Dr. Barry Sears (of Zone Diet Fame) on Lifetime Metabolic Health and Sourcing Omega-3s

In this episode, I’m excited to welcome Dr. Barry Sears, the renowned creator of the Zone Diet and a pillar in our field. Dr. Sears has not only authored bestsellers but has also made incredibly important contributions to clinical practice which we still rely on today: He is, for instance, the scientist who put the use of the AA:EPA ratio on the map. Dr. Sears provides elegant and accessible explanations of the unassailable importance of diet in addressing inflammation, metabolic health, chronic disease, and longevity, and the role that fatty acids play in that milieu. And while he and I might not agree that polyphenols need to be absorbed intact for benefit – there’s plenty of evidence that their postbiotic products are very important players, especially in their interactions with the epigenome – his concerns about the chemical structure of highly concentrated fish oil supplements (with the potential for isomerization, as he argues) has opened my eyes and is important, without doubt. I think the jury is still out as to whether there is a negative influence of isomerization in highly concentrated EPA and DHA, but it’s worthy of further investigation and (importantly) is another factor in the argument for a whole-food approach. – DrKF

Dr. Barry Sears (of Zone Diet Fame) on Lifetime Metabolic Health and Sourcing Omega-3s

Dr. Kara Fitzgerald dialogues with Dr. Barry Sears, a renowned figure in medical research especially noted for his pioneering work on the Zone Diet and its impact on inflammation and chronic diseases. Dr. Sears shares his transition from cancer drug delivery to focusing on diet as a means to control inflammation through dietary manipulation. Together they delve into the significance of eicosanoids and resolvins in inflammation, the balance of omega-3 to omega-6 fatty acids, and the implications of fatty acid ratios, polyphenols, and macronutrient ratios for diseases like diabetes and obesity. Don’t miss Dr. Sears’ thoughts on the potential for isomerization in highly-concentrated fish oils (as used in some clinical trials that haven’t shown benefit). This insightful discussion not only highlights Dr. Sears’ contributions to understanding diet’s role in health but also captures the future of medical practice through nutritional interventions.

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Dr. Kara Fitzgerald – Hi, everybody. Welcome to a New Frontiers in Functional Medicine, where I am interviewing the best minds in functional medicine. And of course, today is no exception. If you’re with me on video, you can see I’m sitting next to really one of the premier scientists in the US, times decades. Let me give you his background and we’re going to jump right in. Dr. Barry Sears is a leading medical researcher. He’s the author of more than 50 scientific publications. He holds fourteen US patents in diverse areas, including IV drug delivery, technology for cancer treatment, cardiovascular disease treatment, and the reduction of insulin resistance. He also has academic appointments at the University of Miami Medical School, Arizona State University, and the University of Cartagena in Colombia. Dr. Barry Sears, welcome to New Frontiers.

Dr. Barry Sears – Thank you very much.

Dr. Kara Fitzgerald – So we had the pleasure of connecting in 2023 at a conference in Mexico City. That was a lot of fun, and actually, we had an exciting dinner. There was a handful of us there and I think I was just really pinging you with questions and it was clear I wanted to get you on the podcast and continue that.

Dr. Kara Fitzgerald – So Dr. Barry Sears, for anybody who doesn’t know, is authored The Zone Diet book, back in the 1990s. It was a massive New York Times bestseller. It was really, I think, probably one of the first massive- I don’t know, you’ll know better than I do, but I it just seems like it was one of the first books that sort of just set off this trend of people considering nutrition. I remember seeing it in my house when I was growing up. It was it was there. It was a fixture. I don’t know if… Yeah. And there it was. So, I want to talk about that, about your movement into that, your biochemistry background. I know you worked on drug delivery, but then you transitioned into nutrition. You really focused on fatty acids as a big piece of it. You brought fish oil to the minds of many, I think, and the importance of it.

Dr. Kara Fitzgerald – And then I just want to dive into what you’re up to today and some of the really compelling conversation we had at dinner. So, give us your backstory and how you got to creating The Zone, and how life changing it was, because it was such a massive book.

Dr. Barry Sears – Well, again, my background, as you correctly point out, had nothing to do with nutrition. It had everything to do with cancer drug delivery and how to deliver cancer drugs more effectively. So, in the early 1980s, I was basically one of the leaders in that area of encapsulating cancer drugs to small nanotechnology platforms and basically delivering them with greater efficacy. But my whole career changed in 1982, when the Nobel Prize in Medicine was awarded for understanding how a group of hormones called eicosanoids basically caused inflammation. And I said, “Well, that’s a much bigger field because every disease state, the underlying cause is unresolved inflammation.” So, I immediately made a transition from cancer drug delivery into basically looking at how to manipulate these hormones, not by a drug, but by the diet, essentially using diet as a very powerful drug to manipulate the levels of these inflammatory hormones. And that led me into a great journey into basically how diet really controls the metabolism of every one of our three trillion cells in the body.

Dr. Kara Fitzgerald – That’s fascinating. So, just give the listeners just a little bit of a background eicosanoids. There’s a lot of clinicians listening, so they’re certainly going to have some background. But what was identified in 1982? What was characterized?

Dr. Barry Sears – What was characterized was the actual structures of the compounds that cause pain. “Ouch. It hurts.” Well, we have to have some inflammation, otherwise we’d be defenseless against microbial infection or basically our injuries would never heal. Though we had to turn on inflammation, we also had to turn it off. And that part only became way more apparent in really the beginning of the 21st century with another group of hormones called, resolvins, that turn off inflammation. So, the idea of we talk about a zone, it is, yes, like a therapeutic zone for a drug.

Dr. Barry Sears – If you give too little of the drug, it doesn’t work. If you give too much the drug, it’s toxic. The same is true of our metabolism, except that the stakes are much higher. Our metabolism is highly balanced in terms of checks and balances, especially in terms of inflammation. So, it’s not saying I want a drug. Drugs are more like light switches. They turn the light on or off. Pretty simple, my grandson can do that. But metabolism is more complex. It’s this dynamic interplay. It’s more like a sound engineer in a recording studio moving the buttons until you get just the right sound and maintain that in a day-to-day equilibrium.

Dr. Kara Fitzgerald – And so that was your that was your epiphany that prompted the creation of the zone and the and the name? The zone has to do with finding that therapeutic sweet spot with nutrition.

