Issue 11: Nov?Dec by International Antiaging Systems (IAS)

magazine

The Bio-Identical Pathway gHeipK

The use of natural / molecules in antiaging

Eradicate your toxins! Improve your performance by reducing your body burdens Why do we age? Dr. Pierpaoli presents his views Bio-identical hormones The role of bioidentical substances to alleviate depression

interview Dr. Babizhayev discusses his research on the reversal and prevention of cataracts

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Bioidentical is a buzz word in antiaging medicine and before this the more commonly used terminology was orthomolecular, a phrase coined by the Nobel Laurate Linus Pauling, essentially meaning "natural to and in the body." Bioidentical is used to mean "exactly the same molecule as the body recognizes or produces." In this way it is important to differentiate from the word "natural-" which whilst meaning "found in nature" does not necessarily mean that it is recognised, or indeed even welcomed by the body. After all the plant deadly nightshade is natural, but it is poison to the body! In recent years numerous bioidentical chemicals have come to the fore, particularly the hormones DHEA, pregnenolone, testosterone, progesterone and estrogens etc. It's easy to believe that these same products have been used for decades, but as I've said before the "devil is in the detail." For example, over generations women have been receiving estrogens extracted from horse's urine (sic). These equine molecules are similar to human molecules and most definitely have an effect, but they are not the same. There in lies the dilemma- for if you do not use bioidentical hormones in the same way, at the same timing and in the same doses as nature- then doesn't common sense indicate that it is likely that side effects and other

contrary issues are more likely to occur?

The International Antiaging Magazine is proud to be regularly contributed, aided and supported by the following leading professionals:

It's incredible to think that these simple facts have been overlooked by the medical community at large. I believe this is because humans like things to stay the same and avoid change wherever possible.

Mircea Dumitru, M.D., Ph.D. is the Editor of the International Journal of Gerontology and Geriatrics, based in Mexico City. Dr. Dumitru was also the personal assistant to Professor Ana Asian, the famous Bucharest physician who developed Gerovital-H3.

Back in the 1920's it was difficult and expensive to synthesize hormones in a laboratory, until some bright spark realised that estrogens could be extracted easily and cheaply from horse's urine and an industry begun. I feel that things seem to be changing for medicine, there is definitely much more awareness of bioidentical molecules than there was 10-years ago, indeed the public appears to be demanding more "natural" approaches to assist their health. So that's what we bring you in this issue of the Antiaging Magazine; examples of how bioidentical chemicals are being used to aid aging and its diseases. We trust that this education allows you to understand more about maintaining your longterm optimal health.

Phil Micans Editor-in-chief

Declaration The International Antiaging Magazine focuses on the latest nutritional, hormonal and drug therapies in use now that show promise in combating the signs o f aging. These signs include the physical, mental and internal changes

Garry F. Gordon, M.D., DO, M.D. (H) is a world-renowned expert in chelation therapy behind many publications, including The Chelation Answer. He is advisor to the American Board of Chelation Therapy and examiner for all chelation physicians, being responsible for Peer Reviewed Chelation Therapy in Arizona.

Brian Halvorsen, BDS, LDS, RCS, FRSH is principal of a holistic practice and author of;"The Natural Dentist a book relating nutrition to dental health. He is also the founder of the "British Dental Nutrition Society" and founding member of the British branch of "The International Academy of Oral Medicine and Toxicology". John lonescu, Ph.D. is one of Europe's leading dermatologist researchers. His work into the causes and progression of numerous skin diseases has led him to develop a comprehensive diagnostic system to enable genetic identification of metabolic failures, which can then result in individualized detox and anti-aging therapies.

Karen Kaufman MS. CCN is a graduate of Skidmore College and received a Master of Science Degree in nutrition from the University of New Haven in Connecticut. She has worked at U-Mass Memorial Health Center and Medical School and currently maintains a private practice. She is also a member of the board of trustees of the Lupus Foundation of New England.

