VITAMIN E – Supreme Performance

Vitamin E is a group of fat-soluble compounds with antioxidant properties that help protect cells from damage caused by free radicals. It was first discovered in the 1920s, and since then, researchers have been studying its numerous health benefits. Vitamin E is essential for the proper functioning of the body, and its benefits are not limited to one particular area of health. In fact, Vitamin E is known to have a positive impact on antioxidation, immunity and infectious disease, and cardiovascular health.

In this long-form article, we will delve into the various benefits of Vitamin E and how it can help support the body’s antioxidation processes, boost immunity and fight against infectious diseases, and promote cardiovascular health. We will examine the scientific research on Vitamin E and explore how it can be incorporated into our daily diet to maximize its benefits. Whether you are looking to improve your overall health or combat specific health concerns, the information presented in this article will be beneficial for anyone seeking to optimize their well-being.

Sources & Structures

The discovery of Vitamin E as an essential nutrient for the body dates back to a series of studies conducted in the early 20th century. During these studies, animals that were fed rancid meat products developed deficiency symptoms, which were later attributed to the depletion of Vitamin E in their bodies. The researchers found that these symptoms could be reversed or “cured” by the administration of wheat germ, a known source of Vitamin E.

Vitamin E is measured in mg or IU due to varying bioactivity among its forms.

Alpha-tocopherol is the form of Vitamin E that the liver typically targets for incorporation into lipoproteins, compared to other forms of Vitamin E. The α-tocopherol isomer is not only commonly used in studies to reverse deficiency symptoms, [1, 2] but also has the highest bioavailability.

In addition to its antioxidant properties, Alpha-tocopherol has been found to impact cell signaling processes. It can independently inhibit smooth muscle cell proliferation, decrease Protein kinase C (PKC) activity, increase phosphoprotein phosphatase 2A activity, and regulate the α-tropomyosin gene. [1, 2]

The inhibition of PKC by Alpha-tocopherol may be due to a reduction in levels of diacylglycerol, which is a PKC activator that can leak from the membrane. [1] This process requires Vitamin E to be a component of the membrane.

Vitamin E has been shown to regulate the expression of certain pro-thrombotic and atherogenic factors, [1] possibly by upregulating phospholipase A2 and cyclooxygenase enzymes. The dose-dependent increase in prostacyclin levels in vivo that has been observed with Vitamin E supplementation [1, 2] may be attributed to these effects.

Main Takeaway: Alpha-tocopherol is the form of Vitamin E that the liver typically targets for incorporation into lipoproteins, compared to other forms of Vitamin E. The α-tocopherol isomer is not only commonly used in studies to reverse deficiency symptoms, but also has the highest bioavailability.

Vitamin E has been shown to regulate the expression of certain pro-thrombotic and atherogenic factors.

Recommended Intake

The daily recommended intake of Vitamin E as α-tocopherol is slightly above 20 International Units (IU). Although synthetic Vitamin E may require a lower overall intake, this difference is accounted for when measuring Vitamin E in International Units.

Deficiency

A deficiency in Vitamin E can lead to myopathies, neuromyopathies, and forms of ataxia.

Overt deficiencies of Vitamin E are uncommon and are typically caused by genetic defects in transport proteins or malabsorption due to alcoholism, Crohn’s disease, cystic fibrosis (without enzyme therapy), or other intestinal diseases. [1]

Subclinical deficiencies of Vitamin E may occur in response to **excess oxidation**, [1] leading to a decrease in erythrocyte lifespan. [1]

Main Takeaway: Genuine Vitamin E deficiencies are uncommon in healthy individuals. Most cases of Vitamin E deficiency are observed in individuals with disease states that significantly impair fatty acid absorption from the intestines, such as Crohn’s disease.

Sufficiency & Excess

The Tolerable Upper Limit (TUL) for Vitamin E intake is 800mg (1,200 IU) for individuals aged 14-18 and 1,000mg (1,500 IU) for adults. The TUL remains the same for adult females during pregnancy or lactation.

Formulations & Variants

There are 8 different forms of Vitamin E found in nature, including tocopherols (which have alpha (α), beta (β), gamma (γ), and delta (δ) variants) and tocotrienols (which also have alpha (α), beta (β), gamma (γ), and delta (δ) variants). [1]

Although all forms of Vitamin E are biologically active, α-tocopherol is often considered the most bioactive form and the true essential vitamin. This is because it is preferentially transported by a specific transportation protein called tocopherol transfer protein (TTP), which brings orally supplemented Vitamin E from the liver to other tissues in the body.

Tocotrienols can be transported in the blood, as their presence in the blood increases after oral administration (faster than tocopherols at the same dosage) and they can be detected in serum platelets and adipose tissue. [1, 2, 3]

Transportation of tocotrienols may affect their benefits seen in vitro, as their efficacy and distribution in vivo can differ from that observed in vitro. It has been suggested that tocotrienols may have greater loading and chronic effects due to less efflux from tissues.

