Tocotrienols: Protectors of Cardiovascular and Bone Health
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How the lesser-known tocotrienol form of vitamin E may be the one we should be studying
Vitamin E has long been heralded for its many health benefits, however, the majority of this research has been focused on the tocopherol forms which are more commonly found in nature. In this interview we chat with Barrie Tan, PhD, tocotrienol expert, about some of the new studies pertaining to the delta- and gamma-tocotrienol forms of vitamin E, and the effects they have on cardiovascular health and beyond.
NutritionInFocus: Tell us a bit about tocotrienols.
TAN: The early days of vitamin E research were centered mostly around alpha tocopherol, followed by gamma tocopherol. Around the same time that gamma tocopherol was becoming of interest, the different properties of tocotrienols were first distinguished. Fifty percent of all tocotrienol research has been in the last 10 years, with most of the fundamental research focused on delta and gamma tocotrienols. About five percent of research pertains to alpha tocotrienols, and this is mainly in the realm of stroke, and injury to the brain.
One thing to consider when comparing tocotrienols with tocopherols is the structure of the molecule. Tocopherols are usually a bit larger. Elements with a structure like the tocotrienols and tocopherols are usually found in the cellular membranes, with the phosphate group pointing out towards the extracellular fluid or cytosol, and the fatty acid tail pointing inward. The shape of both looks like a tadpole, however on the tocopherols, the tail is saturated, making it stiffer, and more mobile in cell membranes. The shape of tocotrienols are also similar to coenzyme Q10 (CoQ10), but the tail is about three times shorter, allowing them to move much more easily both within, and between, cellular membranes.
Before the tocotrienols get to the liver, many of them are already deposited in the miles and miles of the peripheral vasculature and cholesterol molecules being transported within it.
Approximately fifty percent of tocotrienols taken orally are absorbed and accumulate in the fatty tissues. They are absorbed in the lymphatic system, and then eventually reach the liver after about five hours. But before the tocotrienols get to the liver, many of them are already deposited in the miles and miles of the peripheral vasculature and cholesterol molecules being transported within it, and from there, they are also transported into the organs and fatty tissue. They go to the adipose, muscle, liver, and even to the heart, each of these being organs where they are needed for metabolic syndrome.,,
NutritionInFocus: What are the best sources of tocotrienols?
TAN: Tocotrienols are not found as abundantly as tocopherols are in nature. Only annatto, palm oil, and rice bran oil contain high enough levels to process and extract commercially. There are minute amounts of tocotrienols found in macadamia and pistachio nuts, corn, and cranberry seeds at less than 500 parts per million (ppm).
NutritionInFocus: How does the structure of tocotrienols pertain to the health benefits that we see?
TAN: Because 25 to 30 percent of our body is fat, we really need antioxidants to protect this portion of the body, including all our cellular membranes. Within these biological membranes, these antioxidant molecules exist at a ratio of approximately 1:1,000 with the fatty acids and cholesterol in the membrane. Say there are 1,000 antioxidant molecules in the cell membrane – of this 995 are vitamin E, and the rest are things like CoQ10, beta carotene, and lutein. CoQ10 is just too long to fit in naturally as vitamin E does, because vitamin E is half the width of the membrane.
When one takes fish oil they should be taking it with tocotrienols, as this helps shield the fat from oxidization, also protecting it when it becomes nestled within the cellular membrane.
Phospholipids, which form the cellular membranes, are highly challenged due to the heterogeneous environment that they are in. As the most abundant lipid antioxidant, vitamin E is the great protector of all the cellular membranes and organelles within them. It protects us from oxidized tissues, oxidized cholesterol, and oxidization within cholesterol plaques. When one takes fish oil they should be taking it with tocotrienols, as this helps shield the fat from oxidization, also protecting it when it becomes nestled within the cellular membrane. Other fat-soluble antioxidants like rosemary essential oil have a protective effect, but again, it does not naturally go into the cell membranes in the body.
NutritionInFocus: As the “baby boomer” population ages, many health issues that are increasingly common with advancing age are inevitably seen more often in physician’s offices: diabetes, hypertension, cardiovascular disease, and degenerative disease such as osteoporosis. What research behind tocotrienols may support their use for these health conditions?
