The only HGH product world wide backed by 18 years of science that causes the Pituitary Gland to release YOUTHFUL LEVELS of Human Growth Hormone and then allows the Pituitary Gland to make more.
Welcome to Anti Aging Fruits
Opening Hours : Monday to Saturday - 8am to 9pm
Contact : (760) 481-8800
The only HGH product world wide backed by 18 years of science that causes the Pituitary Gland to release YOUTHFUL LEVELS of Human Growth Hormone and then allows the Pituitary Gland to make more.
Men are extremely different than woman when it comes to the risks which arise from low
(HGH) Human Growth Hormone. Men with risky low levels of HGH will suffer from
extraordinary lack of energy and motivation.
HGH in men is exceptionally crucial as the man’s two most significant hormones which build
them up physically and even emotionally are HGH and Testosterone. Women are much more
complicated hormonally speaking.
Please let us make this very clear Protein has been scientifically proven to build human beings
up. Therefore we call the building up process Anabolic…which has NOTHING to do with
steroids…HGH is NOT a steroid but it is the single most important hormone in a man’s body.
Conversely, there are substances that tear the body down and that is called the Catabolic
process and this is highly dangerous for men to be in a catabolic state, ever.
Simply put, if a man is low in HGH he is automatically catabolic.
What exactly does that mean and just how dangerous a risk is this?
It means that when a man is in a catabolic state from low HGH he is not able to replace cells
and tissues faster than his body is breaking them down. What exactly does that mean?
According to Dr. Sam Baxus, one of the world’s foremost authorities for over 40 years on low
HGH…it means that you as a man are needlessly slowly dying faster than their male friends who
do not yet have low human growth hormone blood levels.
There also exits a direct relationship between HGH and testosterone in men such that if a man
is low in HGH it is very likely to have a negative impact Testosterone production. Thus more
muscle weakness, fatigue, more fat lower lean muscle mass, and depression in men.
It means, that every aspect, every part of your body is being torn down piece by piece.
And the leading first symptom for men is lack of energy and low motivation.
Then men notice an increase in fat around the belly area and a loss of tone to their muscles.
This alone is a risk which is certainly not acceptable once a man understands that inner fat
increased around the waistline has clearly been established by cardiologists as an INCREASED
risk of having a sudden and severe Heart Attack.
Demographic studies at the University of North Carolina (chapel Hill) often referred to as the
little Harvard of the South… is known to produce the best studies of risk for illnesses of every
type according to age and the numbers of folks in each age group.
Regarding their study on HGH by age groups something enormously profound was gleaned.
Age 18, is the best age group nationwide according to HGH levels and the almost complete lack
of illness in that age group. We noticed that every 8 years after age 18 there was and is a
dramatic rise in age related disease so if one takes age 18 as nearly perfect for HGH purposes
and we times 18 by 3 we get age 54 the highest group of men by age for heart attacks each
year. Between age 45 and 55 men are at severe risk for heart attacks
Thus if we look at all age related disease due to lack of HGH by this best demographic study
ever done so far, we find an enormous mistake. Generally it has been said we lose 50% of our
HGH output every 30 years past age 20. So it has been said for years that age 50 you make only
half the HGH as you did at 20
BUT if one delves deeply into the University of North Carolina’s massive demographic research
study on age related illness and relationship to HGH levels we easily see that after age 18 we
lose 50% of our HGH output every 8 years after the age 18.
So for men the risks come on generally around age 35 to 40 with belly fat and lack of energy
Next there are changes in the make-up of cholesterol with an increase in the bad LDL and also
an increase in the dangerous Triglyceride levels going up for men.
A man’s stamina decreases when HGH levels are low.
Men experience less lean muscle with low HGH
Men also complain about being more sensitive to heat and cold with low HGH. Men are more
sensitive to light. Especially bright light, which is an indication of breakdown of eye tissue.
Men experience as an early warning sign of low HGH a lack of sexual desire and function.
Eventually, bones density becomes more porous and fractures from a simple trip fall can occur
The immune system starts to breakdown for men if they do not take action and get themselves
on more optimal youthful blood levels of HGH.
Men, you can forgo all these dangerous risks. AAI provides true expert advice and expert HGH
treatment protocols. Women live 10 years longer than men. Come on guys 10 years is a mini
Are non-drugs, like virgin coconut oil, a safer and more effective alternative to stress and depression?
A new study conducted in Malaysia looked at the effects of consuming high-antioxidant
virgin coconut oil on mental health.
Published in the journal Experimental and Therapeutic Medicine and believed to be the
first study of its kind, researchers evaluated the anti-stress and antioxidant effects of
virgin coconut oil in mice with stress-induced injuries. The title of the study is “Anti-
stress and antioxidant effects of virgin coconut oil in vivo.”
The researchers performed several stress tests on groups of mice. Control groups
included untreated mice and mice not subjected to stress and virgin coconut oil was
compared to a commonly prescribed psychiatric drug, Diazepam.
Their results were quite impressive, and suggest that using a high quality virgin coconut
oil can rival antidepressant drugs without the dangerous side effects. The researchers
attributed the success in treatment to the unique mixture of medium chain fatty acids
found in coconut oil rich in saturated fats, and to the antioxidants present in higher
grade, less processed virgin coconut oils.
While we do not endorse the supposed “science” behind psychiatric drugs, which
attempts to measure such things as “neurotransmitters” and “biochemical profiles” as
true indicators of mental health that can be altered by chemical drugs, it is encouraging
to see researchers consider natural foods as alternatives, given the fact that they do
not have all the serious side effects that psychiatric drugs do.
One of the more interesting tests conducted in this study was a measurement of
“immobility time” after a forced swim test. The researchers found that the untreated
mice had a longer immobility time than mice treated with virgin coconut oil. They
attributed this to the high medium-chain fatty acid content of coconut oil, which is
known to produce thermogenesis and increased energy.
One area where virgin coconut oil (VCO) really outperformed the drug Diazepam was in
the area of oxidation and elimination of free radicals. This is something that can be
measured with lipid peroxidation (MDA) and antioxidant enzyme SOD levels. Stress is
known to increase oxidation and the creation of free radicals, leading to neuronal cell
damage and death. Antioxidants, on the other hand, reverse this trend and help
prevent further neuronal damage.
The researchers found:
VCO was able to reduce lipid peroxidation and increase the activity of SOD in the serum
of mice undergoing the forced swim test and the brains of mice subjected to chronic
cold restraint. It was previously reported that VCO is rich in polyphenols and these
antioxidants may contribute to the increased levels of antioxidant enzymes, which
subsequently reduce lipid peroxidation and inflammation in VCO-treated mice.
Restoration of antioxidant levels in the brain may help prevent further neuronal damage
and avoid subsequent depletion of monoamines, including DA. In conclusion, the
present study demonstrated the potential of VCO in preventing exercise- and chronic
cold restraint stress-induced damage and restoring the antioxidant balance. This
promising anti-stress activity may be attributed to the polyphenols and medium-chain
fatty acids present in VCO.
It is high time for a new paradigm in mental health. Drugs are not the solution to stress
and depression. Non-drug alternatives are not only safer, but can be more effective
than pharmaceutical drugs as well.
Anti-stress and antioxidant effects of virgin coconut oil in vivo. Experimental and
Therapeutic Medicine – Jan 2015; 9(1): 39–42
by: Larry Sosna N.D. PhD HHP
The Medical establishment would have all of us believe that coronary heart disease is irreversible and must lead to
either the eventual so called heart attack due to clogged arteries; or to by-pass operations, stents, followed by
balloon angioplasty. They tell us with Statin drugs the patient will then be ok. The statistics paint a very different
picture. Two out of every three people who have had cardiac by-pass surgery will need it again within 10 years.
Ten out of ten cardiovascular patients who have had stent procedures will need them again within 6.4 years.
Clearly, even with massive doses of statin drugs the treatment protocol for cardiovascular patients in use today by
the medical establishment is a failure in the sense that it’s not a cure and the above protocol is an ongoing radical
process for the body to endure.
One need look no further than the case of former President Bill Clinton who had Quadruple by-pass heart surgery,
stent after stent, balloon angioplasty again and again, massive statins and still he had advanced coronary artery
disease(CAD) until he finally discovered a natural, yet very scientific integrative treatment protocol which has
reversed his CAD.
In the 1960’s and 1970’s Nathan Pritikin M.D. developed a unique diet rich in massive amounts of fruits and
vegetables and very low in total calories and fats. Dr. Pritikin developed this protocol after he was diagnosed with
severe atherosclerosis of the coronary arteries. He was so convinced his protocol reversed CAD he left instructions
in his will that when he died he was to have a cardiologist examine the condition of his arteries. Meanwhile
thousands of his patients went off all medications and never had any more coronary artery problems. After Dr.
Pritikin died in 1987, his heart was dissected; the arteries were determined by cardiologists to be clean and in the
condition of a 25 year old.
In 1987, two years after Dr. Pritikin’s death, the Journal of the American Medical Association announced a study
that showed the reversal of atherosclerosis in the coronary arteries of humans who were on the Pritikin protocol as
administered at the Pritikin Longevity centers had been a success.1 Numerous subsequent studies confirmed Dr.
Pritikin was scientifically correct and the medical establishment’s position fatally flawed.2,3
Tens of millions of Americans needlessly perished because the medical establishment refuses to understand the
true causes of Coronary Artery Disease.
The over-promotion of “Statin” drugs has resulted in today’s cardiologists focusing on getting their patients’ total
cholesterol and LDL down to dangerously low levels. Pharmaceutical company advertising has made it appear as if
the only cause of CAD is excess LDL and cholesterol; however over a thousand scientific peer reviewed research
studies show this conclusion to be completely false…
Beginning in 1979, medical researcher scientists made discoveries which clearly indicated that CAD was the result
of the oxidation of LDL that results in the formation of blocked arteries and arterial damage.4,5 Thousands of peer
reviewed studies now reveal how oxidized LDL creates CAD from start to finish.
There are doctors who argue that CAD is all about inflammation and they are correct but what they failed to
realize is that oxidized cholesterol mainly LDL injures endothelial cells and causes this massive inflammation of the
Oxidized LDL causes endothelial cells to secrete ultra-sticky adhesion molecules that allow white blood cells to
penetrate the inner lining of the artery. This is where initial fatty streaks congeal and atherosclerotic plaques
develop in thickening layers.13
Oxidized LDL turns on white blood cell gene expression that enable them to convert into foam cells, which results
in continuous accumulation of oxidized LDL and thick plaque in the coronary arteries.14
Oxidized LDL initiates an inflammatory process by causing foam cells to make molecules that attract
proinflammatory cells and cytotoxins that further inflame the artery linings.15
Oxidized LDL enhances the process whereby immune cells, foam cells, smooth muscle cells, and the lining of
coronary arteries called endothelial cells, degrade collagen, which leads to the rupture of the fibrous plaque. The
extreme heat from the inflammation can cause even small amounts of cholesterol to blow up 40 times their normal
size and clot up an entire coronary artery, thus recently the Harvard study group called this phenomenon Popcorn
Cholesterol. This finally explains why 53% of all fatal heart attacks occur in people with rather low cholesterol,
something until recently which has greatly confused cardiac medical researchers.16
Forty years ago coronary artery disease was the #1 cause of death in America roughly 600,000 people died each
year from CAD. Today despite doctors handing out statin drugs like candy CAD is still the #1 cause of death each
year at roughly 630,000 deaths per year. We have the highest rate of cardiac disease in the entire world despite all
of the most so called state of the art drugs…in fact statin drugs have led some 200,000 people to develop
irreversible muscle wasting syndrome which is always fatal; and statins have also been linked to advanced liver
and kidney disease.
In reality the solution to this problem of oxidized LDL is very simple if you understand plant based biochemistry.
Dr. Pritikin thought the reversal of plaque and CAD was due to the very low intake of fats in the diet he created. In
fact that had little to do with anything, it was the antioxidants from a huge assortment of fruits and vegetables
which prevented LDL from oxidizing in the coronary arteries and thus stopped inflammation and the whole above
described process of oxidized LDL leading to CAD.
The problem with the Pritikin program is it is so very restrictive in calories that most folks simply cannot make a
lifelong commitment to it. We also now know about antioxidants in the form of nutraceutical plant based
supplements 1000’s of times more powerful then eating the fruits and veggies on the Pritikin diet.
We should all breathe easier knowing that when it comes to INHIBITING LDL oxidation we can now stop it cold with
natural biochemicals such as UBIQUINOL CoQ10…. With the exception of Alpha Lipoic Acid and the active
biochemical in Pomegranate (Proanthocyandids, and Polyphenols) nothing is effective as CoQ10, we can actually
now improve the inhibition of oxidized LDL cholesterol by 130%… far greater protection then the Pritikin diet.17
Yet we can go even far greater in reversing CAD by taking Nutraceutical quality Omega 3 oils every day. Omega 3
fish oil, Krill oil and Green Lipid muscle oil are extraordinarily powerful inhibitors of inflammation. The above are
such powerful High Density Lipids the good HDL’s, they can virtually assure that hard LDL cannot clump together,
in fact Eskimos and the arctic circle indigenous peoples account for five million people. They eat huge amounts of
cholesterol from seal blubber and whale blubber yet we have never found even one upon autopsy who had CAD.
Think about that, although they eat a diet 80% pure cholesterol they are completely protected by the 18% of their
diet which is cold water fish oil in the form of wild salmon.18-22
Stacking Powerful Antioxidants… The Sosna Protocol to cure advanced CAD
I have created a unique program by stacking the most powerfully effective antioxidants to reverse CAD for even
the most advanced CAD patient. Besides the above mentioned powerful antioxidants the stacking of nutraceutical
antioxidants also includes:
SAMe, Folic acid, isoflavones, Epigallate-Catchen-3 Galate, Resveratrol, Tocotrienols, Vit. E, Lutein, Lycopenes,
Ascorbyl Palmitate, Gingerols, Silymarin, Bromelain, Calcium D-Glucarate, Punicalagins, Hesperidin, Canthaxathin
and several others if need be. All of these super antioxidants are found only in the bio-diversity of plant based
molecular biochemistry in nature and in scientifically fresh cold pressed ocean based omega 3 fatty acids.
President Clinton is receiving with stellar results a similar protocol to mine…He will not need any more balloon
angioplasty or any other invasive treatments again so long as he stays on this treatment protocol for life.
In addition we have discovered plant extracted sterols can lower LDL by 38% in a very unique manner. They trick
the production of harmful LDL from entering the blood stream and instead send them a signal to enter the large
intestines where they are excreted via normal bowel movements.
In conclusion we have had for a long time the most effective all natural treatment protocol for reversing
cardiovascular disease. All the natural biochemicals I have mentioned are derived from plants, fruits, and marine
life, extracted and highly concentrated by a leading biotechnology company which is ISO 9001 and ISO 17025
While one may be tempted with this information to do it yourself without expert guidance, I strongly urge you to
consider the following. Eighty percent of all stores bought cold water fish oil sold as omega 3 HDL is already rancid
when purchased! Rancid oils have enormous amounts of free radical oxidants which cause CAD. Unless you are
positive you are obtaining your nutraceutical supplements from a true ISO certified biotechnology laboratory be
very careful. The quality and purity of store the supplements will be no more than 20% pure due to their poor
quality extraction methodology, the other 80% may include large amounts of biological fragments, fillers, and
environmental toxins to the point where one is actually consuming enormous amounts of free radical oxidants
which seriously damage the heart, and other organs! Why? Because market competition is so fierce in the
supplement industry over 90% of the drug store and health store brands buy their raw materials from China; where
raw materials for making supplements are extremely inexpensive. The problem is China is the most polluted
industrial toxic country and raw organic material from China to make supplements will have high levels of toxins.
Any supplements made in the USA but sourced from China may be highly toxic. They will never be made by ISO
9001 ISO 17025 biotechnology companies; you simply cannot find this highest quality in health food stores and if
they claim they carry such a high standard ask the manager for a certified copy of ISO 9001 ISO 17025 for the item
you desire to purchase. They cannot produce the above mentioned certifications because there are only several
biotechnology companies worldwide, that have both ISO certifications and they only sell to doctors, dentists,
naturopathic doctors and nutritionists with a PhD.
Peer Reviewed research and footnotes.
1. Roberts CK, Chen AK Bernard JR Effects of short term diet and exercise intervention in youth on atherosclerotic
disease risk factors. Atherosclerosis. 2007 mar; 191 (1) : 98-106
2. Roberts CK, won D, pruthi S, et al. Effects of short term diet and exercise intervention on oxidative stress,
inflammation, MM-9, and monocyte chemotactic activity in men with metabolic syndrome factors. J Appl
Physiol. 2006 may; 100(5): 1657-65.