Although both natural and synthetic vitamin E are chemically identical, there are differences between them. Synthetic vitamin E is a mixture of four isomers, whereas natural vitamin E contains only α-tocopherol (RRR-α-tocopherol). Natural vitamin E sources may also contain other vitamers and tocotrienols that are not present in the synthetic form. The difference between natural and synthetic vitamin E may also affect the absorption and utilization of the vitamin in the body.

Research suggests that synthetic α-tocopherol has only 50% of the affinity for the tocopherol transport protein (TTP) compared to the natural form, which may affect its availability to the body. When comparing the bodily retention of α-tocopherol from natural and synthetic sources ingested in equal amounts (150mg each), it appears that the synthetic form is more readily eliminated through nonoxidative metabolism. Therefore, it is believed that natural vitamin E is more bioavailable to the body than the synthetic form.

Natural food sources of vitamin E may contain a mixture of tocotrienols in addition to α-tocopherol, while synthetic vitamin E is limited to the essential α-tocopherol vitamer and does not include tocotrienols. However, dietary supplements containing pure α-tocopherol do not usually contain tocotrienols regardless of whether they are natural or synthetic.

Gamma-tocopherol is another tocopherol that has been extensively studied, albeit to a lesser extent than alpha-tocopherol. It is a great source of vitamin E in the American diet, mainly through vegetable oil and flour, aka the things you shouldn’t be eating to begin with.

In animals with vitamin E deficiency, γ-tocopherol can exhibit vitamin-like effects, but it is only about 7-13% as potent as α-tocopherol. It is speculated that the elevated γ-tocopherol content in the diet could account for a maximum of 20% of the vitamin E-like activity in the human diet (due to the vegetable oil and flour consumption on the mediocre at best, average person’s diet).

When α-tocopherol is supplemented alone, the concentrations of γ-tocopherol in the serum are known to decrease. For instance, a study administering 1,200 IU of all-rac α-tocopherol over eight weeks found that serum γ-tocopherol decreased to 30-50% of the baseline level. There is an inverse relationship between α-tocopherol and γ-tocopherol concentrations in serum, with elevating levels of α-tocopherol being correlated with lower levels of γ-tocopherol. This relationship has also been observed with β-tocopherol, as its levels decrease with supplemental α-tocopherol at 1,200IU.

The antioxidant properties of γ-tocopherol include its ability to trap nucleophilic mutagens and its contribution to the chemoprotective functions of the antioxidant system glutathione. [1, 2]

In vitro studies suggest that tocotrienols may have stronger antioxidant properties compared to tocopherols. [1] Additionally, tocotrienols may have superior efficacy compared to tocopherols in inducing apoptosis, protecting against some types of cancer, [1] and providing neuroprotection. [1] Tocotrienols may also exert their antioxidant effects indirectly through selenoproteins.

When tested in living organisms, tocotrienols have shown to be more effective than tocopherols in preventing certain types of cancers, as well as providing stronger antioxidant effects, [1] anti-inflammatory effects and better protection of bone health. [1, 2, 3, 4]

Main Takeaway: The term ‘Vitamin E’ encompasses vitamers, which are isomers of the vitamin with similar structures and functions. While α-tocopherol is the only essential vitamin E vitamer, all of them possess biological functions. Although there are some differences in how these vitamers are transported to tissues, they all have the ability to impact peripheral tissues beyond the liver.

Natural food sources of vitamin E may contain a mixture of tocotrienols in addition to α-tocopherol, while synthetic vitamin E is limited to the essential α-tocopherol vitamer and does not include tocotrienols. However, dietary supplements containing pure α-tocopherol do not usually contain tocotrienols regardless of whether they are natural or synthetic.

Gamma-tocopherol is another tocopherol that has been extensively studied, albeit to a lesser extent than alpha-tocopherol. It is a great source of vitamin E in the American diet, mainly through vegetable oil and flour, aka the things you shouldn’t be eating to begin with.

In animals with vitamin E deficiency, γ-tocopherol can exhibit vitamin-like effects, but it is only about 7-13% as potent as α-tocopherol. It is speculated that the elevated γ-tocopherol content in the diet could account for a maximum of 20% of the vitamin E-like activity in the human diet (due to the vegetable oil and flour consumption on the mediocre at best, average person’s diet).

When α-tocopherol is supplemented alone, the concentrations of γ-tocopherol in the serum are known to decrease. For instance, a study administering 1,200 IU of all-rac α-tocopherol over eight weeks found that serum γ-tocopherol decreased to 30-50% of the baseline level.

When it comes to parameters where the mechanism is linked to the antioxidant effects of vitamin E, tocotrienols are believed to be superior to tocopherols at the same dose. This is because tocotrienols have more unsaturated points in their side chain, which gives them more potential to trap oxidation.

Absorption

Just like other fat-soluble nutrients and long chain fatty acids in the diet, vitamin E isomers are taken up from the intestines and transported to lymph tissue through chylomicrons before being distributed to the bloodstream.

