RHR: The Health Benefits of Tocotrienols, with Dr. Barrie Tan

In this episode, we discuss:

• The difference between tocopherols and tocotrienols
• Tan’s discovery of tocotrienols in annatto
• Early studies on tocotrienols
• Benefits of tocotrienols on cholesterol
• Benefits of tocotrienols on cardiovascular and metabolic health
• Benefits of tocotrienols on inflammation and oxidative stress
• Benefits of tocotrienols on cancer prevention and treatment
• How to best utilize tocotrienols

Show notes:

• Barrie Tan’s website
• Tan is offering our listeners the opportunity to download his book The Truth About Vitamin E for free. Visit barrietan.com/book and enter the code Revolution Health for your free copy.
• Achieve your health goals and live your best life with Adapt Naturals. Join the email list at chriskresser.com for the latest updates on the July launch of the Core Plus bundle.

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Hey, everybody, Chris Kresser here. Welcome to another episode of Revolution Health Radio. About 10 years ago, when I created the High Cholesterol Action Plan, which is a digital education program for people with lipid abnormalities, I came across in my research substances called tocotrienols. They’re a form of vitamin E, but not the most common form that you’ve probably heard of. If you have a multivitamin or a supplement that has vitamin E in it, chances are it’s tocopherol, alpha-tocopherol, specifically. And it turns out that tocopherols, even though they’re the best known form of vitamin E, have some downsides.

Studies have shown over the years that supplementing with alpha-tocopherol may increase the risk of cancer and heart disease and cause other problems. Whereas tocotrienols, which are not as well-known and were only discovered in the 1960s and [were] clearly distinguished from tocopherols in the early 2000s, just 20 years ago, are far more beneficial as a family of dietary compounds and have shown pretty remarkable impacts in terms of reduction in cardiovascular risk factors, metabolic risk factors like glucose and insulin, inflammatory markers, like C-reactive protein and interleukin-6, and a wide range of cancer prevention benefits and potentially even cancer treatment. So it’s an exciting family of compounds, and, as I said, I stumbled across them about a decade ago when I was researching natural approaches for lowering [low-density lipoprotein] (LDL) particle number, thus reducing cardiovascular disease risk. I found [that] delta- and gamma-tocotrienols are one of the few natural substances that were known to do that. I’ve been aware of these compounds for many years and [am] using them in my clinical practice. But I realized recently that I had never done a podcast on tocotrienols, and I don’t believe that I’ve ever written a full blog article on them either. So this is my attempt to remedy that.

In order to do that, I asked one of the foremost experts on tocotrienols in the world to join me on the show, Dr. Barrie Tan. Dr. Tan actually discovered the tocotrienol content in annatto. He was in South America and was a pioneer in this field. He earned his PhD in chemistry and biochemistry from the University of Otago in New Zealand and then spent several years as a professor at [the] University of Massachusetts. His work is focused on lipid-soluble nutrients that impact chronic conditions, and he was the first to introduce the benefits of tocotrienols to the nutrition industry and the first to develop a tocopherol-free tocotrienol product that was derived from annatto, which he discovered. He didn’t discover annatto, of course, but he discovered that annatto was a source exclusively of delta- and gamma-tocotrienols.

I was really excited to have the chance to talk with Dr. Tan, as I’ve known of his work for many years, and to hear his fascinating story [about] the discovery of tocotrienols in annatto, and all the amazing research that he has done since then and is still doing on the benefits of tocotrienols on everything from osteoporosis and bone health to metabolic conditions to reduction of the risk of cancer. So I hope you enjoy this interview as much as I did. Let’s dive in.

Chris Kresser:  Dr. Tan, welcome to the show. It’s such a pleasure to have you on.

Barrie Tan:  Thank you. [I] love to be doing this, and I’m glad to be [on] your show.

The Difference between Tocopherols and Tocotrienols

Chris Kresser:  I want to dive right in and talk about a little bit of history here. A lot of listeners will be aware that vitamin E is an antioxidant, and they may have heard back in the ‘70s, ‘80s, ‘90s even, and to this day, in some circles, [that] there’s been a big recommendation to supplement with vitamin E to improve your antioxidant status. But several years ago, there were some disturbing studies about the long-term effects of supplementing with vitamin E. And we’re, of course, going to get more clear about what we’re actually talking about when we say “vitamin E.” But there were some disturbing studies that showed that long-term supplementation with higher doses of vitamin E could actually increase the risk of cancer and heart disease and cause other problems. And I think a lot of people got turned off to the concept of vitamin E supplementation.

I myself wrote about these studies many years ago and was concerned about the impact of long-term supplementation with vitamin E. Then a few years later, [I] discovered that, when it comes to vitamin E, there are actually two different forms, and they’re very different in their biological effect on the body. You were instrumental in this field in making these discoveries and really advancing the knowledge of one of the isomers of vitamin E, tocotrienol, which we’ll be talking about today. Can you tell us a little bit of your story and how you stumbled across tocotrienols and got interested in their biological effects?

Barrie Tan:  Well, thank you for that wonderful introduction. Since you mentioned that vitamin E in the last 20 years has done more harm than good, for example, in some cancers, and in women in many [ways]. When you get a chance to download my book, I describe all these different [ways where] vitamin E could be troublesome. That troublesome vitamin E is referring to alpha-tocopherol because alpha-tocopherol was [the] first to be discovered, and, therefore, you have a long history of usage. Just [to] keep the story simple, the reason alpha-tocopherol [has] done damage is this: there are eight vitamin Es, four tocopherols and four tocotrienols, and they’re all antioxidants because of the head. It has an O-H group that [is] antioxidant. The only distinction between the tocopherol as a group and the tocotrienol as a group [is that] the tocotrienols have three double bonds in the tail, hence “trien.”