3. Roberts CK, Vaziri ND, Bernard RJ. Effects of diet and exercise intervention on blood pressure, insulin,
oxidative stress, and nitric oxide availability. Circulation. 2002 Nov 12;106(20):2530-2.
4. Anderson JW, Konz EC, Jenkins DJ. Health advantages and disadvantages of weight-reducing diets: a computer
analysis and critical review. J Am Coll Nutr. 2000 oct;19(5):587-90
5. Henriksen T Mahoney EM Steinberg D. Enhanced macrophage degradation of low density lipoproteins previously
incubated with cultured endothelial cells: recognition by receptors for acetylated low density lipoproteins.
Proc Natl acad Sci USA. 1981 Oct;78(10):6499-503.
6. Hessler JR, morel DW, Lewis LJ, Chisolm GM. Lipoprotein oxidation and lipoprotein-induced cytotoxicity.
Arteriosclerosis. 1983 May;3(3):215-22.
7. Quinn MT, Parthasarathy S, Fong LG, Steinberg D. Oxidatively modified low density lipoproteins: a potential
role in recruitment and retention of monocyte/macrophages during athero-genesis. Proc Natl Acad Sci USA.
8. Ross R. Atherosclerosis—an inflammatory disease. N Engl J med. 1999 Jan 14;340(2):115-26.
9. Ross R. The pathogenesis of atherosclerosis-an update. N Engl J Med. 1986 Feb 20;314(8):488-500.
10. Yla-herttuala S, Palinski W Rosenfeld ME, et al. Evidence for the presence of oxidatively modified LDL in
atherosclerotic lesions of rabbit and man. J Clin invest. 1989 Oct;84(4):1086-95.
11. Steinberg d, Carew TE, khoo JC, witztum JL. Beyond cholesterol. Modifications of LDL that increase its
atherogenicity. N Engl J Med. 1989 Apr 6,320(14):915-24.
12. Berliner JA, navab m, Fogelman AM, et al. Atherosclerosis: basic mechanisms. Oxidation. Inflammation, and
genetics. Circulation. 1995 May 1;91(9):2488-96.
13. Suits AG, Chait A Aviram M, Heinke JW. Phagocytosis of aggregated lipoprotein receptor-dependent foam cell
formation. Proc Natl acad sci USA. 1989 Apr;86(8):2713-7.
14. Zhang WZ, Vernardos K Finch S, kaye DM. detrimental effect of oxidized LDL on endothelial arginine
metabolism and transportation. Int J Biochem Cell Biol. 2008;40(5):920-8
15. Faloon W. A lethal misconception of epidemic proportion. Life Extension. 2007 May; 13(5):7-14.
Danesh j, Lewington S, Thompson SG, et al. Plasma fibrinogen level and the risk of major
MIT said the field of Glycomics, is “One of the 10 emerging technologies that will change the
world.” Notice, they did not say, one of the 10 medical technologies but one out of ALL
technologies that will change our world. It is as important as DNA and the Genome because the
8 major fundamentals of Glycobiology control both DNA and RNA. We even have the
Glyconome! Glycobiology controls our hormones and how they function…If you cannot get
enough of these 8 essentials life sustaining Glyconutrient’s, no matter how much HGH you take
it will have no effect or a neg. effect I am one of the few true experts in this exploding field. The
value to this more ramped up scientific language is so unique in this article that Google will
get in on these words I am using, KEY in on them and our standing in Google will go up
and up because no other competitor knows the scientific language of this anti-aging
breakthrough.. but Google’s algorithm’s and scrubbers places a very high value when you
write what others cannot or have not. When it is singular, as mine is and only on our
website blog Google loves that! That is why I want to write several articles on this topic so
germane to regeneration and living heathier for much longer. AND, there is big money in
this field selling sugars that heal. Please let me know what you think.
HELP DEFEAT ILLNESS AND GREATLY EXTEND YOU’RE LIFESPAN
Seminal Research by Larry Sosna N.D. PhD HHP
GLYCOBIOLOGY OF LIFE
See and hear what the true great university scientists are saying. “This is the future
today”, declares Dr. Gerald Hart of John Hopkins University…The number one rated
medical/scientific teaching hospital in the entire USA. “We won’t understand
Immunology, Neurology, Developmental Biology or Pathology until we get a handle on
Glycobiology.” ….. “If you ask, what is the Glycome for a single cell type it will be many
thousands of times more complex than the genetic Genome,” says Ajit Varki past
director of the Glycobiology Research and Training Center at Cal Tech. Professor
Raymond Dwek, head of the University of Oxford’s Glycobiology Institute, who
coined the term Glycobiology in 1988 says, “ As recent advances in genetics have
unfolded, the importance of sugars which heal has become ever more apparent.”…..
Varki said, “It’s like we just discovered the continent of North America. Now we have to
send out scouting parties to find out how big it is…..”
New Scientist Magazine, October 2002
I’m certain you have been told many times, sugar is one of the main enemies in life
causing all kinds of disease states and folks that can indeed be true. There are harmful
sugars and there are sugars so vitally important to vigorous good health that without
them we would all have suffered and died a long time ago. In fact, without these
miraculous special sugars we never would have made it out of infancy.
Glyco means sweet, there are bad sugars and ones we cannot live without, they are the
healthy Glyconutrients. If you are on one of those fad diets that does not allow the life
enhancing complex carbohydrates then you cannot make Glycoproteins which are
molecules that combine sugars with proteins as well as glycolipids, which are
combinations of healing complex sugars with fats. The term for these life giving
combinations are called glycoconjugates. These glycoconjugates have brought together
the world’s most brilliant medical scientists to comprehend a field so sophisticated the
combinations of glycoconjugates are infinite in how they arrange themselves to yield a
healthy body free from disease if you have them in high enough blood levels.
It will be useful to provide one with a high level of education concerning the immense
healing powers of a strong personal Glycobiology. Let’s shine some light on what
healthy levels of Glycoconjugates can do for the human body to improve both structure
Immune System Modulation:
Glyconutrients are necessary for healthy immune cells and a body wide capable
immune system function. They have been shown to:
Play a key role in many aspects of cell and tissue regeneration and repair, as well as
cell survival. They have strong positive effects on asthma and allergies in general.
Glyconutrients are one of the very few methods of preventing and or slowing down even
rheumatoid arthritis, lupus, and improves the symptoms of periodontal disease, canker
sores and herpes simplex 1 of the lips.
They have a favorable outcome in suppressing skin reactions and contact dermatitis as
well as inhibiting bronchitis. Many studies show they can prevent arthritis, substantially
reducing pain and increasing joint mobility in osteoarthritis, the most common form of
Glyconutrients and glycoconjugates help to inhibit growth and or tumor cell metastasis
in certain types of cancer. They do this by instructing white blood cells called Natural
Killer Cells to mobilize and seek out and destroy cancer cells. Today there is an entire
field of Glycobiology devoted to cancer research and the NIH and CDC have received
hundreds of millions in government funds to further enhance the field of Glycobiology
and cancer control.
An adequate supply of dietary glyconutritional healing sugars is vitally important during
periods of body wide stress, since glycoconjugates synthesized from eight key sugars
play key roles in many aspects of tissue healing and repair as well as cell survival
during extremely stressful periods. Corticotropin-releasing factor receptor is hormone
glycoprotein that regulates responses to emotional and other types of stress by
coordinating the endocrine, behavioral and immune responses to stress through
hormonal actions in the brain.
The Heart and Glycobiology
Glycolipid Conjugates are responsible for correct Low Density Lipid receptor site
instruction…These Low Density Lipids are the kind of cholesterol that can cause a
blocked artery and thus a heart attack…. But regulation of the dreaded LDL’s by
Glycolipid Conjugation makes the likelihood of artery blockage by LDL’s a very unlikely
Most of us have heard that cold water fish oil is protective to the arteries of the heart.
When we all have high levels of Glycolipids the Omega 3 fatty acids become like a
super biological Teflon…coating the linings of the arteries so the bad types of LDL
cholesterol cannot aggregate and build up on the artery linings from both sides of the
coronary arteries thus in the scientific review of many research cardiologists who have
researched Glycolipid conjugation they have published findings that are very highly
suggestive that proper amounts of Glycolipids in the blood protects against a buildup of
bad LDL aggregation, such that the arteries seem to be fully protected from a heart
attack. The problem is a mass of Americans do not have adequate blood levels of
Glycolipid Conjugates especially, Galactose which is of great importance for normal
heart and brain health.
Glyconutritional high levels of galactose, mannose, galactosamine and sialic acid binds
vitamin B12 to make B12 bioavailable to the cells. In other without the above mentioned
healing sugar combinations you can inject all the B12 in the world and it will not work.
The same combination of Glucoconjugates helps people from drug and alcohol cravings
all of which are injurious to the heart and liver.
AND the exact same above described combination, seriously reduces HUNGER
Gonadotropin hormones are glycoproteins derived from the pituitary gland which
controls the release of many other hormones throughout the body including human
growth hormone (hgh).
Glycosylation of gonadotrophin hormones affects their size, circulatory life span, ease
of movement through cells, storage and secretion, clearance, immunoreactivity and
hormone bioactivity within the entire human body.
Glycosylation of IGF receptors contributes to their tissue regeneration and tissue
differences, which affects their biological activity. If an individual does not have
adequate blood levels of Glycoconjugates (the healing 8 combined sugars) all hormone
activity no matter how much one takes will be seriously insufficient to do their job in the
human body and that can be a health crisis.
Glycoconjugation which does not occur in its proper sequence will lead to a disruption
of insulin formation and correct synthesis and can be causal in some types of diabetes.
The sugars I am about to share with you are so incredible they actually have a
language all of their own. I call them the great hidden code of human life itself. They are
every bit as important as DNA. Amazingly, when these life giving sugars are combined
they can even change mistakes in DNA expression. Mistakes… that can lead to cancer
and every other nightmare type of nightmare illness. However, I am going to show you
how to take a true and certain quantum leap in your ability to regenerate, fight off
virtually all illness, protecting you’re cells, tissues and all of the organs, collectively in all
of our bodies.
You may be thinking this is absurd, sugar is bad for us, correct? Not so simple, just the
sugar D-Ribose is so vital to life that without it we cannot make Messenger RNA and
without messenger RNA you may as well not even make DNA because both are
needed for correct structure and proper functioning of each and every cell, tissue and
organ our bodies. You might even remember from high school biology in the 9th grade
that RNA stands for Ribo Nucleic Acid…and it’s very back bone comes from our good
friend, the amazing D-Ribose SUGAR.
I am very excited to share this science with you. Unfortunately this is a science within
the medical field that is so complex it was not until the 1960’s to 1980’s that we got our
arms around this field of Molecular Glyco-Synthesis. And just like the field of DNA it took
the most brilliant hand full of scientists in molecular bio-science to advance this new
field and show how massively important it is. The field is so important to every phase of
our life cycle; I still study it weekly even though it has been a 20 years endeavor. That is
how important this field is and it is an honor to share this life enhancing information with
you, our family of friends here at AAI …. Though the field to this day is not being brought
to the public with much attention or consistency.
We have given you a small taste of the importance of the 5 carbon sugar D-Ribose now
let’s really delve into the Art and Science of the other life giving sugars.
There are eight Essential Sugars called Saccharides required for Glycoprotein
Synthesis…They are as follows Xylose, Fucose, Mannose, Galactose, Glucose, N-
Acetylglucosamine, N-Acetylgalactosamine, and N-Acetylineuraminic Acid.
What does this mean? It means no expression of protein’s abilities to build up the cells
into tissues and then into organs can occur. No Protein, no big muscles no matter how
hard you work. Actually, no protein , means death That means that without these eight
amazing sugars which create Glycoprotein Synthesis we would not have a body to even
take care of. That is why you must learn how to obtain these super regenerative eight
sugars…if you want to be in a perfected state of excellent health.
Guess what else? We cannot make any HORMONES or even utilize them efficiently
without these super eight sugars but wait there is more good news. Since the early
1990’s Gluco-Scientists found 200 other super sugars from plant based sources,
funding to scientifically evaluate all 200 found so far has several years ago reached the
many hundreds of millions of dollars so are discovering the roles of all 200 sugars.
Mother Nature’s vast array of biochemistry, including these 200 sugars has a specific
purpose. The overwhelming majority of them will be to create an even more complex
language to further healing, cell regeneration and repair. So please don’t be stuck on
eating (sucrose white ultra-refined table sugar) as sucrose in that form is BAD for
Speaking of Hormones, about 10 years ago I learned from Dr. David Wesser M.D.
DDS, a very close friend and teacher, taught if you combine a significant dose of D-
Ribose with Galactose, the human body will regenerate all hormones that have reached
the end of their life cycle, bringing them right back to the top of their life cycle. If you
want to feel like a Greek God, put this into you’re program.
Remember the eight super sugars are a code containing an extensive language. Each
sugar is like a 1000 page book in terms of its ability to communicate instructions
throughout the entire body. Each page in any of the eight books can code and give
hundreds of millions of directions throughout the body. So, we are talking about a code
of life capable of issuing Trillions of life enhancing instructions from the molecular level
to the cells, tissues and organs and even the brain itself gets its instructions to develop
into a brain, as well as sustain you’re brain.
For Illustrative purposes, these molecular communication codes are like precisely
shaped words that protrude from the cells surface and are recognized and understood
by neighboring cells, we call this Glycoform Cellular Communication. It is these eight
amazing Glycoforms that determine your blood type. Imagine that, a sugar
molecule called a Glycoform, N-Acetylgalactosamine will make your blood type A … and
type B blood types are determined by the sugar Galactose. How IMPORTANT are these
eight sugars? You cannot make blood without them, need I say more. Yes indeed there
is so much more but to go further I would need to speak in the language of advanced
The important factor really is on a practical level which asks the question where do I get
these eight super regenerative sugars? Simply call us at AAI and you can learn how to
obtain the Super Eight!
Mechanisms of the Sialidase and Trans-sialidase Activities of Bacterial Sialyltransferases from
Glycosyltransferase Family 80 (GT80).
Mehr K, Withers SG.
Glycobiology. 2015 Nov 17. pii: cwv105. [Epub ahead of print]
Select item 265786732.
Development of Heptylmannoside-Based Glycoconjugate Antiadhesive Compounds against
Adherent-Invasive Escherichia coli Bacteria Associated with Crohn’s Disease.
Sivignon A, Yan X, Alvarez Dorta D, Bonnet R, Bouckaert J, Fleury E, Bernard J, Gouin SG,
Darfeuille-Michaud A, Barnich N.
MBio. 2015 Nov 17;6(6). pii: e01298-15. doi: 10.1128/mBio.01298-15.
Select item 265692243.
Identification of Arsenic Direct-Binding Proteins in Acute Promyelocytic Leukaemia Cells.
Zhang T, Lu H, Li W, Hu R, Chen Z.
Int J Mol Sci. 2015 Nov 10;16(11):26871-26879.
Select item 265625464.
Comparative study of structural models of Leishmania donovani and human GDP-mannose
Daligaux P, Bernadat G, Tran L, Cavé C, Loiseau PM, Pomel S, Ha-Duong T.
Eur J Med Chem. 2015 Oct 30;107:109-118. doi: 10.1016/j.ejmech.2015.10.037. [Epub ahead of print]
Select item 265585155.
Synthesis of di- and tri-saccharide fragments of Salmonella typhi Vi capsular polysaccharide
and their zwitterionic analogues.
Fusari M, Fallarini S, Lombardi G, Lay L.
Bioorg Med Chem. 2015 Oct 30. pii: S0968-0896(15)30121-8. doi: 10.1016/j.bmc.2015.10.043. [Epub ahead of print]
Select item 265540936.
Imaging. RNA catch and release.
Nat Methods. 2015 Sep;12(9):813. No abstract available.
Select item 265532867.
Merging carbohydrate chemistry with lectin histochemistry to study inhibition of lectin binding by
glycoclusters in the natural tissue context.
André S, Kaltner H, Kayser K, Murphy PV, Gabius HJ.
Histochem Cell Biol. 2015 Nov 9. [Epub ahead of print]
Select item 265432578.
Synthesis of cholesteryl-α-D-lactoside via generation and trapping of a stable β-lactosyl iodide.
Davis RA, Fettinger JC, Gervay-Hague J.
Tetrahedron Lett. 2015 Jun 3;56(23):3690-3694. Epub 2015 May 8.
Select item 265419749.
Enhanced Cross-Linking of Diazirine-Modified Sialylated Glycoproteins Enabled through
Profiling of Sialidase Specificities.
McCombs JE, Zou C, Parker RB, Cairo CW, Kohler JJ.
ACS Chem Biol. 2015 Nov 16. [Epub ahead of print]
Select item 2653133610.
Glycoconjugates distribution during developing mouse Spinal Cord motor organizer.
Fazel A, Vojoudi E, Ebrahimi V, Ebrahimzadeh A.