Coingestion of water-soluble vitamin E (Vitamin E-TPGS) has been shown to enhance the absorption of fat-soluble drugs, possibly by increasing the secretion of chylomicrons, which are necessary for the transport of such drugs.

It seems that Vitamin E in the form of acetate and succinate can be absorbed through the skin. However, better absorption can be achieved by using an appropriate vehicle. A small percentage of the absorbed Vitamin E is converted into free form Vitamin E.

Consuming α-tocopherol alone, whether in natural or synthetic form, has been shown to decrease the levels of circulating γ-tocopherol. However, the reverse effect does not seem to occur. It is believed that supplementing both forms in roughly equal amounts is necessary to prevent a reduction in plasma γ-tocopherol levels.

Neurological Distribution

Vitamin E isomers have been found in human cerebrospinal fluid, albeit at lower concentrations than in serum. However, their levels in cerebrospinal fluid seem to be correlated with their levels in serum. Additionally, correlations observed between the isomers in serum may also extend to cerebrospinal fluid.

Metabolism

Metabolism of vitamin E vitamers occurs through a CYP3A-mediated process that converts them into carboxyethyl-hydroxychroman derivatives (CEHCs), [1, 2, 3] both in tocopherols and tocotrienols. This metabolism occurs when excess vitamin E is not used as an antioxidant. CEHCs levels in urine, which increase or decrease with constant vitamin E intake, are believed to indicate no additional antioxidant effects or increased oxidation, respectively.

Neurology

Alpha-tocotrienol has been noted to reduce glutamate-induced release of eicosanoids and confer neuroprotection [1] against glutamate-induced cell death in vitro. This may occur at a concentration low enough to be influenced by supplementation.

Strokes

Although there is mixed evidence [1, 2, 3, 4, 5, 6] for the role of vitamin E in stroke, there’s no evidence suggesting a significant protective effect from overall stroke risk and most evidence suggests no significant interaction.

Memory & Learning

Supplementation of vitamin E in otherwise healthy older women, has failed to find any significant interaction with memory formation or processing.

Cardiovascular Health

A study has indicated a rise in heart failure in metabolically unwell patients who supplemented moderate doses of vitamin E over a prolonged period. However, the long-term effects of vitamin E supplementation in individuals without metabolic complications have not been researched so far.

The changes of vitamin E seen in serum appear to reflect the changes of vitamin E seen in red blood cells.

Vitamin E has been found to be a constituent of LDL particles and is believed to play a role in reducing lipid peroxidation of LDL, which is thought to be an anti-atherogenic effect. Supplementation with high doses of vitamin E has been shown to increase the levels of vitamin E in LDL.

Despite preliminary evidence in rodents, supplementation of vitamin E does not appear to significantly reduce homocysteine concentrations. [1]

Although epidemiological evidence exists suggesting a that sufficient vitamin E intake may protect against cardiovascular disease, [1] the clincal trials examining these effects mostly find little benefit, [1] except in trials in which confounders exist.

A study found that in healthy men, taking 160mg of mixed tocotrienols daily for two months improved the augmentation index, which is believed to reflect arterial stiffness, by 5.3%. However, the study did not find similar effects with lower (80mg) or higher (320mg) doses.

When looking at diabetics, supplementation of high doses of vitamin E as α-tocopherol (1,600 IU) did not result in improved blood flow after eight weeks compared to placebo. In fact, continued supplementation at this dose for one year has been associated with a mild worsening of blood flow.

In a study of young healthy males, supplementation with tocotrienols for two months resulted in a mild reduction of aortic systolic blood pressure at doses of 160 and 320mg (approximately 5%). A lower dose of 80mg did not produce significant effects.

Although intravenous infusion of vitamin E has been shown to significantly inhibit clotting, there is no evidence to suggest that oral supplementation has any effect on bleeding times. However, oral vitamin E supplementation has been linked to a reduced risk of venous thromboembolism in women, and some evidence suggests that γ-tocopherol may also reduce thrombotic risk factors, although this claim is not as well-supported.

Although intravenous infusion of vitamin E has been shown to significantly inhibit clotting, here is no evidence to suggest that oral supplementation has any effect on bleeding times. However, oral vitamin E supplementation has been linked to a reduced risk of venous thromboembolism in women.

Administration of mixed antioxidants, which includes vitamin E, has been found to weaken the favorable effect of combination niacin and simvastatin therapy on HDL2 subfractions in patients with coronary artery disease. [1]

Interactions with Glucose Metabolism

Vitamin E is believed to have potential benefits in diabetes complications by reducing the activity of PKC, which is responsible for mediating the effects of hyperglycemia on cells.

Interventions have failed to find a protective effect of vitamin E supplementation on the glycation of HbA1c, a longer-term measure of blood glucose levels. [1, 2]

Vitamin E supplementation does not protect against the development of diabetes in either healthy women or those with or at high risk of cardiovascular disease. [1]

Supplementation with vitamin E in type II diabetics has shown no or minimal effects on glucose levels and several cardiovascular risk factors, [1] except for minor improvements in oxidation and triglyceride levels.

