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If you asked a group of scientists to name an antioxidant,
most would point to vitamin E as the classic example of a
compound that inhibits dangerous free radicals.
While numerous studies show that vitamin E suppresses free
radicals, there is evidence that commercial vitamin E supplements
do not provide adequate antioxidant protection.
Most vitamin E supplements consist primarily of alpha tocopherol.
Recent studies indicate that a lot more than alpha tocopherol
is needed to protect against degenerative disease.
To obtain optimal health benefits from vitamin E, a mixture
of tocopherols (alpha, beta, delta, and gamma) and tocotrienols
(alpha, beta, delta, and gamma) are required. Some of the
functions of these vitamin E fractions are similar while others
are completely different. When taken together, these various
forms of vitamin E work synergistically as a team to provide
maximum benefits.
In this article, we discuss scientific findings supporting
the value of the full spectrum of vitamin E that includes
the tocopherols and tocotrienols.
The Tocotrienols
In 1995, Life Extension added a small amount of tocotrienols
to a Coenzyme Q10 supplement used by most Life Extension Foundation
members. Evidence at that time showed that tocotrienols could
help protect against free radical-induced disease.
More recent research shows that tocotrienols may be the most
important members of the vitamin E family. In an animal model
of aging, tocotrienols extended lifespan by 19% while reducing
protein carbonylation, a particularly toxic oxidation process
indicative of aging.[1] Not only
have tocotrienols demonstrated a superior antioxidant effect
compared to alpha tocopherol (40-60 times more effective),
but in a clinical study they have been shown to reverse carotid
stenosis (narrowing of the carotid artery due to atherosclerosis),
thus reducing the risk of stroke.
Tocotrienols have also been shown to reduce the level of
LDL (the “bad” form of cholesterol) and apolipoprotein B,
both of which are important risk factors for atherosclerosis
and cardiovascular disease. Furthermore, tocotrienols have
been shown to inhibit the growth of cancer cells. While tocotrienols
are found in high concentration in palm oil and rice bran,
palm-derived tocotrienols are better supported by research.
The difference in effect between tocopherols and tocotrienols
is believed to be caused by a subtle difference in molecular
structure. Tocotrienols have an isoprenoid instead of a phytyl
side chain. Double bonds in the isoprenoid side chain allow
tocotrienols to move freely and more efficiently within cell
membranes than tocopherols, giving tocotrienols greater ability
to catch and fight free radicals. This greater mobility also
allows tocotrienols to recycle more quickly than alpha-tocopherol.
Alpha versus Gamma Tocopherol
Several large studies have shown great benefits of vitamin
E intake in reducing cardiovascular disease and death from
heart attacks, while others have failed to show similar results.[2-8]
This discrepancy may well be due to the fact that only alpha-tocopherol
was studied in isolation, while gamma-tocopherol and toco-trienols
were not considered.
This may also explain why vitamin E as found in food is more
effective than alpha-tocopherol supplements in reducing death
from cardiovascular disease.[9-10]
Food provides a broader spectrum of the vitamin E family than
conventional supplements. For example, vitamin E in the typical
American diet contains considerably more gamma-tocopherol
than alpha-tocopherol[11] in contrast
to supplements that generally contain only alpha-tocopherol,
or insignificant amounts of gamma-tocopherol, tocotrienols
and other members of the vitamin E family.
Moreover, studies indicate that high dose alpha-tocopherol
supplementation considerably decreases the absorption of gamma-tocopherol
and reduces the effects of tocotrienols. One group of scientists
observed that when human volunteers (age 30-60) were given
1,200 IU of synthetic alpha-tocopherol daily for 8 weeks,
plasma gamma-tocopherol decreased in all subjects to 30-50%
of initial values.[12] This is
another indication of the importance of a balanced
vitamin E intake.