Int J Dev Neurosci. 2015 Dec;47(Pt A):2-3. doi: 10.1016/j.ijdevneu.2015.04.016. No abstract available.
Select item 2652635411.
Identification and functional analysis of two Golgi-localized UDP-galactofuranose
transporters with overlapping functions in Aspergillus niger.
Park J, Tefsen B, Heemskerk MJ, Lagendijk EL, van den Hondel CA, van Die I, Ram
BMC Microbiol. 2015 Nov 2;15(1):253. doi: 10.1186/s12866-015-0541-2.
Select item 2652540212.
Candida albicans β-1,2-mannosyltransferase Bmt3 prompts the elongation of the cell-
Sfihi-Loualia G, Hurtaux T, Fabre E, Fradin C, Mée A, Pourcelot M, Maes E, Bouckaert
J, Mallet JM, Poulain D, Delplace F, Guérardel Y.
Glycobiology. 2015 Nov 1. pii: cwv094. [Epub ahead of print]
Select item 2652448113.
Taming the Reactivity of Glycosyl Iodides To Achieve Stereoselective Glycosidation.
Acc Chem Res. 2015 Nov 2. [Epub ahead of print]
HDL Cholesterol and Risk of Type 2 Diabetes: A Mendelian Randomization Study.
Haase CL, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R.
Diabetes. 2015 Sep;64(9):3328-33. doi: 10.2337/db14-1603. Epub 2015 May 13.
Select item 2596831216.
Glypican4 promotes cardiac specification and differentiation by attenuating canonical
Wnt and Bmp signaling.
Strate I, Tessadori F, Bakkers J.
Development. 2015 May 15;142(10):1767-76. doi: 10.1242/dev.113894.
Select item 2596449417.
Glucocorticoid-induced leucine zipper: a critical factor in macrophage endotoxin
Hoppstädter J, Kessler SM, Bruscoli S, Huwer H, Riccardi C, Kiemer AK.
J Immunol. 2015 Jun 15;194(12):6057-67. doi: 10.4049/jimmunol.1403207. Epub 2015 May 11.
Select item 2596420918.
Tamoxifen regulation of sphingolipid metabolism–Therapeutic implications.
Morad SA, Cabot MC.
Biochim Biophys Acta. 2015 Sep;1851(9):1134-45. doi: 10.1016/j.bbalip.2015.05.001. Epub 2015 May 9. Review.
Cardiomyocyte mitochondrial respiration is reduced by receptor for advanced glycation end-
product signaling in a ceramide-dependent manner.
Nelson MB, Swensen AC, Winden DR, Bodine JS, Bikman BT, Reynolds PR.
m J Physiol Heart Circ Physiol. 2015 Jul 1;309(1):H63-9. doi: 10.1152/ajpheart.00043.2015. Epub 2015 Ma
Internalization and accumulation in dendritic cells of a small pH-activatable glycomimetic
fluorescent probe as revealed by spectral detection.
Arsov Z, Švajger U, Mravljak J, Pajk S, Kotar A, Urbančič I, Štrancar J, Anderluh M.
Chembiochem. 2015 Oct 30. doi: 10.1002/cbic.201500376. [Epub ahead of print]
Highly Substituted Cyclopentane-CMP Conjugates as Potent Sialyltransferase Inhibitors.
Li W, Niu Y, Xiong DC, Cao X, Ye XS.
J Med Chem. 2015 Oct 22;58(20):7972-90. doi: 10.1021/acs.jmedchem.5b01181. Epub 2015 Oct 7.
Activation and function of murine primary microglia in the absence of the prion protein.
Pinheiro LP, Linden R, Mariante RM.
J Neuroimmunol. 2015 Sep 15;286:25-32. doi: 10.1016/j.jneuroim.2015.07.002. Epub 2015 Jul 10.
Phospholipase D2 drives mortality in sepsis by inhibiting neutrophil extracellular trap formation
and down-regulating CXCR2.
Lee SK, Kim SD, Kook M, Lee HY, Ghim J, Choi Y, Zabel BA, Ryu SH, Bae YS.
J Exp Med. 2015 Aug 24;212(9):1381-90. doi: 10.1084/jem.20141813. Epub 2015 Aug 17.
Activation of human naïve Th cells increases surface expression of GD3 and induces
neoexpression of GD2 that colocalize with TCR clusters.
Villanueva-Cabello TM, Mollicone R, Cruz-Muñoz ME, López-Guerrero DV, Martínez-Duncker I.
Glycobiology. 2015 Dec;25(12):1454-64. doi: 10.1093/glycob/cwv062. Epub 2015 Aug 11.
[CONTEMPORARY CONCEPTION OF IMMUNE RESPONSE ACTIVATION MECHA- NISM BY
CONJUGATED POLYSACCHARIDE VACCINES].
Kolesnikov AV, Kozyr AV, Schemyakin IG, Dyatlov IA.
Zh Mikrobiol Epidemiol Immunobiol. 2015 May-Jun;(3):97-106. Review. Russian.
[The significance of fucosylated glycoconjugates of human milk in nutrition of newborns and
Lis-Kuberka J, Orczyk-Pawiłowicz M.
Postepy Hig Med Dosw (Online). 2015 Jul 22;69:811-29. Polish.
HUMAN MICROBIOTA. Small molecules from the human microbiota.
Donia MS, Fischbach MA.
Science. 2015 Jul 24;349(6246):1254766. doi: 10.1126/science.1254766. Epub 2015 Jul 23. Review.
Temporary Conversion of Protein Amino Groups to Azides: A Synthetic Strategy for
Lipinski T, Bundle DR.
Methods Mol Biol. 2015;1331:145-57. doi: 10.1007/978-1-4939-2874-3_9.
Plasmodium falciparum Infection of Human Volunteers Activates Monocytes and CD16+
DendriticCells and Induces Upregulation of CD16 and CD1c Expression.
Teirlinck AC, Roestenberg M, Bijker EM, Hoffman SL, Sauerwein RW, Scholzen A.
Infect Immun. 2015 Sep;83(9):3732-9. doi: 10.1128/IAI.00473-15. Epub 2015 Jul 13.
Oral Administration of Lipopolysaccharide of Acetic Acid Bacteria Protects Pollen Allergy in a
Amano S, Inagawa H, Nakata Y, Ohmori M, Kohchi C, Soma G.
Anticancer Res. 2015 Aug;35(8):4509-14.
Intranuclear interactomic inhibition of NF-κB suppresses LPS-induced severe sepsis.
Park SD, Cheon SY, Park TY, Shin BY, Oh H, Ghosh S, Koo BN, Lee SK.
Biochem Biophys Res Commun. 2015 Aug 28;464(3):711-7. doi: 10.1016/j.bbrc.2015.07.008. Epub 2015 Jul 6.
Glycoprotein from street rabies virus BD06 induces early and robust immune responses when
expressed from a non-replicative adenovirus recombinant.
Wang S, Sun C, Zhang S, Zhang X, Liu Y, Wang Y, Zhang F, Wu X, Hu R.
Arch Virol. 2015 Sep;160(9):2315-23. doi: 10.1007/s00705-015-2512-1. Epub 2015 Jul 5.
Modulation of proinflammatory NF-κB signaling by ectromelia virus in RAW 264.7 murine
Struzik J, Szulc-Dąbrowska L, Papiernik D, Winnicka A, Niemiałtowski M.
Arch Virol. 2015 Sep;160(9):2301-14. doi: 10.1007/s00705-015-2507-y. Epub 2015 Jul 4.
Stroke is the third leading cause of death in the United States and results in substantial health-
care expenditures; the mean lifetime cost resulting from an ischemic stroke is estimated at
$140,048 per patient, and this estimation is higher for people over 45 years. Nationwide in 2010,
the estimated direct and indirect costs of stroke totaled $73.7 billion . Although many clinical
trials have been completed in stroke patients, none of these have demonstrated protective
efficacy except for thrombolysis [2, 3]. In the case of cardiac arrest and resuscitation only
hypothermia has been shown to have clinical utility . In some sense the two therapies that
have been effective thus far clinically have broad targets, and do not only affect a single injury
mechanism. In contrast, of the failed trials, many targeted neuron-specific injury mechanisms
. This may reflect too narrow a view of what is needed for brain preservation. A large body of
work has shown that astrocytes play key roles both in normal and pathological central nervous
system functioning . Astrocytes are the most abundant brain cell type, and in addition to their
multiple important homeostatic roles, they organize the structural architecture of the brain, help
organize communication pathways, and modulate neuronal plasticity (for recent review see
[7, 8]). Thus, astrocytes are now thought to be important potential targets for manipulation.
Ischemic stroke is caused by an interruption of cerebral blood flow that leads to stress, cell death,
and inflammation. Neurons are more susceptible to injury than astrocytes when studied under
some in vitroconditions [9, 10]. Neurons have less endogenous antioxidants and are susceptible
to excito-toxicity . Both normally and after ischemia, astrocytes support neurons by
providing antioxidant protection [11, 12], substrates for neuronal metabolism , and glutamate
clearance REF. Although astrocytes are sometimes more resilient than neurons, injury can result
in impaired astrocyte function even when astrocytes do not die. Impaired astrocyte function can
amplify neuronal death . Therefore, many recent efforts have focused on the astrocyte-
neuron interaction and how astrocyte function can be improved after stroke to enhance neuronal
support and survival [10, 15, 16]. A growing body of data demonstrates that astrocytes play a
multifaceted and complex role in the response to ischemia, with potential to both enhance and
impair neuronal survival and regeneration . Many recent studies focus on the astrocyte-
neuron interaction and several investigate ways in which astrocyte function can be improved
after stroke to enhance neuronal survival.
This review provides a brief overview of the pathophysiological events underlying ischemic
brain damage, and considers how these events affect astrocyte-mediated support of neurons. In
addition, we discuss some experimental approaches to enhance the neuronal supportive role of
astrocytes as a novel strategy against stroke. Finally, we explore how these approaches may
eventually be applied in the clinical setting to improve stroke outcome for patients.
2. ASTROCYTE VIABILITY AFTER ISCHEMIA
2.1. In Vitro Studies
In vitro studies have provided substantial insight into the mechanisms governing the survival of
astrocytes following simulated ischemia. These investigations have shown that astrocytes are
generally more resistant than neurons to oxygen-glucose deprivation (OGD) performed in media
at physiologically normal pH, an in vitro model of ischemia [10, 18]. Most neurons in astrocyte-
neuronal co-cultures will die after 60–90 min of OGD, while astrocyte cultures only suffer a
similar extent of injury after 4–6 hours [9, 18, 19]. Different astrocyte populations exist and
astrocytes isolated from different brain regions such as cortex, striatum, and hippocampus differ
in their sensitivity to OGD [15, 20, 21]. Furthermore, Lukaszevicz and colleagues  reported
that protoplasmic astrocytes lose their integrity faster than fibrous astrocytes, which may explain
the regional differences in susceptibility to ischemia between white matter astrocytes which are
fibrous and grey matter astrocytes that are protoplasmic. Although less susceptible to OGD-
induced damaged in vitro studies have highlighted certain elements that are highly toxic to
astrocytes. For example, acidosis has been found to be very effective in killing astrocytes
[23–26], in contrast to neurons, which are protected in acidic conditions [24, 26].
2.2. Focal Cerebral Ischemia
Much of the information about the recovery of astrocytes in vivo has been provided by studies
using immunohistological markers for astrocyte specific proteins, such as glial fibrillary acidic
protein (GFAP) and glutamine synthetase GS; Fig. 1. Using these markers as tools, several
investigations suggest that astrocytes are better preserved than neurons in animal models of
stroke outside the core where all cells die [27–29]. Though neuronal markers are decreased as
soon as 1 hour after MCAO, GFAP expression is preserved over the first 3 hours of reperfusion
after 2 hour MCAO  and GS is increased 3 hours following a 3 hour MCAO . At later
reperfusion periods, GFAP increases in the peri-infarct area that later develops into the glial scar
[29–32]. In contrast, Liu and colleagues  reported the deterioration of some astrocyte
markers prior to that of neuronal markers. Discrepancy in findings may be due to differences in
detection (i.e., protein vs. mRNA) and injury paradigms.
Expression of different astrocytic proteins following stroke. Increased expression of GFAP is a
hallmark of astrocytes activation, as is induction/re-expression of vimentin. Astrocytes normally
express glutamine synthetase (GS) and S100β, genes …
2.3. Forebrain Ischemia
Excitotoxic neuronal injury is a common mechanism in both acute and chronic
neurodegenerative diseases. It has long been appreciated that inhibition of astrocyte glutamate
uptake [34, 35], and more recently inhibition of astrocyte mitochondrial function , impairs
neuronal survival from excitotoxic injury. Brief forebrain ischemia is a model of the delayed
hippocampal neuronal loss seen in patients following cardiac arrest and resuscitation, and in part
involves excitotoxicity. Increased generation of reactive oxygen species (ROS) and
mitochondrial dysfunction in CA1 astrocytes contributes to ischemia-induced loss of GLT-1 and
ultimately to delayed death of CA1 neurons . Our studies and those of other laboratories
have demonstrated that selective dysfunction of hippocampal CA1 subregion astrocytes, with
loss of glutamate transport activity and immunoreactivity for glutamate transporter 1 (GLT-1),
occurs at early reperfusion times, hours to days before the death of CA1 neurons [15, 37, 38].
The heterogeneous degeneration of astrocytic processes and mitochondria was tightly associated
with the appearance of disseminated selective neuronal necrosis and its maturation after
temporary ischemia . By electronmicroscopy the same investigators  found that focal
infarction is exacerbated by temporary microvascular obstruction due to compression by swollen
astrocytic end-feet. However, hypoxia has multiple effects on astrocytes and their ability to
support neuronal viability . For example, hypoxia induces astrocyte-dependent protection of
neurons following hypoxic preconditioning. Yet, hypoxia induces processes in astrocytes that
augment neuronal death in other situations, such as the coincidence of hypoxia with
3. REACTIVE ASTROGLIA: GOOD OR BAD AFTER STROKE?
The astrocyte response to ischemia has traditionally been viewed as detrimental to recovery, as
the astrocyte-rich glial scar has both physical and chemical inhibitory properties [42, 43]. As
components of the glial scar, astrocytes exhibit hypertrophied, interdigitated processes that form
a physical barrier. Astrocytes produce inhibitory molecules including chondroitin sulfate
proteoglycans (CSPGs) that contribute to chemical inhibition [44, 45]. In the acute setting,
astrocytic gap junctions may remain open following ischemia , allowing substances such as
proapoptotic factors to spread through the syncytium, thereby expanding the size of the infarct
. As discussed below, astrocytes can also produce a variety of pro-inflammatory cytokines.
Many studies have shown that decreased astrogliosis often correlates with decreased infarct size.
Nonspecific inhibition of cell proliferation following ischemia using a cyclin kinase inhibitor
decreases astrocyte proliferation and results in improved functional recovery . In addition,
treatment with alpha-melanocyte stimulating hormone , cysteinyl leukotriene receptor
antagonist , cliostazol , and caffeic acid  result in reduced infarct size accompanied
by a decrease in astrogliosis. Treadmill exercise  and acupuncture  are similarly
associated with improved outcome and reduced astrogliosis. Thus, results from several studies
suggest that treatments that decrease infarct size are often accompanied by attenuated astrocyte
response. Despite the frequent association of decreased astrogliosis with improved outcome, it is
difficult to determine cause and effect, since the extent of astrogliosis likely reflects the severity
of the injury, as well as influencing it.
In addition to their role in glial scar formation, astrocytes also respond to ischemia with functions
important for neuroprotection and repair. These include protecting spared tissue from further
damage , taking up excess glutamate as discussed above, rebuilding the blood brain barrier
[54, 55], and producing neurotrophic factors . GFAP knockout mice exhibit larger lesions
than their wild-type littermates following focal ischemia , and mice lacking both GFAP and
vimentin have impaired astrocyte activation, decreased glutamate uptake abilities, and attenuated
PAI-1 expression after ischemia . Application of astrocyte-conditioned media after transient
MCAO results in decreased infarct volume and regained blood-brain barrier function ,
suggesting that factors released by astrocytes following ischemia are important for
Although few studies other than the use of animals lacking vimentin and GFAP have specifically
targeted astrocyte activation after ischemia, there is correlational evidence suggesting that
astrogliosis may be beneficial. Environmental enrichment, which results in reduced infarct size
and improved recovery following ischemia, also leads to increased astrocyte proliferation
[59, 60]. After focal ischemia, aged rats exhibit increased tissue damage and increased astrocyte
hypertrophy, but have decreased astrocyte proliferation compared to young rats . Systemic
infusion of bone marrow stromal cells following MCAO increases gliogenesis and decreases
lesion size [62, 63]. In addition, administration of transforming growth factor α (TGFα), a known
mitogen for astrocytes , following MCAO leads to reduced infarct size and improved
functional recovery . Furthermore, ischemic preconditioning that produces a neuroprotective
state leads to prolonged astrocyte expression of Hsp27 . Finally, mice lacking connexin 43,
the gap junction connecting astrocyte networks that is needed for proper neurotransmitter and
potassium regulation, have increased infarcts following MCAO . Thus, astrocytes have the
potential to be both detrimental and beneficial following ischemic insult, making them promising
targets for manipulation to improve outcome.