TAN: We have found that the delta- and gamma- tocotrienols are able to downregulate HMG-CoA reductase [an enzyme necessary for cholesterol production] and reduce cholesterol. Tocotrienols help to reduce atherosclerotic plaques, improving various markers of endothelial cell activation and plaque stability., They also support the reduction of inflammation and the release of nitric oxide as well. Tocotrienols help to inhibit platelet aggregation, which can be a factor leading to hypercoagulability [“sticky” blood that has a tendency to form clots].
Tocotrienols help to reduce atherosclerotic plaques, improving various markers of endothelial cell activation and plaque stability
Another issue which contributes to cardiovascular disease is poor compliance [flexibility] of the arteries, which can be in part due to atherosclerosis [disease of the arteries]. Because tocotrienols are deposited in the cholesterol and walls of the arteries, they are great for atherosclerosis. In a randomized, placebo-controlled, blinded endpoint study, trends towards improved arterial compliance also were seen with tocotrienol supplementation.
Cholesterol isn’t the only part of the picture in heart disease, as half of the people who die of a heart attack do not have high cholesterol. So, another thing we looked at was the blood levels of high-sensitivity C-reactive protein (hs-CRP), a marker of inflammation. Many people who have heart disease and the classic traits of metabolic syndrome also have chronically high CRP levels. The combination of high cholesterol and elevated hs-CRP is a very bad combination for cardiovascular health.
Knowing these things, we did a dose escalation study with the delta tocotrienols with supplementation ranging from 125 to 500 mg once daily., We saw a bit of a decrease in inflammation and cholesterol at 125 mg, but 250 mg seemed to be the sweet spot. At 250 mg, we found about 15 to 20 percent reduction in total cholesterol and LDL [“bad” cholesterol], and about 40 percent reduction in CRP levels. At 500 mg we found the response wasn’t much better.
Delta and gamma tocotrienols have been found to have an even greater impact on the triglycerides than the total cholesterol, potentially lowering triglycerides up to almost 30 percent.
Hypertriglyceridemia [high triglycerides] often occurs in type 2 diabetes, and abnormalities commonly persist despite proper blood sugar control. Because of the relationship between high triglycerides and blood sugar, it is important to also address the triglycerides. Delta and gamma tocotrienols have been found to have an even greater impact on the triglycerides than the total cholesterol, potentially lowering triglycerides up to almost 30 percent. By doing this, they may promote glucose homeostasis on a longer-term basis.
Many do not think of tocotrienols as important to bone health, however, a recent clinical study has shown just that. In this study, we focused on women that had newly entered menopause, as this is the period in which there is the greatest change in bone density. The women in all groups were given vitamin D and calcium, including the placebo group, as this is known to be important and necessary for bone health. The intervention groups were also given 300 or 600 mg of 90/10 delta/gamma tocotrienols. What we found was that the groups taking tocotrienols had much less bone breakdown, despite the fact that both groups were taking vitamin D and calcium. One thing that was surprising was that the 600 mg group did not do much better than the 300 mg group by the end of the study, although they were doing a bit better at 6 weeks.
NutritionInFocus: And what are some things we might see come out in the future pertaining to tocotrienol research?
TAN: Although we haven’t discussed it today, there is a great amount of research going on with cancer. There also is some research looking at the impact of tocotrienols on the accumulation of beta-amyloid and tau proteins in the brain, both of which contribute to Alzheimer’s disease. Another issue with aging is health of the skin and the eyes. Studies have shown tocotrienols may help to reduce cataracts, protect the skin from ultraviolet radiation and ozone, and reduce levels of melanin, which increases with age and leads to age spots.,,
NutritionInFocus: What are the main take homes for using tocotrienols as a supplement?
TAN: The sweet spot of dosing with delta and gamma tocotrienols really seems to be about 250 to 300 mg once daily for bone and cardiovascular health. In terms of general antioxidant protection, 125 mg a day would be appropriate. However, as the tocotrienols deposit in the adipose [fat] tissues, for a larger individual with a higher BMI [body mass index] or increased central adiposity [“apple” pattern of fat distribution] you may want to go a little higher. Again, it is the main fat-soluble antioxidant that protects the membranes of our cells from damage due to countless environmental and internal stressors every day.
The sweet spot of dosing with delta and gamma tocotrienols really seems to be about 250 to 300 mg once daily for bone and cardiovascular health.
They must always be taken with a fat-containing meal, and not on an empty stomach. If the focus of supplementation is for cholesterol reduction, they should be taken with dinner, which may improve the HMG-CoA reductase inhibiting effect. If someone is taking a supplement with significant amounts of tocopherols as well, this should be taken at least four hours away from the tocotrienols as high levels of tocopherols can negate the positive impact of tocotrienols on physiology.
