At the recent A4M conference in Vegas, I ran into intriguing research from Dr. Barrie Tan, a scientist with a Ph.D. in Chemistry and Biochemistry. For the last 35 years, Barrie has immersed himself in the world of Vitamin E (particularly from annatto) and is considered one of the world’s foremost experts credited with discovering a molecule called “tocotrienol” from three major natural sources:
- Palm: from his native Malaysia…
- Rice: at the invitation of the Prince of Thailand…
- Annatto: chance finding while in Ecuador searching for lutein…
It turned out that palm and rice lacked the potency as they contain too much tocopherol, so Barrie moved his research interest away briefly from tocotrienol when by serendipity he found the best-in-class tocotrienol in the annatto plant from the Amazon. Since then, Barrie’s relationship with annatto has spanned 20 years. Barrie has worked with the US Armed Forces on using tocotrienol on “radiation countermeasures” and pioneered the science behind the annatto working with the leading scientists in the world to prove the multiple benefits of tocotrienol.
Meanwhile, everyone (lay folk and nutritionist) is languishing with the lack-luster non-performing tocopherol, which Barrie calls the “wrong way to E.” Most tocopherol trials failed and did not deliver. But in multiple clinical trials spanning chronic diseases, including cardiovascular disease, metabolic syndrome, non-alcoholic fatty liver disease, osteopenia, and inflammation, tocotrienol from annatto has proven clinical benefits. Barrie is currently working on multiple cancer trials after preliminary success with end-stage patients.
This is because not all forms of Vitamin E are created equal…
…Vitamin E is not a single nutrient, but rather a complex made up of 8 distinct compounds: 4 tocopherols and 4 tocotrienols. These components have slightly different chemical structures, and these differences impart unique properties that influence their biochemical functions and their effects in the body. Most conventional supplements are typically rich in tocopherols—alpha-tocopherol, in particular—but the tocotrienol fractions have unique effects across a variety of tissues that make them desirable to supplement on their own, without tocopherols.
Tocotrienols, especially delta-tocotrienol as sourced from the annatto plant (bixa orellana), have shown impressive effects in supporting overall health. Tocotrienols are associated with significantly positive effects on cardiovascular health, particularly with regard to influencing healthy cholesterol and triglyceride levels. They may also be beneficial for a healthy inflammatory response, an important asset since chronic inflammation is a factor in damage to the cardiovascular system.
Having a positive influence on lipids (fats in the blood), tocotrienols may be beneficial for those with a buildup of fat in the liver, as well as those who need help managing blood sugar and insulin levels. Clinical research also suggests tocotrienols may be a valuable addition to the supplement regimens of those who need nutritional support for strong, healthy bones.
Here is a recent remark of Jonathan Lizotte, Designs for Health Founder and Board Chairman:
“The health benefits realized by annatto tocotrienol go beyond that of any other nutrient I know. It’s the one supplement I would want with me if I were stranded on a desert island! This is a change for me as after 35 years in this industry, my top desert island supplements have switched between magnesium and fish oil and now it stands firmly as annatto tocotrienol alone. A minimum of 150 mg per day is a must for every adult alive.”
Apart from tocotrienol, Barrie discovered and has extracted the first-in-class geranylgeraniol (GG), also from the annatto plant. GG has benefits as 1) testosterone and progesterone booster; 2) pain alleviation and; 3) sarcopenia, myopathy and muscle building from this endogenous nutrient. GG is the last common step between plant and mammal (has huge implications), and may possibly be the last frontier in anti-aging nutrients. Here are Dr. Tan’s two anti-aging bottom-line nutrients: tocotrienol (exogenous) will work from outside-in, and geranylgeraniol (endogenous) will work from inside-out.
After recording this podcast, I did a bit of additional research so that I could determine whether or not I should throw out all my supplements that have any forms of alpha tocopherol.
