Novel Method Combats Chronic Inflammation |
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The most valuable thing
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Reprinted with permission of Life
Extension®
Novel Method Combats Chronic
Inflammation
Chronic inflammation
is implicated in diseases as diverse as cancer, heart attack,
senility, and arthritis. Excess production of certain
“cytokines” is involved in inflammation’s earliest stages. A
family of black tea compounds called theaflavins favorably
regulates genes involved in the production of proinflammatory
cytokines.
Scientifically
reviewed by: Dr. Gary Gonzalez, MD, in January 2021. Written by:
Julius G. Goepp, MD.
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For the past 16 years, green tea polyphenols have
grabbed the headlines,1 but a related family of black tea
compounds called theaflavins is capturing the attention of longevity
researchers.2
Theaflavins possess a unique ability to
favorably influence human health by regulating genes that produce inflammatory cytokines and
other toxic factors implicated in degenerative disease and aging. By
modulating inflammation at its earliest stages, theaflavins represent a
new tool in the fight against inflammation-related pathologies such as
cancer, heart disease, senility, and arthritis.
Tea Extracts and Theaflavins
The past decade has seen a veritable explosion of
data on the active components of tea.3 The flavonoid
epigallocatechin gallate (EGCG) found in green tea is widely known for
its disease-preventing capabilities,4 and now its sister
molecules, the theaflavins, are beginning to share the spotlight. What
has researchers particularly excited is how theaflavins exert their
health-promoting benefits by favorably altering our genes. This
phenomenon, known as “nutrigenomics,” will be fully explained in this
article.
Theaflavin Inhibits Inflammation
Much of the misery of
age-related conditions such as cardiovascular disease, diabetes, chronic
pain, and even cancer can be laid at the feet of inflammatory processes
that presumably originally evolved for the preservation of our health. A
lifetime of exposure to oxidation and inflammatory stimuli leaves us
awash in molecules known as cytokines and chemokines, which are used by
immune system cells to signal each other and react to potential threats.
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Theaflavin Inhibits Inflammation
Long-term effects of these cytokines include
increased tissue oxidation and further inflammation, which perpetuates
the cycle and increases our risk for a myriad of chronic conditions.
These inflammatory signaling molecules, of course, are the protein
products of specific genes, and their production is regulated by transcription factors, as is all genetic activity in the
body. Many nutrients help prevent or mitigate chronic disease either
“upstream” in the process by preventing oxidation or “downstream” by
inhibiting the effects of cytokines once produced. The remarkable
ability of theaflavins to target specific gene transcription factors may
allow for exquisite control of inflammation exactly when and where it
starts—when inflammation-producing genes are “switched on” to start
manufacturing cytokines.
Children’s health researchers
at the University of Cincinnati described theaflavin’s novel
anti-inflammatory characteristics in a 2004 paper,5 in which
they identified the effect of varying concentrations of theaflavin on
cells in a laboratory culture dish. The researchers were specifically
interested in the gene that produces the inflammatory cytokine
interleukin-8 (IL-8), which is responsible for much of the acute
inflammation seen in conditions such as asthma, gum disease, and
inflammatory bowel disease.6,7 Remarkably, theaflavin
inhibited IL-8 production, even at very low concentrations. Even more
remarkably, the effect was traced to theaflavin’s ability to inhibit the
transcription of the IL-8 gene—in other words; theaflavin blocked the
gene from actually expressing its product, the inflammatory cytokine.5
This pinpoint accuracy opens the door to many specific applications of
theaflavin as an anti-inflammatory nutrigenomic agent.
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Theaflavins—Working at the Genetic
Level to Control Age-Related Disease
The first studies of theaflavins as
modulators of genetic transcription began to appear at the turn
of the present century, with recognition that theaflavins could
control the expression of genes involved in cancer production,
and a possible role in cancer chemoprevention as a result8,9
(remember that cancer, like heart disease, has direct
connections with inflammation, particularly in its earliest
stages).
