A Better Understanding of Vitamin E

Part 4: FDA Changes the Traditional 400 IU Vitamin E Supplement; Brain Health and Alzheimer’s Disease Research, An Interview with Maret G. Traber, Ph.D.

vitamin E

The U.S. Food and Drug Administration (FDA) has now followed through on the 2000 DRI for vitamin E that we have been discussing with Maret Traber, Ph.D. FDA has decided to change the labeling of vitamin E supplements along with other nutrients including vitamin D in the upcoming Nutrition Facts Panel information for dietary supplement labels. At first read, the changes may appear to be innocuous, technical and minor, but they will have profound effect on consumers and be confusing at first. The good news is that the changes are good, in line with the 2000 DRI and will help in the long run after the public becomes educated about them. Dr. Traber wonders how this will be handled by the dietary supplement industry.

We have been chatting with Dr. Traber about her research on the basics of vitamin E’s essential nutritional function. Now, let’s look at some of the possible non-essential roles of vitamin E alpha-tocopherol and discuss possible supranutritional preventive roles in brain health.

Last month, we discussed Dr. Traber’s findings of the essential role of vitamin E in brain health. Could this essential role also play a part in restoring function in brains damaged by vitamin E deficiency or oxidative stress? So, once again, I am calling on Dr. Traber, a leading expert on vitamin E, to discuss its role in health.

vitamin connection
Maret G. Traber, Ph.D.

Dr. Maret G. Traber is the Helen P. Rumbel Professor for Micronutrient Research in the Linus Pauling Institute and a professor in the nutrition program, College of Public Health and Human Sciences, at Oregon State University. She received her Ph.D. in nutrition from the University of California, Berkeley, CA. She currently serves on the editorial boards of Free Radical Biology & Medicine and the Journal of Nutrition.

Dr. Traber served on the National Academy of Sciences, Institute of Medicine, Panel on Dietary Antioxidants to develop the 2000 Dietary Requirements for vitamins C and E, selenium and carotenoids. She is considered one of the world’s leading experts on vitamin E. She pioneered the use of deuterium-labeled vitamin E for studies evaluating vitamin E status in humans. Her studies caused a paradigm shift in our understanding of the mechanisms regulating vitamin E availability in humans. Her work has provided the scientific basis for understanding the complex role of vitamin E in human health.

She has published over 190 peer-reviewed and 110 invited papers in highly regarded journals. She pioneered the methodologies for evaluating vitamin E status in humans, and through this, identified key mechanisms for regulating vitamin E bioavailability in humans. In 2013, she received the Pfizer Consumer Healthcare Nutrition Sciences Award, presented by the American Society for Nutrition and the DSM Nutritional Science Award 2013 on Fundamental Research in Human Nutrition. Current research projects include vitamin E bioavailability and requirements in humans using advanced pharmacokinetic methodologies; assessment of the interactions of vitamin E and K; and determination of the mechanisms of vitamin E function during embryogenesis using zebrafish.

Passwater: Dr. Traber, we have been discussing the basics of vitamin E, and as they say on television, “Breaking News!” FDA has just updated the Dietary Supplement Label regulations to reflect the latest nutritional science. In May 2016, FDA announced changes to the Food Facts label for packaged foods and supplements that take effect in 2018 for large companies. The agency also published a proposed amendment in the Federal Register that it intended to make additional changes to some nutrients including vitamin E (1). This proposal is now a Final Rule as of May 27.

Will this change to the Code of Federal Regulations (CFR), Title 21 (Food & Drugs), Part 101.36 (Subpart C for Specific Nutrition Labeling Requirements and Guidelines) affect the nutritional labeling for vitamin E for both supplements and food? Will the 400 IU vitamin E capsule go the way of the dodo bird?

Traber: FDA has published that the DRI for vitamin E is 15 mg/d of alpha-tocopherol (2). You can download the document (2), in which FDA also said that alpha-tocopherol is the only form of vitamin E that is maintained in blood and has biological activity. The current RDA for vitamin E is limited to the four 2R-stereoisomeric forms (RRR, RSR, RRS and RSS) of alpha-tocopherol.