Michael Kientze, M.D. specializes in gynecology, endocrinology and psychiatry and focuses on holistic preventative medicine. He is the author of several books and as Director of the Klentze-lnstitutes is engaged in numerous modern biotechnologies including stem cells, genomics and proteomics. He is also the secretary general of the European Society of AntiAging Medicine (ESAAM). Marios Kyriazis, M.D., MSc MIBiol has a postgraduate qualification in Gerontology from the King's College, University of London, and a postgraduate qualification in Geriatric medicine granted by the Royal College of Physicians. He has written extensively on longevity and healthy aging and is a founding member of the British Longevity Society.

consisting o f the diseases and disorders that include cancer, arthritis and senile dementia etc. However, the main focus is upon prevention o f such aging diseases and disorders for the "healthy-aging" individual.

Phil Micans, PharmB., MS has degrees in Pharmacology and Food and Vitamin Technology. Since 1986 he has been actively involved in antiaging medicine. Today, Phil is the Editor of the International Antiaging Magazine, Chairman to the International Antiaging Conference and is also the Vice President of International Antiaging Systems.

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John Morgenthaler has been active in the feld of nutritional medicine since 1986. As a founder of Smart Publications, John has co-authored numerous health books, including Smart Drugs, Stop the FDA, Better Sex Through Chemistry, Natural Hormone Replacement for Women, and GHB: The Natural Mood Enhancer.

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Walter Pierpaoli, M.D. is a pioneering research physician who introduced the concept of melatonin supplements to the worid through his best selling book, The Melatonin Miracle. He is Director of the Jean Choay Institute for Biomedical Research, Switzerland. Recently the Walter Pierpaoli Foundation for Life Sciences has been established in Italy.

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Jonathan Wright, M.D. is Medical Director of the Tahoma Clinic in Washington State. Working with natural medicines since 1973, Dr. Wright is a distinguished pioneer in nutrition and vitamin therapy. He is a recognised sex hormone expert and has authored and co-authored numerous ground-breaking publications. Imre Zs.-Nagy, M.D. is Professor of Gerontologyy at the University of Debrecen, Hungary. He is a teacher in experimental gerontology and was a pupil of the science of Fritz Verzar. He has published 275 papers, chapters and books, given 340 scientific lectures. He is founder (1982) and Editor-inChief of the journal Archives of Gerontology and Geriatrics. Listed alphabetically by last name

November 2006

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Dentistry, aging and your health (part II)

Case studies bioidentical hormones Dr. Marios Kyriazis describes how he has used various bioidentical hormones in his practice.

Specifically he describes how he has used them, (along with synergistic nutritional approaches) to bring satisfactory results for his patients. Furthermore, he describes a number of case histories of why his patients came to see him and how his combined beneficial approaches affected their outcomes. What's more, Dr. Kyriazis also makes some comparisons of bioidentical hormones to conventional ones and how they differ.

In this article, Dr. Halvorsen completes his two part feature describing the types of advice he gives to his patients to help them remove heavy metals from their body. You may recall that in part one he described the issues of heavy metals, particularly mercury; its sources (including those outside of dentistry) and why it is essential that we do everything we can to reduce these body burdens from our lives. If you read this article you will discover for yourself one of the most effective detox programs currently available.

Bioidentical mood enhancers (part I)

P 29

Bioidentical substances are not just limited to hormones as some may think. Bioidentical can also recognize the precise substances the body is looking for in the diet. These key nutritional factors and essential aminoacids etc., form vital roles in methylation, an action which aids in the creation of new molecules, as well as assisting all energy, repair and production processes to take place. This first part of a two part article looks at the role of bioidentical substances in alleviating depression and improving that feel good factor, an essential part of enjoying life to the full.

The Russian cataract cure We took an opportunity at the recent London Antiaging Conference to interview Dr. Mark Babizayev. He was an invited speaker lecturing on his research behind cataract formation and what could be done to slow and reverse their progress. His presentation included before and after pictures of reversed cataracts in human eyes, results that had been achieved by eyedrops containing the natural dipeptide nacetylcarnosine. Dr. Babizayev wanted to explain to us that there are differences and what to look out for to ensure long-term efficacy and safety to help maintain vision.

regulars

Dr. Walter Pierpaoli is one the world's great antiaging researchers. After many years spent in the company of mice, Dr. Pierpaoli's experiments have led him to some very specific conclusions about the reasons behind why we age. His central thesis focuses on the cyclicity of life, the rotation of the earth and the wake-sleep rhythms that we all face. He explains these effects on our endocrine (hormone producing) system, particularly upon the pineal, the place where the unique and strange molecule melatonin is produced.