Theaflavins—Working at the Genetic
Level to Control Age-Related Disease
By 2006, biologists in Iowa were
already able to review the multiple sites at which theaflavins
exert their gene-regulating effects: they (along with other
polyphenols) up- or down-regulated production of enzymes involved in cancer production,
they inhibited metastasis by blocking the effects of genes that
produce enzymes making tissues more permeable to malignant
cells, and they reduced the formation of new blood vessel growth
needed for tumors to spread by blocking production of vascular
endothelial growth factor, or VEGF. The review article concluded
that “green and black tea polyphenols act at numerous points
regulating cancer cell growth, survival, and metastasis,
including effects at the DNA, RNA, and protein levels.”1
Further studies have supported and
expanded upon this work, progressively building the case for a
specific group of theaflavin extracts from black tea.10
In 1999, biochemists in Taiwan investigated the effects of
various tea components, including theaflavins, on induction of
inflammatory molecules in mouse cells in culture.11 A
group of four theaflavins was found to potently inhibit
production of those inflammatory molecules.
In 2000, other scientists in the same
group were able to demonstrate that these theaflavin extracts
could reduce inflammatory cytokine production even in the face
of stimulation by one of the most powerful inducers of
inflammation known, a bacterial molecule called
lipopolysaccharide (LPS).12 Importantly, this group
also began the process of identifying the specific fractions, or
groups of factors, in the theaflavin extracts that were the most
powerfully active in blocking production of the inflammatory
cytokines.
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By 2002, these productive researchers
had further extended their findings, demonstrating that the most
active fractions of the theaflavin extracts could prevent
inflammation on the skin and paws of mice that was induced
experimentally with a toxic substance.13 Another
Taiwanese researcher also published a 2002 report showing that
the most active fraction of theaflavins was a potent cancer
chemopreventive, chiefly through suppressing genes involved in
tumor promotion and inflammation.14 In 2004, Japanese
researchers were able to pin down platelet anti-aggregating
effect to those same highly active fractions of theaflavins.15
Since 2005, the number of scholarly
papers describing the powerful anti-inflammatory, anticancer,
and longevity-enhancing qualities of these highly active
theaflavin fractions has blossomed to several dozen studies,
each providing more high-resolution details about just how these
molecules act,16-20 and broadening their beneficial
effects to prevention of ischemia-reperfusion injury following
strokes,16,21 alcohol-induced pancreatitis,22
colitis,23 cigarette smoke-induced lung damage and
cancers,24-26 cardiovascular disease,27
and even parasitic infection.28
WHAT YOU NEED TO KNOW: THEAFLAVINS
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Inflammation
is intimately involved in aging and the manifestations
of age-related diseases—in fact, the two processes are
so closely intertwined they have recently been dubbed
inflammaging by an internationally recognized expert.
Many dietary approaches to
countering the effects of inflammation are effective,
but the emerging science of nutrigenomics offers insight
into highly targeted nutritional supplements such as the
theaflavin family of molecules extracted from black tea.
Theaflavins, like other
nutrigenomically active molecules, exert their powerful
effects by promoting activity of genes involved in
controlling inflammation, and suppressing activity of
genes involved in promoting inflammation.
Highly purified theaflavin
extracts have been shown to reduce damage caused by
inflammation-based diseases such as cancer,
cardiovascular disease, diabetes, and other age-related
conditions.
A human study of purified
theaflavin extracts produced dramatic reduction in
disease-causing mediators of inflammation, including
levels of CRP. This effect has been directly associated
with longevity.
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Protecting Against Vascular Diseases
Evidence that tea confers health benefits is millennia-old,
but the mechanisms by which it works have only recently been
revealed. It is known from epidemiologic studies, for example,
that drinking multiple cups of tea per day reduces low-density
lipoprotein (LDL). Cardiologists at Vanderbilt University
studied the impact of a theaflavin-enriched green tea extract on
lipid profiles of subjects with mild-to-moderately elevated
cholesterol.29 Studying 240 men and women in China,
the researchers randomly assigned patients to receive either
placebo or a theaflavin-enriched green tea extract (375 mg)
daily for 12 weeks. At the end of the study, the theaflavin-supplemented
patients experienced decreases in their total cholesterol by 11%
and LDL by 16%. Placebo recipients had no change at all. No
significant adverse effects were observed, and the researchers
concluded that this theaflavin-enriched extract was “an
effective adjunct to a low-saturated-fat diet.”