Unlike the formerly used measure of vitamin E activity (the IU), the 2000 DRI suggested that vitamin E activity should be measured as only as milligrams of 2R-tocopherol. This will account for the difference in activity between naturally occurring and synthetic vitamin E. Therefore, FDA’s proposed §101.9(c)(8)(iv) would change the units of measure for vitamin E to replace “IU” with “mg,” representing mg of alpha-tocopherol. Section 101.36(b)(2)(ii)(B) for the labeling of dietary supplements includes a reference to §101.9(c)(8)(iv), which, as proposed, designates the units of measure for declaring vitamin E as “milligrams of either RRR-alpha-tocopherol or a combination of RRS-, RSR-, RSS- and RRR-alpha-tocopherol.” From what I understand, FDA announced on May 27 that it incorporated its proposed amendment published in the Federal Register as a Final Rule that will be incorporated into the official CFR regulation for Nutrition Facts.

Passwater: This may not sound like a big step, but it affects a popular supplement: the 400 IU vitamin E capsule. Similarly, it affects vitamin D supplements, which will change from IU to micrograms. What was once a 400 IU pill will be labeled 20 mcg! Regarding vitamin E, previously, the standard of activity was based on the synthetic alpha-tocopherol acetate, where 1 mg of alpha-tocopherol acetate was set as 1IU. Now, the IU has been totally discarded and replaced with milligrams where 1 mg of natural vitamin E (RRR-alpha-tocopherol) can be labeled as 1 mg of vitamin E, but 2 mg of synthetic vitamin E (all-rac-alpha-tocopherol) must be labeled as 1 mg of vitamin E.

FDA has now ruled that (paragraph iv) the following RDIs, nomenclature and units of measure are established for vitamin E.

Previously, the conversion between weights of the various forms and IU were as follows: One milligram of the synthetic vitamin E as all-rac-alpha-tocopherol was defined as 1 IU of vitamin E. It took only 0.67 mg of natural vitamin E as RRR-alpha-tocopherol (formerly and incorrectly called d-alpha-tocopherol) to equal 1 IU. Thus, a bottle labeled as containing 400 IU capsules of natural vitamin E contained 268 mg of vitamin E as RRR-alpha-tocopherol and a 400-IU capsule of synthetic vitamin E contained 400 mg of all-rac-alpha-tocopherol (formerly incorrectly called dl-alpha-tocopherol). Under the upcoming regulations, the same amount of natural vitamin E would be labeled “vitamin E, 268 mg.”
Would consumers recognize the 268 mg capsules of vitamin E as their old 400 IU of natural vitamin E? Similarly, the capsules formerly labeled as 400 IU of synthetic vitamin E as all-rac-alpha-tocopherol acetate would now be labeled as 180 mg of vitamin E. Same question: Will consumers recognize this as their old 400 IU of synthetic vitamin E?

Traber: I am curious about how the industry will handle this. Since the new labeling law will be a major change for vitamin E labeling, it may be time to start educating consumers. In fact, I would like to know what the industry will be doing with the new equivalent of the old 400-IU pill. Will the quantities be adjusted slightly to yield even numbers so that it is the equivalent natural vitamin E labeled 300 mg and synthetic vitamin E 200 mg? Or will companies add even more milligrams to each form to bump the label number up to 400 mg? That would be require larger pill sizes and be more expensive. Or, would consumers buy the 200-/300-mg strengths and then take twice as much to equal the former 400 number? An educational program should be initiated so that consumers won’t be confused or misled.

An educational program should be initiated so that
consumers won’t be confused or misled.