So the tail is a little bit shorter, and, in simplistic terms, the shorter tail allows it to insert into the cell membrane, and it can circle around going much faster to capture free radicals, and hence is a more potent antioxidant. Tocopherol can’t do that. [But] that doesn’t explain why tocopherol is toxic or potentially could be if you take huge amounts.

The reason is because the alpha-tocopherol has a transport protein, meaning that it has a chaperone to ensure it’s entering into the body. When people take 400 milligrams, [or] 1000 milligrams, or even 2000 milligrams, a huge amount goes in, is conserved, and it’s not coming out. The tocotrienol[s] have no such luck. The body only takes whatever it needs, [and] whatever it does not is not going to go in. So that would be the main reason [for] one compared to the other.

Dr. Tan’s Discovery of Tocotrienols in Annatto

So now, [here’s] the story. I went to South America about 25 years ago to look for lutein. I’m sure you have interviewed other people on lutein for the macula. At the time, it was 1989, 1990. Very few people [had] heard about lutein. I [had] because my entire studies when I was an assistant professor at the University of Massachusetts was on carotenoid. They are unconjugated double bonds, so I studied beta-carotene, alpha-carotene, lycopene, [and] astaxanthin.

Chris Kresser:  These are now terms that everybody has heard of, but back in 1989, they were unfamiliar, right?

Barrie Tan:  Yeah.

Chris Kresser:  So you were down in South America looking for a source of lutein? Is that what you were doing?

Barrie Tan:  Yeah, a source of lutein. [I was there with that] goal, and I [found it]. But fate has it that literally 30 feet away from me, I saw these beautiful annatto plants.

I was in South America then, and subsequently, I’ve been to many countries. I saw this plant. Think of a fruit that you eat; you will always have a fleshy part. Where the fleshy part is in this fruit, the pod is the fruit. When I opened the pod [of the annatto], the fleshy part [was] air. So it’s a very unusual fruit in that it doesn’t have a mesocarp, unlike papaya, apple, pear, oranges, [and] everything else. [It’s] just empty, and when you touch it, it stains your hand. [The] British nickname is the lipstick plant because it stains your hand, and instantly, I knew that [it] was a carotene.

Now, this is [a] long [time ago]. I knew that, among chemicals, probably one of the most unstable organic chemicals is carotene. Not omega-3, by a longshot. If you know omega-3 is unstable, this will be far more unstable. Now in life, when you see carotene like beta-carotene in carrot, [and] lycopene in tomato, you have to put it in a sauce and turn the heat up. I’m actually telling you something simple, but you get the gist. You have to cook it before you can see the oil turning color. That means that the carotene is well-preserved inside the cytoplasm. Individual cells of each of those. If you live in New England, [like] where I’m [at] in Massachusetts, think [of a] lobster, think [of a] crustacean. They’re usually greenish, yucky green, [or] bluish color. The moment you cook them, [they] immediately become brilliantly orange or pink. That means that in the crustacean, they deprotonate and the carotene comes up. They are well-preserved. All this to say [that] nature does it this way. This is the only exception to the rule. Because it’s not bound to anything; it stains your hand. I have many thoughts in life. Most of them come up in a dead end. This is one of those that did not dead end. I thought, “There must be a powerful antioxidant that preserves this carotene from degradation.” Little did I know, it was tocotrienol. I was guessing. It would be a polyphenol, this antioxidant. It was a pure stumbling on it; [I was] looking for carotene like lutein, and then I stumbled onto this approximately 20 to 25 years ago.

Chris Kresser:  A very serendipitous accident.

Barrie Tan:  Yes.

Chris Kresser:  It turned out that you had stumbled on a pure source of delta- and gamma-tocotrienol. Whereas palm and rice and other sources of tocotrienols have a mixture of delta- and gamma-tocotrienol [and] alpha- and beta-tocotrienol, which are less potent, and then tocopherols, which can actually interfere with the actions of tocotrienols, which we’ll come back to. Just sticking with the historical view here, tocopherols in vitamin E as a family were discovered in the 1920s or something. About 100 years ago, right?

Barrie Tan:  Yes.

Chris Kresser:  When was tocotrienol discovered? When was it discovered that tocopherol was not the only form of vitamin E?

Barrie Tan:  Actually, you touched on something auspicious, you [could] say. It’s exactly 100 years ago [that] alpha-tocopherol was discovered by two pediatricians [at] UC Berkeley. It is a very American affair. They extracted it and [saw] that without the alpha-tocopherol, [a] fetus is unable to get to full term. It is precisely that [which] makes alpha-tocopherol and all the tocopherols and tocotrienols a vitamin. It is not because of its antioxidant property; it’s that. Otherwise, [it would] never become a vitamin. If you fast forward 40 years, [it] was about the 1960s [when] the USDA lab and [a] University of Liverpool professor together jointly discovered [it]. At the time, they [didn’t] have chromatography. They saw a shadow spot next to the main spot of alpha-tocopherol. For normal tocopherol, you have alpha, beta, delta, [and] gamma. Very simple, four Greek letters. But if you look at old literature, you will see nu, epsilon, zeta, and phi tocopherol. Those nu-, epsilon-, beta-, and phi-tocopherol[s] were mislabeled. They were tocotrienol[s]. They just thought that they were tocopherol[s].

Chris Kresser:  I see.

Barrie Tan:  You know when they corrected that? Almost in the year 2000. They finally [got] to correct it, and then they [became] properly called alpha-, beta-, delta-, and gamma-tocotrienol.

Chris Kresser:  You’re saying in some way, they were discovered back in the 1960s. But they, at that time, were still believed to be part of the tocopherol family, and they weren’t properly distinguished as a separate family called tocotrienols—alpha, beta, delta, and gamma—until just 20 years ago, basically. A little over 20 years ago.