4. ASTROCYTE-MEDIATED INFLAMMATION AFTER STROKE: A DOUBLE-EDGED
Inflammation plays both detrimental and beneficial roles in brain ischemia, depending upon the
timing and severity of the inflammation. Within minutes after injury, injured neurons in the core
and penumbra of the lesion and glial cells in the core produce pro-inflammatory mediators,
cytokines, and reactive oxygen species, which activate both astrocytes and microglia .
Activated astrocytes can produce the proinflammatory cytokines IL-6, TNFα, IL-1α and β,
interferon γ, and others [68–70]. High levels of these cytokines can be detrimental to ischemic
recovery [71–75] by directly inducing apoptosis of neuronal cells and/or increasing toxic nitric
oxide levels  and inhibiting neurogenesis . Indeed, inactivation of astrocyte NfκB
signaling, shown to induce astrocyte production of pro-inflammatory cytokines , decreases
cytokine production and protects neurons after ischemic injury . Hsp72 overexpression is
associated with lower NfκB activation and lower TNFα . In addition to cytokines, reactive
astrocytes also produce chemokines following ischemia . Chemokines upregulate adhesion
molecules in vascular endothelial cells, resulting in attraction of immune cells, which may
worsen ischemia-induced damage . Overall, some aspects of the local inflammatory response
contribute to secondary injury to potentially viable tissue and lead to apoptotic and necrotic
neuronal cell death hours to days after injury , while other aspects are beneficial.
Although the potential benefits of inflammation after stroke have received relatively little
attention so far, indirect evidence suggests that some specific inflammatory reactions are
neuroprotective and neuroregenerative [84–91]. In addition to providing defense against the
invasion of pathogens, inflammation is also involved in clearing damaged tissue, and in
angiogenesis, tissue remodeling, and regeneration . This is probably best studied in wound
healing, which is severely compromised if inflammation is inhibited [89, 91]. There is also
evidence suggesting that specific inflammatory factors can be protective in some circumstances.
IL-6, produced by astrocytes acutely after MCAO , is likely neuroprotective early after
ischemia . Interestingly, ischemic preconditioning resulting in protection appears to be
dependent on TLR-4 signaling, and is accompanied by increased TNFα, NFκB, and COX-2
expression . Indeed, in vitro work has shown that administration of TNFα in combination
with Hsp70 results in decreased expression of pro-apoptotic proteins following hypoxia .
Thus, it is important to consider these factors, along with timing, when trying to determine the
best strategy to reduce damage and improve recovery and regeneration.
5. ASTROCYTE SUPPORT OF NEURONS AFTER STROKE
5.1. Antioxidant Production
One hallmark of the cellular response to ischemia is a rapid, dramatic increase in damaging free
radicals, including nitric oxide (NO), superoxide, and peroxynitrite . Nitric oxide synthetase
levels increase as soon as 10 minutes after induction of MCAO , followed by NO production
that persists for at least one week after MCAO . Nitric oxide can cause cell death by
inducing the release of cytochrome-c from mitochondria, leading to apoptosis . Nitric oxide
can also induce necrotic death . Furthermore, the production of nitric oxide and other free
radicals can modify oxidative metabolism and impair ATP production [13, 19]. Changes in
mitochondrial properties can further limit oxidative metabolism . Not surprisingly, several
studies have shown that antioxidant treatment enhances neuroprotection and recovery after
The release of glutathione and SOD by astrocytes has been reported and is suggested to play an
important role in maintaining and enhancing neuronal survival, yet they are able to reduce
ascorbate for further neuronal antioxidant defense Fig. (2) [10, 102–106]. Interestingly, neurons
cocultured with astrocytes exhibit higher levels of glutathione compared with neurons cultured
alone . Although astrocytes upregulate SOD after cerebral ischemia , they do not
appear to increase levels of glutathione in ischemic conditions . It is unknown whether
ischemia alters astrocytic ascorbate levels, but osmotic swelling from ischemia results in
increased astrocyte release of ascorbate in vitro , suggesting that similar mechanisms may
occur in vivo.
Mechanisms of astrocyte support of neurons important in stroke. Antioxidant defense includes
release of glutathione and ascorbate. Regulation of extracellular levels of ions and neuro-
transmitters, especially K+ and glutamate, strongly influences neuronal …
Several treatments that attenuate ischemic injury result in increased glutathione levels [111, 112].
SOD converts superoxide into oxygen and hydrogen peroxide. Similar to glutathione, many
treatments that ameliorate stroke damage are accompanied by an increase in SOD [113, 114].
Furthermore, rodents overexpressing SOD1 have significantly smaller injuries after both focal
and global ischemia [115, 116], while mice with decreased SOD1 have larger infarcts .
Finally, ascorbate can also reduce oxidative stress . Treatment with dehydroascorbic acid, a
blood-brain-barrier-permeable precursor to ascorbic acid, is protective after MCAO .
Dehydroascorbic acid is taken up by astrocytes and released as ascorbic acid , a process
increased by propofol , a treatment that can be protective after stroke . In summary,
astrocytes are important producers of antioxidants in the normal CNS, and astrocyte production
of these molecules after stroke may enhance neuronal survival and protect astrocyte function.
5.2. Glutamate Regulation
Astrocytes are key players in the regulation of neuro-transmitters in the CNS. Astrocytes make
glutamine, the precursor for the neurotransmitters glutamate and GABA  Fig. (2). Astrocyte
production of neurotransmitter precursors is impaired after MCAO, and alterations in neuro-
transmitter levels occur throughout the brain following stroke, possibly contributing to neuronal
death [123, 124].
Astrocytes are primarily responsible for glutamate uptake in the normal brain using the astrocyte
specific glutamate transporters GLAST and GLT-1 (Fig. 2) [125–127], as excess glutamate leads
to cell death via excitotoxicity . Glutamate transporter levels in astrocytes decrease acutely
following global ischemia [38, 129] and neonatal hypoxia-ischemia , most likely
exacerbating neuronal death as a result of glutamate-induced excitoxicity. Despite the therapeutic
potential of increasing astrocyte glutamate transport after stroke, few groups have explored this
possibility. Carnosine, shown to be protective after focal ischemia, may partially be effective
because it prevents loss of GLT-1 on astrocytes, resulting in attenuated excitotoxicity . In a
more direct assessment of how post-ischemic astrocyte glutamate transporters contribute to
neuronal survival, our laboratory has shown that upregulation of GLT-1 on astrocytes using
ceftriaxone protects CA1 neurons after global ischemia , similar to its effects in focal
cerebral ischemia .
5.3. Potassium Uptake and Energy Metabolism
Astrocytes also regulate neuronal activation by extracellular potassium uptake  Fig. (2).
Neurons release potassium after activation, and increased extracellular potassium leads to
neuronal hyperexcitability , a phenomenon that occurs in ischemic conditions . In
addition to regulating neuronal activation, proper maintenance of ion gradients, such as
potassium, is important in regulating cell volume in both normal and ischemic conditions
[135, 136]. Astrocytes increase potassium transporter activity in response to transient in
vitro ischemia . Due to its effects on both neuronal activity and cell volume, increasing
astrocytic potassium uptake may be a possible therapeutic target for stroke.
Astrocytes are also integral to normal maintenance of neuronal metabolism. When astrocytes
take up extracellular glutamate as a result of neuronal activity, the Na+/ K+-ATPase, along with
AMPA signaling, triggers astrocyte uptake of glucose from the blood, as astrocytic endfeet
contact capillaries [138, 139]. This glucose is then made into lactate, a substrate for neuronal
energy, to further “fuel” active neurons  Fig. (2). As mentioned above, astrocytes produce
glutathione. In addition to its antioxidant properties, glutathione is needed for the conversion of
methylglyoxal, a toxic by-product of metabolism, into D-Lactate by glyoxalase 1 .
Although the role of astrocyte metabolism is relatively well-established in normal tissue, the
post-ischemic role of astrocyte metabolism maintenance is less clear . After ischemia,
astrocytes upregulate glucose transporters in order to provide energy to stressed/dying neuronal
cells [143,144]. Ethyl pyruvate, a derivative of the energy substrate pyruvate, is neuroprotective
after stroke only when astrocytes are viable, suggesting that astrocytes are necessary for
improvement in post-ischemic energy metabolism .
6. NOVEL STRATEGIES TO IMPROVE THE NEURONAL SUPPORTIVE ROLE OF
Although few studies have specifically targeted astrocytes for repair after stroke, there is some
evidence that this can be a successful strategy. Recent results indicate that induction of BDNF in
astrocytes by galectin-1 reduces neuronal apoptosis in ischemic boundary zone and improves
functional recovery . In addition, protection by pyruvate against glutamate neurotoxicity is
mediated by astrocytes through a glutathione-dependent mechanism . Our recent study
demonstrated that enhancing astrocyte resistance to ischemic stress by overexpressing protective
proteins or antioxidant enzyme results in improved survival of CA1 neurons following forebrain
ischemia Fig. (3) . Two well-studied protective proteins, heat shock protein 72 (Hsp72) and
mitochondrial SOD, were genetically targeted for expression in astrocytes using the astrocyte-
specific human GFAP promoter. In both cases protection was accompanied by preservation of
the astrocytic glutamate transporter GLT-1, and reduced evidence of oxidative stress in the CA1
region . Similarly, selective overexpression of excitatory amino acid transporter 2 (EAAT2)
in astrocytes enhances neuroprotection from moderate hypoxia-ischemia .
Targeted over-expression of Hsp72 in astrocytes reduces the vulnerability of CA1 neurons to
forebrain ischemia. Selective overexpression of Hsp72 in astrocytes by expressing it from the
astrocyte specific GFAP promoter was achieved by unilateral stereotaxic …
7. TRANSLATING INSIGHTS INTO PROTECTION INTO CLINICAL APPLICATIONS
Many factors have been identified that likely contribute to the failure in translation seen so far
with stroke therapies. Currently, the only approved stroke therapy is thrombolysis induced by
intravenous administration of recombinant tissue plasminogen activator ; however, because
of a short therapeutic time window, only a small fraction of patients benefit from this treatment.
Hypothermia is the only accepted acute treatment to reduce brain injury following cardiac arrest
and resuscitation . Thus far many clinical trials have focused on treatments that would likely
be beneficial to neurons, with fewer studies focused on mechanisms that might benefit all cell
types or specifically targeting other cell types, such as astrocytes. Often the consequence of these
treatments on the astrocyte response is not considered. Several examples of past and ongoing
clinical trials are discussed below, with specific attention to how these treatments may alter
astrocyte response or viability.
Several clinical trials have targeted manipulation of the inflammatory response to ischemia, as
stroke patients with systemic inflammation exhibit poorer outcomes . Although anti-
inflammatory therapy decreases infarct size and improves neurological sequelae in experimental
animal models of stroke , human trials with anti-neutrophil therapy have not shown a clear
benefit [151, 152]. In addition, recent clinical trials in which anti-CD11/18 antibodies were
administered to human subjects were unsuccessful . Likewise, a double-blinded, placebo-
controlled clinical trial in which anti–ICAM-1 antibody was administered within 6 hours of
stroke symptoms showed disappointing results . In understanding these results it is
important to recall that while experimental stroke is relatively homogeneous concerning size,
territory, and etiology, with more consistent inflammatory response, human stroke is extremely
heterogeneous , with different vascular territories and extents of injury. In addition, these
mediators are known to affect many organ systems beyond the central nervous system. Systemic
administration of anti-inflammatory agents may have exacerbated the relative state of
immunocompromise seen in stroke patients, thereby confounding the outcome. Furthermore,
inflammation and astrocyte response are likely closely connected. Although there is little
evidence for a direct relationship between neutrophils and astrocytes, it has been shown that
mice with a blunted inflammatory response exhibit increased loss of GFAP-positive astrocytes
after cortical stab injury . Because astrocytic glial scar formation is important in protection
of spared tissue from further damage , it is possible that treatments that drastically attenuate
inflammation lead to a stunted astrocyte response that is deleterious to recovery.
Another drug that has advanced to clinical study is DP-b99, currently in phase III studies for
acute stroke. DP-b99 is a membrane active chelator derivative of the known calcium chelator,
BAPTA spell out . A lipophilic chelator of calcium, zinc and copper ions, DP-b99
sequesters metal ions only within and in to cell membranes. This clinical trial is especially
attractive because sequestration of calcium, zinc, and copper are potentially beneficial not only
to neurons, but also to astrocytes. It has been shown in Alzheimer’s disease that beta amyloid
increases astrocyte calcium influx, which causes decreased glutathione levels . Zinc
chloride is toxic to astrocytes as well as neurons in vitro . Similarly, astrocytes exposed to
neocuprine exhibit increased copper influx and undergo apoptotic cell death . Approaches
that benefit multiple cell types, including astrocytes, are more likely to be successful.
Other current ongoing clinical trials focus on neuroprotective agents for the purpose of aiding
neurological recovery after stroke. Minocycline (Phase I), edavarone (Phase IV), propanolol (a
β-blocker; phase II and III), and more recently arundic acid have been previously shown to be
protective and enhance neuronal survival in stroke [161–165], though by targeting different
mechanisms. Some additional completed and ongoing trials are summarized in Table 1.
Preclinical research needs to consider these clinical results, and assess effects on astrocytes as
well as neurons.
Overview of Some Completed and Ongoing Clinical Trials for Stroke
Although anti-inflammatory strategies to diminish ischemic brain injury have failed thus far,
continued elucidation of the complex interactions involved in modulating the inflammatory
response may still enable novel therapeutic approaches that translate successfully into clinical
Traditionally, stroke research has focused on neurons and often ignored effects on glial cells. It is
increasingly evident that glia are vital to both normal CNS functioning and also play important
roles in neuropathological conditions. Although astrocytes form an inhibitory glial scar following
ischemia, they also perform functions necessary for neuronal survival and well-being, such as
maintaining low extracellular glutamate levels and providing antioxidant protection. Because
they have a great many functions, astrocytes are attractive candidates as therapeutic targets. By
striving to shift astrocytes towards a pro-reparative, neuronal-supportive phenotype following
stroke, future clinical therapies may well be more successful in protecting neurons from ischemic
damage and promoting repair.
This work was supported by NIH grants CM49831, N5053898, and NS014543 to RGG.
1. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, Ford E, Furie K,
Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, Ho PM, Howard V, Kissela B, Kittner S, Lackland D,
Lisabeth L, Marelli A, McDermott MM, Meigs J, Mozaffarian D, Mussolino M, Nichol G, Roger VL,
Rosamond W, Sacco R, Sorlie P, Roger VL, Thom T, Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J.
Heart disease and stroke statistics–2010 update: a report from the American Heart
Association.Circulation. 2010;121:e46–e215. [PubMed]
2. Blakeley JO, Llinas RH. Thrombolytic therapy for acute ischemic stroke. J. Neurol.
3. Marder VJ, Jahan R, Gruber T, Goyal A, Arora V. Thrombolysis with plasmin: implications for stroke
treatment. Stroke. 2010;41:S45–S49. [PMC free article] [PubMed]
4. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose
survivors of out-of-hospital cardiac arrest with induced hypothermia. N. Engl. J.
5. Howells DW, Porritt MJ, Rewell SS, O’Collins V, Sena ES, van der Worp HB, Traystman RJ, Macleod MR.
Different strokes for different folks: the rich diversity of animal models of focal cerebral ischemia. J.
Cereb. Blood Flow Metab. 30:1412–1431. [PMC free article] [PubMed]
6. Kettenmann H, Ramson BR. Neuroglia. New York: Oxford University Press; 1995.
7. Nedergaard M, Ransom B, Goldman SA. New roles for astrocytes: redefining the functional
architecture of the brain. Trends Neurosci. 2003;26:523–530. [PubMed]
8. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta
Neuropathol. 2010;119:7–35.[PMC free article] [PubMed]
9. Goldberg MP, Choi DW. Combined oxygen and glucose deprivation in cortical cell culture: calcium-
dependent and calcium-independent mechanisms of neuronal injury. J.