Dr. Barry Sears – Exactly. When I first wrote the book, my editor said, ‘What do you want to call the book?’ I said, ‘Let’s call it The Therapeutic Zone. She said, ‘This is the dumbest idea I’ve ever heard.’ She crossed out the word ‘therapeutic’ and said, ‘We’ll call it The Zone.’ And we hope, we hope we can sell a few copies. No one had ever really anticipated the response they got. So, I was as surprised as anyone.

Dr. Kara Fitzgerald – That’s amazing. So, eicosanoids, the structure was characterized… It’s so fascinating to me because, you know, I’m in the world now where we’re characterizing resolvins. Was it gaining traction, before you, that the pain-derived, pro-inflammatory eicosanoids are coming from arachidonic (acid). I mean, you put that idea on the map that we had this massively skewed ratio. That was part of your work. Talk about that. That’s so fundamental to the fabric of anyone practicing functional medicine, integrative medicine, I mean, it’s so fundamental to how we think about our patient cases, you know, switching the polyunsaturated ratio, and here you were kind of laying the groundwork for that.

Dr. Barry Sears – Well, because again, we talk about the building blocks – the building blocks of eicosanoids that cause of inflammation and the building blocks of the resolvins to turn off inflammation are fatty acids. They are essential fatty acids. They cannot be made by the body. They must be made in the diet. But again, we’re talking about a dynamic relationship. I had to have some that turn on inflammation, but they have to be balanced by those turning off. And what is apparent to me some 40 years ago that the changes we are getting a greater input in our diet of the building blocks for inflammatory eicosanoids, at the same time seeing a dramatic dropping off of the omega-three fatty acids in our diet, which are necessary to make the resolvins.

Dr. Barry Sears – Now, it was a little more complex than that because now we bring in the diet. What controls the underlying control besides the absolute amounts? It’s a balance of two other hormones in the body. One is called glucagon and the other is called insulin. And that’s controlled by the ratio of protein to carbohydrate in the diet. So now you say, ‘”Oh my God, I’ve got to think- now I’ve got the balance of omega six to omega-3, but the balance of protein to carbohydrate to keep these eicosanoids in that zone and resolvins in the zone.” So, basically now the body can perform at peak efficiency.

Dr. Kara Fitzgerald – So, just thinking about that, if we and linking carbohydrate protein over to eicosanoid production, I mean, if you’re consuming a lot of carbs and you’re cranking out insulin and insulin actually turns on production of the fatty acid synthase enzymes, and you start to produce a bunch of arachidonic acid.

Dr. Barry Sears – That’s right. Basically, the worst of all possible worlds. And so basically, we had those two of different trends coming together at the same time in the 1980s, it became apparent, but now we can see, looking back some 40 years, and saying that was a very, very bad combination, and we’re paying the price for it of yes, we see inflammatory conditions like obesity.

Dr. Barry Sears – Obesity is an inflammatory condition, but every chronic disease is an inflammatory condition. It says we just have not achieved that right balance between those two components of basically turning on and turning off inflammation. And that being said, once you can, you usher in a whole new era of medicine. Now you’re basically saying, “Let’s go back to the soundboard where we get that right sound and then use the least amount of drugs if need be.” So rather than basically becoming a pharmaceutical-driven healthcare system, we want to get back to looking at the bigger picture, saying you cannot dissociate the diet from basically metabolism. Metabolism is incredibly complex, and this is why most medical students fall asleep in those lectures. They say, “Oh, it’s too complex. I’m falling asleep.” It’s just, you know, it is complex. But if you can break that complexity, then you have basically the keys to a new pathway of how to practice medicine in the 21st century.

Dr. Kara Fitzgerald – What is the basic Zone Diet? You know, what are the principles of it.

Dr. Barry Sears – Well, I stole it all from your grandmother. So, the basic principles are saying, first of all, you need some protein at each meal. Okay. How much? Well, you need about 30g of protein at each meal. Why? To stop hunger. What’s the hottest drug right now? Wegovy, Ozempic. How do they stop hunger? Basically, you inject hormones that go to the brain and they say stop hunger. But that system has already been in our body for hundreds of millions of years. It’s the protein in our diet at each meal that can basically activate those signals to go to the brain and say stop eating. Now, this is important because the most powerful drug we have known to medical science is called calorie restriction. It works. It works all the time. And why? Because if you basically restrict calories without restricting nutrition, you can activate the master switch and every one of your 30 trillion cells is called AMPK (AMP-activated protein kinase). And once you activate AMPK, you now have the master switch under your control that can turn on and turn off inflammation.

Dr. Barry Sears – Okay, so getting 30g of protein, that’s the amount of protein you could fit in the palm of your hand. That’s what every dietitian says. Well, should I take more? No, because now you affect other gene transcription factors that basically turn on inflammation. Should I take less? No, you won’t get satiety. You’ll always be hungry. And now say, “Okay, I got the protein. What about the carbohydrates?”

Dr. Kara Fitzgerald – You’re tweaking that though for body habitus, I would imagine it’s not a one size fits all.

Dr. Barry Sears – Two reasons for protein needs: one to stop hunger that seems to be invariant. Invariant for male, female, elite athlete, non-elite athlete. Now there’s a second aspect: How much protein do I need to maintain my lean body mass? That’s dependent on your physical activity level and your lean body mass. That can be higher. But for the vast majority of us, people like you and I, who are not elite athletes, 30g of protein is about all we need.

Dr. Kara Fitzgerald – So you’re looking at maybe 90g a day then, if you’re thinking three meals. Is that where you’re tagging? Okay, so a relatively robust amount of protein.

Dr. Barry Sears  – Robust, except the fact is, you know, every dietitian says, “Yeah, eat about the amount of protein as the palm of your hand, no more no less.” But you have to balance that with carbohydrates. Now which ones and how much? Well now we get into basically the Miller Lite time where you have people arguing saying “Oh you know carbs make you fat, no fat makes you fat.” This is like the old Miller Lite commercials. “Less filling. Tastes great. Less…” Guys you missed the point. You need some carbs to balance off the protein. How much? About 40g. Okay, which ones? The ones your grandmother told you to eat. Vegetables. “You can’t leave the table till you eat all your vegetables.” Why? Two reasons. One, it’s hard to overconsume vegetables. Two. They contain other things such as fermentable fiber and polyphenols. And so basically what you’re doing, you’re getting a good chunk of these extra nutrients that help fine-tune that metabolism.