There is also evidence that tocotrienols may provide some specific benefits (improving lipid profiles), but they are not necessarily meant to be a replacement for tocopherols. The literature around the tocopherols is clouded by the isomeric form of alpha tocopherol – specifically the synthetic “racemic” configuration used in most supplements (especially inexpensive, poorly researched Vitamin E and multivitamin formulations). Instead, using the complete R (racemic) form of alpha tocopherol alongside with the mixed tocopherols is a good approach, and that is what is utilized in the multivitamin I personally use (this one).
Synthetic vitamin E derived from petroleum products is manufactured as all-racemic alpha tocopheryl acetate with a mixture of eight stereoisomers. In this mixture, only one alpha-tocopherol molecule of the eight molecules found in Vitamin E is in the form of RRR-alpha-tocopherol (12.5% of the total). But natural alpha-tocopherol is always completely the RRR-alpha (or ddd-alpha) form. The synthetic dl,dl,dl-alpha (“dl-alpha”) form is not as active as the natural ddd-alpha (“d-alpha”) tocopherol form. This is mainly due to reduced vitamin activity of the 4 possible stereoisomers which are represented by the l or S enantiomer at the first stereocenter (an S or l configuration between the chromanol ring and the tail, i.e., the SRR, SRS, SSR, and SSS stereoisomers).
In nature, alpha-tocopherols naturally occur in the d- isomer form, which is more active than the synthetic racemic dl- isomer form. The alpha form of tocopherol was originally designated d-alpha-tocopherol on the basis of its optical activity. The alpha-tocopherol form constitutes 90 percent of the tocopherol found in humans, with the largest quantities in blood and tissues. Normal blood plasma consists of 83-percent d-alpha-tocopherol and 13-percent d-gamma-tocopherol. It has been found that long-term supplementation with just an d-alpha-tocopherol vitamin E supplement results in blood plasma levels of d-gamma-tocopherols being lowered by 30 to 50 percent. As a result, some researchers now recommend, to those who are interested in taking a vitamin E supplement, to select one with mixed tocopherols.
Naturally sourced d-alpha-tocopherol can be extracted and purified from seed oils, or gamma-tocopherol can be extracted, purified, and methylated to create d-alpha-tocopherol. In contrast to alpha-tocopherol extracted from plants, which is also called d-alpha-tocopherol, industrial synthesis creates dl-alpha-tocopherol. This synthetic dl-alpha-tocopherol has approximately 50% of the potency of d-alpha-tocopherol. Manufacturers of dietary supplements and fortified foods for humans or domesticated animals then convert the phenol form of the vitamin to an ester using either acetic acid or succinic acid because the esters are more chemically stable, providing for a longer shelf-life. The ester forms are de-esterified in the gut and absorbed as free alpha-tocopherol (more info on this here).
Brain spinning yet? Here's the bullet points:
a) The “natural” form is “d” or “R”. It is a way for chemists to capture nature-made compounds as they rotate optically. “d” is for dextro, and “R” is for rectus, meaning plant-derived vitamin E optically rotates to the right only.
b) The synthetic form is “dl” or “RS”. It is a way for chemists to capture a man-made compounds as they rotate optically both to the right (d, R) and left (l, S), hence the designations “dl” or “RS”. Chemists refer to these compounds as racemic mixtures. The “dl” version is used more commonly in labels provided manufacturers are even transparent to label so.
c) In the man-made synthetic version, and in order to make alpha-tocopherol cheaply, chemists have difficulty controlling the optical rotation of these compounds. In the case of a racemic vitamin E alpha-tocopherol, 8 alpha-tocopherols are produced.
d) Only one of the 8 alpha-tocopherols produced in chemical synthesis is nature-identical (meaning 1-in-8 is actually d-alpha-tocopherol), therefore 87.5% chemically-produced alpha-tocopherols are never found in nature. These 7-of-8 alpha-tocopherols are counterfeit Es.