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November 2006 j a m

BIO-IDENTICAL HORMONES

BLOIDENTICA HORMON TREATME Until a few years ago, the use of non-synthetic hormones were confined to only a small number of patients treated in specialist centres. The fact is that nonsynthetic (bio-identical) hormones have been around for many years, but most mainstream physicians are still unaware of their benefits.

by Marios Kyriazis, MD

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November 2006

BIO-IDENTICAL HORMONES

T h e three different types of estrogen Estrogen hormones exist in three main types: estone, estradiol and estriol. Estrone (El), levels are high in post-menopausal women (whereas the other t w o types are low, so the overall effect is a net deficiency of estrogens).

These mainstream physicians treat their patients with synthetic hormones, i.e. hormonal compounds created artificially in the laboratory. These hormones may indeed have a good therapeutic potential, and have helped millions of people across the world. The problem is, because their chemical structure is artificial, they may not have the full range of benefits necessary for optimal health. In addition, these synthetic compounds have a high risk of side effects, precisely because they d o n ' t interact naturally and smoothly with the body. Synthetic hormones are specifically manufactured to be different than the body's own hormones. One reason for this is t h a t synthetic hormones can be patented and used commercially by only one manufacturer who reaps all the profits.

Estrone is considered t o be a weaker variant of estradiol (see below) but its concentration has t o be balanced according t o the levels of the other t w o estrogen types. Estrone is usually released from

fat tissue, and this

is one

reason

why

menopausal women tend t o put weight on: it is a natural reaction of their

body which tries

increase its fat reserves so that t o hold more estrone. This can then be made available t o the

By contrast, hormones t h a t are the exact replicas of our own body's hormones are called 'bio-identical'. These are natural compounds which are adjusted in the laboratory in order to make t h e m look and act exactly as your body's own hormones. In this respect, bioidentical hormones are not necessarily 'natural'. They are taken from natural sources but are then modified in the laboratory to make t h e m resemble the structure of a human hormone. By the way, it is also worth r e m e m b e r i n g t h a t 'natural' does not always

body, at a time when natural production of estrone decreases. Estradiol (E2) is the second and main type of estrogen produced by the ovaries, but becomes deficient during the menopause. Estradiol is usually active against several symptoms of the menopause

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such as night sweats and hot flushes. It works particularly well when administered as patches, creams o r under the tongue.The reason for this is that

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Finally, estriol (E3) is quite a weak type of estrogen.

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These three types of estrogen are commercially available either separately, o r in combinations of two, o r all three. For example, a preparation called Biest速 contains 80% estriol and 20% estradiol.

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Another preparation,Triest速, contains 80% estriol,

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estrogens of 90% estriol, 7% estradiol and 3% estrone. These amounts are considered t o be the closest t o the natural female levels. Formulated by Jonathan W r i g h t MD. To find o u t m o r e call: 1-866-800-4677 o r go online

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November 2006

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imply that a particular compound is safe. That said bio-identical hormones are considered to be a much better alternative to synthetic ones, if used correctly by a specialist practitioner.

the menopause, my usual advice for women with mild symptoms (such as hot flushes, sweating, low mood, tiredness, sexual disinterest, and poor sleep) is to try herbs and plant remedies first. Examples of these are isoflavones, either in tablet form or

The most commonly used bioidentical hormones are estrogens and progesterone. These are obtained mostly from soya beans. Another bio-identical hormone, testosterone, is usually obtained from wild yam. Other bio-identical hormones are DHEA, melatonin, thyroid hormone, androgens, pregnenolone, growth hormone and variations of these.