Dr. Barry Sears – So track one: How much protein at each meal? Thirty grams. How much carbohydrate? Forty grams. Now how much fat? A dash. What’s a dash? A small amount. It might be a tablespoon of, you know, olive oil, especially extra virgin olive oil. Could be, basically, fourteen almonds or two tablespoons of guacamole. Now what you’ve done is you’ve constructed a drug for the next five hours that will keep your metabolism under control. The secret is to repeat it every five hours the rest of your life. And people say, “Oh, I rather take a drug.” I say, okay, I gave you an opportunity. But the fact is, you’re looking at a drug that only basically has a small impact on metabolism versus a dietary program that has a major impact.

Dr. Kara Fitzgerald – And why are you limiting carbs to vegetables? And what kind of vegetables?

Dr. Barry Sears – Well, first of all-

Dr. Kara Fitzgerald – I mean, you explained the polyphenol piece and the fermentable fibers, so, yeah, put a pin in that. Just where are you at with carbs as a broad category?

Dr. Barry Sears – As a broad category, you can say that of all the carbs, the vegetables are the best, followed by the fruits. It’s easier to overconsume fruits and they contain a lot more simple sugar. Ten you have the grains. The grains are going to speed flush of the body with carbohydrates quickly and that will increase the hormone insulin. And then you have the worst of the worst, the white carbohydrates. They have no polyphenols, that’s why they’re white, and they rush into the bloodstream, lickety split, and that pumps out insulin that basically disturbs the whole aspect of our metabolism. We call it insulin resistance. It turns out it’s a little more complex than that, but it is basically, looking to find an appropriate mixture that you can go through life on a day-by-day basis. Now, does it work? Well, yeah. Let’s look at insulin resistance, the primary cause of most inflammatory diseases. How long does it take to reduce insulin resistance following this type of a program?

Dr. Barry Sears – The data is pretty clear: four days. So “Geeze, in four days, if I eat like this, I’ve cleared up the body?” No, four days helps you bring it down, but to keep it down, you’ve got to follow it the rest of your life. And so, who would be the group of people most applicable to basically reducing insulin resistance? Diabetics. And our studies at Harvard demonstrated that within three months of following this type of program, the diabetics went from basically being diabetic to non-diabetic.

Dr. Kara Fitzgerald  – And these are obviously type two diabetics.

Dr. Barry Sears – Yes. Now, what happened after I stopped giving them the dietary advice? Human nature comes back, and of course, the levels went right back up again. But if you’re willing to treat food like a drug – it doesn’t have to taste like a drug – but basically, understanding the biochemical consequences. You’ve got a very powerful way to basically orchestrate your metabolism, which is the key to maintaining a longer healthspan, which is defined as longevity minus years of disease loss due to chronic disability.

Dr. Kara Fitzgerald – You’re recommending a relatively modest amount of fatty acids and you specifically say olive oil being a monounsaturated fatty acid, it’s not going to increase the omega-3s, it’s not going to increase the omega-6s. So, yeah…

Dr. Barry Sears – It’s neutral. Now from the standpoint of the fine tuning, like the soundboard, now you say, “Okay, I want to add more omega-3 fatty acids. How much? Do you guess? No, you test. You can test your blood using a fingerstick test and say, am I taking enough omega-3 fatty acids? So, now you begin to titrate your blood because you’re unique to everyone else. So, you get the ratio of arachidonic acid to EPA in an appropriate zone. Again, we need some inflammation, but not too much.

Dr. Kara Fitzgerald – Right.

Dr. Barry Sears – And likewise, the polyphenols., I ate an apple today. Is that enough polyphenols? No. So how do you know if you’re taking enough polyphenols? Another simple blood test: glycosylated hemoglobin.

Dr. Barry Sears – Because the polyphenols, they activate a gene transcription factor known as Nrf2 that basically reduces oxidative stress and reduces the impact on glycosylated hemoglobin. So now, the only two supplements you really need are basically polyphenols and omega-3 fatty acids, and you can fine tune those by a blood test.

Dr. Kara Fitzgerald – Okay. So, I want to get- You’ve been great at sending me papers. In fact, folks, as usual, we’ll pack our show notes full of these papers if you go over to the website, drkarafitzgerald.com, all the transcription and Barry’s papers, he’s been really prolific, and you’re good at sending me anything that’s relevant in the conversation we might be having. I appreciate that. So, looking at this polyphenol to A1C connection, any publication I can put on my website, I’d be interested too, and, you know, bridged by Nrf2. What’s your range for a good A1C?

Dr. Barry Sears – Well, the range, they say anything under 5.6, you’re okay. You’re not well, but you’re okay. So, my definition of being well is you want to keep the A1C between 4.9 and 5.1%.

Dr. Kara Fitzgerald  – Okay. And are you looking at, just out of curiosity, any other variables? Like, what do you think about fasting insulin levels or are you really hanging your hat on A1C?

Dr. Barry Sears – Your ultimate aspect? Are you controlling insulin resistance? That’s why I always like to use HOMA-IR (Homeostatic Model Assessment of Insulin Resistance). This is coming from both the fasting glucose and fasting insulin. If you put in a small equation, out comes a number. If it’s less than one, you have no insulin resistance. It means you’re well. That’s about 1% of Americans. Between 1 and 2, that might be normal, but you’re not well, but you’re not sick. Once it hits two, you start to have insulin resistance, and now, basically, you have entered into a world of pain.

Dr. Barry Sears – The first consequence of increased insulin resistance is excess body fat, followed by diabetes. And once you have diabetes, you’re now four times more likely to get heart disease and twice as likely to get Alzheimer’s. Those aren’t the only diseases. Virtually everything has a strong associated association with increased insulin resistance.

Dr. Kara Fitzgerald – Okay. So let me just say this, there’s a podcast where I just talked to Nathan Price, who’s a fascinating scientist at the Institute for Systems Biology, and they published a really cool paper in 2019 looking at biological age and some of the chronic conditions we see commonly, and diabetes was the number one age accelerant. And so, age being the biggest risk factor for all the chronic diseases, you can see how it absolutely lights the fire, and this whole inflammation phenomena that you’ve been talking about for many, many years, you know, it’s right there.

Dr. Barry Sears – It’s been there, but now finding a system that people in the real world can follow, and basically guidelines. How do I know how I’m doing? Well, the tests I’ve talked about are very simple tests, but they basically give you guidelines, like buoys. They give you a navigational channel. As long as you stay within the channel, life’s going to be okay. Once you get outside that channel, basically, you’re on unchartered waters. So, we are looking at insulin resistance as a marker, a surrogate marker, of a disrupted metabolism. Now that is all due to inactivity of AMPK. We can’t measure AMPK, but we can measure insulin resistance. So, we now have of a watch guard saying, “Okay, whatever disease state I have, my number one goal is to reduce insulin resistance. And the primary drug there that has an unlimited therapeutic index is called food.”