Skeletal Muscle & Physical Performance

During exercise, oxidative stress is thought to contribute to the production and release of interleukin six (IL-6) from skeletal muscle into the bloodstream. Antioxidants have been shown to reduce or eliminate the release of IL-6. Vitamin E, when combined with vitamin C, has been found to suppress the release of IL-6 from muscle into the serum.

A deficiency of vitamin E results in skeletal myopathies [1] associated with damage and prooxidative changes to the mitochondria.

Supplementation with vitamin E does not seem to enhance endurance exercise performance [1] compared to a placebo, even though it may have antioxidant effects in athletes.

Bone & Joint Health

The use of α-tocopherol vitamin E supplementation does not appear to be associated with a decreased risk of rheumatoid arthritis development in females when compared to placebo.

Supplementing rodents with low doses of vitamin E seems to enhance bone tissue growth, [1] while providing excessively high levels of vitamin E may result in bone tissue loss, according to rodent studies.

Epidemiological studies indicate that having a good vitamin E status and taking vitamin E supplements are protective against fractures in elderly individuals. The increased risk of fractures observed when vitamin E intake falls below 5mg per day (7.5 IU, which is equivalent to 33% of the recommended daily intake) may explain this. However, there is no evidence of dose-dependent protective effects above 10mg per day.

Inflammation & Immunology

Research has found that α-tocopherol supplementation can enhance lymphocyte proliferation in aged mice, compared to other vitamers. [1] In elderly humans, supplementation with 200mg of α-tocopherol has been shown to increase Peripheral Blood Mononuclear Cell (PMBC) proliferation when induced ex vivo. However, the increase is reduced when taken alongside 2.5g of EPA+DHA.

Supplementation of α-tocopherol at doses ranging from 50-100mg for six months in healthy older individuals has been associated with decreased IFN-γ concentrations.

Studies have reported that vitamin E, specifically α-tocopherol, can promote the proliferation and secretion of IL-2 in various immune cells such as purified T-cells, splenocytes (with effect on proliferation but not IL-2 secretion) and naive T-cells. However, vitamin E does not seem to affect the proliferation of memory T-cells.

When healthy older adults were supplemented with 50mg and 100mg of α-tocopherol daily for six months, it resulted in an increase in circulating IL-4 concentrations with a trend towards increasing IL-2.

Although IL-2 is considered an inflammatory (Th1) cytokine and IL-4 an anti-inflammatory (Th2) cytokine, this change may be seen as pro-inflammatory, but due to age-related shifts towards Th2, [1] it is also believed to have an immunosupportive effect for the elderly.

Supplementation of 200mg of either pure α-tocopherol or mixed tocotrienols does not appear to increase IL-4 in otherwise healthy young individuals.

Administration of 500mg of vitamin E, either as α-tocopherol or mixed vitamers (primarily α-tocopherol and γ-tocopherol), for eight weeks resulted in changes to the vitamin E content of neutrophils that corresponded to those observed in plasma.

In a study conducted on healthy elderly individuals, supplementing with different doses of vitamin E (60 IU, 200 IU, and 800 IU) for a period of four months did not result in significant changes in the response of neutrophils in vitro against Candida albicans.

In vitro studies have shown that vitamin E has the ability to stimulate T-cell proliferation, and the specific vitamer used may impact the response.

Supplementation of low doses of vitamin E has been shown to improve immune function in the elderly, [1, 2] who may have compromised immune function due to impaired T-cell function.

According to in vitro studies, α-tocopherol may promote mast cell degranulation, which has a pro-allergenic effect, while tocotrienols may have the opposite effect by suppressing degranulation.

Allergies & Asthma

Epidemiological research has shown that increased intake of vitamin E is associated with a reduced risk of asthma in women. In individuals with asthma, there is a reduced activity of the antioxidant system in the lungs, including those associated with vitamin E. [1]

In a clinical trial, nonsmoking asthmatics who were on corticosteroids received either 500mg of vitamin E (as α-tocopherol) or a placebo for six weeks. The study found that the group receiving the supplementation had a slight improvement in responsiveness to methacholine compared to the placebo group. However, no significant changes were observed in other measured parameters, including FEV1, FVC, morning peak flow, bronchodilator use, and subjective symptoms.

Interactions with Hormones

Supplementing vitamin E has been shown to lower cortisol levels in cattle, while studies in rats suggest that a deficiency in vitamin E may increase cortisol levels. [1, 2]

However, studies on vitamin E supplementation in humans have not demonstrated any significant benefits [1] compared to placebo.

There is limited evidence regarding the effect of vitamin E supplementation on prolactin levels in healthy individuals. However, a study found that uremic patients who were given vitamin E supplements experienced a reduction in prolactin levels.

Administration of 800mg α-tocopherol daily for a month in healthy elderly individuals did not significantly alter circulating levels of T3, T4 (free or total), or the uptake ratio of T3 in comparison to placebo. Four weeks of 800mg α-tocopherol in young males and females not on contraceptives, however, has led to a slight decrease in thyroid hormones.