Menopause Treatment In my practice, I use several of the above compounds, usually in combination with other nutrients and herbal supplements. With regards to

from foodstuffs such as soya and red clover. In addition herbal remedies such as black cohosh, evening primrose oil and dong quai (a Chinese herb) taken in combination, may be helpful in reducing the

symptoms of the menopause. If symptoms are severe and interfere with the patient's everyday life, then it may be time to try hormone replacement. Most women I see are initially prescribed synthetic estrogens by their own physician. But many experience side effects such as weight gain, fluid retention and nausea. Also, the risk of breast or other cancer is relatively increased with the long term use of synthetic hormones. For these reasons, I recommend bio-identical estrogens and progesterone treatment when relevant. These hormones have other long-term benefits like protection against osteoporosis, heart disease and age-related brain problems. A major problem associated with the menopause is depression. This is caused by fluctuating or sustained estrogen deficiency and can thus

"I recommend bio-identical estrogens and progesterone treatment when relevant. These hormones have other long-term benefits like protection against osteoporosis, heart disease and age-related brain problems." Case study 1 Marie is a 42 year old stock market broker from Europe. She suffered from night sweats, depression, low energy and loss of libido for about a year, despite following a healthy lifestyle and taking several menopausal support remedies (black cohosh, dong quai and soya). After evaluation of her estrogen levels it became obvious that she needed hormone replacement. I started her on a combined bio-identical estrogen preparation called Esnatri速 (containing estriol 1.8 mg, estradiol 0.14 mg and estrone 0.06 mg) together with Transmist速 spray which is a newer form of bio-identical progesterone. She noticed an immediate initial improvement within two weeks. She continued to improve over a period of three months, but then she reached a plateau. Her depression and sexual problems disappeared completely, but her night sweats continued in a less severe form. I advised her to double her original daily dose and this ensured that her symptoms improved even further. Continued laboratory testing confirmed that her levels remained within normal range.

Case study 2

Jane, a 50 year old solicitor from London, has been on Esnatri速 (triple estrogen) cream for over two years.

While she experienced positive benefits during this period, she started noticing that her daily dose was not sufficient to completely relieve her menopausal symptoms (particularly tiredness and sexual disinterest). She was not keen of increasing the dose of her triple estrogen cream and she did not experience any added benefits following treatment with soya or red clover. She eventually decided to add cobalt supplements (cobalt is a mineral which helps estrogen work more effectively in the body), in addition to her cream. She was also started on a daily dose of 25 mg DHEA. This worked like magic and, at the time of writing, remains symptom free.

November 2006

iaiTI

BIO-IDENTICAL HORMONES estrogen works in two separate ways:

effectively be treated with bioidentical estrogens (1). Indeed, as you can see from the example in Box 2 (case studies) a typical menopausal patient will suffer from some degree of depression, which usually improves after bio-identical hormonal treatment. Another menopausal problem is memory loss. There is a debate whether any hormonal treatment (synthetic or bio-identical) can benefit memory loss (2) but in my experience most women who take bio-identical estrogen also report that their memory generally improves. Bio-identical hormones are usually given transdermal^, meaning that they are applied directly on the skin, rather than used in tablet form. The benefit of this is that the hormone bypasses the bowel and the liver (where it is neutralised), so it stays active for longer. An equally beneficial way of using bio-identical hormones is by sublingual spray, i.e. spray used under your tongue. This ensures a

good absorption rate, with suitable amount of hormone reaching the tissues through the blood stream, bypassing the liver. On many occasions, menopausal women will require additional bioidentical hormonal support. This can be achieved with hormones like DHEA, pregnenolone and thyroid hormone, depending on the results of individual hormone blood or saliva testing. In addition, it is possible to use bio-identical growth hormone (GH), as opposed to synthetically produced GH. The aim here is to provide more energy and vitality, and boost the actions of estrogens in general. This can also be true of middle aged and older men, who may need extra support for their immune, muscular and skeletal systems. Research performed at the Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy confirms that bio-identical

â&#x20AC;˘(a) It interacts with special cell receptors, such as ER-beta 1 or ERbeta 2. These receptors recognise specific chemical configurations of the estrogen molecule and permit it to act on the cell, helping it to stimulate other enzymes and compounds that result in a reduction of the clinical symptoms of the menopause. â&#x20AC;˘(b) Bio-identical estrogens are able to activate the body's own production of estrogen. In other words, the bioidentical estrogen molecule is not only active on its own right, but can also stimulate the ovaries and other tissues to further produce estrogens, thus optimising the amount of estrogens available (3).