Passwater: Well, that is why we are chatting now and why we have gone through all of the boring vitamin E basics to get everyone on the same page. Larger companies may have until 2018 to decide, but certainly changes will be forthcoming. This update for vitamin E is largely based on what we have discussed earlier. Your discovery of the function of the tocopherol transfer protein (TTP) has enabled us to make some very important conclusions about the basic biochemistry of vitamin E. In the previous three columns, we focused on the following points:

1. The chemical form of vitamin E that is an essential nutrient for humans is alpha-tocopherol, and alpha-tocopherol only. The beta, delta and gamma forms are not essential for humans and are not retained in the body.
2. No matter which form of alpha-tocopherol is ingested orally—unesterfied “free,” or the esters, such as acetate or succinate—digestive enzymes in the intestinal tract will convert these esters to the free form (if they are not already in the free form).
3. There are no known clinical benefits of one vitamin E ester (such as alpha-tocopheryl acetate or alpha-tocopheryl succinate) over the other as they are both converted back to free vitamin E (alpha-tocopherol) in the digestive tract.
4. The “free” alpha-tocopherol is absorbed into the bloodstream and then transported to the liver.
5. In the liver, the alpha-TTP selects the alpha-tocopherol for transfer to the plasma. Chemically, the form known as R,R,R-alpha-tocopherol (naturally found in plants), as well as the other three “2R” forms of alpha-tocopherol, which are known as R,R,S-alpha-tocopherol, R,S,R-alpha-tocopherol and R,S,S-alpha-tocopherol, are the only four forms of alpha-tocopherol known to be salvaged or conserved by alpha-TTP. Alpha-TTP does not select the four “2S” forms of alpha-tocopherol present in synthetic alpha-tocopherol, or the beta-, gamma- and delta-tocopherol forms found in food.

We have also discussed your latest findings on vitamin E and brain health. As we addressed last month, you found that vitamin E not only protects DHA, an important component of brain and nerve cells, but it also affects the flow of DHA into brain cells. The amount of DHA in the brain is improved by vitamin E and, importantly, a specific phospholipid-containing DHA (i.e., DHA-PC) is a critical part of the cellular membrane of every brain cell that is depleted when there is a vitamin E deficiency. This fat has been described as an important biomarker of Alzheimer’s in elderly humans. Low blood levels of DHA-PC is an indicator of Alzheimer’s disease in humans and low DHA-PC is associated with low vitamin E levels in brains. Moreover, your studies have shown that the vitamin E-deficiency also decreases levels of compounds called “lyso PLs,” which deliver DHA into the brain.

Vitamin ConnectionDr. Traber, you commented in Part 3 that it was surprising to find that vitamin E, DHA-PC and Alzheimer’s disease may be inter-related. So, let’s chat a little more about this relationship now.

We do not imply that Alzheimer’s disease is caused by a vitamin E deficiency, but it is known that oxidative damage is often found when examining damaged brains.
Alpha-tocopherol is essential to protect cell membranes, but according to the 2000 DRI, it can also affect other mechanisms. The 2000 DRI Committee, of which you were a member, stated that vitamin E has been shown to inhibit the activity of protein kinase C, an enzyme involved in cell proliferation and differentiation in smooth muscle cells, platelets and monocytes (3).

What did the 2000 DRI say regarding vitamin E studies in Alzheimer’s disease?

Traber: Several factors can lead to increased oxidative stress that causes neuronal cell death. For example, amyloid beta-peptide that accumulates in the brains of Alzheimer’s patients can initiate protein oxidation and lipid (fats including DHA) peroxidation, eventually killing brain cells. (4) Vitamin E has been shown in the test tube to prevent this (5). This is all supportive evidence that vitamin E may be important for reducing the risk of Alzheimer’s disease, but clinical studies are needed to establish cause-and-effect evidence. In 1997, a two-year, double-blind, placebo-controlled, randomized, multicenter clinical trial involving 341 Alzheimer’s patients with moderately severe impairment found treatment with 2,000 IU of vitamin E daily significantly slowed disease progression (6).

Passwater: Well, that sure exceeds the RDA for vitamin E as an essential nutrient. It could be called a “mega” or supranutritional dose. I’m sure that the safety of 2,000 IU daily was established for years before the clinical study was approved. The safety of this dosage was discussed in the interview with Manfred Eggersdorfer, Ph.D., in the November 2015 column (7).