Two studies conducted over extended periods have not found any changes in thyroid function. The first study, which included participants aged 24-62 years (mean 28 years), was conducted over an average of 3 years with daily supplementation ranging from 100-800 IU/day. The second study, conducted over 12 weeks, involved healthy college students who received 900 IU of vitamin E daily.

Anti-oxidant

Vitamin E is known to possess chain-breaking anti-lipid peroxidation properties. It is particularly effective in lipoproteins, where it is incorporated by the liver.

The term ‘chain-breaking’ refers to the ability to interrupt a series of oxidative events initiated by free radicals. [1] Even during vitamin E deficiency, it appears that vitamin E retains its ability to act as a central chain-breaker, interrupting the series of oxidative events.

Administration of 400-800 IU vitamin E supplementation to individuals with atherosclerotic plaques has been linked to a significant reduction in the risk of cardiovascular events. Vitamin E’s ability to reduce levels of prothrombotic factors [1] may be a potential mechanism of action for the observed results. Supplementing with 300IU doses of vitamin E has been found to improve lipid peroxidation markers in individuals with coronary spastic angina, which may contribute to the observed reduction in cardiac events associated with vitamin E supplementation.

Pro-oxidant

In vitro studies suggest that vitamin E (α-tocopherol) can act as a pro-oxidant, [1, 2] rather than an antioxidant, when present in LDL particles, which may explain why it does not always have a positive effect on atherosclerosis.

The pro-oxidative effect of alpha-tocopherol in LDL particles in vitro may be due to its ability to sequester free radicals, leading to its own pro-oxidative state. This effect can usually be countered by co-antioxidants such as Vitamin C. However, if the newly-formed alpha-tocopherol radical cannot be acted upon by a co-antioxidant, it may accelerate the lipid peroxidation that it initially suppressed. [1]

Lipid Peroxidation

When 800IU α-tocopherol for two months before an Ironman marathon did not show any significant effect on serum lipid hydroperoxides levels before or immediately after the race. However, a significant increase in F2-isoprostanes (an oxidative product formed from lipid peroxidation) was observed after 90 minutes relative to placebo. This finding suggests that supplementation with α-tocopherol may not effectively prevent lipid peroxidation during high-intensity exercise.

DNA Damage

In a study conducted on type II diabetics, supplementation of 1,200 IU α-tocopherol daily for four weeks showed an exacerbation in oxidative DNA damage after an oral glucose tolerance test by 13.6% compared to placebo. No significant difference in damage was observed before the administration of the glucose tolerance test. There is no evidence suggesting that 400 IU of vitamin E supplementation causes an increase in DNA damage in type II diabetics who have not undergone a glucose tolerance test.

Peripheral Organ Systems

Rectal administration of high doses of vitamin E may help reduce symptoms in people with ulcerative colitis.

Nonalcoholic fatty liver disease (NAFLD/NASH) is a condition characterized by elevated oxidative stress, and vitamin E, being an antioxidant, is thought to play a therapeutic role in treating the symptoms of the condition.

Research suggests that high dose vitamin E supplementation in individuals with NAFLD may be more effective than a placebo in reducing elevated serum enzymes and other factors [1, 2] indicating liver damage. However, there is conflicting evidence on whether vitamin E can reduce fat accumulation in the liver and the resulting fibrotic score. [1, 2] It appears that the benefits of vitamin E supplementation may only be seen in individuals with evidence of inflammatory liver damage, rather than as a standalone treatment.

Research suggests that cigarette smoking may accelerate the removal of α-tocopherol from the bloodstream. However, co-supplementation with vitamin C and other antioxidants appears to slow down this process. Therefore, smokers may require higher amounts of vitamin E and other antioxidants, although the specific amount required is not yet established.

While mixed antioxidant supplements have been associated with lower risk of cataract formation, it remains unclear if this is due to the benefits of individual nutrients, such as zinc. Vitamin E alone has not been found to have any significant protective effects against the development or progression of cataracts. [1]

Administration of vitamin E (100mg/kg intravenously) in rabbits improved levels of antioxidative biomarkers such as glutathione and MDA when compared to the control group. Additionally, when coadministered with testosterone, vitamin E was able to prevent the decline in these biomarkers typically observed with testosterone alone.

Interactions with Cancer Metabolism

There is a small decrease in some cancer risk with daily supplementation of vitamin E (as alpha-tocopherol) according to some large-scale epidemiological studies. [1]

A cohort study conducted in China with 132,837 participants showed that during the follow-up period, 267 individuals (0.2%) developed liver cancer. Comparing the intake of vitamin E supplements from the base sample to the group that developed liver cancer, it was found that the consumption of vitamin E supplements was associated with a lower risk of cancer occurrence, with a hazard ratio of 0.52 (almost half the risk) and a 95% confidence interval of 0.3-0.9. Additionally, dietary intake of vitamin E was also found to be inversely related to the development of liver cancer.