Other Bio-Identical Hormones Progesterone Women produce progesterone from their ovaries and adrenal glands throughout adult life. Although progesterone is generally considered to be a 'female' hormone, it is also produced in the testicles and adrenal glands of men. Progesterone has a range of actions, from modulating the reproductive cycle to protecting the brain and improving mood. Bioidentical progesterone is available in cream, skin patches or spray. The majority of my patients who are using bio-identical estrogens are also using bio-identical progesterone. Testosterone This is the typical 'male' hormone responsible for maintaining energy, strength, libido, bone tissue and muscle mass. As with the case of progesterone, testosterone is also

Dr. Jonathan Wright from the Tahoma Clinic says about bio-identical hormones: " W h i l e no therapy is completely risk free, in approximately 20 years we've observed very, very few adverse effects. Bio-identical hormone therapy is far and away less risky than the use o f horse urine and progestins, which w o m e n should surely avoid (6).

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November 2006

present in women but at lower concentrations. Men over the age of 45-50 who complain of depression, tiredness, loss of sexual desire, impotence, or muscle weakness are increasingly treated with bio-identical testosterone, usually with good results. However, it is important to be under the supervision of a knowledgeable physician, who will perform regular tests aimed at establishing the concentration of the hormone. DHEA The levels of the hormone de-hydroepi-androsterone (DHEA) usually fall with age, resulting in a variety of physical and mental symptoms such as muscle weakness, immune system impairment and memory loss. I normally use DHEA in association with other bio-identical hormones particularly in middle aged women and older men. But this must only be used after initial blood or saliva test are performed, and then the dose is titrated according to clinical and laboratory response. The usual dose is around 25 mg daily, but some women may need half this amount. Treatment with bio-identical hormones is heavily based on laboratory measurements of the patient's own hormonal situation. Once the initial laboratory test has been performed, the patients takes the hormonal therapy prepared specifically for her needs and then the dose is adjusted according to clinical response or/and further laboratory testing. Bio-identical hormonal treatment is not something you should take lightly, and without medical supervision. Also you or your physician should ensure that you are using products from reputable,

established suppliers who may be able to provide background information and support when necessary.

Safety issues Some doctors doubt that bioidentical hormones are safer than synthetic ones. These professionals believe that, in principle, the two types of hormones are bound to have the same risks and side effects. For example, two years ago, researchers from the Columbus Regional Drug Information Center, Columbus, USA, performed a comprehensive review of existing research about both synthetic and bio-identical hormones. They concluded that there was little available research to suggest that any treatment method had an advantage over the other. They did find however those bioidentical hormones may indeed reduce some of the symptoms of the menopause (4). By contrast, others say that the bio-identical molecule is recognised by the body as a 'friendly' molecule and so it does not increase the risk of any side effects. These doctors believe that if bio-identical hormones are used in recommended doses, under medical supervision and not for long periods (say, over 10 or 15 years) then the risk of side effects is reduced. However, do have in mind that bioidentical hormones are not perfect. It may be necessary to adjust the dose, or stop the treatment completely, either because it is not fully effective or because of side effects. But in my experience I have not yet encountered anybody who reported any significant adverse effects after using bio-identical hormones. A relatively common problem is that

" M e n over the age o f 4550 w h o complain o f depression, tiredness, loss o f sexual desire, impotence, or muscle weakness are increasingly treated with bio-identical testosterone"

iwmim the initial recommended dose proves not strong enough and some of the symptoms remain. In those situations, it is necessary to increase the dose or add other products to maximise the effect. Drs. J. McKee and S. Warber from the Family Medicine Department, University of Texas, remarked: "Hormone replacement therapy (HRT) has been the mainstay of therapy for menopausal symptoms (but) women and their physicians are seeking alternatives that do not carry the risks associated with HRT. Exercise has been shown to help some women with hot flashes, as have relaxation techniques and deep