Dr. Kara Fitzgerald – Yeah. That’s right. Or fasting. And I want to I want to return to fasting, but before we do, I just want to get the optimal AA:EPA ratio. And I just want to let listeners know, clinicians out there who are looking routinely at fatty acids, we can get big fatty acid panels covered by insurance now. I mean, we’re looking at very detailed omega-3s, omega-6s, omega-9s, saturates, etc. We just have access to awesome data these days and every laboratory analyzing fatty acids includes your ratio. You put this on the map. And so, I want to give credit where credit is due, and that’s the, excuse me, it’s the AA:EPA ratio. So, speak about what’s optimal for you. Reference ranges change with labs, so what’s the specimen and what’s optimal. And you know, I just find it really kind of cool that this was what you put on the map many years ago.

Dr. Barry Sears – Well, the optimal ratio, at least from our clinical trials, is between 1.5 and 3. The higher the ratio, the more inflamed you are. The average American is about 20. To my last knowledge-

Dr. Kara Fitzgerald  – So, 1.5 AA to 3 EPA. So, you’re going to have a little more arachidonic?

Dr. Barry Sears  – Yes. You need to.

Dr. Kara Fitzgerald – Always. Yeah. You do need some. Yeah.

Dr. Barry Sears – But when you’re up to 20, you’ve got too much excess, and now inflammation is spreading in every organ in the body. So, all of our clinical trials that we do, we always titrate to that goal.

Dr. Barry Sears – How much does a person need? It depends. And that’s why you get into the personalization of functional medicine. How much I need? Well, let’s check the blood. The blood will tell you. Likewise, how many polyphenols do I need? Let’s check the blood. The A1C is a pretty good, easy marker to determine if I need more polyphenols. Highly likely that I need less. And so now you have, as really kind of navigational stabilizers along with the diet, saying I can now fine-tune and personalize a program for the individual. One size does not fit all.

Dr. Kara Fitzgerald – Going back to the original conversation, obviously carbs, insulin resistance, will push arachidonic acid endogenous synthesis, and so that would be something you would use to drop that AA like a stone that doesn’t require actually supplementing with fatty acids. Bringing supplementation in, are you using flax, or are you using fish oil, or using fatty fish? I mean, what are you doing to raise omega-3s?

Dr. Barry Sears – Well, I use purified omega-3 concentrates. One, they’re purified. Most fish are not, and they basically carry a fair amount of toxins. In terms of flax, it has no benefits whatsoever because it’s transformation into the longer chain of omega-3 fatty acids is incredibly slow and inefficient. So, it’s not a very good source of modulating that balance of resolvins and eicosanoids.

Dr. Kara Fitzgerald (00:27:40) – You’re not impressed by the lignin content and the fiber?

Dr. Barry Sears – Oh, the fiber is fine. That’s great because again, the fiber is what our microbes need to survive. Basically, they break down the fiber, the fermentable fiber into small short-chain fatty acids, which are not only a fuel source for the cells in the gut, but more importantly, they act as signaling agents. So, again, that’s why fiber is so important, especially fermentable fiber. So, from that standpoint, flaxseed is a great source of fiber. It’s just a poor source of omega-3 fatty acids that can affect the balance of eicosanoids to resolvins.

Dr. Kara Fitzgerald – Okay, so supplementation of a purified EPA/DHA. And what kind of dosage are you looking at in general?

Dr. Barry Sears – Again it depends on the disease state. For the average person who doesn’t have any chronic disease, probably 2.5g of omega-3 fatty acids per day.

Dr. Kara Fitzgerald – Strictly EPA to DHA? All of them.

Dr. Barry Sears – The combination is a 2 to 1 ratio. Now, that seems like a lot, since the average American takes in about 125 mg. But that’s exactly what every child in America had to take four generations ago when their mother gave them a tablespoon of cod liver oil. World’s most disgusting food, still is, but that contained about 2.5g of omega-3 fatty acids. So again, we have- But what if you have a disease that has higher levels of inflammation, especially in the brain, like severe brain trauma? Those we have gone higher, about 16g per day.

Dr. Kara Fitzgerald – Yeah.

Dr. Barry Sears – So it depends on where the inflammation is located and the individual.

Dr. Kara Fitzgerald – And folks, we’ll post some of those case reports using really high dose omega-3s in traumatic brain injury, they’re incredibly interesting. I mean, we could leapfrog here into talking about dementia, where there’s some evidence that we don’t deliver effectively in the brain once the dementia is present and so higher doses could be indicated there as well. And then, of course, I want to talk to you about some of the new omega-3 structures. So, I’m going to put a pin in those two and we’ll circle back. But before we do that, I just want to talk about the caloric restriction piece because you brought that up immediately.

Dr. Kara Fitzgerald – So there’s the information from the nutrition that you’ve just outlined, but there’s also caloric restriction is being really one of our important tools. Or time-restricted eating, I guess we could also say.

Dr. Barry Sears – Well, again, it all comes down to two things. One, restricting calories but without restricting nutrition. But people are always trying to find a new clever wrinkle saying, “I know if I eat in a certain window that will do everything.” I’m saying not quite. Here’s my take on calorie restriction. Eat your first meal as soon as you wake up. Eat your last meal before the sun goes down. Now, why is that? Because it’s the change in the intensity of light that basically changes how our body works on a metabolic aspect. This is why studies are quite clear that there’s no benefits of quote, unquote intermittent fasting to continuous calorie restriction. None whatsoever. Second aspect. Intermittent fasting in the morning is of a lot better than intermittent fasting later on in the day.

Dr. Barry Sears – So again, you’re looking at, basically, trying to time your metabolism with the circadian rhythms driven by the intensity of the sunlight. And so that’s why you had those two points when the sunlight intensity is changing the greatest in the morning and the evening. Those are the two times that are my start and stop points. Now, if you live in Boston during the summer you may say “Great news! I can eat all day long.” But then if you live in Boston during the winter you may say, “Bad news, I can eat only a short period of time.” Those are the rules. That’s why a lot of people move down to Florida. You can basically eat longer periods of time, both summer and winter. So intermittent fasting- And it doesn’t take into account the balance of protein, carbohydrate, and fat, it says just eat two meals a day and basically that’s it. What do you tend to do? You eat more calories in those two meals than you would in three meals. Or more calorie per meal than if you had three meals. It’s the amount of calories per meal that has the greatest effect on calorie restriction, but those calories still have to be balanced.