A Swedish study found that patients with coronary heart disease
had lower levels of gamma tocopherol and a higher alpha-to-gamma
ratio than healthy age-matched subjects.[13]
While alpha-tocopherol has long been known as an important
antioxidant, research has now shown that the complete vitamin
E team is much more effective. The different vitamin E forms
have complementary effects as free radical scavengers. Together
they can fight a wider spectrum of free radicals than alpha-tocopherol
alone.
One research group found that gamma-tocopherol is significantly
more effective than alpha-tocopherol in inhibiting the powerful
and harmful oxidizing agent peroxynitrite.[14]
While alpha-tocopherol can to some extent inhibit free radical
generation, gamma-tocopherol is able to trap and remove existing
free radicals as well as highly toxic compounds such as peroxynitrite.[15]
Gamma tocopherol can, therefore, protect cells against the
mutagenic and carcinogenic effects of the very damaging reactive
nitrogen species (See the antioxidant section).
Tocotrienols and Lifespan Extension
Recent experimental research confirms the connection between
tocotrienols, reduced oxidative damage, and increased life
span. Palm-derived tocotrienols were chosen for a study of
the aging process at the Life Science Research Center in Japan.[16]
The study was conducted on a model organism commonly used
in anti-aging research, the nematode known as C. elegans (Caenorhabditis
elegans). This species of worm is widely used in basic life
science research due to the fact that is has genetic sequences
similar to humans.
The study demonstrated that tocotrienols, but not alpha-tocopherol,
significantly extended the average life span of the organisms.
Nematodes exposed to a tocotrienol enriched (80ug/ml) growth
medium lived 19% longer than the control group. A lower concentration
(8ug/ml) of tocotrienols extended their average lifespan by
9%. When alpha-tocopherol was tested instead of tocotrienols
it had no effect on lifespan. The study also examined carbonylated
proteins, which are destructive products of protein oxidation
that accumulate during aging in both nematodes and humans.
In humans about a third of proteins become carbonylated in
the latter third of life, leading to serious degenerative
changes in the structures and regulatory systems of the body,
including for example the wrinkling of skin. (For further
discussion of protein carbonylation, see Carnosine
article on page 24 in the January 2001 issue of Life
Extension magazine).
Protein carbonyl accumulation in the nematodes was a mirror
image of their survival curve, increasing from 1.1nmol/mg
protein in young animals to 2.8nmol/mg in “old age” (15 days).
In the nematodes treated with tocotrienols protein carbonyls
rose about half as much during the course of aging, to only
1.9nmol/mg at age 15 days.
Ultraviolet (UV B) irradiation of the nematodes shortened
their average life span by 12%. However, when tocotrienols
were added to the medium prior to irradiation, the irradiated
nematodes lived as long as the non-irradiated control group.
Interestingly, their lifespan increased even more when tocotrienols
were added soon after irradiation, and exceeded that of the
non-irradiated group, indicating that tocotrienols are more
than chain-breaking antioxidants, and are, in fact, capable
of repairing damage that has already occurred. Alpha-tocopherol
did not lend significant protection from irradiation.
Tocotrienols and Cardiovascular Disease
One of the most striking discoveries in tocotrienol research
is their ability to clear atherosclerotic blockage (stenosis)
in the carotid artery, giving them the potential to significantly
reduce the risk of stroke. Stroke often occurs when atherosclerotic
deposits travel upstream and cut off the blood supply to part
of the brain.
Tocotrienols show promise as a natural and safe alternative
to risky surgery for this condition because of their ability
to reverse carotid stenosis, not merely stop its progression.
This was demonstrated in a clinical trial testing the effect
of tocotrienols on carotid atherosclerosis.[17]
The results of this 18-month trial were remarkable.
Fifty patients with carotid stenosis were randomly assigned
to receive either 160 mg daily of palm tocotrienols (gamma
and alpha forms) with 64 mg of alpha-tocopherol in palm oil,
or palm oil only as a placebo. After 6 months the dosage in
the treatment group was increased to 240 mg of tocotrienols
with 96 mg of alpha-tocopherol.