Dr. P. Watt from the Joseph F. Sullivan Center, Charleston, U S A says: " W i t h an unprecedented number o f w o m e n reaching midlife, the impact o f menopause has become a significant public health issue. Recent findings have left women and practitioners questioning traditional hormone replacement therapy and searching for reasonable alternatives. G r o w i n g numbers o f women in this country are choosing to use natural progesterone and estrogen to treat symptoms

menopause (5). November 2006 i a m

BIO-IDENTICAL HORMONES breathing. Dietary changes to incorporate whole foods and soy are thought by some to help with menopausal symptoms, and are recommended because of a positive impact on heart disease and obesity; soy isoflavones may also help with menopausal symptoms. Botanicals such as black cohosh and red clover have been shown in some studies to decrease severity and frequency of hot flashes. We recommend that HRT be prescribed when other measures have failed to adequately control symptoms. Bioidentical hormones are preferred in our practice". (8).

Conclusion Bio-identical hormones are now a modern and well-researched concept. These are generally believed by many health practitioners, to be a much better alternative to the synthetic hormones, and many more physicians are becoming increasingly confident in using them. Compared to just 10 years ago, bioidentical hormonal treatment has come a long way, and it is now considered to be a cutting-edge mainstream therapy.

TWm Bio-identical hormones are now a modern and well-researched These are generally believed by many health practitioners, to be after alternative to the synthetic hormones, and many more oming increasingly confident in using them.

1. Douma SL, Husband C, O'Donnell ME, Barwin BN, Woodend AK. Estrogen-related mood disorders: reproductive life cycle factors.ANS Adv Nurs Sci. 2005;28(4):364-75. 2. Kok HS, Kuh D, Cooper R, van der Schouw YT, Grobbee DE, Wadsworth ME, Richards M. Cognitive function across the life course and the menopausal transition in a British birth cohort. Menopause 2006; 13(1): 19-27. 3. Cappelletti V, Miodini P, Di Fronzo G,

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November 2006

Daidone MG Modulation of estrogen receptor-beta isoforms by phytoestrogens in breast cancer cells. Int J Oncol. 2006;28(5):1185-91. 4. Boothby LA, Doering PL, Kipersztok S. Bioidentical hormone therapy: a review. Menopause. 2004;ll(3):356-67. 5. Watt PJ, Hughes RB, Rettew LB, Adams R. A holistic programmatic approach to natural hormone replacement. Fam Community Health. 2003;26(l):53-63. 6. Wright JV. Bio-identical steroid hormone replacement: selected observations from 23 years of clinical and

Dr. M.L. Stefanick from the Department of Medicine, Stanford University in California comments: "By 2001, approximately 15 million US women were using estrogen therapy, with or without progestins. The 2002 Women's Health Initiative report of greater harm than benefit of combined estrogen plus a progestin resulted in a precipitous decrease in estrogen and progestin use and a serious reevaluation of menopausal hormone therapy, as well as increased interest in alternative approaches to managing menopausal symptoms, including use of bioidentical hormones" (7).

laboratory practice. Ann N Y Acad Sci. 2005;1057:506-24. 7. Stefanick ML. Estrogens and progestins: background and history, trends in use, and guidelines and regimens approved by the US Food and Drug Administration. Am J Med. 2005; 19;118(12 Suppl 2):64-73. 8. McKee J, Warber SL. Integrative therapies for menopause. South Med J. 2005;98(3):319-26.

We welcome this comprehensive article from Dr. Pierpooli. It covers in detail his long standing research into aging, as well as the trials and tribulations he has faced on the way, but fundamentally he describes his thoughts and ideasall borne of his research and liaisons with many other leading researchers to the answer- why do we age? The mythology and the dogmatic views of aging are based on the apparently inescapable fact that death is a "natural" conclusion of life and that a "disease" of known or elusive nature is preceding death. This attitude towards aging and death is an integrant part of all past and present societies, to the extent that all social and economic structures have been, and are now founded on the relatively rapid course of human life, with predictable "variations" depending on a large variety of socioeconomical and environmental factors. In fact all research on aging has been based, not on the understanding of the causes of a disease-free death, but on the possibility to delay aging.