Research suggests that higher levels of vitamin E in the blood before a prostate cancer diagnosis and increased vitamin E intake may be linked to lower incidences of advanced prostate cancer and decreased prostate cancer-related deaths among smokers. However, observational studies examining the connection between vitamin E and prostate cancer, including all types of cases (not only advanced cases), are inconclusive as to whether vitamin E has a small protective effect or no effect at all.

Supplementation of α-tocopherol at a dosage of 400 IU has been associated with a mild increase in prostate cancer risk [1] in otherwise healthy men when smoking is not taken into account.

New studies suggest that antioxidants may have the potential to promote certain types of cancer in high-risk populations such as smokers. Genomic analysis of lung cancers has shown that genes responsible for activating the endogenous antioxidant program have a greater number of mutations, indicating that reducing reactive oxygen species may actually facilitate the development of cancer. [1]

Research has indicated that specific oncogenes, which are genes linked with promoting cancer when they are dysregulated, can activate the endogenous antioxidant program through NRF2, and in doing so, promote the development of tumors. [1]

Studies using a mouse model for lung cancer have shown that supplementation with vitamin E or the antioxidant acetylcysteine can promote carcinogenesis and reduce expression of the tumor-suppressor protein p53. Although this does not definitively demonstrate that antioxidants promote cancer in humans, it does suggest that caution is warranted when considering antioxidant supplementation in high-risk populations, such as smokers.

Longevity & Life Extension

One meta-analysis reported a slight but statistically significant increase in all-cause mortality associated with α-tocopherol supplementation at doses above 400IU. The study primarily focused on individuals with pre-existing health conditions and high risk of cardiovascular disease. The effect of low-dose vitamin E supplementation on mortality is uncertain and requires further investigation. It is also unknown whether these findings apply to healthy populations.

The impact of vitamin E supplementation on all-cause mortality could vary depending on the population studied and may be influenced by the consumption of other nutrients, particularly vitamin C.

PMS & Menopause

In young women with primary dysmenorrhea, supplementation of 400-500IU vitamin E per day, starting 2 days prior to menstruation and continuing for 3 days, appears to alleviate symptoms. [1, 2]

Alzheimer's Disease

Vitamin E, with its antioxidant properties, may have a *potential neuroprotective effect against Alzheimer’s disease (AD). AD is associated with increased oxidative damage in the brain, and certain forms of vitamin E have been linked to a reduced risk of developing mild cognitive impairment or AD.

While high-dose vitamin E supplementation has been shown to slow disease progression in individuals with mild to severe Alzheimer’s disease, the efficacy of lower doses in this population remains untested. Additionally, vitamin E supplementation does not appear to be beneficial for individuals with mild cognitive impairment or cognitive decline unrelated to Alzheimer’s disease. [1]

Parkinson's Disease

A meta-analysis conducted on observational studies published from 1996 to 2005 found that vitamin E supplementation may potentially have a protective effect against Parkinson’s disease. Studies have found that patients with Parkinson’s disease have increased levels of vitamin E in certain regions of their brain, which may be a compensatory mechanism in response to oxidative damage. This finding suggests that increasing vitamin E levels through supplementation may potentially limit the oxidative damage associated with Parkinson’s disease. In vitro studies have shown that vitamin E can reduce oxidative damage to striatal dopaminergic neurons, which is linked to the pathology of Parkinson’s disease.

According to research conducted on a mouse-model, vitamin E deficiency does not seem to increase the susceptibility of the brain region to oxidative stress. In a rat model of Parkinson’s disease induced by rotenone, administration of vitamin E (specifically α-tocopherol) via intramuscular injection at a dose of 100 IU/kg body weight was found to reduce the pathological decrease in dopamine and the increase in lipid peroxidation.

The DATATOP study investigated the effects of selegiline, vitamin E (2,000 IU daily as α-tocopherol), or their combination on Parkinson’s disease in humans, but failed to find any protective effects with vitamin E supplementation compared to the placebo group.

Amyotrophic Lateral Sclerosis (ALS)

Levels of vitamin E, specifically α-tocopherol, have been assessed in the blood and cerebrospinal fluid of individuals with ALS compared to healthy individuals, but there is no significant distinction between the two groups. [1, 2, 3]

There is some evidence indicating that high serum levels of α-tocopherol are associated with a reduced risk of developing ALS. However, studies investigating the effects of α-tocopherol supplementation have produced mixed results. Some studies suggest that long-term intake of α-tocopherol may have a protective effect against ALS, but short-term supplementation does not seem to offer any benefits.

Ataxia with Vitamin E Deficiency (AVED)

Patients with Ataxia with Vitamin E Deficiency (AVED), a genetic disease that impairs vitamin E transport, exhibit several neurological disorders. However, high-dose vitamin E supplementation can alleviate the symptoms and halt disease progression.