Dr. Barry Sears – Some might say “It’s so hard. Can’t you just make it easy?” If it was easy, everyone could do it. It’s not that hard, but basically it requires a little discipline.

Dr. Kara Fitzgerald – Right. So, if you’re in Florida and you think, “Yay, I can eat whenever” you’re being really mindful of quantity. That’s the break.

Dr. Barry Sears – Even in Florida, the sun does go down. So, I say “Okay, make sure that last bit of food has gotten into your mouth before the sun has gone down.”

Dr. Kara Fitzgerald – It’s pretty interesting. I mean, there certainly are studies really looking at circadian rhythm and dietary patterns these days and that’s fascinating that you realized that some time ago. Caloric restriction. About how much do we want to be dropping? Like how much? What’s caloric intake for, you know, the average 70 kg / 150-pound person? What are we looking at for numbers here?

Dr. Barry Sears – Well, we have now the calorie studies, which is basically about fifty million dollars’ worth of studies asking what happens when you give calorie restriction. Well, the first thing with the calorie restriction, they were very compliant for about the first of, you know, three weeks.

Dr. Kara Fitzgerald – That’s right, and then that was a 25% restriction. The calorie-

Dr. Barry Sears – Eventually at 10%, but-

Dr. Kara Fitzgerald – That’s right.

Dr. Barry Sears – But if you had that balance, remember, if that balance of protein, carbohydrate, and fat, 1500 calories per day is a lot of food because most of the carbohydrates are coming from non-starchy vegetables. So, you’re getting the greatest nutrient amount in the least caloric amount balanced with the protein to stop hunger. You can’t do calorie restriction if you’re always hungry. It’s not going to work.

Dr. Barry Sears – And you also have to basically have a great source of micronutrients. You’re going to get those primarily from the vegetables. So, you’re going to be eating a lot of vegetables just like your grandmother told you.

Dr. Kara Fitzgerald – Right. Fat is very satiating as well.

Dr. Barry Sears – Exactly. And because of the fiber content and the basically, the length of time, because the satiety signals are not evenly distributed through your gut. They’re primarily in the lower part of the intestine, the ileum, and the colon. And those satiety signals, the longer you can maintain them, the less hungry you are. That’s a secret of Wegovy. I’m not hungry. Unfortunately, with Wegovy, you’re also malnourished because you’re not hungry and you’re not eating enough protein, so about 40% of the weight loss is lean body mass.

Dr. Kara Fitzgerald – Yeah, they have shown that. Yeah. I mean, it could-

Dr. Barry Sears – That could be muscle, could be heart, liver, kidney, brain. These are things you don’t want to lose.

Dr. Kara Fitzgerald – Right, right. I mean, it could be effective if it was combined with intelligent eating. But I even see colleagues in the broader sort of nutritional science space, maybe not – maybe the scientific space, the longevity space – very adherent to profound caloric restriction, or time-restricted eating windows where they’re having one meal a day. There’s the one meal a day crew. And to me, that just strikes me as very difficult to get nutrients from food if you’re going to do one meal a day and I think it just sets individuals up for malnutrition.

Dr. Kara Fitzgerald – I mean, we certainly see people coming into our clinical practice who have adopted some of these really restrictive patterns that are popular now, you know, having some fallout. And then we see disordered eating arise because the psyche is going to rebel with these, for some individuals. Some individuals have a lot of discipline but we can definitely see malnutrition start to present itself with some of these really restrictive patterns.

Dr. Barry Sears – And rather than say malnutrition, I’d say basically, long term metabolic disturbances. And so again, people are always trying to say, “I discovered something that nobody else has ever seen before.” And I’m saying, “Hey, get real.” The fact is the verities of medicine and nutrition have been pretty consistent since the beginnings of recorded history. We just have now the science to go deeper into the metabolism and say, “Oh my God, now I know how important it is.” Because the key factor you’re looking for is to activate AMPK. This is your master regulator and the most powerful tool we have in medical science to do that is calorie restriction.

Dr. Kara Fitzgerald – Yeah. Okay. That’s great. That’s awesome. We’ll circle back and talk a little bit about AMPK. First, thoughts on dementia and higher-dose fatty acids to assist in crossing the blood brain barrier, because there’s a real deficit, I think.

Dr. Barry Sears – Well, there is-

Dr. Kara Fitzgerald – A deficit of synthesis of local synthesis. Yeah. Go ahead.

Dr. Barry Sears – This is why the APOE4 allele is so important in terms of predicting who’s likely to get Alzheimer’s. Because that allele is also connected with the transporter that basically moves the fatty acids from the blood into the brain. But the people who have that allele, it’s only 1 to 2% of the population. So here we had to go back and say, do we have a marker of Alzheimer’s much earlier than you’re likely to have Alzheimer’s? Well, before I say, “Where’s my car keys?” The answer is the levels of insulin resistance. So, okay, my first sign is my HOMO-IR is no longer is no longer one, I want to start paying closer attention to my diet because it’s really insulin resistance that is really the underlying cause, not only of Alzheimer’s, but also Parkinson’s. Both of those diseases can be viewed as the batteries are running down in different parts of the brain. It’s in the frontal cortex in Alzheimer’s.

Dr. Barry Sears  – It’s in the locomotion areas for Parkinson’s. And basically, what controls the production of energy in the brain? Mitochondria. And what controls mitochondria? AMPK. So again, all roads begin to converge back. I can look at things like Alzheimer’s or Parkinson’s as basically the batteries are running down. And so, what can I do to get those batteries working better? Well, I have to activate AMPK. And what’s my best easily seen blood marker? The levels of insulin resistance. So basically, we keep on coming back to the same aspects that say the body is giving us simple signals from the blood that allow us to adjust our diet for our particular biochemistry and our particular philosophy. I don’t care where the protein comes from. It can come from non-animal sources, just make sure you get 30g of protein at every meal and balance it off with the carbohydrates, the vegetables being the best because it’s hard to overconsume them, but fruits are fine too, just be a little on the careful side, and a dash of fat.

Dr. Barry Sears – And then basically look at your blood test again and say, do I need extra supplemental omega-3 fatty acids or extra supplemental polyphenols? And call it a day.

Dr. Kara Fitzgerald – What would those supplemental polyphenols be?