Barrie Tan:  Isn’t that amazing?

Chris Kresser:  It is amazing.

Barrie Tan:  The reason I got into that was [in the year] 1982, I was much younger than I am now and still living in the same place, Hadley, Massachusetts, two hours inland from Boston. I was an assistant professor at [the] University of Massachusetts, and it was there [that] I started to study palm and rice and discovered this. By that time, I already knew about these tocotrienols, [but] I wasn’t expecting it in palm. And then I discovered [it] in palm.

So my timing of getting it is not by design, [but] by default. Much of my life is like this. I happened to be in the right place studying palm oil, and then I happened to be in South America looking for something else, and something [happened that] distracted me to do this. Now, my life and career [rests] on this. There’s so much on this tocotrienol that we have [studied]. Given a chance, I can explain later what we have done in clinical trials and animal studies on this. It would be amazing if our audience and listeners [did] not seriously consider using this amazing phytonutrient given to us by nature.

Chris Kresser:  Yes. As we were talking about before we started the recording, I’ve been fascinated by tocotrienols and using them in my practice for many years, and have been surprised that not many clinicians know about them and even fewer patients or individual people know about them. So I am looking forward to diving into the benefits of tocotrienols and how they can help us optimize our health in this modern world that we’re living in that, unfortunately, [has] so many threats in terms of sources of inflammation and oxidative stress and all the other challenges that we face.

Before we do that, I want to look a little bit [at the fact that] tocotrienols were a little disappointing at first for us in the research literature for what maybe was a surprising reason. The early studies on tocotrienols you mentioned in your book were somewhat disappointing. Why was that?

Early Studies on Tocotrienols

Barrie Tan:  Early [on], I wasn’t the only person involved in it. At the time, there [was] an abundance of tocotrienols that you could get from palm oil because palm oil was available. Annatto was nowhere to be seen. I stumbled onto [that] almost 20 years [later]. It was only from palm oil, and coincidentally palm oil contained 25 percent alpha-tocopherol. So when they gave it to animals [in] studies, the cholesterol and the lipids [of the animals] would drop. Then when they did clinical studies sometime later, they noticed that [out of] five studies, two worked and two didn’t and one [was] in between. So it’s 50/50. [There’s] no statistical anything like that, so it was very disappointing. Then [a] University of Wisconsin professor and [I] said, “Hey, we’ve got to find out why because we cannot just do a lot of clinical studies when it’s so equivocal.” So they stopped clinical studies. That means another 15 years [had] been wasted. This [was] a very painful time for researchers. They stopped. They published a seminal paper in 1997 that simply stated [that] they were guessing that the alpha-tocopherol is not innocuous, which they earlier presumed. Remember, in nature, we thought [that] if something is good, then a symmetry, a combination of that is good. Ordinarily, that is true.

Chris Kresser:  Especially in plant medicine, that’s usually true, where you have the full spectrum of compounds.

Barrie Tan:  Yes, that is true. Now one has to ask, if the possibility of synergism exists, then any rational thinking person should also accept the possibility [that] antagonism may also be there. Usually, it isn’t. But in this case, as an exception, it is. So they removed all the alpha-tocopherols, they used the delta- and gamma- [tocotrienol, and] it work[ed] to lower cholesterol and lower lipids. Then they used the same amount of tocotrienol, [but] they added in [a small] amount of tocopherol, [and] they noticed a slight drop, not too significant. In another study, they increased the tocopherol, and then they saw that the [tocotrienol] ability to lower cholesterol [went] down, and eventually, [they] increased the amount [of tocopherol until there was the] same amount of tocotrienol and tocopherol, and it completely inactivated the tocotrienol ability to lower cholesterol.

So they came up with a conclusion that alpha-tocopherol mitigates or interferes with the function of tocotrienol. Twenty-five years later, we have systematically seen that if you add alpha-tocopherol, [it] not only inhibits the ability of tocotrienol to lower cholesterol and lipid, [but] it also inhibits the tocotrienol ability to go after cancer and other chronic conditions. So now we clearly know this.

Chris Kresser:  That was an amazing discovery, and so helpful in terms of advancing the field of research on the benefits of tocotrienols. I want to pause here to make [it] clear [to] the listeners why this is such an important discovery. Most multivitamins contain alpha-tocopherol, and most supplements that people would choose off the shelf contain alpha-tocopherol. So even if you were to take tocotrienols separately, if you’re simultaneously taking a high dose of supplemental tocopherol, you’re basically canceling out the potential benefits of those tocotrienols.

In your book, you mentioned that this is true for supplements, but not true for the amount of tocopherol that you would get from a healthy normal diet. So what is the threshold? And when do people need to be concerned about their tocopherol intake?

Barrie Tan:  If you take a normal diet with normal vegetable oil and meat, because the fat may contain vitamin E, typically, one would get about 10 to 15 milligrams of alpha-tocopherol at the most. And that may be combined with other gamma-tocopherol, which has no strong vitamin E properties. But let’s say 10 to 15 milligrams. At 10 to 15 milligrams, if you were to take 100 milligrams of tocotrienol, so the tocopherol is about a 10 to 15 percent proportion, the interference would be minuscule, if any. Sometimes people take about 300 milligrams, [making] the composition of alpha-tocopherol about 5 percent or less, [and] then [it] would not matter.

Learn more about tocotrienols and the amazing potential they hold to benefit your health, in this episode of Revolution Health Radio #chriskresser #vitaminE #antioxidants

When it begins to matter is when it is about 20 percent and above, like 20 or 30 percent. That would be if somebody is taking 200 IU or 400 IU alpha-tocopherol or 1000 IU. If you take [that] much, then you completely swamp the ability of tocotrienol function.