Boston cardiologists studied the impact of black tea and its
theaflavin components supplementation on endothelial dysfunction30
in a study that randomly assigned 66 patients with coronary
artery disease to consume either black tea or water. The study
was designed in a “cross-over” fashion so that all subjects got
both the tea and the water at different times (this allows
comparisons within individuals as well as between subjects). The
findings were dramatic: both short- and long-term tea
consumption significantly improved blood flow in arteries, as
detected by ultrasound measurements. This flow is controlled by
endothelial cells and is typically decreased in patients with
cardiovascular diseases. The researchers concluded that, “short-
and long-term black tea consumption reverses endothelial
vasomotor dysfunction in patients with coronary artery disease.”
In a British study of healthy men aged 18-55 years, subjects
were given black tea or placebo for four weeks, and the effects
on their platelet activation were measured. By the end of the
study, the tea-drinking group had significantly fewer platelet
“clumps,” or aggregates, than the placebo group.31
NUTRIGENOMICS: DIETARY CONTROL OF GENETIC
EXPRESSION
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The laws of genetic inheritance were first described
in the mid-19th century, and from that time practically
until the present we’ve tended to think of specific
genes as permanent fixtures of each individual—we get
our genes from our parents and they define our traits,
such as hair and eye color,
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etc. By the early 20th century it was clear that
genes could specify, or “code for,” unhealthy traits as well, and we all learned about
inherited diseases such as sickle cell anemia and cystic
fibrosis in high school biology. But it has only been
within the past two decades that we have come to
understand just how dynamic our genes really are.
We now understand that while individual genes may be
the simple equivalents of “blueprints” on our
chromosomes that tell cells how to make the specific
enzymes and other proteins that define us, those genes
are under exquisite control by a host of complex and
interrelated systems collectively called transcription
factors. Transcription factors may be thought of as the
general contractors that, depending on the body’s needs,
“order” production of necessary products built according
to the genetic blueprints. And transcription factors, it
turns out, are themselves controlled by a host of
molecular influences—including a growing number of
specific nutrients. The study of how these nutrients
work to control the genes’ production levels is called
nutrigenomics.44 Well-known nutrigenomics
molecules include, for example, the omega-3 fatty acids,
which regulate lipid profiles,45 insulin
responses,46 and inflammatory mediators,47
and the spice-derived curcumin molecule that shuts down
transcription factors involved in inflammation and
cancer production.48
In fact, according to acclaimed scientist Peter J.
Gillies, PhD, “Nutrigenomics may provide the nutritional
sciences with a molecular basis for positioning
nutritional bioactives, functional foods, and designer
diets to preemptively offset chronic disease.”44
Dr. Gillies goes on to note that, “With the expansion of
research and the development of shared nutrigenomic
databases, it may well become possible to define and
track the influence of targeted nutrition on
inflammation and the aging process.” In just the past
two years, a host of other prestigious scientists have
weighed in, supporting the pursuit of nutrigenomics as a
vital framework for better understanding human biology
and our relationship with our diets and our
environments.2,43,49-56
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Why was this study so significant? This study represented an
important first step in understanding how tea components
actually influence gene transcription, and therefore in
understanding the role of tea
components in nutrigenomic
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influences on health. Here’s how:
platelets, the tiny cell fragments involved in blood clotting,
stick together (aggregate) when activated in an important step
in the cardiovascular disease process. The triggers for platelet
activation include oxidative stress and inflammation, which
cause transcription factors to increase the activity of genes
making proteins involved in the aggregation process, acutely
increasing cardiovascular disease risk.32-34
In other words, the British
researchers had found that tea components must act as
nutrigenomic factors, modulating production of these potentially
lethal proteins. This groundbreaking finding led the way for
further research investigating which tea components were
responsible for it nutrigenomic activity and how to utilize
theaflavin consumption to influence health and longevity.