Dr. Barry Sears – Well, there’s 8000 polyphenols. “Oh, my God, I’ve got to go to a GNC every four hours.” No, it turns out most polyphenols do not get into the blood. Now, they are broken down by microbes in the gut to smaller phenolic fragments that can get into the blood, but they’re not as effective in changing the levels of AMPK as a full polyphenol. Now, we can ask which polyphenols actually get in the blood. Now we go from 8000 to about one. There’s one subclass of polyphenols, they’re called delphinidins, and these are the most water soluble of polyphenols. Where do you find these? Red wine. “Great news. I can drink my way to immortality.” Unfortunately, to get enough delphinidins, you have to drink about four bottles of red wine per day.

Dr. Barry Sears – So you can see little problems down the road with that strategy. So again, there are polyphenols- And we also know that the delphinidins seem to be the most powerful in basically destroying what are called zombie cells.

Dr. Barry Sears – So if we can get those into the blood, without drinking the four bottles of red wine per day, then basically we have another way of adding on to that fine-tuning mechanism to activate AMPK in every organ in our body.

Dr. Kara Fitzgerald – So, why the attachment to absorbing an intact polyphenol? I mean, the microbiome transforms them into these beautiful postbiotics that have been demonstrated to be potently active.

Dr. Barry Sears – Well, I always use human data, which is always a kind of a short amount.

Dr. Kara Fitzgerald – Well, I’m mentally referencing human data here in postbiotics. I mean, we evolved…

Dr. Barry Sears – The more complex the polyphenol, the more it can basically interact, in this case with the sirtuins that now affect upstream regulator AMPK and turn on that.

Dr. Barry Sears – So as you get the smaller phenolic fragments, they’re not nearly as effective as a full-fledged polyphenol if – and that’s a big if – if we can get it into the blood intact. And this is shown in a study a decade ago looking at elderly Tuscans still eating the old Mediterranean diet. And the researchers said now we can take these old Tuscans and look at one parameter of mortality and say we would expect the more polyphenols they consume, the longer they will live. They did the study and did all the data analysis, and there was no relation, none whatsoever, between the levels of polyphenols consumed and their time of death. They said this makes no sense. So, they went back and said, wait a minute. The polyphenols probably have to get into the blood. They’re hard to measure in the blood, but they had to leave the blood, usually by the urine. So, they took the urine samples, and now they found exactly what they’re looking for. Those who had the most polyphenol fragments in the urine lived 31% longer. So again, it’s really the complexity of the phenolic aspect acting as an allosteric activator, other sirtuins, which now start a whole metabolic process that activates AMPK.

Dr. Kara Fitzgerald – Okay. So that makes absolute sense and there’s a number of studies looking at the postbiotic products in urine and associating those with gene change, you know, looking at epigenetics now, so that’s a thing. What I’m going to do, I mean, I want you to send me these delphinidin papers so we can check it out. And the people listening today who want to dive in can go to the website and read some of the research that you’re referencing. I mean, I think we’re in agreement here when you talk about the Tuscans having high evidence of polyphenol consumption, looking at urine, I think that’s, you know, that’s in alignment with my thinking as well.

Dr. Kara Fitzgerald – But I want to jump over to what we were talking about at dinner, which was really incredibly compelling to me. I’m always paying attention to the science on omega-3 fatty acids. I teach on this. I have for the last- Well, you know, I’ll be teaching shortly to the Institute for Functional Medicine and for the last 12 years now on omega-3 fatty acids. And I’m paying attention to these new pharma studies coming out. I mean, I remember when we were waiting on them and now we’ve got some data and the data is decidedly mixed. I would say that, since they do these composite endpoints where they compile all the events, they want to look at into one bundle, they often don’t see anything significant. And I think that’s the fault of trying to frame basically a nutrition study through the lens of pharma. So, when you tease out the endpoints, all of the studies without exception show some degree of benefit with regard to heart disease, stroke, etc.

Dr. Kara Fitzgerald – You can tease these out and I go through those data every year and there’s always something new, sometimes pro, sometimes con, but there’s always something hot to talk about in the omega-3 space. It’s pretty funny. But one of the things that’s been interesting, and sort of given pause to the community, is this notice that some of these larger trials, these pharma trials, show either a trend towards aFib, not quite at significance or frank significance. The STRENGTH trial was one of them using a carboxylic acid EPA/DHA combination at four grams. That trial was actually halted. When they went back and did an analysis of the data, again, they did show some benefit, but they stopped it short a pretty significant chunk of time, and there was a little bit of an increased risk of AFib. Same with the REDUCE-IT, that was a nonsignificant trend. The OMEMI trial showed again, a significant trend in a certain demographic.

Dr. Kara Fitzgerald – But the ASCEND and the VITAL (studies), which were just under a gram, VITAL looking at healthy individuals, no increased risk in that population. But those other larger trials, where they were using high dose omega-3s, of pharma omega-3s, showed in some cases a trend towards AFib. I do want to say for anybody listening to this that the actual risk, you know, when you drill down, it was reported as 37% increase when they did this meta-analysis, which will make everybody freak out. But when you look at the risk within, how they obtain that percentage, I think overall it was only about 2.5% developed aFib, and just a micro amount of those were associated with the omega-3s. But when you and I were talking, you just really had some interesting thoughts and I wanted you to just share your thoughts on this finding.

Dr. Kara Fitzgerald – And of course, we also know from earlier studies, so let me layer this in, that omega-3s are protective against aFib. So, this came as a surprise to the community for sure.

Dr. Barry Sears – Well let’s start with the last question you posed. It turns out if you look at large-scale studies, the higher the levels of omega-3 fatty acids in the blood, the less aFib you have.

Dr. Kara Fitzgerald – Right.

Dr. Barry Sears – Well, that sounds great. Omega-3 fatty acids are good for you. Now the studies you mentioned, as you correctly point out, are drug studies. Drug companies know nothing about omega-3 fatty acids, but they do know something about marketing. I want to get the highest concentration and say, “I’m the winner.” So, when you looked at the STRENGTH trial, first of all, it was using free fatty acids. Anybody who knows anything about omega-3 fatty acids knows that free fatty acids are incredibly unstable. They cause oxidative stress.