Benefits of Tocotrienols on Cholesterol

Chris Kresser:  Let’s dive in now to the features of tocotrienols, perhaps starting with their cardiovascular protective benefits. That’s how I first learned of them, [when] I created a digital education program called the High Cholesterol Action Plan. My [clinical] practice was full, [and] I wasn’t able to see as many patients as I wanted to, and I knew so many people were struggling with high cholesterol and other lipid abnormalities. So I wanted to create an educational program that condensed a lot of what I had learned in my research and [from] treating patients, and give people [the] tools that they could use safely on their own to improve their lipid profiles.

In my research, I had learned about the important difference between LDL cholesterol and LDL particles, and that LDL particles, according to many lipidologists, are really the driving force behind heart disease, not so much cholesterol. It’s in the particle, but the particle itself. The issue was [that] there was a lot of research [and] a lot written on how to lower cholesterol, but there were very few substances, either pharmaceuticals or natural substances, that had been shown to actually lower LDL particles. I found some studies suggesting that delta- and gamma-tocotrienols could do this, and I started using them in my practice and had amazing results. I saw significant changes in LDL particle numbers, [apolipoprotein B] (ApoB) came down, [and] I even saw changes in lipoprotein(a), [Lp(a)], which is thought to be mostly genetic and not modifiable by diet. And then I saw C-reactive protein (CRP) come down. I saw oxidized LDL come down because of their effects as antioxidants. And I became a tocotrienol convert. Tell us a little bit about the research on tocotrienols and lipids and other cardiovascular risk factors.

Barrie Tan:  I think what you just talked about, LDL going down, particle size, and the oxidized LDL, [CRP], ApoB, LP(a), and [high-density lipoprotein] (HDL). We’ve done many studies on it. But before I dive into that, I just want your audience to know that [it] was a while back when we did that. Today, we have covered, to the extent that we could, [using] tocotrienol on chronic conditions. You can ask me later what [the] different kinds [are]. But this was the first one we went after. The second one we went after was a big thing for me to bite, but I bit on it, and right now, we’re still working on it. And that chronic condition is cancer. We have eight clinical trials in Denmark on cancer. [I’m] excited about that. But alright, let’s get back to it.

Chris Kresser:  We will definitely talk about cancer because to me, that is one of the most exciting potential applications of tocotrienol is [the] prevention and perhaps even treatment of cancer. As we all know, that’s a growing problem and something that we desperately need new therapeutic tools for. So, yes, let’s come back to that. Maybe we could talk a little bit about the mechanism because this is a fascinating thing about tocotrienols is [that] they reduce the activity of HMG-CoA, which is the same enzyme that’s targeted by statin drugs, which everybody listening to this [show] is familiar with. So maybe we could start there.

Barrie Tan:  Since you mentioned HMG-CoA, that is a pathway for making cholesterol, yes. And if you look at it, again, they have a farnesyl group. If you look carefully [at] the farnesyl group, it’s not so dissimilar from some of the side chains of a statin drug, which is classically used for lowering cholesterol. I know the audience is not looking at this visually, [but] if I block away the O-H group, that whole thing is a farnesyl group. So when you take tocotrienol, the tocotrienol with the farnesyl group downregulates the HMG[-CoA] reductase enzyme, telling the liver to make less of the reductase enzyme, and, therefore, it’s making less cholesterol. So it’s a very gentle process, and hence, we have never seen people complaining about muscle problems of any kind or [coenzyme Q10] (CoQ10) drop of any kind, [which] is a consequence of taking a statin drug. If this were to be a tocopherol, I know the audience cannot see where my finger is pointing [on the diagram], [but] there is a double bond here. One, two, and the last one is where my pinky is, those three. If you remove the three double bonds, the tail will be a tocopherol, that is not a farnesyl anymore. That’s a phytyl, and a phytyl is unable to downregulate the HMG[-CoA] reductase. Only this farnesyl could. And then, while I’m at [it], this farnesyl tail is perfect. If you think of a cell membrane cell wall, of all natural ingredients that are antioxidant, a tocotrienol is perfectly able to snug into a membrane, and it is there [that] it is an antioxidant. Otherwise, there are so many antioxidants. Pick one. There’s resveratrol. Astaxanthin, very powerful and well known. They are not going to compartmentalize here. Why? Resveratrol, for example, has four O-H groups, hydroxy groups, and astaxanthin has about two or three. So it is a two-headed snake. All the O-H groups [are] making it stick out. Nothing is able to stick into the lipid membrane. This molecule, can you see [it]? The O-H group here sticks out. This entire tail has to go into the membrane. I have never seen [this] in nature. There was an Austrian professor in the 1980s [who] decided to answer this question so long ago. He decided that if you boil it down and extract all the antioxidants from a cell, [then] what are those antioxidants coming up on the very top, which [is] about 90 percent of it? They are tocopherol and tocotrienol. And the remaining 10 [percent] are CoQ10 and a smidgen amount of beta-carotene. [There’s] no mention of any other. They’re not there. They protect elsewhere, but not the cell. And the cell is what [needs] the most protection.

Chris Kresser:  Eventually, I’d love to do a video podcast for this reason, so we can show people instead of just telling them.

I want to linger on a couple of things here because I think they’re really, really important. The first is that, in your book, you refer to the action of tocotrienols and the HMG-CoA enzyme that statins affect, as discriminate cholesterol reducers. In other words, they do it in a way that is, you said, more gentle, but also more [discriminating]. Whereas statins, if we could use an analogy, are more of a sledgehammer in terms of just slamming the HMG-CoA enzyme so that very little cholesterol is produced. And that, of course, has potential downsides.