e) Even the “natural” vitamin E on the market (d-alpha-tocopherol) is not truly nature-derived, but semi-synthetic. They were chemically synthesized (via chemical methylation process) to convert all isomeric tocopherols to alpha-tocopherol.
f) Item 2e) was done because the currency (until recently) for vitamin E is “IU” not “mg”. For example: Alpha-Tocopherol: 10mg=10IU; Gamma-Tocopherol: 10mg=1IU; Tocotrienols 10mg=Low/Unknown
This makes synthetic vitamin E manufacturers more profitable (for decades)! This currency of vitamin E is completely erroneous. FDA stopped the usage of ‘IU’ for vitamin E only last year.
Dr. Tan also provided me with the following information that further reflects the benefits of tocotrienols and the fact that's it's not necessarily bad to consume a natural form of tocopherol, but that adding tocotrienols in or replacing the tocopherol with tocotrienol could give even more benefit:
a) When we talk about “isomers”, I am referring to the closely related compounds of a series a plant makes. In vitamin E tocopherols, they are prefixed by alpha-, beta-, gamma-, and delta-, referring to the number and position of methyl groups on the phenol ring. This ingenuity of the plant kingdom with respect to methyl groups greatly affect the antioxidative (and hence free-radical capturing) capability of that isomeric tocopherol. In complex heterogeneous systems – meaning cells and cell walls and food matrices, not homogeneous oils and fats – very often the ranking priority of antioxidant potency of tocopherols is delta- ≥ gamma- > alpha-; beta- is less studied and nearly not found in nature.
b) These “isomers” are also analogous in the vitamin E tocotrienol series. [Tocotrienols were discovered in the 1960s, 40-50 years after tocopherols (1920s), therefore their discovered functions are similarly delayed.] In complex heterogeneous systems – meaning cells and cell walls and food matrices, not homogeneous oils and fats – very often the ranking priority of antioxidant potency of tocotrienols is delta- ≥ gamma- > alpha-; beta- is less studied and nearly not found in nature.
c) There is a difference in the “tail” of the vitamin E molecule. A saturated (no double bonds) tail is characteristic of tocopherol. It is longer than the unsaturated (3 double bonds) tail characteristic of tocotrienol. The most important implication of the tail is in the phospholipid protection of cell walls that constitute all the 38 trillion cells in the human body. University of California/Berkeley’s Lester Packer showed this almost 25 years ago (1995). Tocopherol’s longer tail anchors deeply into the membrane, spins on the bean-shaped cell at 1x speed to capture run-away oxygen radicals that cling to the unsaturated phospholipid-PUFA of lipids. Tocotrienol’s shorter tail anchors shallowly into the membrane, spins on the bean-shaped cell at 50x speed to capture run-away oxygen radicals that cling to the unsaturated phospholipid-PUFA of lipids. Tocopherol and tocotrienol do the same thing, just that tocotrienol mops up the fragile (labile) lipid radicals 50x faster than tocopherol. Therefore, a tocopherol acts like a local policeman capturing the bad guys in town, whereas tocotrienol is like a state trooper, capturing the bad guys state-wide.
d) At about the time the huge alpha-tocopherol trials were raging (1980s) – and before the negative results descended – University of Wisconsin/Madison’s Asaf Qureshi showed for the first time that tocotrienol has differentiated functions from tocopherol. It was lipid reduction (1980s), cancer reduction (1990s), metabolic syndrome reduction (2000s), and other chronic conditions (2010s). I have been involved in this tocopherol-turned-tocotrienol vitamin E revolution. To date, we have been involved with 15+ clinical trials with annatto tocotrienols alone.
e) Using alpha-tocopherol is a goner, natural or synthetic. We even revisit the original claim where alpha-tocopherol became a “vitamin” superstar (1920s). It was a vitamin because it brings the embryo-fetus to full term; it was discovered as a fertility vitamin, later evolved into an antioxidant vitamin. One of our studies showed that delta-tocotrienol (from annatto) is a good/safe replacement in reproductive health. The researchers concluded, “The present study showed novel findings on the ability of annatto delta-TCT in providing promising effects on embryonic development, which might serve as an alternative to alpha-TOC.”
f) There is some utility to mixed tocopherols, however, I contend that we have enough mixed tocopherols in our diet. In the Western world – comparing North America to Europe – our US-based diet has more mixed tocopherols, whereas the Europe-based diet has more alpha-tocopherol. We do not need supplemental mixed tocopherols (without intrinsic harm) but we definitely do not need alpha-tocopherol (with intrinsic harm).