...Walter Pierpaoli, M.D. is a pioneering research physician

Our preliminary and largely incomplete work on the function of the pineal gland insinuated into us the idea that aging is solely a genetically inherited neuroendocrine "program" of certain structures in the brain, which are responsible, from birth to death, for the optimal maintenance of the body in relation to the variables of the environment in which we live. This environment is dominated by two principal elements, namely daily and seasonal changes of light and temperature. Our initial work on the beneficial, night administration of melatonin to aging mice and the pineal-young-to old pineal grafting demonstrate, in their experimental crudeness, that these interventions

"after a certain age, the pineal gland actively promotes aging"

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certainly interpretable and amenable to an external modulation. This is perfectly feasible exactly like the interference with growth and puberty, where Nature offers us many natural models in animals and man. If puberty can be delayed or accelerated, so it is for aging which is, in its typical expression, a progressive decay of central, adaptive neuroendocrine functions resulting in metabolic diseases, immunodepression and cancer.

dramatically affect the health conditions and the life span of the animals. Our present conclusion is that an enormous amount of work is now needed to better understand our findings because the most obvious information is still missing. Man is a "product" of evolution on the planet Earth and the duration of his life is a part of the neuroendocrine program which evolved as an adaptive process to circadian and seasonal variability, to comply with Nature's needs, whose aims are beyond our comprehension, but certainly did not consider our longing for a long and healthy life!

...man is a 'product' of evolution on the planet Earth

the pineal gland, at least in our experimental models with rodents, is at the same time an "aging clock", a "life clock" and a "death clock"

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The more I read about aging, the least I understand its attributes, which are predominantly sociologic rather than biologic. First of all, the conviction that "physiologic senescence" is a kind of inevitable and inescapable fact of life such as growth and puberty, precludes a priori to us a different view of aging. In fact we are psychologically incapacitated to see what is in front of us, namely a genetically inherited and evolutionary rooted program in the brain and in the neuroendocrine system which must be understood before we can interpret and possibly modify it. This inability to develop a new view of aging is an innate mental inertia which escapes any "logic". The worst enemy of life and health is the myth of aging! If we possess a "genetic program" for growth, puberty, procreation and aging, the expression of this program is

I wish to summarize here the leading elements of the conceptual basis and of the experimental models which have demonstrated the aging-postponing effects of administration of melatonin in the nocturnal hours in old mice and rats, and the even more remarkable capacity of a pineal gland from younger donors to prolong the expected life span in presenescent, older mice and rats, when it is transplanted into the recipient's thymus. No details will be described and the reader can refer to the literature (6, 9, 10-13, 16-19, 2325). The neuroendocrine and the systems are interdependent

immune

The interdisciplinary medical research now named "Neuroimmunomodulation" (NIM) emerged in the course of the last 35 years as an inevitable consequence of the demonstration that no separation exists, during ontogeny and embryogenesis and also in adult life, in the function of the brain, the neuroendocrine and the immune systems (3,9,14,15,20-22). As many like to describe it, they "talk to each other". The earlier studies carried out in many experimental and natural models, such as e.g. the neonatally thymectomised mice (14,15,20-22), the hypopituitary dwarf mice (3,14,15), and in particular the genetically thymus-less nude mice (10,15,21,22), all indicated that many hormones control immunity and also that immune cells affect the maturation and function of fundamental neuroendocrine organs, both in the hypothalamus, in the hypophysis and in basic endocrine glands such as the thyroid, the adrenals and the gonads (9,14,15,20-22). In addition, it was observed that many natural or induced diseases or "syndromes" resembling a "precocious aging" in mice were closely linked to a derangement of the bi-directional regulation of the neuroendocrine and of the immune systems in the course of postnatal growth (21,22). It