Dr. Barry Sears – So again, they have a patent on it. A patent on a bad form of omega-3 fatty acids. The other studies like the REDUCE-IT, they said we’re going to basically just say it’s all about EPA, so we’ll keep on cranking out our molecular distillation to get higher and higher and higher concentrations and say, We’re number one. Look how high our EPA levels are.” The trouble is that the longer you put these omega-3 fatty acids under the distillation process, you get isomerization. The double bonds now turn nutrients into anti-nutrients. And so, you either have the wrong form that’s guaranteed to cause massive oxidative stress, or you’ve isomerized the fatty acids so that now the pharmaceutical product is causing, basically, an anti-nutrient effect as opposed to a pro-nutrient effect. So again, this is one of the aspects of people have to kind of look and say the drug companies do not make these. They don’t have the knowledge. They buy the stuff and say, fine, we’ll put our name on it, call a day.

Dr. Barry Sears – But the fact is this is a problem that as you go to higher concentrations for marketing purposes, that you’ll get more isomerization. Now, that being said, are you saying I have to go back to taking cod liver oil? No, but there are new technologies that can basically concentrate omega-3 fatty acids without the heat that causes the isomerization and this is called supercritical fluid technology. And when using supercritical fluid technology, it’s more expensive, but basically, the temperature never rises much above 50°C. Molecular distillation is about 200°C. Bad things happen at high temperatures. But then that goes back to saying, looking at the population studies, the higher levels of omega-3 fatty acids you have, the less aFib you have.

Dr. Kara Fitzgerald – So, first of all, looking at isomerization, it makes sense to me. And when we had this conversation in 2023, I came home from that Mexico City conference and I had a follow up chat with Dr. Jeff Bland, the father of functional medicine, and he agreed that this change in structure could be certainly be happening, and so there could be byproducts present in some of these very high doses that could be doing untoward things.

Dr. Kara Fitzgerald  – However, they certainly haven’t been identified. And I did due diligence in attempting to find data on this and I didn’t find anything. Certainly, we’ve looked at, you know, there have been publications looking at oxidized fatty acids. Those have been published, but those tend to be, you know, those are supplement companies. Those are OTC supplement companies where you can see that there’s a broad range of quality. So, you can certainly see oxidation there. But you’re implicating pharma. I mean, you’re saying these products where there’s all sorts of controls going into developing them are producing these byproduct compounds that are really largely undetected and unstudied and that these are driving the, you know, the micro amounts. So, I still want to say that the incidence of EPA/DHA associated AFib in these larger studies is still very negligible.

Dr. Kara Fitzgerald – And we’re still seeing benefit when we tease out those endpoints. But nonetheless, it’s alarming to see it at all. And your suggestion is that’s caused by yet to be identified compounds. Really, it’s the process of making them that seems to have you convinced that they’re there.

Dr. Barry Sears – And it goes back to my early work about 30 years ago working with them, the leaders in the field of manufacturing. They had developed what is called a smell test that they could basically take the GC’s- You may say “Smell test. What kind of science is this?” Well, you could essentially, using mass-spec (mass spectrometry), you could basically not see any changes, but you could smell, as they came through, their dramatic impact and say, “Wow! What was that?” There’s almost nothing on the chromatogram yet, basically it was giving rise to great amounts of some type of interaction with the olfactory signals going to the brain. But this is arcane knowledge.

Dr. Barry Sears – All the early pioneers in fish oil manufacturing, they’re all dead. Their knowledge basically died with them. And so now you have people who have no knowledge. The manufacturing drug companies don’t make this, they just buy from others and put it in their pill. Unlike when they make a drug, they’re actually doing the chemical manufacturing. So, there’s really no inherent knowledge in the pharmaceutical venue about omega-3 fatty acids and their susceptibility to isomerization and oxidation. So again, we have the blind leading the blind. But you’re quite right. The concept is really what’s called the number needed to treat. Saying, “Show me what are the benefits?” I’ll use an example: statins. If you’ve never had a heart attack and the doctor says, I want you to take statins for the rest of your life because you have high cholesterol, you want to ask, “Okay, doctor, what’s the chance that I will not get a heart attack if I take statins for the rest of my life at this dose?”

Dr. Barry Sears – And the answer is 1 in 112. Now when you go to Vegas and put all the money on 36, that’s a better bet than 1 in 112. So, the fact is, that’s why we have to take all the things you get from the pharma, from marketing, and say, a 38% difference? No. Tell me what’s the needed to treat and also what is the needed to harm? A good a good rule of thumb for any drug, the need to treat should be five or less. I’ll give you one example. Aspirin. If I have a really bad headache. I’ll take a big boy aspirin. So, what’s the chances that it will treat my headache? Pretty good.

Dr. Barry Sears – Now everything is context dependent. What if I take a baby aspirin to prevent a heart attack? What is my number needed to treat to prevent one heart attack by taking a baby aspirin. The answer is 3360. So, what, it doesn’t work? You’re right. Baby aspirin doesn’t work for preventing a heart attack, but it does a great job, it’s one of the best drugs known to mankind to stop a headache. So, we have to kind of look between the lines of this relative risk versus the absolute risk, and then ask what’s the number needed to treat, that I will get a benefit for taking this drug? So again, there’s as much, basically, misinformation coming out of the drug industry and their marketing as comes off the internet.

Dr. Kara Fitzgerald – My exploration of this for myself and how I’m going to treat my patients, how I myself am going to approach fatty acids for my family and so forth has been, you know, just again, sort of the understanding that food first is where it’s at. That the structures delivered in a whole food approach are those that we evolved with, that we understand, that are, to your point, most stable.

Dr. Kara Fitzgerald – You’re talking about the supercritical process of developing an EPA/DHA compound and I think we’re going to have to post on that, we’ll need to understand a little bit more about it, versus some of these structural changes to be able to get very high concentrations. And we’re seeing these in a lot of products, I think, beyond big pharma. So whole food first and foremost. I think there’s a place for considering cod liver oil again, I don’t know that we’re going to take it in a tablespoon. Certain cod liver oil products have the resolvins, to your earlier point, present in them. And then you’re talking about supercritical. But it certainly has given me pause even as we see benefit, but to your point, it perhaps takes a lot to see that benefit. Anyway, this is a really interesting and potentially game changing conversation, you know, how we approach the ubiquitously prescribed EPA and DHA.