Furthermore, in the literature, there have been numerous studies where tocopherols have proven to be beneficial, including non-alcohol fatty liver disease (there actually is an extensive review of the literature showing that alpha tocopherol helps fatty liver). But, during a recent literature search on NAFLD, Dr. Tan found that 800IU/day of alpha-tocopherol (a huge amount) worked on adults, but failed to work in adolescents with NAFLD. He showed that annatto tocotrienols (absent of tocopherols) worked on adults with NAFLD (we did not trial children). In the trial(s), tocotrienol mitigated NAFLD based on many extensive biomarkers in a much shorter time period. He is confident that this is due to tocotrienol’s ability to access the phospholipids of cells in general, and the liver in particular, to bring about this dramatic effect. More dramatically, tocotrienols – but not alpha-tocopherol – reduce severe inflammation and oxidation (of lipid products) in NAFLD and hepatitis C patients. All known antioxidants (e.g., CoQ10, lycopene, beta-carotene, astaxanthin, lutein, curcumin, resveratrol, etc.) amount to <10% deposited in the cell phospholipids, all vitamin E molecules amount to >90%! This one-of-a-kind structure allows tocotrienol to access cell walls (especially liver cells) to perform their functions “fast and furious.
Ultimately, like all vitamin trials, the vitamin E debate is marred by cheap forms and inadequate dosing. The tocotrienol class is definitely something to watch, but to date doesn't surpass the mixed tocopherols in my mind, especially if you A) aren't “overdosing” with mixed tocopherols and B) aren't using the synthetic form.
During our discussion, you'll discover:
-How Dr. Tan discovered annatto and became interested in vitamin E…9:05
- Began while an assistant prof at U of Mass in Amherst
- Palm oil in his native Malaysia is orange; is bleached out when it's processed
- Received grant from the Malaysian government to research
- Research process on palm oil:
- Remove all fats and oil
- Remove all kerosene colors (orange)
- 25% of what was left was alpha-tocopherol, the most common variant of vitamin E
- Remainder was tocotrienol
- Led to research on different forms of lung cancer (stopped soon after)
- Prince of Thailand hired him to research
- Buddhists don't like anything mitochondrial related
- Wanted plant-derived, not animal-derived research
- Most beneficial results came from rice bran oil (contained tocotrienol)
- Research funding slowed due to a slow economy in 1987
- Needed a break in 1998 from studying tocotrienol; this led to studying treating macular degeneration
- Vitamin E is made up of 8 different compounds
- 4 of them are tocopherols; 4 are tocotrienols
- The most common are tocopherols, particularly alpha-tocopherols
- Tocotrienols are less common and are the locus of Dr. Tan's research
- Research on the efficacy of vitamin E as it pertains to exercise was primarily done on tocopherols
- Vitamin E was discovered in 1922 at Berkeley
- Was extracted from spinach
- Assisted in bringing fetus to full-term
- Alpha-tocopherol is the “currency” of vitamin E; all other strains (delta, gamma tocopherol) is converted into alpha during processing
- Even “all-natural” alpha-tocopherol is partly synthetic
- How to undo the damage from an alpha-tocopherol heavy supplement:
- Best thing is to stop taking alpha-tocopherol supplement
- Ideal intake of alpha-tocopherol is 15 mg per day, derived from natural foods
- If you didn't get all that, get this… A vitamin E supplement is not derived from what we would find in nature. It is only a few strands of tocopherol, mostly alpha-tocopherol. The original use of alpha-tocopherol has long outlived its purpose. Dr. Tan advocates for the other strands, particularly tocotrienols for humans to derive the full benefits of vitamin E.