If you inhibit that whole enzymatic pathway, you’re not just reducing cholesterol, you’re reducing CoQ10 and other important substances that come out of that pathway. Whereas with tocotrienols, not only do they have a more gentle impact on that enzyme, [but] they don’t seem to interfere with CoQ10 production, and that may explain why there are really no side effects when taking tocotrienols compared to statins where people can experience, in some cases, pretty serious myopathy, sexual dysfunction, and even severe disorders like rhabdomyolysis in some rare cases. I think that’s a really important function of tocotrienols that I want to make sure everybody understands. The other piece of this is [that] it looks like tocotrienols don’t just affect cholesterol; they can also reduce triglycerides, which is a very important function when it comes to both cardiovascular and metabolic health. Do they do that? What’s the mechanism for that, the impact on the liver? But through a different pathway, I assume?

Benefits of Tocotrienols on Cardiovascular and Metabolic Health

Barrie Tan:  The triglyceride pathway is less studied than cholesterol, and even though [it’s] less studied, it [was] my understanding that it had greater clinical significance. We were studying people who have high cholesterol, [but] otherwise, not diabetic or pre-diabetic. But we consistently noticed that the triglyceride dropped. The mechanism is [that] on tocopherol, the triglyceride drop and the triglyceride synthesis is another pathway called [sterol regulatory-element binding protein] (SREBP), some other related thing. I put it in the back of my head that the triglyceride dropped. I have been a member of the American Diabetes Association for some 30 years, and I’ve [listened] to people again and again, to the different talks and mechanisms that they have. Usually, they look for some kind of clinical endpoint. Then I never forgot Professor Gerald Reaven, [who] was about to retire, [and was] a medical doctor endocrinologist from Stanford University. He was the one [who] noted in the mid-‘70s, late ‘80s that there [was] a cluster of metabolic disorders. He [could] define that the triglyceride went up before they became diabetic, [and] the sugar [went] up. [But] because he couldn’t understand how to bind them all together, he called it syndrome X, which later was defined and is [now] called metabolic syndrome. It was that gentleman who came up with it. And now, unless you’re older, you probably did not even know it was called syndrome X before.

He told me that before people have hyperglycemia, their triglycerides go up first, and I got it in my head that hypertriglyceridemia precedes hyperglycemia. I never forgot it. So when somebody is diabetic, they always have high triglyceride [in addition to] high sugar. But [in] somebody who is pre-diabetic, they have high triglyceride, [but] the sugar is not at the legal limit where they are diabetic. Because of the triglyceride issue, in the last 15 years, we have done two to three studies on diabetes and pre-diabetes, and [also] three studies on people with fatty liver disease. In diabetes and pre-diabetes, we consistently see that the management of the lipids is controlled and the sugar is under control. When we say [the] sugar [is] under control, we measure it a little bit more symptomatically than emotionally, so to speak. Emotionally means we’ll look at the fasting sugar the next day. It’s an important number. A1C would be what maps the sugar in the last 90 days. But we went further. We wanted to see how this is with insulin. The American Diabetes Association said that you should measure the insulin as well as the sugar together. They call it the HOMA-IR, [which] is hemostasis [where] you look at the insulin and sugar together. When we saw that the HOMA-IR was able to drop, we knew for sure that [it] is controlling the sugar and also increasing the sensitivity of the insulin.

Ladies and gentlemen, tocotrienol is able to increase the sensitivity of insulin. That is big. With that, then you can see that the control of the sugar is coming back. It’s from out of kilter to in kilter. I’m encouraged by that. We went all out. My company’s a small company. We went all out [with] this study. [We did a] three-month study and then a six-month study, finish and publish and work. And now we’re completing a 12-month study on people with confirmed non-alcoholic fatty liver disease, which is another side of metabolic syndrome. We saw three things. The inflammation is in control, the liver enzyme [aspartate aminotransferase] (AST), [alanine aminotransferase] (ALT) is in control, the sugar, including the HOMA-IR, is in control, [and] we even saw that the extent of steatosis, the fat in the liver, and fibrosis, [are] also in control. Ladies and gentlemen, this is a nutritional supplement. I am so thrilled because approximately 25 to 30 percent of Americans have fatty liver [disease]. You would think about 30 years ago, [this] kind of cirrhotic liver would have come from alcohol drinking. Of course, that still won’t go away. But who would have guessed [that] by consuming [a] high amount of fat, especially saturated fat, you can also have [a] liver that looks cirrhotic like somebody damaged by alcohol.

Chris Kresser:  Yeah, and lots of processed and refined carbohydrates play a big role there with a non-alcoholic fatty liver, and those numbers continue to go up, unfortunately, every year. Having a natural and safe tool to combat that is just remarkable. I know from your book and from research that I’ve read that the mechanism for many of those benefits is thought to be [that] the tocotrienols activate [peroxisome proliferator-activated receptor-alpha] (PPAR-alpha), which is a protein that controls the genes that are involved with burning fatty acids for fuel. This is a protein that’s received a lot of attention in the research literature over the past 10, 20 years as metabolic syndrome rates have skyrocketed and gone through the roof. It’s a target of drug research and drug discovery. And here, we have a natural compound, an essential vitamin, or a family of vitamins that can activate this compound, which is amazing.

Barrie Tan:  Thank you for bringing that up. The PPAR, I sometimes forget about that. It increases the oxidation of the fatty acid to convert energy. There’s PPAR, and then the other one is SREBP. It encourages [the] control [of] the synthesis of triglycerides. So one is controlling the triglyceride synthesis and the other one is converting the fatty acid to energy. Those are the two routes. I have not delved as much into the mechanism for the triglyceride one as I did with the cholesterol one, because I was so stunned by the [fact] that it’s able to control the triglycerides. So I went more on the clinical side in this one. I answered the way I did just now. I mean, my goodness, it’s able to reduce scarring tissue of the liver and reduce fat storage in the liver. That is big news. So I’m really glad. Shortly in the future, I will be speaking more [in] those areas.