You spoke about a clinical study that was published in 1997. What have more recent studies shown?

Traber: More recently, in 2014, a clinical study involving elderly patients having mild-to-moderate Alzheimer’s disease was published in the Journal of the American Medical Association (8). The objective was to see if starting treatment in the earlier stages would lead to even better results.

This study was larger than the 1997 study. It was a multicentered study involving 14 Veterans Affairs medical centers, 33 researchers and 613 patients. It was also randomized and placebo controlled. The patients were taking a pharmaceutical drug (one of several acetylcholinesterase inhibitors) prior to and during the study.

This clinical study also used 2,000 IU of vitamin E per day for an average of 2.3 years. Interestingly, this study was not only placebo-controlled, but it also compared vitamin E to the pharmaceutical memantine (Namenda) as well as studied using both vitamin E and the pharmaceutical together.

Guess what? The best results were obtained with the vitamin E by itself! The vitamin E alone group had an annual rate of decline in functional performance decreased by an average of 20%. Functional performance includes normal day-to-day tasks such as bathing, shopping, eating and preparing meals. These are important functions that allow patients to maintain their independence longer and/or ease the burden of their caregivers. These functions are more valued by the patients than memory, which unfortunately was not observed to be improved in the study.

All of the patients declined during the study, but those taking vitamin E alone declined 19% less and delayed their progression of the disease by 6.2 months. Caregiver hours increased less in the vitamin E group.

There were no significant differences in the groups receiving the placebo or memantine alone or memantine plus alpha-tocopherol. These findings suggest a benefit of alpha-tocopherol in mild-to-moderate Alzheimer’s disease by slowing functional decline and decreasing caregiver burden.

It is also important to note that mortality was decreased in the vitamin E group. The mortality rate was 7.3% for the vitamin E group, 11.3% for the memantine group, 9% for the memantine plus vitamin E group and 9.4% for the placebo group. There were no differences in serious adverse effects.

Passwater: This certainly establishes a foundation for more studies. It is exciting to see that vitamin E has been shown to have some benefit. Unfortunately, today’s pharmaceuticals are only modestly effective in slowing functional decline and delaying the need for institutionalization. They don’t work for everyone and even when they do help, they only help for a short time. Plus, the drugs are expensive and have “bothersome” side effects. The researchers found no adverse effects of 2,000 IU of vitamin E over placebo. Plus, vitamin E has additional benefits compared with prescription drugs in that it is widely available, doesn’t require a prescription and is inexpensive. It can be used along with currently available Alzheimer’s pharmaceuticals.

An editorial in the same issue of JAMA as the article stated, “For vitamin E, the results of this trial are encouraging because of the significant difference from the placebo group observed for the primary outcome and the absence of severe side effects”(9).

Dr. Traber, I believe that when Alzheimer’s disease researchers learn more about your findings on how vitamin E functions to protect brain cell membrane levels of DHA-PC and compounds called “lyso PLs,” which deliver DHA into the brain, the role of vitamin E will become clearer to them. You have published additional studies to consider (10–13). Yes, vitamin E helps protect DHA and lyso-PC-DHA via its antioxidant function, but instead of looking only at the antioxidant activity of vitamin E, the relationship with DHA should be amplified by adding DHA itself to the regimen.

If vitamin E helps rebuild the neurons (as well as help protect them from oxidation), then why not give patients more DHA for vitamin E to work with? B-complex vitamins could be added to improve cognition. Nutrients work together as a team and testing only one nutrient at a time independently limits their interaction.

Traber: Good points. I think you and your readers will be interested in our 2012 publication in Neurology that showed distinct nutrient biomarker patterns detected in plasma are accountable for a significant degree of variance in both cognitive function and brain volume (12). As we state in our introduction in the article, given the interactive nature of nutrient action and metabolism, it is not surprising that a single or few nutrient approaches for neurodegenerative disease are tenuous. Food frequency questionnaires (FFQ) have traditionally been used to construct dietary patterns. FFQ are subject to faulty recall of dietary intake and does not account for variability in nutrient absorption, both of which are issues in the elderly. In this article, we describe a method to capture the effect of nutrients in combination, and construct nutrient biomarker patterns using principal component analysis. People who consume good diets that are high in fruits, vegetables and rich in good fats like DHA protect their brains!