-The major differences between alpha-tocopherols and tocotrienols…30:55
- Tri = 3; E = double bond
- Tocopherol has a head with an OH group; tail is saturated
- Tocotrienol tail has 3 double bonds, so it is unsaturated; head is smaller than tocopherol
- Lipid antioxidants are the low-hanging fruit for our body to be oxidized
- Astaxanthin is a powerful singlet antioxidant (efficacious in an environment that is oxygen-deficient)
- >90% of antioxidants in the phospholipid cells are vitamin E molecules
- Remaining ~10% are hydrocarbon caratonoids
- Beta carotene and lycopene contain nothing else than hydrogen and carbon
- 1995 study by Dr. Lester Packer of UC Berkeley:
- Used electron-resonance spectroscopy to compare alpha-tocopherol and tocotrienol
- Concluded that both capture free radicals, to protect the lipid from oxidation
- However, tocotrienol is 50 times more effective in protecting the cell
- Comparison: Tocopherol is like municipal police within a small jurisdiction; tocotrienol is like a state trooper with far larger jurisdiction
- Tocotrienol recruits to cancer cells 10X more than tocopherol
- Critics say that only alpha-tocopherol is found in the blood; therefore all advocacy for tocotrienol is moot
- Only alpha-tocopherol has a “transport protein”, which chaperones a particular molecule to a site of action
- The transport protein ensures the conservation of alpha-tocopherol (which is why supplementation is bad news)
-Dr. Tan's discovery of the amazing annatto plant while living in South America…43:20
- Went to find lutein and zeaxanthin
- Discovered the annatto while searching for marigold flowers in Brazil
- It was nicknamed the “lipstick plant” due to its intense red color on the inside
- South Americans called it “achuite”; is used as a food coloring
- Dr. Tan recognized the annatto to be a caratenoid:
- Carotene in nature has to be protected by something due to its instability (plants changing color in the spring)
- Because the annatto did not change color, he realized it was a potentially powerful antioxidant
- Biggest surprise of his research:
- Did not contain polyphenols, nor any type of tocopherol.
- It contained primarily delta-tocotrienol, which had been shown to be the most potent form of vitamin E.
- The plant is naturally free of any type of tocopherol
-How the annatto plant is used to treat non-alcoholic fatty liver disease (NAFLD)…52:30
- NAFLD is the new name for “metabolic syndrome”
- 20% of youth and 40% of adults in America are obese
- 3 of 5 risk markers:
- Elevated triglycerides
- Reduced HDL
- Increased weight circumference
- 80-100 million Americans have NAFLD in some form
- The liver is very intolerant of fat
- Symptoms resemble those of alcoholics, hence the name “non-alcoholic”
- Notable data from Dr. Tan's study:
- Gave people 600 mg of tocotrienol vitamin E; 300 mg twice daily
- 70 patients; double-blind; placebo controlled
- Did at the beginning, 3 months after, 6 months after
- 3 months: lost average of 10 pounds
- 6 months: lost average of 17 pounds
- Waist circumference dropped 3 cm
- Use caution when purchasing products using the words “liver support” in its packaging
-The other compound Dr. Tan found in the annatto plant in addition to tocotrienols…1:03:10
- GG: geraniol geranial
- It's an endogenous nutrient, naturally produced by the human body
- Helps with the synthesis of testosterone
- Older folks take it, not for the sex drive, but to have a zest for life
- Required for the synthesis of caratenoid
- GG is a prerequisite for the synthesis of CoQ10
- GG is currently in development; not currently on the market
- Its use as a pain management tool is complimentary, but not similar to, CBD
-And much more!
Resources from this episode:
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