Dr. Barry Sears – It goes back to basically first principles. You are what you eat. You can’t run from that. And so, I say, what we can do now, we couldn’t do twenty years ago. We now have enough information on the mysteries of metabolism to make some pretty good assessments of basically, what is our goal? Our goal is not to treat the symptoms of a disease. It’s to maintain wellness. So how do we define wellness? I think a pretty good starting point is your levels of insulin resistance. So, if you can keep the resistance low that keep that HOMA-IR less than one, then you’ve got a pretty good chance of going through life without developing chronic disease and earlier aging. So again, how do you do that? Basically, you’ve got to restrict calories, but you need adequate protein, the right type of carbohydrates, a little fat, and we have to make a couple-

Dr. Barry Sears – But the more you do that, the less you have to supplement as a navigational aid. And when you have a terrible diet, you have to put in massive amounts of supplements or drugs to counterbalance the underlying cause-

Dr. Kara Fitzgerald – Yeah. That’s right. And I think, you know, and to your point, when they look at AFib risk in populations consuming omega-3s and a whole food diet, so not supplementing, there is a clear risk reduction in aFib in those with the highest adipose levels or blood levels. I mean, there’s a clear risk reduction in the dietary consumption of omega-3 fatty acids in AFib. A clear risk reduction.

Dr. Barry Sears – And this comes to the aspect of, you know, this pharma mentality saying, drugs are bad, but nutrients are good and I’ll put them in a capsule. I’m saying, same mentality. You’re looking for magic pills. You know, so again, you really want to be looking at saying okay, now that we understand metabolism to a greater extent, what are the dietary things which are under our responsibility, and supplements or drugs should be secondary. Secondary helpers. Not the primary tools in the toolkit.

Dr. Kara Fitzgerald – Yeah. And so, it makes sense. We often look at the quantity of omega-3s present in circulation, but I can see why you lean on the ratio because it’s that information. So, perhaps it’s not how much but it’s the relative amount. It’s pretty fascinating.

Dr. Barry Sears – Exactly. It’s really the context. You need some inflammation but not too much.

Dr. Kara Fitzgerald – Yeah.

Dr. Barry Sears – As we come back to that word, zone, over and over and over again. Your goal is to try to find that right zone using the food you eat to basically have your primary marker, insulin resistance, always low. And if you’ve done that, you’re going to go through life pretty well.

Dr. Kara Fitzgerald – Well you’re doing well. You know, it was great to meet you and I know part of your backstory is wanting to prevent the ubiquitous cardiovascular disease that was present in your family.

Dr. Barry Sears – Well and, so far, I’ve done a pretty good job. I’ve also found out why I had that background. My whole family had a long background of early death from cardiovascular disease. But it turns out that for myself and my brother, we both have incredibly high levels of LP(a) (lipoprotein (a)). Guinness Book of World record levels. Now I can’t change that. But what you can do, you can basically change how your body responds to that. So again, this explains a lot about why we had the genetic history. My father was a world class athlete and he died in his early 50s because we had a genetic problem that basically says bad break. But you can overcome it if you’re willing to basically put in the effort and the work. And what’s the benefit? A longer and better life.

Dr. Kara Fitzgerald  – Did you decide to layer medication into your approach or are you using completely nutrition sort of zone-based approach?

Dr. Barry Sears – Well, it’s still high.

Dr. Kara Fitzgerald – Yeah, right. Absolutely. But people I mean-

Dr. Barry Sears  – So what you’re looking to do is say, okay, now we’ll use nutrition. I call it metabolic engineering – it makes it a little classier – metabolic engineering to decrease the negative side effects of a high level of LP(a).

Dr. Kara Fitzgerald  – That’s right. Yeah. We’ve got at least one blog on our website and Lp(a) we can link to you folks. Yeah, this would be a whole other conversation. There’s Lp(a) in half of my family as well, and I lost my grandfather to a sudden cardiac death when he was 60, so I know that story. And, yeah, it’s incredibly difficult. You really need to address everything around the Lp(a) to render the Lp(a) a non-variable.

Dr. Barry Sears  – Or address the consequences if you have high levels of Lp(a), saying okay, I can’t fix this, but I can’t fix the consequences, so I can live with it.

Dr. Kara Fitzgerald – Yeah. I think it’s an approach that makes sense to me. Well, listen, Dr. Sears, it was great to have you on New Frontiers today. I just want to thank you so much for joining me, and we’ll have to do it again.

Dr. Barry Sears  – It was a lot of fun.

Dr. Sears is a leading medical researcher. He’s the author of more than 50 scientific publications. He holds 14 U.S. patents in diverse areas, including intravenous drug delivery technology for cancer treatment, cardiovascular disease treatment, and the reduction of insulin resistance. He also has academic appointments at the University of Miami Medical School, Arizona State University, and the University of Cartagena in Columbia.

bsears@drsears.com

Websites

http://www.drsears.com/

http://www.zoneliving.com/

http://www.inflammationresearchfoundation.org/

Dr. Barry Sears

Zone Living website

The Zone Diet

Dietary Control of Inflammation and Resolution

Inflammation Research Foundation

The STRENGTH trial – Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk The STRENGTH Randomized Clinical Trial

OMEMI Trial – Effects of n-3 Fatty Acid Supplements in Elderly Patients After Myocardial Infarction: A Randomized, Controlled Trial

A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High-Risk Patients With Hypertriglyceridemia and on Statin (REDUCE-IT)

ASCEND Study

VITAL Study

Today Show appearance discussing zombie cells

Dr. Nathan Price

Longitudinal Study – Multi-omics Biological Age Estimation and Its Correlation with Wellness and Disease Phenotypes

The Determinants of Glycemic Responses to Diet Restriction and Weight Loss in Obesity and NIDDM

High Glycemic Index Foods, Overeating, and Obesity

The Why WAIT Program: Improving Clinical Outcomes Through Weight Management in Type 2 Diabetes

The Relationship Between Urinary Total Polyphenols and the Frailty Phenotype in a Community-Dwelling Older Population: The InCHIANTI Study

A Randomized Clinical Trial Evaluating the Efficacy of an Anthocyanin–Maqui Berry Extract (Delphinol) on Oxidative Stress Biomarkers

Delphinol® standardized maqui berry extract significantly lowers blood glucose and improves blood lipid profile in prediabetic individuals in three-month clinical trial

Bioavailability Study of Maqui Berry Extract in Healthy Subjects

Therapeutic uses of high-dose omega-3 fatty acids to treat comatose patients with severe brain injury

Dissociation of C-Reactive Protein Levels from Long-Chain Omega-3 Fatty Acid Status and Antidepressant Response in Adolescents with Major Depressive Disorder: An Open-Label Dose-Ranging Trial

Effect of six month’s treatment with omega-3 acid ethyl esters on long-term outcomes after acute myocardial infarction: The OMEGA-REMODEL randomized clinical trial

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