the omega-3s. EPA and DHA, suppress arachidonic, suppress thromboxane, and some of the prostanoids that have changed the distribution of prostanoids. So, within reason, it’s not a bad thing.

Dr. Kristina Harris Jackson: It’d be hard to get that much. I like it’d be hard to get to that point.

Dr. Norman Salem: You know, I feel like I’m contradicting myself here. We need ARA, but in the Western world, we have a super abundance of linoleic in our diet. And it’s excessive and it drives… I, you know… I know Bill doesn’t always buy this, but…it drives up ARA, and perhaps above the level which is necessary.

Dr. Bill Harris: I think what I heard you ask Tina was, in the pregnant or lactating woman, if she’s just taking DHA, will that suppress arachidonic synthesis in her, for her baby. Would that be a bad thing. Or could you even do that?

Dr. Norman Salem: Yeah, we’ve never recommended a pregnant woman to supplement ARA. That’s, again, because her stores are probably adequate.

Dr. Bill Harris: Yeah.

Dr. Norman Salem: So, her metabolism will be somewhat decreased. Her ALA metabolism will be decreased. But she’s taking pre-formed DHA. So, 90% of, of her composition’s coming in from that anyway.

Dr. Bill Harris: Right.

Dr. Norman Salem: She’s fine. And her level’s going up. Her absolute level, and her, all her organs, and in the bloodstream. And her body stores of what she’s able to supply the infant is going up. And the infant’s levels are going up. You know, the fetal levels are going up. Or, if they’re breastfeeding, the levels in the child will be going up.

Dr. Kristina Harris Jackson: I have one more question. There’s so many studies in pregnant women with DHA or fish oil, and the early ones seemed like they really focused on the neurodevelopment and the visual development. And a lot of those had mixed results. Why do you think those results were mixed, and not a clear home run?

Dr. Norman Salem: Well I think, frankly, the Dallas group was the most expert in doing visual studies. They were visual scientists, and they didn’t have to do huge studies to find significant results. And I believe their results and they did good studies. But some of the large studies have failed. I don’t want to oversimplify it, but in many cases, you wonder if and how much of the supplement was actually taken. The compositional studies show the levels are not always, I think, what is expected. And, in most cases, I think they stopped. You know, they gave the supplement, and then stopped it and studied a much later outcome. That’s a pretty tough road to hoe for any nutrient, to say we’re just going to give it to you for six weeks early in your life, then we’re going to test you on it in a year-and-half or five years. That’s a tough criterion.

Dr. Bill Harris: Yeah. Good, good point.

Dr. Norman Salem: You know, so there’s a lot of reasons why some of these studies have not really worked out.

Dr. Kristina Harris Jackson: I’ve always thought that measuring outcomes relating to behavior, neurocognition or vision has to be such a precise outcome they’re so complicated. Especially the cognition — how do you measure a baby’s cognition? How do you measure a baby’s neurodevelopment? Those outcomes have to be very precise to see any kind of differences. I think that’s why a lot of the preterm birth DHA data is so strong, because it’s just an easy, obvious outcome.

Dr. Norman Salem: Yeah. And another problem with a lot of the studies is that they used those Bayley’s Scales. And they really weren’t designed for a cognitive assessment, as Sue Carlson and her coworkers have pointed out in the literature.

Dr. Kristina Harris Jackson: Well that was good. I’m glad we got to talk about this aspect of DHA and how it’s functioning. That was really fascinating. Anything else you guys would like to say? Before we head out?

Dr. Bill Harris: I think that’s very good, very interesting how it makes those membranes slippery.

Dr. Kristina Harris Jackson: That’s a great visual in my brain right now.

Dr. Kristina Harris Jackson: All right, thank you so much, Norm.

Dr. Norman Salem: It’s been fun. My favorite topic.

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