At the end of the study, ultrasound scans of the carotid
artery demonstrated that none of the patients in the control
group had improved during the trial, while ten showed a worsening
of their condition (increased stenosis). In the tocotrienol
group, however, atherosclerosis was reduced and blood flow
to the brain improved in 7 of 25 patients, while the condition
had worsened in only two patients. No adverse side effects
were reported in either group.
Tocotrienols and statin drugs such as lovastatin both lower
cholesterol by suppressing the activity of the enzyme HMG-CoA
reductase, although through different mechanisms. The statins
are thought to affect the enzyme through competitive inhibition,
while the tocotrienols accelerate enzyme degradation and decrease
the efficiency of mRNA translation of the enzyme.[18]
This difference in mechanism is believed to be a reason for
the absence of adverse side effects with tocotrienols, contrary
to the common side effects of the statin drugs.
HMG-CoA reductase is the enzyme that permits the body to
synthesize its own cholesterol from a precursor called mevalonate.
The mevalonate pathway is also of great importance in regulating
cell growth and proliferation. The ability of tocotrienols
to inhibit this pathway, therefore, enables them to inhibit
cancer growth (see more in the cancer section).
Some studies have demonstrated a significant reduction of
both total and LDL cholesterol with tocotrienols administered
to patients with high serum lipids. In a double blind, crossover
study on 25 patients with high cholesterol levels, the patients
in the treatment group were given 4 capsules daily of 50 mg
tocotrienols mixed with palm oil, while the control group
received only corn oil. At the end of the 8-week trial period,
total cholesterol and LDL cholesterol had decreased significantly
(15% and 8%) in the 15 subjects given the palm tocotrienols.
There was no change in the control group.[19]
Total cholesterol and LDL-cholesterol were reduced even more
(17 % and 24 % respectively) when tocotrienols were added
to a low fat, low cholesterol diet and alcohol-free regimen
in another double-blind, longer-lasting trial (12 weeks).[20]
Other important cardiovascular risk factors were reduced by
tocotrienols. Apoli-poprotein B and lipoprotein(a), strong
predictors of cardiovascular disease[21-23],
as well as thromboxane B2 and platelet factor 4 were all significantly
lowered in the tocotrienol-treated group (15%, 17%, 31% and
14% respectively).
Thromboxane B2 contributes to cardiovascular disease through
proinflammatory activities and platelet aggregation. It is
formed from pro-inflammatory prostaglandins through the function
of the enzyme cyclooxygenase (COX-2), which is known to be
involved in the development of both inflammatory and neoplastic
(cancerous) disease. The significant reduction (31%) of thromboxane
B2 in this tocotrienol study is interesting, suggesting possible
similarities with gamma-tocopherol,which is known to be a
COX-2 inhibitor.[24]
While both alpha and gamma-tocopherol have been shown to
reduce platelet aggregation and delay thrombus formation,
gamma-tocopherol was shown to be significantly more potent
in a study on rats.[25]
Tocotrienols were studied in combination with the statin
drug lovastatin in another study. The 28 patients with elevated
cholesterol levels in this double blind, cross-over clinical
trial were placed on the American Heart Association Step-1
diet before beginning the treatment. After 35 days on the
diet, they were given low doses of lovastatin, tocotrienols
and alpha-tocopherol (and combinations of these agents) in
stages of 35 days each, while staying on the diet. The combination
of lovastatin (10mg) and palm tocotrienols (50mg) had a lipid-lowering
effect of 20-25%, while tocotrienols or lovastatin alone in
the same dosages reduced LDL-cholesterol 18% and 15% respectively.
No side effects were reported during the study. It is important
to note that dosages of cholesterol-lowering drugs should
not be reduced on the basis of this preliminary study.[26]
Supplementation with gamma-tocotrienol alone, or in combination
with alpha-tocopherol, to rats fed a diet rich in fat for
6 weeks, showed a significant reduction in total and LDL cholesterol,
triglycerides and reactive oxidation products, particularly
hydroper-oxides.[27] The powerful
antioxidant effects of tocotrienols will be discussed later
in this article.
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References on Page
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