10. Swanson RA, Ying W, Kauppinen TM. Astrocyte influences on ischemic neuronal death. Curr. Mol.
Med. 2004;4:193–205. [PubMed]
11. Dringen R, Hirrlinger J. Glutathione pathways in the brain. Biol. Chem. 2003;384:505–516. [PubMed]
12. Wilson JX. Antioxidant defense of the brain: a role for astrocytes. Can. J. Physiol.
13. Rossi DJ, Brady JD, Mohr C. Astrocyte metabolism and signaling during brain ischemia. Nat.
14. Nedergaard M, Dirnagl U. Role of glial cells in cerebral ischemia. Glia. 2005;50:281–286. [PubMed]
15. Ouyang YB, Voloboueva LA, Xu LJ, Giffard RG. Selective dysfunction of hippocampal CA1 astrocytes
contributes to delayed neuronal damage after transient forebrain ischemia. J.
Neurosci.2007;27:4253–4260. [PMC free article] [PubMed]
16. Xu L, Emery JF, Ouyang YB, Voloboueva LA, Giffard RG. Astrocyte targeted overexpression of Hsp72
or SOD2 reduces neuronal vulnerability to forebrain ischemia. Glia. 2010;58:1042–1049.[PMC free
17. Anderson MF, Blomstrand F, Blomstrand C, Eriksson PS, Nilsson M. Astrocytes and stroke:
networking for survival? Neurochem. Res. 2003;28:293–305. [PubMed]
18. Giffard RG, Swanson RA. Ischemia-induced programmed cell death in
astrocytes. Glia. 2005;50:299–306. [PubMed]
19. Almeida A, Delgado-Esteban M, Bolanos JP, Medina JM. Oxygen and glucose deprivation induces
mitochondrial dysfunction and oxidative stress in neurones but not in astrocytes in primary culture. J.
Neurochem. 2002;81:207–217. [PubMed]
20. Xu L, Sapolsky RM, Giffard RG. Differential sensitivity of murine astrocytes and neurons from
different brain regions to injury. Exp. Neurol. 2001;169:416–424. [PubMed]
21. Zhao G, Flavin MP. Differential sensitivity of rat hippocampal and cortical astrocytes to oxygen-
glucose deprivation injury. Neurosci. Lett. 2000;285:177–180. [PubMed]
22. Lukaszevicz AC, Sampaio N, Guegan C, Benchoua A, Couriaud C, Chevalier E, Sola B, Lacombe P,
Onteniente B. High sensitivity of protoplasmic cortical astroglia to focal ischemia. J. Cereb. Blood Flow
Metab. 2002;22:289–298. [PubMed]
23. Bondarenko A, Chesler M. Rapid astrocyte death induced by transient hypoxia, acidosis, and
extracellular ion shifts. Glia. 2001;34:134–142. [PubMed]
24. Giffard RG, Monyer H, Choi DW. Selective vulnerability of cultured cortical glia to injury by
extracellular acidosis. Brain Res. 1990;530:138–141. [PubMed]
25. Swanson RA, Farrell K, Stein BA. Astrocyte energetics, function, and death under conditions of
incomplete ischemia: a mechanism of glial death in the penumbra. Glia. 1997;21:142–153. [PubMed]
26. Tombaugh GC, Sapolsky RM. Mechanistic distinctions between excitotoxic and acidotic hippocampal
damage in an in vitro model of ischemia. J. Cereb. Blood Flow Metab. 1990;10:527–535. [PubMed]
27. Chen Y, Swanson RA. Astrocytes and brain injury. J. Cereb. Blood Flow
28. Lee MH, Kim H, Kim SS, Lee TH, Lim BV, Chang HK, Jang MH, Shin MC, Shin MS, Kim CJ. Treadmill
exercise suppresses ischemia-induced increment in apoptosis and cell proliferation in hippocampal
dentate gyrus of gerbils. Life Sci. 2003;73:2455–2465. [PubMed]
29. Li Y, Chopp M, Zhang ZG, Zhang RL. Expression of glial fibrillary acidic protein in areas of focal
cerebral ischemia accompanies neuronal expression of 72-kDa heat shock protein. J. Neurol.
30. Schroeter M, Schiene K, Kraemer M, Hagemann G, Weigel H, Eysel UT, Witte OW, Stoll G. Astroglial
responses in photochemically induced focal ischemia of the rat cortex. Exp Brain
31. Van Beek J, Chan P, Bernaudin M, Petit E, MacKenzie ET, Fontaine M. Glial responses, clusterin, and
complement in permanent focal cerebral ischemia in the mouse. Glia. 2000;31:39–50. [PubMed]
32. Yamashita K, Vogel P, Fritze K, Back T, Hossmann KA, Wiessner C. Monitoring the temporal and
spatial activation pattern of astrocytes in focal cerebral ischemia using in situ hybridization to GFAP
mRNA: comparison with sgp-2 and hsp70 mRNA and the effect of glutamate receptor antagonists. Brain
33. Liu D, Smith CL, Barone FC, Ellison JA, Lysko PG, Li K, Simpson IA. Astrocytic demise precedes delayed
neuronal death in focal ischemic rat brain. Brain Res. Mol. Brain Res. 1999;68:29–41. [PubMed]
34. Dugan LL, Bruno VM, Amagasu SM, Giffard RG. Glia modulate the response of murine cortical
neurons to excitotoxicity: glia exacerbate AMPA neurotoxicity. J.
Neurosci. 1995;15:4545–4555. [PubMed]
35. Rosenberg PA, Aizenman E. Hundred-fold increase in neuronal vulnerability to glutamate toxicity in
astrocyte-poor cultures of rat cerebral cortex. Neurosci. Lett. 1989;103:162–168. [PubMed]
36. Voloboueva LA, Suh SW, Swanson RA, Giffard RG. Inhibition of mitochondrial function in astrocytes:
implications for neuroprotection. J. Neurochem. 2007;102:1383–1394. [PMC free article] [PubMed]
37. Chen JC, Hsu-Chou H, Lu JL, Chiang YC, Huang HM, Wang HL, Wu T, Liao JJ, Yeh TS. Down-regulation
of the glial glutamate transporter GLT-1 in rat hippocampus and striatum and its modulation by a group
III metabotropic glutamate receptor antagonist following transient global forebrain ischemia. Neuro-
pharmacology. 2005;49:703–714. [PubMed]
38. Yeh TH, Hwang HM, Chen JJ, Wu T, Li AH, Wang HL. Glutamate transporter function of rat
hippocampal astrocytes is impaired following the global ischemia. Neurobiol.
39. Ito U, Hakamata Y, Kawakami E, Oyanagi K. Degeneration of astrocytic processes and their
mitochondria in cerebral cortical regions peripheral to the cortical infarction: heterogeneity of their
disintegration is closely associated with disseminated selective neuronal necrosis and maturation of
injury.Stroke. 2009;40:2173–2181. [PubMed]
40. Ito U, Hakamata Y, Kawakami E, Oyanagi K. Temporary focal cerebral ischemia results in swollen
astrocytic end-feet that compress microvessels and lead to focal cortical infarction. J. Cereb. Blood Flow
Metab. 2010 [PMC free article] [PubMed]
41. Vangeison G, Rempe DA. The Janus-faced effects of hypoxia on astrocyte
function. Neuroscientist.2009;15:579–588. [PMC free article] [PubMed]
L-Theanine and Caffeine in Combination Affect
Human Cognition as Evidenced by Oscillatory alpha-
Band Activity and Attention Task Performance1–3
1. Simon P. Kelly,
2. Manuel Gomez-Ramirez,
3. Jennifer L. Montesi, and
4. John J. Foxe*
1. Cognitive Neurophysiology Laboratory, Nathan S. Kline Institute for Psychiatric Research,
Program in Cognitive Neuroscience and Schizophrenia, Orangeburg, NY 10962 and Program
in Cognitive Neuroscience, Department of Psychology, City College of the City University of
New York, New York, NY 10031
1. ↵*To whom correspondence should be addressed. E-mail: email@example.com.
Recent neuropharmacological research has suggested that certain constituents of tea may have modulatory
effects on brain state. The bulk of this research has focused on either L-theanine or caffeine ingested alone
(mostly the latter) and has been limited to behavioral testing, subjective rating, or neurophysiological
assessments during resting. Here, we investigated the effects of both L-theanine and caffeine, ingested
separately or together, on behavioral and electrophysiological indices of tonic (background) and phasic (event-
related) visuospatial attentional deployment. Subjects underwent 4 d of testing, ingesting either placebo, 100
mg of L-theanine, 50 mg of caffeine, or these treatments combined. The task involved cued shifts of attention to
the left or right visual hemifield in anticipation of an imperative stimulus requiring discrimination. In addition to
behavioral measures, we examined overall, tonic attentional focus as well as phasic, cue-dependent
anticipatory attentional biasing, as indexed by scalp-recorded alpha-band (8–14 Hz) activity. We found an
increase in hit rate and target discriminability (d′) for the combined treatment relative to placebo, and an
increase in d′ but not hit rate for caffeine alone, whereas no effects were detected for L-theanine alone.
Electrophysiological results did not show increased differential biasing in phasic alpha across hemifields but
showed lower overall tonic alpha power in the combined treatment, similar to previous findings at a larger
dosage of L-theanine alone. This may signify a more generalized tonic deployment of attentional resources to
the visual modality and may underlie the facilitated behavioral performance on the combined ingestion of these
2 major constituents of tea.
Previous SectionNext Section
In recent years, several potential health benefits of drinking tea (Camellia sinensis) have come to light through
systematic study of the effects of its constituent compounds (1,2). Although anecdotal evidence abounds, the
psychological and neurophysiological effects of tea have received relatively little experimental investigation and
thus remain unclear. Popular claims have centered on generalized state changes such as the reduction of
stress and induction of relaxed wakefulness. Psychopharmacological studies have indeed demonstrated mood
effects that support these claims and have further shown that tea affects elements of cognition (3,4). Although
caffeine (1,3,7-trimethylxanthine) is by far the constituent most studied, with findings of increased alertness and
speeded reaction time (RT)4 predominant (5,6), there exists evidence that caffeine alone cannot fully account
for the positive effects of tea drinking. Tea has been shown to raise skin temperature to a higher level (7), to
increase critical flicker fusion threshold (4), and to reduce physiological stress responses and increase
relaxation ratings (8) when compared with coffee or other control beverages matched for caffeine level.
L-Theanine (γ-glutamylethylamide), a unique amino acid present almost exclusively in the tea plant, has
recently received research interest in the neuroscience community with findings of neuroprotective effects [see
Kakuda (9)] and mood effects indexed both by subjective self-reports (10) and via psychological and
physiological responses to stress (11). Using electroencephalographic (EEG) recordings in humans, Kobayashi
et al. (12) and Juneja et al. (13) reported that activity within the alpha frequency band (8–14 Hz) increased in
reaction to L-theanine ingestion when measured during a state of rest. This was of interest to the attention
community, as the alpha rhythm has long been known to be sensitive to overall attentional states (i.e., intensity
aspects such as arousal) (14) and, further, is involved in the biasing of selective attention (15,16). In
intersensory attention tasks, where the relevant modality is cued ∼1 s before a compound audiovisual target
stimulus, parieto-occipital alpha power in the intervening period is increased for attend-visual trials relative to
attend-auditory trials (15,17). In Gomez-Ramirez et al. (18), this differential effect of cue information on
anticipatory alpha amplitude was found to be larger on ingestion of 250 mg of L-theanine relative to placebo. In
addition, tonic (background) alpha amplitude was relatively decreased for L-theanine, in apparent contradiction
to the findings of Juneja et al. (13). In a follow-up study, we tested whether an analogous alpha-mediated
attention effect seen in visuospatial attention tasks (16,19–22) is also affected by L-theanine ingestion (M.
Gomez-Ramirez, S. P. Kelly, J. L. Montesi, and J. J. Foxe, unpublished results). L-Theanine, at a dosage of
250 mg, was not found to increase the differential effect of attention. However, in a replication of the previous
intersensory attention study (18), overall tonic alpha was greatly reduced on L-theanine.
An immediate question, given this replication, is whether this tonic alpha reduction occurs at lower dosages
of L-theanine, closer to the amount ingested through a typical serving of tea. In the present study, we
administered a lower dosage of 100 mg to address this. Also of critical interest is whether the ingestion of
caffeine, another major component of tea, exerts behavioral and/or neurophysiological effects during such a
demanding visuospatial attention task, when ingested alone or when ingested together with L-theanine. Here
we present data from a 4-d experiment using a balanced repeated-measures design, with subjects receiving
either placebo (P), L-theanine alone (T), caffeine alone (C), or the combination of L-theanine plus caffeine
(T+C) on each day. We assessed effects of treatment with regard to basic behavioral measures of RT and
accuracy [including the so-called discriminability index (d′), which is independent of individual detection criteria],
and in relation to both tonic and phasic attentional processes as indexed by alpha power.
Previous SectionNext Section
Sixteen (5 female) neurologically normal paid volunteers, aged between 21 and 40 y (mean 27.5 y),
participated in the study. All subjects provided written informed consent, and the Institutional Review Board of
the Nathan S. Kline Institute for Psychiatric Research approved the experimental procedures. All subjects
reported normal or corrected-to-normal vision. Four subjects were left-handed. The mean habitual tea
consumption across the subjects was 3.7 cups/wk, and for coffee, 3.8 cups/wk (∼250 mL/cup). Subjects arrived
at the laboratory in the morning between 0900 and 1200 h, having abstained from all caffeinated beverages for
the previous 24 h.
The timing of treatment administration relative to testing was based on published reports of amino acid
concentration and plasma concentration changes over time.L-Theanine concentration has been found to
increase significantly within 1 h after administration in rats, to continue to increase gradually up to 5 h, and to
decrease thereafter, with complete disappearance evident after 24 h (23). Peak plasma caffeine concentration
is reached between 15 and 120 min postingestion in humans, with a variable half-life typically between 2.5 and
4.5 h (5). Accordingly, participants abstained from consuming caffeine for at least 24 h before testing and
began experimental task runs 30 min after ingestion of any given treatment. Subjects underwent 4 d of testing,
ingesting either placebo, 100 mg of L-theanine, 50 mg of caffeine, or these treatments combined. Subjects
were uninformed of the treatment, which was served in 100 mL of water, with the placebo treatment consisting
only of water. Both theanine and caffeine are tasteless in water solution.
Stimuli and task.
Subjects were seated 150 cm from a CRT monitor and were instructed to maintain fixation on a central cross
(white on midgray background) at all times. Each trial began with a centrally presented arrow cue (“S1”) of 100-
ms duration, with equal probability pointing leftward or rightward toward 1 of 2 bilateral locations centered at a
horizontal distance of 4.2° from the fixation cross and 1.2° above the horizontal meridian. Each location was
marked by 4 dots outlining a 2.4° × 2.4° square. The cue consisted of a circle of 1° diameter with an embedded
arrow, designed to minimize any sensory effects related to physical differences between the left and right cues.
The colors of the arrow and circle were red on green for half of the blocks of recording and green on red for the
other half, with the order counterbalanced across subjects and days of testing. Red and green values were
precalibrated for each subject to be approximately isoluminant by flicker photometry. Then, 933 ms after cue
onset, a second imperative stimulus (“S2”) was presented at the left or right marked location (valid or invalid
with respect to cue direction) with equal probability. The S2s (100 ms duration) consisted of either a white × or
+ (0.75° × 0.75°) embedded in a circular array of 8 small circles such that the overall stimulus diameter was
1.95°. The target stimulus was chosen randomly at the beginning of each experimental run of ∼4.5 min, and
thereafter standard and target stimuli were equally likely on each trial. Subjects were instructed to shift their
attention covertly to the location indicated by the cue, to respond by pressing a mouse button with the index
finger of the right hand when a target S2 appeared on that side, and to ignore stimuli appearing on the invalid
side entirely. Trials were separated by a 1633-ms interval. A total of 100 trials were presented per run. Subjects
completed 20 runs on each day of testing.
Continuous EEG data, digitized at 512 Hz, were acquired from 164 scalp electrodes and 4 electro-oculographic
(EOG) electrodes with a pass-band of 0.05–100 Hz. Off-line, the data were low-pass filtered up to 45 Hz and
rereferenced to the nasion. Noisy channels, identified by taking the SD of amplitude over the entire run (from
first to last stimulus presented) and checking whether it is >50% greater than that of at least 3 of the 6 closest
surrounding channels, were interpolated. Horizontal EOG data were recorded using 2 electrodes placed at the
outer canthi of the eyes, allowing measurement of eye movements during testing. Based on a calibrated
mapping of EOG amplitude to visual angle, trials were rejected off-line if eye gaze deviated by >0.5° during the
Behavioral data analysis.
We employed a d′ as our principal performance metric, taking into account the accuracy of responding on
nontargets as well as targets and controlling for individual differences in detection criteria. The value of d′ was
derived from the hit rate (proportion of all valid targets detected) and false alarm rate (proportion of all valid
nontargets incorrectly responded to), calculated only from trials containing no eye movements or artifacts.