Benefits of Tocotrienols on Inflammation and Oxidative Stress

Chris Kresser:  So I want to touch on a couple of other mechanisms, which I think are important because they underlie all chronic, modern diseases, and those are inflammation and oxidative stress, including cancer. We can use this as a segue to talk about cancer and maybe briefly touch on bone health on the way because that’s also a consequence of inflammation. Tocotrienols are powerful antioxidants, as you’ve mentioned several times. I thought it was interesting in your book that you mentioned that alpha-tocopherol, which again, is the form that many people supplement with, can actually increase the oxidation of LDL, whereas tocotrienols are decreasing LDL oxidation and other forms of oxidative stress. What’s going on there?

Barrie Tan:  Yes, that study was done by an oncologist in Chicago. As soon as I [stumbled upon] that paper, almost 15 years after it was published, I desperately was trying to contact this professor. She had moved on to San Francisco, and I [was] unable to reach her. Her study was very simple. She was treating women with breast cancer and heard that many of them [took] antioxidants, especially alpha-tocopherol. She was able to get an institutional review board to do a study whereby they [took] tocopherol and then she [was] able to biopsy the tissue and then biopsy the tissue [again] one month after, so that you have the cells to study these from the breast. These are women with confirmed breast cancer. She was expecting to find that the alpha-tocopherol would provide strong antioxidative protection [and] that the cancer cell [would] be [under] control and reduce damage. She found the exact opposite. It was pretty alarming. She found that instead, there was no protection, and she saw certain biochemical markers suggesting that the cancer cell was proliferating. When I saw the cancer marker was proliferating, I went to look at tocotrienol on those cancer markers [in] our studies we did, and then I said, “Oh my goodness; the tocotrienol is supposed to go after those markers and nail it.” And that’s why the cancer went away in breast cancer, and there are many, many studies like this.

But I was not able to contact her. I was able to dish out papers that show that when people give tocotrienol and it works, and then they add back tocopherol systematically, it can systematically and progressively and dose-dependently inactivate the ability of the tocotrienol to kill the breast cancer. After that, they’ve done it with colon cancer, prostate cancer, and many other cancers. All that to say, alpha-tocopherol can mitigate. But the one that this professor did was even more surprising. She did not [give] tocotrienol. She just gave them alpha-tocopherol, and the alpha-tocopherol increased [the cancer]. Unrelated to [that] study, the Harvard study shows that [a] high intake of alpha-tocopherol may even cause cancer. There it is; I’m just bearing it out.

If I say more, it will look like I’m trying to demonize alpha-tocopherol. I believe when people [have] a normal, healthy diet [where they’re] attaining about 10 to 15 milligrams of alpha-tocopherol, that is good enough. If you supplement vitamin E, please supplement tocotrienol.

Chris Kresser:  I couldn’t agree more. Science is a process of learning and continually disproving our hypotheses and being willing to admit when we were wrong, and hopefully, making better choices going forward.

Barrie Tan:  [I agree] 100 percent.

Chris Kresser:  With alpha-tocopherol, that’s the story. And that’s been the story with many, many other things that seemed promising initially, and then turned out to be not so promising. We also have a tendency in this country, especially, to think if a little bit of something is good, then a lot of it must be better. And that’s not always the case, as we’ve learned with alpha-tocopherol.

I want to touch briefly on the anti-inflammatory properties of tocotrienols because those are pretty remarkable. Like I said, and everybody who listens to this show knows, inflammation is at the root of all modern disease[s]. So anything that’s anti-inflammatory is going to, by definition, have a wide range of impacts across a wide range of inflammatory conditions.

In your book, you highlighted a few of the studies mentioning inhibition of nuclear factor kappa beta [(NF kappa B)] and [tumor necrosis factor] (TNF alpha), C-reactive protein, [methylmalonic acid] (MDA), and nitric oxide, which are fairly specific to cardiovascular disease but [are] also players in many other inflammatory conditions. And that delta-tocotrienol has specifically been shown to reduce inflammation and restore mobility in people with arthritis. They’ve also been shown to increase total endogenous antioxidant status. So that’s a pretty impressive spectrum of anti-inflammatory activities.

Barrie Tan:  Yes. Now on this, you mentioned some of them, NF kappa B, tumor necrosis factor, [and] antioxidant status. We consistently see these in animal studies and also in clinical studies. But I’d like to talk about inflammation this way. I got onto this inflammation thing because [of] Paul Ridker.  He is the person [who] popularized and underwrote the understanding of [CRP]. Professor Paul Ridker [is a] Harvard Medical School professor. He spent 20, 25 years [publishing] so many studies on [CRP]. When it’s all said and done in your lipid panel, there is only one thing to look for to measure your CRP. That’s amazing. And how did he come up with it? He said that half the people that have cardiovascular disease that turned really bad potentially have high cholesterol and oxidized LDL, like you mentioned earlier. But the other half of people who have cardiac arrest and problems like these have high inflammation.

So he set out the path to a reliable way to study inflammation. This [CRP], which is about 30,000, 40,000 size molecular weight protein, that is under stress, is being synthesized in the liver and oozing into the blood [and] you can easily measure [it]. This inflammation protein also is produced if you have an infection. So when you have an infection, [and] you measure CRP, the number is not realistically meaningful. You want chronic inflammation for which the CRP will do. So he did that, and we have consistently sized [CRP] in people with hypercholesterolemia, in people [who] have high triglyceride, like pre-diabetes, in people who have diabetes, and now in several studies in people [who] have fatty liver, their [CRP] consistently dropped. So in other words, a drop [in] inflammation is important and we see them. It may not be the smoking gun itself; it could be the triglyceride drop and the [CRP] drop. So it could be a hand in glove thing, independent of each other. However, I want to touch on another point.