Bio: Barrie Tan, PhD, earned his doctorate in chemistry (University of Otago, New Zealand; 1979), and was a professor of chemistry and food science/nutrition at the University of Massachusetts, Amherst from 1982 to 1992. His research expertise includes lipid-soluble nutrients (carotenoids, E vitamers, CoQ10, and omega-3’s). He is considered one of the first people to introduce tocotrienols’ benefits to the nutrition industry, and is the developer of a tocopherol-free tocotrienol product derived from annatto. Today, his research focuses on lipid-soluble nutrients that impact chronic conditions. Dr. Tan is the senior editor of Tocotrienols: Vitamin E Beyond Tocopherols (2013) and continues to collaborate with numerous universities worldwide to further tocotrienol research.
Click here to see References
 Allen L, et al. Effects of delta-tocotrienol on obesity-related adipocyte hypertrophy, inflammation and hepatic steatosis in high-fat-fed mice. J Nutr Biochem. 2017;48:128-37.
 Wong WY, et al. Anti-inflammatory gamma- and delta-tocotrienols improve cardiovascular, liver and metabolic function in diet-induced obese rats. Eur J Nutr. 2017;56(1):133-50.
 Shibata A, et al. alpha-Tocopherol Attenuates the Triglyceride- and Cholesterol-Lowering Effects of Rice Bran Tocotrienol in Rats Fed a Western Diet. J Agric Food Chem. 2016;64(26):5361-6.
 Rahman TA, et al. Atheroprotective effects of pure tocotrienol supplementation in the treatment of rabbits with experimentally induced early and established atherosclerosis. Food Nutr Res. 2016;60:31525.
 Kooyenga DK, et al. Antioxidants modulate the course of carotid atherosclerosis: A four-year report. Micronutrients and Health. Nesaretnam K, Packer L, editors. Illinois: AOCS Press; 2001. p. 366-75.
 Muid S, et al. Delta- and gamma-tocotrienol isomers are potent in inhibiting inflammation and endothelial activation in stimulated human endothelial cells. Food Nutr Res. 2016;60:31526.
 Qureshi AA, et al. Tocotrienols-induced inhibition of platelet thrombus formation and platelet aggregation in stenosed canine coronary arteries. Lipids Health Dis. 2011;10:58.
 Rasool AH, et al. Arterial compliance and vitamin E blood levels with a self-emulsifying preparation of tocotrienol rich vitamin E. Arch Pharm Res. 2008 Sep;31(9):1212-7.
 Qureshi AA, et al. Dose-dependent modulation of lipid parameters, cytokines, and RNA by delta-tocotrienol in hypercholesterolemic subjects restricted to AHA Step-1 diet. Brit J of Med & Med Res. 2015;6(4):351-66.
 Qureshi AA, et al. Impact of delta-tocotrienol on inflammatory biomarkers and oxidative stress in hypercholesterolemic subjects. Clin Exp Cardiology. 2015;6(4):1000367.
 Zaiden N, et al. Gamma delta tocotrienols reduce hepatic triglyceride synthesis and VLDL secretion. J Atheroscler Thromb. 2010 Oct 27;17(10):1019-32.
 Shen CL, et al. Tocotrienol supplementation suppressed bone resorption and oxidative stress in postmenopausal osteopenic women: a 12-week randomized double-blinded placebo-controlled trial. Osteoporos Int. 2018 Jan 12.
 Aggarwal BB, et al. Tocotrienols, the vitamin E of the 21st century: its potential against cancer and other chronic diseases. Biochem Pharmacol. 2010 Dec 1;80(11):1613-31.
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 Abdul Nasir NA, et al. Reduction of oxidative-nitrosative stress underlies anticataract effect of topically applied tocotrienol in streptozotocin-induced diabetic rats. PloS one. 2017;12(3):e0174542.
 Yap WN, et al. Gamma- and delta-tocotrienols inhibit cutaneous melanosis (hallmark of melanoma) by suppressing constitutive and UV-induced tyrosinase activation. 102nd Annual Meeting of the American Association for Cancer Research; April 5, 2011; Orlando, FL2011.
 Michihara A, et al. Delta-tocotrienol causes decrease of melanin content in mouse melanoma cells. J Health Sci. 2009;55(2):314-8.
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