Ceiling effects on hit rate were corrected in the standard way by assuming 0.5 misses, and similarly, a floor
effect of zero false alarms was corrected to 0.5. RT was measured as the time (in milliseconds) from the point
of S2 onset at which the mouse button was correctly pressed in response to valid target trials.
To control for the potential confound of practice effects on the behavioral data, the order of treatments across
the 4 d of testing was fully counterbalanced across subjects. This is a standard procedure and ensures
unbiased comparison across conditions. However, in the case of the present data, the variance in behavioral
measures arising from the day of testing (order effect) far superseded that arising from treatment. Thus, a
normalization of these measures was necessary to remove the variance caused by practice, and this was
carried out by transforming each data point to a z-score with respect to the mean and SD of all scores
measured on that day (d 1, d 2, d 3, d 4). Because the distribution of scores for each day contains an equal
number of data points from each treatment, it cannot result in any bias for treatment but, rather, optimizes
statistical power to test for treatment effects.
Electrophysiological data analysis.
EEG data were epoched from −300 ms before to 1100 ms after cue onset and baseline-corrected relative to
the interval −100 to 0 ms, with an artifact rejection threshold of ±100 μV applied. Mean alpha amplitude was
calculated using the temporal spectral evolution (TSE) technique (15). TSE is carried out simply by filtering
each epoch with a passband of 8–14 Hz, rectifying, then averaging across trials. The averaged TSE waveforms
were then smoothed by averaging data points within a sliding 100-ms window.
The first analysis concerned tonic (background) alpha amplitude, which was found to decrease on L-theanine in
our previous 2 studies (18, M. Gomez-Ramirez, S. P. Kelly, J. L. Montesi, and J. J. Foxe, unpublished results).
Tonic alpha was measured as the integrated TSE amplitude within the baseline period −200 to 0 before the cue
stimulus, regardless of the direction of attentional deployment (i.e., to the left or right hemifield). The dependent
measure was computed as the baseline alpha amplitude averaged across 6 electrodes, chosen on the basis of
the grand-average scalp distribution of alpha amplitude, collapsed across the 4 d.
In a second analysis, we tested lateralized, anticipatory alpha amplitude for effects of attention and possible
interactions with treatment. We normalized alpha amplitude relative to baseline by dividing the TSE amplitude
by the mean amplitude within the baseline interval (−200 to 0) and log-transforming, making the measure
equivalent to a percentage change from baseline. This narrows down the analysis to attention-related
differential activity, independent of tonic effects. The anticipatory alpha dependent measure was computed as
the integrated TSE amplitude over the postcue interval 500 to 900 ms, ending just before the S2. Amplitude
was averaged across 6 electrodes over each hemisphere, determined based on grand-average difference
topographies (cue-left minus cue-right) collapsed across the 4 d.
A 4-d balanced repeated-measures design was employed, with subjects receiving 1 of the 4 treatments
(including placebo) on each day in counterbalanced order. SPSS for Windows (version 12.0) was used for all
statistical analyses. Tests were conducted with an α level of 0.05 unless otherwise stated. In the analysis of
behavioral data, we tested specifically for improvements in performance as a result of any of the 3 treatments.
Thus, 1-tailed, paired t-tests (df = 15) were conducted between the placebo condition and each of the 3
treatments for hit rate, RT, and d′ measures. Because 3 t-tests were performed including the same placebo
data, we applied a Bonferroni-corrected α-level of 0.016 here.
To test for effects of tonic alpha amplitude, a 1-way ANOVA was carried out with the factor of treatment having
the levels P, T, C, and T+C. Follow-up protected ttests were then conducted to unpack significant differences
existing between each of the T, C, and T+C conditions and the P condition. Further post hoc paired
comparisons among the 4 treatment conditions were conducted as appropriate through additional t-tests.
To test for effects on pretarget alpha amplitude a 4 × 2 × 2 ANOVA was carried out with factors of treatment (P,
T, C, T+C), attention (cue-left, cue-right), and hemisphere (left, right). To unpack a potential 3-way interaction,
we reduced the alpha cueing effect (typically seen as a hemisphere × attention interaction) to a single measure
by adding the differential over the 2 hemispheres, i.e., subtracting cue-right from cue-left on the left
hemisphere, subtracting cue-left from cue-right on the right hemisphere, and summing these 2 values. Thus
reduced, testing of treatment effects on the alpha cueing effect, as found in the analogous intersensory study of
Gomez-Ramirez et al. (18), could be done via paired t-tests comparing each of the 3 treatments T, C, and T+C
Previous SectionNext Section
Behavioral performance was significantly improved on the combined treatment (T+C) in terms of hit rate (P <
0.016) and d′ (P < 0.002). There was also a significant improvement in d′ on C compared with P (P < 0.016),
but not in hit rate. There were no significant effects of L-theanine, and no effects of any of the 3 treatments on
RT (Fig. 1).
Download as PowerPoint Slide
Mean hit rate (proportion of targets detected) (upper panel), mean d′ (middle panel), and mean RT (lower
panel) when subjects ingested placebo (P),L-theanine (T), caffeine (C), or these treatments combined (T+C).
Values are means (n = 16). Asterisks indicate difference from P: *P < 0.05, **P < 0.01).
There was a significant effect of treatment on tonic alpha amplitude (P < 0.02). Follow-up t-tests revealed that
alpha was significantly lower for T+C than P (P < 0.02). P did not differ from either T or C (see Fig. 2). Tonic
alpha differed between T+C and T (P < 0.005) but not between T+C and C.
Download as PowerPoint Slide
TSE waveforms at midline electrodes from which the baseline tonic alpha measure was derived (upper panel).
Cue-left and cue-right trials are collapsed. Integrated amplitude over the baseline period for each treatment,
with significant difference from placebo marked with an asterisk (lower panel). The electrodes from which tonic
alpha measures were derived are marked on the 168-channel montage.
The typical alpha cueing effect was readily apparent in both the nonnormalized alpha amplitude waveforms and
normalized pretarget measures (Fig. 3) for each treatment day. A strong attention × hemisphere interaction
(P < 0.0005) was found on the pretarget anticipatory alpha measures as expected, reflecting the typically
observed alpha-mediated cueing effect. In addition, there was a significant 3-way interaction among treatment,
attention, and hemisphere (P < 0.05). When we reduced the alpha cueing effect to a single metric as described
above, the effect was smaller on C than P (P < 0.02) but did not differ for the T or T+C conditions.
Download as PowerPoint Slide
(Upper panel) TSE waveforms over left and right hemispheres, with cue-left (solid) and cue-right (dashed)
superimposed, collapsed across treatment. The overall alpha-mediated spatial cueing effect is highlighted.
Electrode sites for cueing effect measurement are marked on the montage. (Lower panel) Normalized alpha
measures forming the dependent variable in tests for effects of treatment on the alpha cueing effect (P,
placebo; T, L-theanine; C, caffeine; T+C, combined).
Previous SectionNext Section
This study was aimed at extending our knowledge of the effects of compounds contained in tea on the
cognitive function of attention. Testing relatively low-dosage treatments of L-theanine alone (100 mg), caffeine
alone (50 mg), and their combination, we observed an interesting pattern of effects for both behavioral and
electrophysiological measures. Whereas no behavioral effects on hit rate were apparent for either treatment
alone at the low dosages tested here, when both L-theanine and caffeine were ingested together, hit rate
underwent an enhancement of ∼3%. In terms of d′, improvements were seen for both caffeine alone and L-
theanine plus caffeine, the latter having a larger effect size (0.55 vs. 0.42 calculated as Cohen’s d). Given the
absence of any difference in hit rate for caffeine, the d′ effect must result from subjects making fewer false
alarms on caffeine.
Tonic alpha amplitude was not found to decrease significantly on the lower dosage of L-theanine. This indicates
that the effect is dose dependent because a drop was seen in both of our previous studies using a 250-mg
dosage (18, M. Gomez-Ramirez, S. P. Kelly, J. L. Montesi, and J. J. Foxe, unpublished results). There was,
however, a significant decrease in tonic alpha for the combined treatment. That this decrease marks a synergy
between the 2 compounds is suggested by the numerical difference in the alpha decrease caused by L-
theanine with and without caffeine (Fig. 2). That is, it seems unlikely that the greater decrease on the combined
treatment is simply a linear sum of the decreases from each compound alone. Because only single dosages of
each compound were tested, however, a fair degree of caution is appropriate in the interpretation of synergy at
this juncture. This study marks the third finding of decreased alpha as a result of L-theanine ingestion (albeit a
partial cause here) to date, demonstrating the reliability of the effect. At this point, the question of whether it
translates to an improved functional brain state requires serious consideration. Should the finding of a decrease
be received with positive connotations for health and/or mental capabilities?
In the 80 y since the discovery of alpha waves (24), alpha has been measured in almost any experimental
situation and human population, with significant effects abounding, but with a complicated picture and quite
disparate theoretical frameworks arising (25–26). A consistent principle appears to be that stronger alpha infers
positive functioning across individuals (27,28), whereas phasic changes within individuals reflect immediate
stimulus processing and anticipatory enhancement and/or suppression, with a greater retinotopically specific
decrease in alpha being predictive of better detection performance (21). The tonic depression of alpha during
task performance over the day of testing, as observed here, is neither an individual trait nor a phasic event-
related response but a lasting, tonic treatment effect, making it difficult to draw comparisons with such previous
studies. The finding of increased alpha on ingestion of theanine has previously been taken to indicate
increased relaxation without increased drowsiness (13). But this qualification appears tenuous in light of other
observations of treatment-related increased alpha, e.g., during marihuana-induced euphoria (29). Can “good”
and “bad” really be ascribed to increases and decreases in alpha, in whatever direction? Certainly, that this
treatment-related decrease in tonic alpha does not have negative implications is suggested, if not already by
the fact that tea has been keenly, routinely consumed for centuries, by the concomitant facilitation in behavioral
performance found here in terms of both hit rate and d′.
Previous studies have reported a drop in absolute alpha power during resting with eyes open on ingestion of
caffeine at higher dosages, e.g., 200 mg (30) and 400 mg (31). Although alpha amplitude was numerically
lower on 50 mg of caffeine alone here, this did not reach significance (P = 0.18). From this, it is clear that alpha
effects of both L-theanine and caffeine are dose dependent, demonstrating that full characterization of dose-
response functions in future studies is called for.
Evidence of a synergistic relationship between L-theanine and caffeine has been presented in recent
behavioral studies. Parnell et al. (32) reported improved speed and accuracy on an attention-switching task at
60 min and reduced susceptibility to distracting information during a memory task at both 60 and 90 min
following ingestion of a combination of L-theanine and caffeine in the same dosages as used here. Haskell et
al. (33) administered a large battery of cognitive tests before and after consumption of a drink containing either
placebo, 250 mg of L-theanine, 150 mg of caffeine, or their combination. These authors found improvements in
simple and numeric working memory RT, sentence verification accuracy, and alertness ratings for the
combined treatment but not for either treatment alone. Using a similar crossover design but with a greater
dosage of caffeine (250 mg) than L-theanine (200 mg), Rogers et al. (34) found that L-theanine tended to
counteract the caffeine-induced rise in blood pressure but did not interact with caffeine-induced increases in
either alertness or “jitteriness” on state anxiety scales. Although the measures examined in these investigations
and our study are quite distinct in nature, an emerging possibility is that the presence of synergistic effects
closely hinges on dosages. That is, it may be that theanine was not effective in augmenting the caffeine-
induced effects in Rogers et al. (34) because these were present at a saturated level. In the present study,
lower dosages were used, and a significant drop in tonic alpha was observed for L-theanine and caffeine
ingested together but not for either L-theanine or caffeine when ingested alone. However, the absence of a
significant difference between the caffeine-alone and combined treatments calls for caution in making strong
claims of synergy at this point.
Similar to our previous visuospatial attention study (M. Gomez-Ramirez, S. P. Kelly, J. L. Montesi, and J. J.
Foxe, unpublished results), we did not find any change in the alpha differential cueing effect for the L-theanine-
alone treatment. However, it is interesting that the cueing effect was found to be smaller on caffeine alone but
not for the combined treatment. This result was unexpected and thus will bear replication and further
investigation. For now, it appears that within visual space, attentional biasing as indexed by alpha amplitude is
not affected by L-theanine. In contrast, the cued biasing of attention between sensory modalities does appear
to be affected (18). A tentative interpretation of the current pattern of results is thatL-theanine works to enhance
the tonic apportionment of attentional resources to the visual modality and does so to a significant degree when
a large dosage is ingested by itself or in combination with caffeine when a smaller dosage is ingested.
Other articles in this supplement include references (35–44).
Previous SectionNext Section
↵1 Published in a supplement to The Journal of Nutrition. Presented at the conference “Fourth International
Scientific Symposium on Tea and Human Health,” held in Washington, DC at the U.S. Department of
Agriculture on September 18, 2007. The conference was organized by the Tea Council of the U.S.A. and was
cosponsored by the American Cancer Society, the American College of Nutrition, the American Medical
Women’s Association, the American Society for Nutrition, and the Linus Pauling Institute. Its contents are solely
the responsibility of the authors and do not necessarily represent the official views of the Tea Council of the
U.S.A. or the cosponsoring organizations. Supplement coordinators for the supplement publication were
Lenore Arab, University of California, Los Angeles, CA and Jeffrey Blumberg, Tufts University, Boston, MA.
Supplement coordinator disclosure: L. Arab and J. Blumberg received honorarium and travel support from the
Tea Council of the U.S.A. for cochairing the Fourth International Scientific Symposium on Tea and Human
Health and for editorial services provided for this supplement publication; they also serve as members of the
Scientific Advisory Panel of the Tea Council of the U.S.A.
↵2 Author disclosures: S. P. Kelly, M. Gomez-Ramirez, and J. L. Montesi, no conflicts of interest; J. J. Foxe
received an honorarium and travel support from the Tea Council of the U.S.A. for speaking at the Fourth
International Scientific Symposium on Tea and Human Health and for preparing this manuscript for publication.
↵3 Supported by a grant from the Lipton Institute of Tea in association with Unilever Beverages Global
Technology Centre in Colworth House, Sharnbrook, UK.
↵4 Abbreviations used: C, caffeine-alone condition; d′, discriminability index; EEG, electroencephalographic;
EOG, electro-oculographic; P, placebo condition; RT, reaction time; T, theanine-alone condition; T+C,
combined condition; TSE, temporal spectral evolution.
Yang CS, Landau JM. Effects of tea consumption on nutrition and health. J Nutr. 2000;130:2409–12.
Abstract/FREE Full Text
Blumberg J. Introduction to the Proceedings of the Third International Scientific Symposium on Tea and
Human Health: role of flavonoids in the diet. J Nutr. 2003;133:3244S–6S.
FREE Full Text
Quinlan PT, Lane J, Moore KL, Aspen J, Rycroft JA, O’Brien DC. The acute physiological and mood effects of
tea and coffee: the role of caffeine level.Pharmacol Biochem Behav. 2000;66:19–28.
Hindmarch I, Rigney U, Stanley N, Quinlan P, Rycroft J, Lane J. A naturalistic investigation of the effects of
day-long consumption of tea, coffee and water on alertness, sleep onset and sleep
quality. Psychopharmacology (Berl).2000;149:203–16.
Fredholm BB, Battig K, Holmen J, Nehlig A, Zvartau EE. Actions of caffeine in the brain with special reference
to factors that contribute to its widespread use.Pharmacol Rev. 1999;51:83–133.
FREE Full Text
Smith A. Effects of caffeine on human behaviour. Food Chem Toxicol.2002;40:1243–55.
Quinlan P, Lane J, Aspinall L. Effects of hot tea, coffee and water ingestion on physiological responses and
mood: The role of caffeine, water and beverage type.Psychopharmacology (Berl). 1997;134:164–73.
Steptoe A, Gibson EL, Vounonvirta R, Williams ED, Hamer M, Rycroft JA, Erusalimsky JD, Wardle J. The
effects of tea on psychophysiological stress responsivity and post-stress recovery: a randomised double-blind
trial.Psychopharmacology (Berl). 2007;190:81–9.
Kakuda T. Neuroprotective effects of the green tea components L-theanine and catechins. Biol Pharm
Lu K, Gray MA, Oliver C, Liley DT, Harrison BJ, Bartholomeusz CF, Phan KL, Nathan PJ. The acute effects
of L-theanine in comparison with alprazolam on anticipatory anxiety in humans. Hum
Kimura K, Ozeki M, Juneja LR, Ohira H. L-Theanine reduces psychological and physiological stress
responses. Biol Psychol. 2007;74:39–45.
Kobayashi K, Nagata Y, Aloi N, Juneja LR, Kim M, Yamamoto T, Sugimoto S. Effects of L-theanine on the
release of α-brain waves in human volunteers. Nihon Nogeikagaku Kaishi. 1998;72:153–7.