Breaking News: Human Study With
Highly Active Theaflavin Extracts
The studies listed above only begin to
tell the theaflavin story—a similarly overwhelming body of
literature supports their effectiveness in switching off the
genes involved in virtually every cancer type,1,35,36
for example, as well as in modifying the way liver cells handle
cholesterol and other fats.37 Of course, the most
exciting news always has to do with human studies, and how any
given supplement might benefit human health and preventing human
disease. While there are numerous studies of the impact of tea
drinking on the health of large human populations (epidemiologic
studies), there are still no published studies on the effects of
the specially purified, highly active theaflavin extracts we
have been discussing. But late-breaking news is about to change
that—with data too recent to have yet been published, a private
company has revealed the outlines of a compelling human trial
using just one such extract. Let us review what the company was
able to share with us about this exciting, still-proprietary
information, in advance of publication in a peer-reviewed
journal.
The study was conducted in 2007 with
12 human volunteers. Eight of the subjects were supplemented
with the highly purified theaflavin extract
for one week, while four received
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placebo. At the end of
the week, the subjects received injections of a bacterial cell
membrane component called LPS, one of the most powerful stimulators of inflammation known to science. LPS
in modest doses can induce shock, coma, and even death, so
naturally these were only minute and safe doses, but clearly the
volunteers were expected to show some evidence of acute
inflammatory reactions. In addition to clinical monitoring, the
investigators drew blood samples to monitor for early signs of
inflammation, particularly those involving the “inducible”
cytokines such as TNF-alpha, IL-6, IL-8, and C-reactive protein
(CRP).38,39
Astonishingly, the
supplemented subjects had a 56% reduction in levels of these
cytokines even before they received the inflammatory challenge!
Equally importantly, supplemented subjects experienced a 52%
increase in levels of the protective, anti-inflammatory cytokine
called IL-10,39 which is involved in prevention of
viral respiratory infections, for example.40 The
supplemented patients also demonstrated lower rates of
production of the inflammation-generating transcription factor
NF-kB (71%), the cytokine-generating enzyme COX -2 (72%), and
the adhesion molecule ICAM-1.39
C-reactive protein
rose dramatically as expected in the placebo recipients—this
protein is a sensitive marker of acute inflammation, and
chronically elevated levels of CRP are known to be a risk factor
for advanced atherosclerosis. Remarkably, that elevation was 75%
greater in the placebo group than in the theaflavin supplemented
group.39
The ability of this
highly active theaflavin extract to offset inflammatory
cytokines points to a broad range of applications in human
health in inflammatory conditions such as joint stiffness,
muscle soreness, arthritis, osteoporosis, cardiovascular
problems, diabetes, periodontal disease, and age-related immune
dysfunction.
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Pulling it All Together—How
Theaflavins Promote Health and Longevity
There is a plethora of solid data on
theaflavins’ nutrigenomic effects—modulating the activity of
genes involved in the inflammatory cascade that leads to cancer,
heart disease, diabetes, and other age-related conditions. But
these are more than just numbers—reduction or control of those
powerful genetic functions is likely to produce measurable
results in individual humans. In fact, the term “inflammaging”
has recently been coined by Professor Claudio Franceschi, a
researcher in aging at the University of Bologna, to describe
the inevitable accumulation of products of inflammation
associated with advancing age.41 Modern
risk-screening protocols aimed at identifying those at highest
risk for early demise now routinely incorporate at least one
measure of inflammation,42 and Professor Jose Ordovas
of the Tufts University School of Graduate Biomedical Sciences
has observed that “studies have established a ‘diet/genetic
interaction’ that further modulates markers of inflammation,
producing both positive and negative effects, depending on the
net changes in gene expression.”43 Taken together,
these researchers’ comments suggest that dietary interventions
to reduce inflammation will enhance health, prevent disease, and
ultimately promote longevity and quality of life. The highly
purified theaflavins now available as supplements, with their
targeted, nutrigenomics mechanisms of action, certainly deserve
a place in any responsible, scientifically based program of
preventive health maintenance.
If you have any questions on the
scientific content of this article, please call a Life Extension
Wellness Specialist at 1-800-226-2370.
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