Nutrient Interactions

Polyunsaturated Fatty Acids

Polyunsaturated fatty acids (PUFAs) contain multiple double bonds in their structure, making them highly susceptible to lipid peroxidation. In contrast, monounsaturated fatty acids (MUFAs) have a single double bond, making them less susceptible to oxidation. Saturated fatty acids, on the other hand, are largely resistant to oxidation under normal conditions. [1]

Research has suggested that the increase in lipid peroxidation resulting from the oral intake of high doses of PUFAs is not as significant as the one resulting from the injection of the same amount of PUFAs into rats, which leads to their integration into organ tissue. [1] This difference is not completely accounted for by vitamin E levels in rats given adequate vitamin E intake in the short term, [1] although a vitamin E-deficient diet clearly does lead to increased peroxidation and damage. Increasing dietary PUFAs may increase the requirement of vitamin E. [1] The increased need of vitamin E is known to correlate with the degree of fatty acid unsaturation, with more highly-saturated PUFAs reducing vitamin E stores more.

An adequate oral intake of vitamin E in humans has been estimated to be 0.6mg (approximately 1 IU) of α-tocopherol per gram of linoleic acid and may be higher for fatty acids with more than two double bonds (most dietary PUFAs).

Sesamin

Sesamin has been found to inhibit the metabolism of vitamin E vitamers by inhibiting tocopherol-ω-hydroxylation. As this process occurs most rapidly with gamma vitamers such as γ-tocopherol and γ-tocotrienol, [1] oral consumption of sesamin may cause an elevation or enhancement of plasma and tissue levels of these vitamers. [1, 2]

Coenzyme CoQ10

Coenzyme Q10 is a molecule found in mitochondria that has a critical role in producing energy for the body, as well as playing an important role in the endogenous antioxidant system. Vitamin E supplementation (1,200mg α-tocopherol) combined with CoQ10 prior to an exercise test reversed the expected reduction in serum CoQ10 from exercise-induced oxidation (39%) into a mild increase (8.5%).

Alpha-Lipoic Acid

Alpha-lipoic acid (ALA) is a mitochondrial compound involved in energy metabolism. It is commonly taken with L-Carnitine supplements, as they are related in mechanisms. ALA provides a short but potent reduction of oxidation by increasing antioxidant enzymes, and may decrease blood glucose acutely.

Alpha-Lipoic Acid (ALA) and vitamin E have a synergistic relationship as ALA can recycle vitamin E similar to how vitamin E recycles vitamin C. [1]

It has been observed that Alpha-Lipoic Acid and vitamin E exhibit synergy in terms of their anti-clotting properties, which may have cardioprotective effects or increase the risk of bleeding depending on the dose.

Vitamin K

Vitamin K is primarily recognized for its role in blood clotting and functions through a group of proteins called ‘vitamin K dependent proteins’ that are activated by vitamin K levels in the body.

Supplementation of vitamin E up to 800 IU over short or long term [1] does not necessarily increase clotting time in otherwise healthy adults, as reported by various studies. It has been observed that vitamin E can enhance the effects of warfarin, which is an anticoagulant that works by antagonizing vitamin K. [1]

The role of vitamin K and its activity in these effects of vitamin E are uncertain. One study reported no harmful consequences of vitamin E supplementation (900 IU α-tocopherol) on PIVKA-II, a biomarker for vitamin K status. Conversely, another study that employed a more accurate measuring instrument and administered 1,000 IU vitamin E over a 12-week period observed a minor increase in PIVKA-II, which implies reduced vitamin K status. However, other indicators of vitamin K status such as carboxylated osteocalcin and plasma phylloquinone remained unaffected.

Safety & Toxicity

After controlling for other factors, the consumption of high doses of vitamin E supplements (above 400 IU per day) has been associated with increased mortality from all causes. Other analyses have challenged these findings, [1] and there have been counterarguments made in response to them. [1]

Certain researchers have proposed that although there is insufficient evidence to support the general use of vitamin E supplements, there is still a possibility that some specific populations may derive benefits from them.

There is a possibility that tocotrienols could be a safer option than vitamin E for inhibiting the spread of cancer cells due to their higher bioactivity, which means that a lower dose is required to achieve the same effect, and their tendency to accumulate in tumors and tissues rather than in the blood. However, these benefits have not been conclusively proven, and further research is necessary.

Application of topical α-tocopherol (vitamin E) on scars has been reported to cause more erythema and irritation compared to control gels that do not contain vitamin E. [1]

According to other reports, applying vitamin E to broken skin (for example, after a chemical peel or dermabrasion) may cause contact urticaria, eczematous dermatitis, and reactions similar to erythema multiforme. [1]

Summary

Tldr; Alpha-tocopherol is the form of Vitamin E that the liver typically targets for incorporation into lipoproteins, compared to other forms of Vitamin E. The α-tocopherol isomer is not only commonly used in studies to reverse deficiency symptoms, but also has the highest bioavailability.

Vitamin E has been shown to regulate the expression of certain pro-thrombotic and atherogenic factors.