Juneja LR, Chu DC, Okubo T, Nagato Y, Yokogoshi H. L-Theanine—a unique amino acid of green tea and its
relaxation effect in humans. Trends Food Sci Technol. 1999;10:199–204.
Adrian ED, Matthews BHC. The Berger Rhythm: Potential changes in the occipital lobes in
man. Brain. 1934;57:355–85.
FREE Full Text
Foxe JJ, Simpson GV, Ahlfors SP. Parieto-occipital ∼10 Hz activity reflects anticipatory state of visual
attention mechanisms. Neuroreport. 1998;9:3929–33.
Kelly SP, Lalor EC, Reilly RB, Foxe JJ. Increases in alpha oscillatory power reflect an active retinotopic
mechanism for distracter suppression during sustained visuospatial attention. J
Abstract/FREE Full Text
Fu KM, Foxe JJ, Murray MM, Higgins BA, Javitt DC, Schroeder CE. Attention-dependent suppression of
distracter visual input can be cross-modally cued as indexed by anticipatory parieto-occipital alpha-band
oscillations. Brain Res Cogn Brain Res. 2001;12:145–52.
Gomez-Ramirez M, Higgins BA, Rycroft JA, Owen GN, Mahoney J, Shpaner M, Foxe JJ. The deployment of
intersensory selective attention: a high-density electrical mapping study of the effects of theanine. Clin
Worden MS, Foxe JJ, Wang N, Simpson GV. Anticipatory biasing of visuospatial attention indexed by
retinotopically specific alpha-band EEG increases over occipital cortex. J Neurosci. 2000;20:RC63 (1–6).
Kelly SP, Lalor EC, Reilly RB, Foxe JJ. Visual spatial attention tracking using high-density SSVEP data for
independent brain-computer communication. IEEE Trans Neural Syst Rehabil Eng. 2005;13:172–8.
Thut G, Nietzel A, Pascual-Leone A. Alpha-band electroencephalographic activity over occipital cortex
indexes visuospatial attention bias and predicts visual target detection. J Neurosci. 2006;26:9494–502.
Abstract/FREE Full Text
Rihs TA, Michel CM, Thut G. Mechanisms of selective inhibition in visual spatial attention are indexed by
alpha-band EEG synchronization. Eur J Neurosci.2007;25:603–10.
Terashima T, Takido J, Yokogoshi H. Time-dependent changes of amino acids in the serum, liver, brain and
urine of rats administered with L-theanine.Biosci Biotechnol Biochem. 1999;63:615–8.
Berger H. Uber das elecktroenzephalogramm des menschen I. Arch Psychiatr Nervenkr. 1929;87:527–70.
Klimesch W, Sauseng P, Hanslmayr S. EEG alpha oscillations: the inhibition-timing hypothesis. Brain Res
Brain Res Rev. 2007;53:63–88.
Nunez PL, Wingeier BM, Silberstein RB. Spatial-temporal structures of human alpha rhythms: theory,
microcurrent sources, multiscale measurements, and global binding of local networks. Hum Brain
Klimesch W. EEG alpha and theta oscillations reflect cognitive and memory performance: a review and
analysis. Brain Res Brain Res Rev. 1999;29:169–95.
Dockree PM, Kelly SP, Foxe JJ, Reilly RB, Robertson IH. Optimal sustained attention is linked to the spectral
content of background EEG activity: Greater ongoing tonic alpha (∼10 Hz) power supports successful phasic
goal activation.Eur J Neurosci. 2007;25:900–7.
Lukas SE, Mendelson JH, Benedikt R. Electroencephalographic correlates of marihuana-induced
euphoria. Drug Alcohol Depend. 1995;37:131–40.
Siepmann M, Kirch W. Effects of caffeine on topographic quantitative
Deslandes AC, Veiga H, Cagy M, Piedade R, Pompeu F, Ribeiro P. Effects of caffeine on the
electrophysiological, cognitive and motor responses of the central nervous system. Braz J Med Biol
Parnell H, Owen GN, Rycroft LA. Combined effects of L-theanine and caffeine on cognition and
mood. Appetite. 2006;47:273.
Haskell CF, Kennedy DO, Milne AL, Wesnes KA, Scholey AB. The effects of L-theanine, caffeine and their
combination on cognition and mood. Biol Psychol.2008;77:113–22.
Rogers PJ, Smith JE, Heatherley SV, Pleydell-Pearce CW. Time for tea: mood, blood pressure and cognitive
performance effects of caffeine and L-theanine administered alone and together. Psychopharmacology
Arab L, Blumberg JB. Introduction to the Proceedings of the Fourth International Scientific Symposium on Tea
and Human Health. J Nutr.2008;138:1526S–8S.
Henning SM, Choo JJ, Heber D. Nongallated compared with gallated flavan-3-ols in green and black tea are
more bioavailable. J Nutr. 2008;138:1529S–34S.
Auger C, Mullen W, Hara Y, Crozier A. Bioavailability of polyphenon E flavan-3-ols in humans with an
ileostomy. J Nutr. 2008;138:1535S–42S.
Song WO, Chun OK. Tea is the major source of flavan-3-ol and flavonol in the U.S. diet. J
Kuriyama S. The relation between green tea consumption and cardiovascular disease as evidenced by
epidemiological studies. J Nutr. 2008;138:1548S–53S.
Grassi D, Aggio A, Onori L, Croce G, Tiberti S, Ferri C, Ferri L, Desideri G. Tea, flavonoids, and NO-mediated
vascular reactivity. J Nutr. 2008;138:1554S–60S.
Arts ICW. A review of the epidemiological evidence on tea, flavonoids, and lung cancer. J
Hakim IA, Chow HHS, Harris RB. Green tea consumption is associated with decreased DNA damage among
GSTM1 positive smokers regardless of their hOGG1 genotype. J Nutr. 2008;138:1567S–71S.
Mandel SA, Amit T, Kalfon L, Reznichenko L, Youdim MBH. Targeting multiple neurodegenerative diseases
etiologies with multimodal-acting green tea catechins. J Nutr. 2008;138:1578S–83S.
Stote KS, Baer DJ. Tea consumption may improve biomarkers of insulin sensitivity and risk factors for
diabetes. J Nutr. 2008;138:1584S–8S.
MICANS PharmB, PHIL
The National Institute on Aging (NIA) announced the final results of testing from three government labs regarding the
patented antioxidant nordihydroguaiaretic acid (NDGA). All three labs agreed that NDGA extended lifespan by a
resounding 12% in mice (1) (see Figure 1).
When some read this astounding news, they were skeptical. With a note of cynicism and doubt in their voices, they
said this report was probably hyperbole and the Federal government is not to be trusted. Yet these same three
government labs had also conducted lifespan studies with much-hyped anti-aging remedies, resveratrol, curcumin,
green tea, oxaloacetic acid and triglyceride oil (2) and found that these five supplements did not extend lifespan in
During the 1980s, researchers extensively tested NDGA in humans, mice and dogs. Results indicated that NDGA
extended lifespan in a variety of mammals. Even the US Patent and Trademark Office approved these results and
granted a patent. This office granted Dr. Richard Lippman a patent for NDGA, as part of a formula developed to slow
aging and extend human lifespan based on his extensive and convincing NDGA research (3).
Background Study of NDGA
Before Dr. Lippman was awarded a US patent on NDGA, several attorneys voiced skepticism. In firm language, they
stated that every law school student knows that two types of patents are never granted: a patent on a perpetual
motion machine and a patent on a fountain-of-youth remedy. Apparently, Dr. Lippman convinced patent examiners
that his clinical human, mice and dog studies of NDGA were sufficient to warrant a patent with claims to retard human
aging. These studies were also sufficient for the drug licensing authorities of Sweden and Italy to grant Dr. Lippman
marketing rights to sell NDGA under the name ‘Aging Control Formula 228’ (ACF228®).
Interestingly, a prominent American businessman, A. Glenn Braswell, had heard Dr. Lippman’s story, but Braswell
doubted that it was sold at the Vatican pharmacy in Rome, Italy. Consequently, he took his wife on a sudden trip to
Rome—and, to his surprise, found that ACF228 was indeed sold at the Vatican pharmacy with the pope’s blessings!
ACF228® Is Based on Extensive Free Radical Research
Today, we know free radicals are not antiwar activists out on bail. But when Dr. Richard Lippman was doing research
in Sweden many years ago, most people thought the term ‘free radicals’ referred to some kind of hippie politics.
No one then knew about these molecular sharks’ devastating effects on the human body and their role in aging.
Indeed, only twenty-five years ago, free radical chemistry and the toxic effects of free radicals on the human body
were unknown to most of the general public and even to many doctors and medical researchers.
Dr. Lippman first learned about the free radical theory of aging as an undergraduate student. When he began doing
graduate research work in cell biology, he and his colleagues held conferences at Pharmacia-Upjohn and the
University of Uppsala to discuss the exciting findings of Professor Denham Harman, whose experimental work at the
University of Nebraska in the 1950s showed that the life spans of mice could be extended 50%
with special antioxidant supplementation. The press and public responded; “So what?”
However, Sweden is well known in science and engineering for its industrial and technical advances. And Lippman
was the leader of a large medical staff that encouraged progressive research.
Raising Funds for Research
Dr. Lippman wanted to take Harman’s work one-step further and explore the relationship between free radicals and
aging. He turned to Professor Sven Brolin, chair of the University of Uppsala’s Department of Medical Cell Biology
and Professor Gunnar Wettermark, chair of the Royal Institute of Technology’s Department of Physical Chemistry, for
assistance in raising funds for research.
Dr. Lippman was successful, receiving significant medical and chemical grants from the Swedish Research Council to
develop antiaging strategies based on Harman’s groundbreaking discovery of the action of free radicals and the role
of radical scavengers (antioxidants) in destroying or inhibiting them. The Swedish Research Council financed years of
Dr. Lippman’s research at the Royal Institute of Technology in Stockholm and at the University of Uppsala,
Scandinavia’s oldest university, which has an anatomy lecture hall built in the 15th century.
Dr. Lippman’s research into the role that free radicals play in the breakdown of the aging body led him to develop one
of the most potent antioxidant combinations yet known, a unique antioxidant cocktail containing NDGA and called
No Typical Scientist
Dr. Lippman’s normal lab attire—jeans, a khaki shirt, and ostrich leather boots—breaks from the conventional notion
of a white-coated scientist. Before his work in antiaging research that made him famous, he ate junk food. Now, a
typical lunch for him is salmon sashimi and salad or bi bim bop with a bowl of miso soup. He even developed his own
recipe for sugar-free, gluten-free, walnut cinnamon pumpkin muffins.
In speaking, Dr. Lippman presents an easy smile and laugh. He may not look like a typical scientist, but his passion
for longevity research is real. His innovative research into free radical pathology helped put antioxidants on the map,
in the dictionary and in the supermarket.
Once funding was in place, Dr. Lippman gathered a team of five prominent Swedish scientists to help him develop
methods for measuring free radicals and biochemical changes related to aging: Professor Agneta Nilsson, a
nutritionist and alternative medical professional with advanced degrees in nursing and teaching; Dr. Ambjörn Ågren,
MD, PhD, who had received numerous awards in the field of emergency medicine; Professor Mathius Uhlén, PhD, a
civil engineer, molecular biologist, and, later, professor and chair of the Royal Institute of Technology’s Department
Molecular Biology; Evald Koitsalu, an engineer and expert in computer hardware and software; and Dr. Kaj
Alverstrand, a psychologist and consultant to Volvo.
With these tremendous financial and personnel resources, Dr. Lippman was able to achieve great leaps in the field of
antiaging. Indeed, Paul Glenn of the Paul Glenn Foundation for Antiaging Research said that Dr. Lippman’s work
was; “light years ahead of everyone else!”
Dr. Lippman’s research resulted in a patent for NDGA and a product that promotes better health and longevity:
Cellular Model—A Better Choice
The research team’s first task was to find a cellular model rather than an animal model to test for life extension, since
the Harman model of waiting for mice to grow old and die was costly and took years of patience before the results
The Lippman team had access to many different types of living cells in culture, such as human cells of the heart,
brain, liver and central nervous system. In 1980, Lippman invented special probes that would penetrate cell interiors
without harming them. For the first time in the history of cell biology, scientists were able to measure free radicals in
living cells (4). The first probe, carnitinylmaleate luminol (CML), measured superoxide radicals in live human liver
cells. Dr. Lippman and his team went on to test many different combinations of antiaging nutrients.
Developing the formula combinations was a tedious process. Live cells were harvested from biopsies, then separated
and kept metabolically alive in special culture dishes heated to a constant 98°F. The live cells were removed as
needed by the research team and tested for their health by means such as measurements of adenosine triphosphate
(ATP), the power source or ‘gasoline’ of most cell activities.
Then the cell cultures were impregnated with special CML probes and incubated with different mixtures of vitamins
and known antiaging nutrients. Lippman’s team eventually tested 227 different mixtures to find an optimal mixture
with pronounced longevity-promoting characteristics. Mixture number 228 was found to work best, and this and
several other promising mixtures such as 223 were tested further in mice and human volunteers. Now named
ACF228®, the mixture proved successful in extending mice health and life spans, (see Figure 2)
Scientific Community Astounded
The team published its results in more than twenty prominent medical journals. The work astounded the Swedish
scientific community and Lippman was nominated for a Nobel Prize in Medicine in 1996.
Further tests were conducted on hundreds of human volunteers recruited from several Swedish hospitals (3). The
volunteers were tested to establish their normal levels of fatty-acid peroxides, which are free-radical downstream
products, and then were fed varying amounts of ACF228® and other nutrients. Once again, the mixture known as
ACF228® caused normal peroxide levels to decline the fastest. Lippman and his researchers performed other human
tests that indicated ACF228® also had beneficial effects on the skin and sexual function (3).
“We found that the ACF228® formula truly is beneficial,” Dr. Lippman says. “It was especially helpful for middle-aged
and older people; their liver function became like that of teenagers. Often people experience reduced liver function as
they age, especially if they have abused their bodies with heavy
consumption of alcohol and a high sugar diet, causing metabolic syndrome (5). This nutrient mix offers protection
from a multitude of free radicals in the body.”
Ultimately, the ACF228® formula was approved for use by regulatory agencies in both Sweden and Italy and then
patented in the United States.
Indeed, based on these criteria, Dr. Lippman could rest easy. But he isn’t resting. The energetic, youthful-looking
father of three sons and four grandchildren still goes to his lab daily. And what is this Nobel Prize nominee working on
today for the betterment of humankind tomorrow? Dr. Lippman continues his medical research at the behest of
International Antiaging Systems, focusing on improved methods of delivering important vitamins and hormones via
transdermal patches and creams. “Failure to absorb nutrients is a tremendous problem, and 80% of Americans have
problems swallowing pills and capsules,” he says (5).
“The response to ACF228® worldwide has been enormous,” says Dr. Lippman; “that it is indeed gratifying. You know,
we should all be able to live to 120 years and perhaps even beyond. We don’t because of the free radical damage
and declining repair hormones our cellular systems sustain. Our brains shrink, our arteries become hardened and our
liver function declines, mostly because of free radical pathology and damaged endocrine glands. Aging is the ultimate
disease; if ACF228, with its unique blend of natural ingredients can help people to prevent their premature onset,
then I will have lived my life knowing that it has been a success.”
1. Strong, R et. al., Oct. 2008, Aging Cell, 7(5), pp. 641-650.
2. Strong, R et. al, Jan 2013, J Gerontology, 68(1), pp. 6-16.
3. Harman, D., Jul. 1956, J Gerontology, 11(3), pp. 298-300.
4. Lippman, R, 1987, US Patent No. 4,695,590.
5. Lippman, R, 1980, Experimental Gerontology, vol. 20, pp. 46-52.
5. Lippman, R. 2009, Stay 40, Outskirts Press Inc., Boulder, Colorado.
Men are exclusively simple, when it comes to a man’s critical hormones, which build a man up,
and causes regeneration of muscles bones and some extremely crucial brain function. These all
lie in a man’s ability to make youthful blood levels of Testosterone. Always remember it is
testosterone that keeps all muscles in the body at their normal size and ability to function in a
A man produces testosterone when the posterior pituitary’s release of LH which then triggers
the release of HCG which further instructs a man’s testicles to make testosterone. The other
super powerful regenerator of all cells tissues and organs is HGH human growth hormone.
These two hormones kept at youthful blood levels will stop a man from early stage Andropause.