I recently heard Professor Ridker give a talk. Remember, this gentleman has given 30 years of his life [to] doing  [CRP studies], and he said something I noticed that’s a small shift in the tectonic plate. I thought you might make note of this and ask your other future interviewees. He said that there are times besides [CRP, that] there is another additional marker, also under right inflammation, that would be really hand in glove in the inflammatory thing. When he said that, I just stood up. He said that [the] marker should be interleukin-6. He explained why it shouldn’t be NF kappa B and [TNF]. None of these things are good. He said that the NF kappa B and [TNF] is further up. So that means that everything downstream [is] dependent, so you don’t know which is [which]. The [CRP] is further down, and the interleukin is just slightly above.

When he said that, I went back to all our studies that we did [on] interleukin-6, and they systematically dropped. And when we studied, we just tritely said, “You see? It also contains inflammation.” But this is not what Professor Ridker said. He said that this interleukin-6 is important. So I must tell the audience here [that] sometimes I do something, [and] I haven’t fully got the foggiest idea why I [do it]. I did that because I genuinely [knew] it was inflammation, and then somebody told me and I looked. So there is no way I can contrive to make my number funny. I’m just doing it. I’m hoping that in science, if my name ends up in any place someday when I’m long gone, I gave my best shot. And if it works, then I should let the world know. It’s very pleasing for me to find out I did this and somebody else says later that this interleukin-6 is hand in glove with [CRP]. So inflammation is important [and] hands down, tocotrienol will reduce inflammation.

Chris Kresser:  That’s great because that was one of my questions that I had written down. Because we test interleukin-6 and [CRP] on every patient [who] comes into our clinic, and I did see changes in both of those markers with tocotrienol. So I was going to ask you if you’d actually studied that because I didn’t see it in the eBook. Great. Let’s talk about that.

Barrie Tan:  By the way, the reason I did not put it in the eBook is because I did it, but I didn’t know it was so important. But now in my next [publication], I will put it in there.

Benefits of Tocotrienols on Cancer Prevention and Treatment

Chris Kresser:  I want to talk about cancer. All the other benefits we’ve talked about so far are amazing in and of themselves. But the effects on cancer are perhaps the most exciting potential clinical applications of tocotrienols, for so many reasons. Maybe we could start with mechanisms. And I understand these aren’t all fully understood yet. We talked earlier in the show about tocotrienols’ ability to inhibit the HMG-CoA reductase enzyme. And that is, of course, the pathway for cholesterol production and CoQ10. But it plays a unique role in cancer, too, where cancer can hijack that enzyme to spread cholesterol through the tumor and make it worse. It’s been discovered that tocotrienols affect that enzyme, and that may be one of the mechanisms by which they impact cancer risk.

Barrie Tan:  There are many mechanisms like cell signaling. I almost don’t want to accept them because they’re very primary where the nucleus [makes] some kind of signaling, and you will see a whole lot of this published [on] tocotrienol. [There are] two that I hold [a] strong pillar to. One, you mentioned, [is] cholesterol. In the making of any cell, including cancer cells, they have cell walls. And [the] cell wall contains the highest content of cholesterol in order to get the fluidity and the movement of the cell. When you take tocotrienol, [it] controls the internal structure of the cell membrane by controlling the synthesis of the de novo cholesterol. So that’s it, because it controls that. Several authors have published on this, [and] I can send you those papers as review papers.

Another time I can explain how that is also critically important for the infection of COVID[-19]. You have to [do] another interview [with] me. It is a very tantalizing topic where the entrance of the [COVID-19] virus is also through lipid [rafts] that [are] lined with cholesterol, but that’s another topic [for] another time.

Chris Kresser:  Okay.

Barrie Tan:  So that’s one major mechanism. The other mechanism would be when the cancer is more than one millimeter in diameter. When you have that, a tiny tumor is formed. When the tiny tumor is formed, they have to have an organization to bring nutrients to it. They cannot just by osmosis suck nutrients from elsewhere. In order to do that, it’s a plumbing job. They drill a hole in a nearby artery and make [an] artificial artery and feed to itself. That process is [called] angiogenesis. “Genesis,” new, [and] “angio” means artery, to bring [a] new artery into it. And one strategy to kill cancer is anti-angiogenesis. In other words, you create a system to chop off the feeding tube to the tumor, and, if it is wired to grow like a dinosaur, it would also die like a dinosaur fast if it doesn’t have the food. And tocotrienol is one of the most potent anti-angiogenic agents. So the two mechanisms would be the stifling of the cholesterol that you mentioned and the ability of the tocotrienol to perform anti-angiogenesis on the tumor itself. Those are the two major reasons [it goes] after cancer.

Chris Kresser:  That’s fascinating. I know from my own research and your book [that] there are anti-clotting and anti-tumor effects; tocotrienols can inhibit circulating cancer cells, which are responsible for recurrence and relapse of cancer, [and] they have been shown to promote chemosensitization, which can make chemotherapy work better when patients need to have it. There are specific studies showing benefits in recurring ovarian cancer and that tocotrienols may inhibit signals that estrogen sends to breast cancer cells. So there could be a benefit there in estrogen-positive breast cancers.

So many exciting things to explore in terms of the impact on cancer cells. Let’s talk a little bit about how people can utilize tocotrienols. One thing that is important to make clear is that, unfortunately, there are not really any sufficient dietary sources of delta- and gamma-tocotrienol. Unlike some other compounds that we study for these kinds of benefits that you can find in significant amounts in food, [with] delta- and gamma-tocotrienols, it’s not like we can just eat more apples or strawberries or something and get a therapeutic dose of tocotrienol.