Passwater: Dr. Traber, thank you for once again for informing us about the latest research in vitamin E nutrition. In a future column, let’s discuss your research with vitamin E and vitamin K, as well as why metabolic syndrome patients and obese persons may need more vitamin E, but cannot utilize all that they do consume. WF

dr. passwaterDr. Richard Passwater is the author of more than 45 books and 500 articles on nutrition. Dr. Passwater has been WholeFoods Magazine’s science editor and author of this column since 1984. More information is available on his Web site, www.drpasswater.com.

1. “Food Labeling: Revision of the Nutrition and Supplement Facts Labels,” Federal Register, March 3, 2014, www.federalregister.gov/articles/2014/03/03/2014-04387/food-labeling-revision-of-the-nutrition-and-supplement-facts-labels#h-65, accessed June 13, 2016.
2. “Food Labeling: Revision of the Nutrition and Supplement Facts Labels,” Federal Register, May 27, 2016, www.federalregister.gov/articles/2016/05/27/2016-11867/food-labeling-revision-of-the-nutrition-and-supplement-facts-labels#h-127, accessed June 13, 2016.
3. Food Nutrition Board, Institute of Medicine, Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (National Academy Press, Washington, D.C., 2000), www.ncbi.nlm.nih.gov/books/NBK225483, accessed June 13, 2016.
4. J.N. Keller, et al., “Induction of Mitochondrial Oxidative Stress And Dysfunction In Synaptosomes By Amyloid Beta-Peptide,” J. Neurochem. 69 (1), 273–284 (1997).
5. R. Subramaniam, et al., “The Free Radical Antioxidant Vitamin E Protects Cortical Synaptosomal Membranes From Amyloid Beta-Peptide(25-35) Toxicity But Not From Hydroxynonenal Toxicity: Relevance To The Free Radical Hypothesis Of Alzheimer’s Disease,” Neurochem. Res. 23 (11), 1403–1410 (1998).
6. M. Sano, et al., “A Controlled Trial Of Selegiline, Alpha-Tocopherol, Or Both As Treatment For Alzheimer’s Disease,” N. Engl. J. Med. 336 (17), 1216–1222 (1997).
7. R.A. Passwater, “New Evidence About the Safety of Vitamin E Supplements,” WholeFoods Magazine 38 (11) 49–53 (2015).
8. M.W. Dykstra, et al., “Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease. The TEAM-AD VA Cooperative Randomized Trial,” JAMA, 311 (1), 33–44 (2014).
9. D.A. Evans, et al., “Vitamin E, Memantine, and Alzheimer Disease,” JAMA 311 (1), 29–30 (2014).
10. M.Q. McDougall, et al., “Lipidomics and H2(18)O Labeling Techniques Reveal Increased Remodeling Of DHA-Containing Membrane Phospholipids Associated With Abnormal Locomotor Responses In Α-Tocopherol Deficient Zebrafish (Danio Rerio) Embryos,” Redox Biol. 8, 165–174 (2016).
11. J. Choi , et al., “Novel Function of Vitamin E in Regulation Of Zebrafish (Danio Rerio) Brain Lysophospholipids Discovered Using Lipidomics,” J. Lipid Res. 56 (6), 1182–1190 (2015).
12. G.L. Bowman, et al., “Nutrient Biomarker Patterns, Cognitive Function, And MRI Measures Of Brain Aging,” Neurol. 78 (4), 241–249 (2012).
13. G.L. Bowman, et al., “Reliability and Validity Of Food Frequency Questionnaire And Nutrient Biomarkers In Elders With And Without Mild Cognitive Impairment,” Alzheimer Dis. Assoc. Disord. 25 (1), 49–57 (2011).

Published in WholeFoods Magazine August 2016