The daily recommended intake of Vitamin E as α-tocopherol is slightly above 20 International Units (IU).

A deficiency in Vitamin E can lead to myopathies, neuromyopathies, and forms of ataxia.

The term ‘Vitamin E’ encompasses vitamers, which are isomers of the vitamin with similar structures and functions. While α-tocopherol is the only essential vitamin E vitamer, all of them possess biological functions. Although there are some differences in how these vitamers are transported to tissues, they all have the ability to impact peripheral tissues beyond the liver.

Gamma-tocopherol is another tocopherol that has been extensively studied, albeit to a lesser extent than alpha-tocopherol. It is a great source of vitamin E in the American diet, mainly through vegetable oil and flour, aka the things you **shouldn’t be eating** to begin with.

Just like other fat-soluble nutrients and long chain fatty acids in the diet, vitamin E isomers are taken up from the intestines and transported to lymph tissue through chylomicrons before being distributed to the bloodstream.

Alpha-tocotrienol has been noted to reduce glutamate-induced release of eicosanoids
and confer neuroprotection against glutamate-induced cell death _in vitro_. This may occur at a concentration low enough to be influenced by supplementation.

Although there is mixed evidence for the role of vitamin E in stroke, there’s no evidence suggesting a significant protective effect from overall stroke risk and most evidence suggests no significant interaction.

There’s indication for a rise in heart failure in metabolically unwell patients who supplemented moderate doses of vitamin E over a prolonged period.

The clincal trials that examined the role of Vitamin E in protecting against cardiovascular disease mostly find little benefit, except in trials in which confounders exist.

When looking at diabetics, supplementation of high doses of vitamin E as α-tocopherol (1,600 IU) did not result in improved blood flow after eight weeks compared to placebo. In fact, continued supplementation at this dose for one year has been associated with a mild worsening of blood flow.

Supplementation with tocotrienols for two months resulted in a mild reduction of aortic systolic blood pressure at doses of 160 and 320mg (approximately 5%). A lower dose of 80mg did not produce significant effects.

Vitamin E supplementation does not protect against the development of diabetes in either healthy women or those with or at high risk of cardiovascular disease.

Supplementation with vitamin E does not seem to enhance endurance exercise performance compared to a placebo, even though it may have antioxidant effects in athletes.

The use of α-tocopherol vitamin E supplementation does not appear to be associated with a decreased risk of rheumatoid arthritis development in females when compared to placebo.

The use of α-tocopherol vitamin E supplementation does not appear to be associated with a decreased risk of rheumatoid arthritis development in females when compared to placebo. Epidemiological studies indicate that having a good vitamin E status and taking vitamin E supplements are protective against fractures in elderly individuals.

The increased risk of fractures observed when vitamin E intake falls below 5mg per day (7.5 IU, which is equivalent to 33% of the recommended daily intake) may explain this. However, there is no evidence of dose-dependent protective effects above 10mg per day.

Supplementing with α-tocopherol may not effectively prevent lipid peroxidation during high-intensity exercise.

Research suggests that cigarette smoking may accelerate the removal of α-tocopherol from the bloodstream. However, co-supplementation with vitamin C and other antioxidants appears to slow down this process. Therefore, smokers may require higher amounts of vitamin E and other antioxidants, although the specific amount required is not yet established.

Vitamin E has been found to be inversely related to the development of liver cancer.

One meta-analysis reported a slight but statistically significant increase in all-cause mortality associated with α-tocopherol supplementation at doses above 400IU. The study primarily focused on individuals with pre-existing health conditions and high risk of cardiovascular disease. The impact of vitamin E supplementation on all-cause mortality could vary depending on the population studied and may be influenced by the consumption of other nutrients, particularly vitamin C.

In young women with primary dysmenorrhea, supplementation of 400-500IU vitamin E per day, starting 2 days prior to menstruation and continuing for 3 days, appears to alleviate symptoms.

Vitamin E, with its antioxidant properties, may have a potential neuroprotective effect against Alzheimer’s disease (AD). AD is associated with increased oxidative damage in the brain, and certain forms of vitamin E have been linked to a reduced risk of developing mild cognitive impairment or AD.

While high-dose vitamin E supplementation has been shown to slow disease progression in individuals with mild to severe Alzheimer’s disease, the efficacy of lower doses in this population remains untested. Additionally, vitamin E supplementation does not appear to be beneficial for individuals with mild cognitive impairment or cognitive decline unrelated to Alzheimer’s disease.

There is some evidence indicating that high serum levels of α-tocopherol are associated with a reduced risk of developing ALS. However, studies investigating the effects of α-tocopherol supplementation have produced mixed results. Some studies suggest that long-term intake of α-tocopherol may have a protective effect against ALS, but short-term supplementation does not seem to offer any benefits.

Patients with Ataxia with Vitamin E Deficiency (AVED), a genetic disease that impairs vitamin E transport, exhibit several neurological disorders. However, high-dose vitamin E supplementation can alleviate the symptoms and halt disease progression.

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