How to Best Utilize Tocotrienols

Barrie Tan:  In terms of a protocol, I would say this. To set the baseline, I did a study one time to try to find out how much, in a typical American diet, we probably get. [We probably get] up to but no more than five milligrams of tocotrienol in our diet. That’s somewhat comparable [but] a little less than, tocopherol, which I mentioned [is] about 10 to 15 milligrams. Unless someone eats a lot of palm oil, and then there [are] thoughts that people may not want so much saturated fat from palm oil. Even in South America, [if] you take a lot of annatto, then you might potentially be able to get about 10 to 15 milligrams tops. So five milligrams or less is what we expect. I would say if a person is healthy [and] you have no other condition of any kind whatsoever, no family history of this and that, [then] probably 100 to 200 milligrams [of] tocotrienol as antioxidant protection will be adequate. How did I come up with that? We came up with that when we studied healthy elderly [people]. We gave them 125 milligrams [of tocotrienol] and measured [their] MDA, methylmalonic acid, and then we measured the antioxidant status, and then the [CRP], and we noticed that they were good for people who are 60, 65 years old. Otherwise, [nothing] happened to them.

Then [with] a mild chronic condition from pre-diabetes to diabetes, or a family history of breast cancer [or] other cancer, or [being] overweight, or something like that, or high triglycerides, [then] 200 to 400 milligrams would do it based on a clinical study. It would be only on malignancy and things like that, which we have shown in studies [on] people with pancreatic cancer and certainly ovarian cancer [that are] published. The other three not yet published are colon cancer, lung cancer, and breast cancer. I’m holding my breath when they will be published, in the next 12 to 24 months. [They’ll] probably come back suggesting somewhere between 400 [and] 600 milligrams. Remember, they are that high because they are already malignant changes. It’s a little different, [although] yes, it is a chronic condition of sorts. So you have 100 to 200 milligrams [for] normal antioxidant protection [and] 200 to 400 for some of those milder conditions chronically. Usually, it’s a dysmetabolism of your metabolites in your body. Metabolic syndrome, in other words. And then 400 to 600 milligrams on malignancy types.

Chris Kresser:  Fantastic. And I know at those higher doses, it’s important to do a divided dose where you don’t want to exceed 300 milligrams per meal because the absorption won’t be as good as if you took it in more than one dose.

Barrie Tan:  Yes, thank you, Chris. I know that you [will] fill in the blanks for me, which I wrote in the book, but sometimes I speak so fast I forget.

Chris Kresser:  That’s okay. I’m a clinician, too, so I’m always thinking about how people actually do things.

Barrie Tan:  Yeah, thank you. I would say that because tocotrienol is a lipid, just take it with a meal. A good one-half of it will be absorbed just by taking advantage of the emulsification and your bile salts that add together and absorb it. Do not take tocotrienol that is previously emulsified, particularly with [a] synthetic. If you put [it with an] artificial synthetic, of course, it’s going to absorb. But I don’t want to do that. I want to take advantage of my body, with only one exception. If your audience has malabsorption, [maybe] because their gallbladder [was] taken out, or they [otherwise] have a dysfunction of the fatty acid metabolism, then, in that case, you may have to take it with a teaspoon of MCT, [or] a phospholipid like lecithin. You can do that. But otherwise, for the normal audience, just take [it] simply with a meal. That will be just fine.

Chris Kresser:  I want to let everybody know who’s listening, you may have heard the announcement [that] I’m launching my own supplement line called Adapt Naturals in July. It’s going to feature a set of products that are designed [for] what I think pretty much everybody needs to promote optimal health and longevity. And you won’t be surprised, Dr. Tan, to learn that tocotrienols are going to be a part of that stack.

Barrie Tan:  Wow, thank you. Thank you.

Chris Kresser:  So, when I thought of nutrients like that, [which] have incredible benefits across a wide spectrum of inflammatory conditions, and we haven’t even had a chance to get into brain health and prevention of dementia and Alzheimer’s [disease] and bone health and post-menopausal women and protection against radiation exposure and immune health and all the other things, we’ll have to do a part two. To do that in a way with a substance that has really no known contraindications, that doesn’t have side effects, that doesn’t put you at higher risk for something else if you supplement with it over a long period of time. In my 15 years of doing this work, I haven’t come across many compounds that fit those criteria. So, I’m definitely going to be including this, and we’ll have more information about this supplement stack and how you can take advantage of tocotrienols in the near future. So everybody, stay tuned for more on that.

Dr. Tan, you are a wealth of knowledge. I want to salute you and thank you for your pioneering work on tocotrienols. I’ve already benefited [from them] as a clinician, and I’ve been able to help so many people with everything from lipid abnormalities to metabolic issues to other inflammatory conditions using tocotrienols. So I just want to personally thank you for your contribution in this area and would love to have you back for part two. I know we chatted about [geranylgeraniol] as a potential topic, and then when the studies on cancer that you mentioned are published, I would love to chat with you about the results of those, as well.

Barrie Tan:  Thank you so much. If we were to do this in another year or so, even on tocotrienol, we have a two-year-long study on men and women with obesity, which has carried a lot of burden, and we gave them tocotrienol. We’re finishing up a fatty liver disease study [that was] 12 months long. And then the third [study is] the cancer study. So the tocotrienol is worthy of us [talking about] that. The [geranylgeraniol] one is just dramatic, [but] I don’t want to add anything because we don’t have the time here. The [geranylgeraniol] one clearly is for the synthesis of menaquinone-4, CoQ10, and muscle. Muscle for myopathy, for people who take statins, and muscle for the elderly who have [a] loss of muscle mass like sarcopenia. Those are big issues that [geranylgeraniol] can mitigate. I’m so grateful you gave me the chance to talk. I love to come on and [be] able to provide the information. So it’s a blessing to you and I and also to the audience that will hear this. Thank you so much for inviting me.

Chris Kresser:  Absolutely. Thank you for joining me, and thank you [to] all the listeners for listening. Keep sending your questions to ChrisKresser.com/podcastquestion, and we’ll talk to you next time.

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