In fact with the correct program of Antioxidants added to the protocol along with the right
energy metabolites and a man never will enter into the debilitating state of advanced
Andropause…. All medical research scientists agree low testosterone is a main cause of male
Andropause….The inability for a man to make youthful blood levels of testosterone. Interesting
that the virtually all male board of American Medical Association (the AMA) does not recognize
the validity of male Andropause….. Ego and false pride changes nothing, when you can no
longer make the 2 critical male hormones at youthful blood levels, the reality is just like female
menopause, men change….and that change leads to old age, decrepitude which is horrific, and
Testosterone is made in great abundance in young men age 13 to 30. Testosterone is the
combination on the molecular level of Cholesterol, the B vitamins and Oxygen.
However as we age past age 35 there is a large drop off in about 70% of male production of
testosterone according to the national Institute for Health (NHI) If this drop off in production of
testosterone is to severe and too quick, the heart being a muscle can quickly get too small and
not be able to be strong enough to meet cardiac blood stroke volume….the amount of blood
needed by the entire body per beat of your heart. This can lead to a very sudden electrical
storm within the heart muscle causing severe arrhythmias’ followed by death according to the
Harvard ten year medical study on the human heart…. And we are not talking about a few men
dying this way per year, the CDC estimates nearly 150,000 men die each year caused by the
above mentioned severe loss of testosterone…
All men can avoid the above described horror by taking swift action and getting a blood test
done to see what your testosterone levels are….forget about the reference range we look at
what is the OPTIMAL range for testosterone at youthful levels I keep mine at 800 to 950. Most
men over 45 will come in with blood levels of roughly 250 to 475, AAI’s team of
scientist/doctors consider that range to be dangerously low.
So if you have symptoms of:
1. Low Energy, sudden fat built up around your waistline over the last 2 years,
2. Poor sleep
3. Inability to concentrate
4. Lower sex drive
5. And irritability….you are looking at Low Testosterone
6. If you have severe loss of testosterone you could lose hair, have muscle tears, and even
bone fractures…even if you are in your late 40’s and 50’s
Once we here at AAI restore you to youthful levels of testosterone you will have these great
1. Decrease in body fat
2. Increased Muscle tone
3. Stronger muscles and bones
4. Improved mood
5. Higher sex drive
6. Improved sleep
7. Enhanced sense of well being
8. A stronger healthier heart
9. Increased stamina for work, play, and exercise
There is another factor in young men today showing up with low testosterone. The new
generation of pesticides sprayed on crops to give a bigger yields by killing bugs, is only one
molecule different then Estrogen the prime female hormone. Here at AAI we have a protocol
for removing the entire pesticide residues in your body.
Men need certain other aspects to be exceedingly healthy:
2. Supplements with Nutraceutical(pharmaceutical-grade nutritional supplements that are
prescription strength, free from all contaminants…and fully absorbed by the body
3. Stop Smoking
4. Eat more fiber from ground organic Flax, prevents intestinal cancers.
5. Minimize stress, with yoga, meditation or structured relaxation exercises 20 min. each
6. Limit Xenoestrogens, substances in your diet that may mimic estrogen.
7. You must get 7 to 8 hours of deep restful, uninterrupted sleep each night
8. Allow us at AAI to place you on the most accomplished hormone optimization protocol
with the correct package of energy supplements and antioxidants.
Another incredible aspect of testosterone is that it can prevent type 2 diabetes and it can help
prevent cancer of the prostate according to the current Harvard Chief of Urology. In 1938 the
then, Chief of Urology at Harvard wrote a research paper with over 22 mistakes in it…one of
which was the statement that testosterone can cause cancer. That mistake in his research is still
quoted unto this very day even though 4 years ago the most accomplished urologist in modern
times at Harvard went into the basement of the medical research building…..found the 1938
research paper, and completely demolished it as mistake riddled especially with regard to
testosterone, saying and publishing that testosterone actually prevents prostate cancer
according to all of his research.
You know… that makes so much common sense….the #1 male hormone being testosterone for
a man, would of course be designed by nature to help all aspects of the male body….which
thankfully it does !
Select item 263167337.
Hormonal determinants of the severity of andropausal and depressive symptoms in middle-aged
and elderly men with prediabetes.
Rabijewski M, Papierska L, Kuczerowski R, Piątkiewicz P.
Clin Interv Aging. 2015 Aug 20;10:1381-91. doi: 10.2147/CIA.S88499. eCollection 2015.
Erectile dysfunction, loss of libido and low sexual frequency increase the risk of cardiovascular
disease in men with low testosterone.
Ho CH, Wu CC, Chen KC, Jaw FS, Yu HJ, Liu SP.
Aging Male. 2016 Jan 11:1-6. [Epub ahead of print]
Select item 264444483.
Hormonal determinants of erectile dysfunction and lower urinary tract symptoms in middle-aged
and elderly men with prediabetes.
Rabijewski M, Papierska L, Kuczerowski R, Piątkiewicz P.
Aging Male. 2015 Dec;18(4):256-64. doi: 10.3109/13685538.2015.1083972. Epub 2015 Oct 7.
Select item 264184684.
Interventions for sexual dysfunction in people with chronic obstructive pulmonary disease
Levack WM, Poot B, Weatherall M, Travers J.
Cochrane Database Syst Rev. 2015 Sep 30;9:CD011442. doi: 10.1002/14651858.CD011442.pub2. Review.
Select item 264133405.
Is there a relationship between the severity of erectile dysfunction and the comorbidity profile
in menwith late onset hypogonadism?
Yassin AA, Nettleship JE, Almehmadi Y, Yassin DJ, El Douaihy Y, Saad F.
Arab J Urol. 2015 Sep;13(3):162-8. doi: 10.1016/j.aju.2015.06.003. Epub 2015 Jul 7.
Free PMC Article
Select item 263704026.
Erectile Dysfunction and Sexual Hormone Levels in Men With Obstructive Sleep Apnea:
Efficacy of Continuous Positive Airway Pressure.
Zhang XB, Lin QC, Zeng HQ, Jiang XT, Chen B, Chen X.
Arch Sex Behav. 2016 Jan;45(1):235-40. doi: 10.1007/s10508-015-0593-2. Epub 2015 Sep 14.
Select item 263167337.
Hormonal determinants of the severity of andropausal and depressive symptoms in middle-aged
and elderly men with prediabetes.
Rabijewski M, Papierska L, Kuczerowski R, Piątkiewicz P.
Clin Interv Aging. 2015 Aug 20;10:1381-91. doi: 10.2147/CIA.S88499. eCollection 2015.
Free PMC Article
Select item 262055468.
Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male
Hypogonadism: A Systematic Analysis.
Seftel AD, Kathrins M, Niederberger C.
Mayo Clin Proc. 2015 Aug;90(8):1104-15. doi: 10.1016/j.mayocp.2015.06.002. Epub 2015 Jul 20. Review.
Select item 260303509.
Erectile dysfunction is a prognostic indicator of comorbidities in men with late onset
Almehmadi Y, Yassin DJ, Yassin AA.
Aging Male. 2015;18(3):186-94. doi: 10.3109/13685538.2015.1046044. Epub 2015 Jun 1.
Select item 2564386610.
Does testosterone supplementation increase PDE5-inhibitor responses in difficult-to-treat
erectile dysfunction patients?
Aversa A, Francomano D, Lenzi A.
Expert Opin Pharmacother. 2015 Apr;16(5):625-8. doi: 10.1517/14656566.2015.1011124. Epub 2015 Feb 3. Review.
PMID2563707Similar articlesSelect item 2556257612Erectile dysfunction is associated
with low total serum testosterone levels and impaired flow-mediated vasodilation in
intermediate risk men according to the Framingham risk score.
Novo S, Iacona R, Bonomo V, Evola V, Corrado E, Di Piazza M, Novo G, Pavone C.
Atherosclerosis. 2015 Feb;238(2):415-9. doi: 10.1016/j.atherosclerosis.2014.12.007. Epub 2014 Dec 9.
Select item 2515802013.
Sjögren’s syndome and extragonadal sex steroid formation: a clue to a better disease control?
Konttinen YT, Stegajev V, Al-Samadi A, Porola P, Hietanen J, Ainola M.
J Steroid Biochem Mol Biol. 2015 Jan;145:237-44. doi: 10.1016/j.jsbmb.2014.08.014. Epub 2014 Aug 23. Review.
Select item 2497555114.
Marked testosterone deficiency-related symptoms may be associated to higher metabolic risk
inmen with low testosterone levels.
García-Cruz E, Leibar-Tamayo A, Romero-Otero J, Asiaín I, Carrión A, Castañeda R, Mateu L,
Luque P, Cardeñosa O, Alcaraz A.
J Sex Med. 2014 Sep;11(9):2292-301. doi: 10.1111/jsm.12615. Epub 2014 Jun 26.
Select item 2493654615.
Successful fertility restoration after allogeneic hematopoietic stem cell transplantation.
Gharwan H, Neary NM, Link M, Hsieh MM, Fitzhugh CD, Sherins RJ, Tisdale JF.
Endocr Pract. 2014 Sep;20(9):e157-61. doi: 10.4158/EP13474.CR.
Free PMC Article
Select item 2492583016.
Prevalence and predictors of concomitant low sexual desire/interest and new-onset erectile
dysfunction – a picture from the everyday clinical practice.
Salonia A, Clementi MC, Ventimiglia E, Colicchia M, Capogrosso P, Castiglione F, Castagna G,
Boeri L, Suardi N, Cantiello F, Damiano R, Montorsi F.
Andrology. 2014 Sep;2(5):702-8. doi: 10.1111/j.2047-2927.2014.00236.x. Epub 2014 Jun 13.
Select item 2490275617.
Testosterone deficiency in patients with erectile dysfunction: when should a higher
cardiovascular risk be considered?
Martínez-Jabaloyas JM; DE-SDT study group.
J Sex Med. 2014 Aug;11(8):2083-91. doi: 10.1111/jsm.12596. Epub 2014 Jun 5.
Select item 2489891918.
Low free testosterone levels predict disease reclassification in men with prostate cancer
undergoing active surveillance.
San Francisco IF, Rojas PA, DeWolf WC, Morgentaler A.
BJU Int. 2014 Aug;114(2):229-35. doi: 10.1111/bju.12682. Epub 2014 May 4.
Select item 2482803219.
Cross-sex hormone therapy in trans persons is safe and effective at short-time follow-up: results
from the European network for the investigation of gender incongruence.
Wierckx K, Van Caenegem E, Schreiner T, Haraldsen I, Fisher A, Toye K, Kaufman JM, T’Sjoen
J Sex Med. 2014 Aug;11(8):1999-2011. doi: 10.1111/jsm.12571. Epub 2014 May 14.
Select item 2479399420.
Hormonal control of spermatogenesis in men: therapeutic aspects in hypogonadotropic
Pitteloud N, Dwyer A.
Ann Endocrinol (Paris). 2014 May;75(2):98-100. doi: 10.1016/j.ando.2014.04.002. Epub 2014 Apr 29. Review.
Human Growth Hormone (HGH)
Larry Sosna N.D. PhD HHP
It seems like everyone has heard about HGH Human Growth Hormone. But what is it? And is it
safe to take? HGH is 191 Amino Acids in an Exact Molecular Structure. It is NOT a Steroid! Given Correctly at the right dosage it is very Safe and Effective…
If I may be so bold as to talk to you just like we were friends and neighbors, I would be very
You see over 35 years ago, I was just about to die from a serious yet common virus
which normally just shows up on the lip as a sore. Well, that is just what happened AND for
some reason it jumped right on up through my nose, through my sinus and attacked my brain
and spinal cord. All I heard from the doctors was get ready young man, because it seems like
you’re time is up. But guess what? I sure got lucky and did not die like they all said I would. It
was really bad though. I spent 3 years in bed and another 2 years in a wheel chair until I got a
little bit better and one of my friends, also a doctor told me I should take HGH Human Growth
Hormone…and that I might get better. Well, that was the first good news anyone gave me in 5
See, think about it like this. Growth Hormone is like a five star general. It’s very smart and just
like a five star general it can and does give orders and commands to everything in our whole
body. Amazing right! So let say you lived in the condo just down the hall on the same floor as
me and you would come and visit me so I would not get so lonely. Because that’s the kind of
friend you are, a real good and decent one.
You noticed each week I was getting a lot better suddenly, and when you came to visit you
wanted to know how in the world did I go from being flat on my back, to moving around and
even walking a bit. Naturally being a friend you had, and maybe still have lots of questions
about how in the world does Growth Hormone make a guy as bad off as me so much better
week after week.
Well, the research doctors explained it very simply by saying that HGH human growth hormone
or just plain GH growth hormone, being the 5 star general, gives orders to the cells in the body
to repair themselves. Growth Hormone can tell any cell at all…say a skin cell, or a nerve cell, or
a heart cell to repair and regenerate itself during deep restful sleep at night. In my situation I
needed lots of repair and regeneration to the nerve cells of my brain and spinal nerves.
It seemed as if I was the only person to survive this type of horrible viral damage to my brain
and spinal nerves they said maybe a few have lived but in a life long coma. So, please listen to
the next part of my journey… because it’s Super Amazing…They tell me that I am going to Italy
to be treated by a woman who won the Nobel Prize in 1985 exactly the time I needed her
because she discovered something very close to growth Hormone which I needed called Nerve
Growth Factor… which when we are in our mother’s womb…Grows all of the billions of Nerves
that become our BRAIN and spinal nerves. I was the first person on this planet to get shots of
nerve growth factor which Dr. Rita Levi Montalcini won the Nobel Prize for and guess what
I made a discovery which made me a little famous within Nerve Scientists and Regenerative
Medicine Experts… few that existed back then. What you ask? I discovered that unless a person
with nerve damage or any other long term illness GETS very youthful blood levels of Growth
Hormone to activate the Nerve Growth Factor! Remember Growth Hormone is the Five Star
General, so I could feel the injections of Nerve Growth Factor not making me better… so I did
some basic arithmetic and decided I needed both Nerve growth Factor and Blood levels of
GROWTH HORMONE which would be normal for the average healthy 14 year old young adult.
In 12 months of doing the treatment this way, I went back to Italy 100% healed. No more wheel
chair. The new program had regenerated all of me and repaired all damaged nerves to my
brain and spine. I got better and in the process of needing to do maintenance each week and
each month throughout the years….I became an acknowledged expert in the field of Growth
Hormone Programs, Regeneration Therapies and all the Tissue Growth Factors of the body
starting with Nerve Growth Factor.
As you age, growth hormone declines dramatically. There are new studies that predict that for
every 18 years after age 18…Growth Hormone Declines by 50%. Thus, according to the University
of North Carolina at Chapel Hill….known for being the best at medical studies based on age and
by large groups of people by their age… called demographic medical research studies… We can
see that if you add 18 years to age 18 in just 3 times a person would go from age 18 to age 54
and we see in just 1 more cycle a person is then age 72 and if we go just 1 more cycle a
person becomes age 90… If we follow this very simple method, we see a virtually perfect
predictive model for all age related disease and illness. In this model, aging is an illness in and of
itself. WHY? Because there is simply not enough growth hormone available at or above age 50
to mobilize or put more simply, to turn on the specific nerve growth factor and all the other
tissue growth factors such as muscle growth factor, or skin growth factor, or liver and kidney
growth factor, BONE GROWTH FACTOR…which decline in tandem with growth hormone to be
able to do youthful levels of cell repair and regeneration and thus all the age related issues
including wrinkled skin seen on the face and age related illnesses debilitate folks in time. It is
horrible to see unnecessary Bone Lose and see little old men and women hunched way
over…unable to straighten back up.
So what can we do? We can give much more youthful blood levels of Growth Hormone by
injection, in fact by a very tiny needle so small most folks hardly if ever even feel it. I certainly
do not feel it and I have been giving myself Growth Hormone shots for 25 years.
What else can we do that very few other places can do? We can give our beloved family of
clients all of the specific Tissue Growth Factors including Nerve Growth Factor. We can get
our clients back to youthful levels of both HUMAN GROWTH HORMONE and ALL TISSUE
GROWTH FACTORS so as to be always consistent in producing cell repair and regeneration for
our client’s entire body and not just a few aspects of the body.
I am now age 63 as of Jan. 27 and I have the physiology of a 30 year old and often feel
younger than that.
Advantages to this protocol:
Better Eyesight vision… especially at Night
Increased Cardiac output (stronger more youthful heart muscle)
Enhanced Sex Drive
Loss of FAT around the waist
Increase in lean body muscle
Much Faster Wound Healing
Hair and Nails Grow Longer Faster (Women Love it)
Improves Daily Energy
Emotional ability to Deal with Stress
Much Improved Sleep
According to Dr. Daniel Rudman, in New England Journal of Medicine….Age Reversal
And so much MORE
Please come to AAI and see me and the outstanding loving and caring staff….Because you will
become part of our family of beloved clients by phone or in person we live a great part of our
lives to reverse you’re age and allow you to feel incredibly youthful again.
Kindly, Larry Sosna N.D. PhD HHP