W H Y D O W E AGE? was thus progressively understood that some basic neuroendocrine alterations in the course of early life or, conversely, some missing cellular or humoral elements of the thymo-lymphatic, immune system during early ontogeny, were responsible for the emergence of physical and functional deficits which closely mimic "senescence" (21,22). This was also confirmed by studies with mice kept at a low caloric diet (8). The "story" of the work is now also summarized in a popular book (18). A number of data from our laboratory addressed us later to the idea that the most crucial aspect of aging could be an aging-related, progressive blunting and finally abrogation of hormonal cyclicity, in particular of day-night circadian periodicity, a basic rhythm which determines the daily fluctuation of all hormones and all physiological functions, immunity, reproduction and sleep included (11-13,16,19,23-25). Our experiments considered the use of melatonin simply because some observations in athymic nude mice and in mice kept under permanent illumination for several generations had shown, in the first instance a reconstitution of immunity (10), and in the second case an impairment of growth, "runting" or "wasting" which closely resembled aging (7). We started in 1985 the experiments which led to the present evidence that in fact the pineal gland and one of its products, melatonin, play a fundamental role in the initiation and in the progression of aging (17,23-25). The pineal gland and "neuro-immunomodulation of aging": an inborn program The three models developed in order to evaluate whether or not the progressive alteration of pineal function in the course of aging is in fact a possible cause of aging, were based on the consideration that if the pineal gland, thanks to its known bidirectional linkage with the entire neuroendocrine system, is the "master gland" of the body, its own progressive "aging" in the course of life may result in the desynchronization of all functions and in particular of those metabolic pathways which maintain the integrity of the neuro-hormonal (endocrine) and of the immune systems. Although we still do not know why the pineal gland itself ages, we have demonstrated that the pineal gland and at least one of its products, namely melatonin, are key elements to start understanding why we age. It is in fact beyond any doubt that a very significant aging postponing effect is achieved in aging mice (and rats) with nocturnal administration of melatonin or young-to-old pineal grafting (11,12,1619,23-25). However, an even more remarkable observation derived from the young-to-old and old-toyoung, pineal cross-transplantation model, which revealed that an acceleration of aging is achieved when a younger animal is grafted with an older pineal gland after removal of its own pineal (6). This striking finding opened to us an unexpected field of investigation. It seems in fact that, after a certain age,

the pineal gland actively promotes aging, as if the inborn program for pubertal maturation and reproductive function would inevitably lead to another step of the maturational events, namely aging. This is even more evident if we consider that the implantation of a young pineal gland into the thymus of older mice does not result into any life prolongation if the recipient is too old (unpublished). It means that once the endogenous pineal has aged, no intervention can prolong life. There exists a critical age in presenescent or definitely senescent mice when both pineal grafting or melatonin administration affect positively the life span. But beyond a certain age, apparently the old mouse owns pineal determines itself the termination of life. This is clearly shown by the acceleration of aging in pinealectomized young mice implanted with an old pineal gland (6) but even if a normal; non-pinealectomized young mouse is implanted with the pineal gland from a very old donor mouse. This extraordinary observation forced us to recognize that there might exist a "death clock" in the pineal gland whose "program" cannot be modified unless the aging pineal is removed in due time and replaced with a younger pineal. We are thus in front of a completely new element for the evaluation of the causes of aging and of the significance of biological death. We can infer that the pineal gland, at least in our experimental models with rodents, is at the same time an "aging clock", a "life clock" and a "death clock", depending on its chronological stage from birth to death. If this is the case, a large number of experiments are needed to assess these crucial temporary steps in mammals, man included. This is even more relevant than the further work aimed at the investigation of the mechanisms, or they should proceed in parallel with those studies. We are generally prone to study the details before understanding how the pineal gland itself, thanks to its links to the entire neuroendocrine network, programs aging. In the next section I will suggest some of the investigations which, in my view, must be carried out in order to decipher some basic aspects of pineal aging on the basis of our earlier and current findings. The rotation theory of aging: what needs to be done now? Here are a few examples. A) Pinealectomy at different ages. If the pineal gland is a chronological scanner of growth, puberty, fertility and finally aging, we must perform extensive experiments of pinealectomy in rodents, in order to evaluate whether the consequences of pinealectomy will differ depending on the age when removal of the gland is performed. It is in fact obvious that the consequences of pinealectomy may be profoundly different or even negligible depending on the age and sex of the animals. We have observed that the thermocoagulation (cauterization) procedure is not adequate to remove the pineal gland. Surgical

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W H Y D O W E AGE? removal of the entire pineal gland with its stalk is mandatory and its complete absence must be confirmed at autopsy and by histological analysis. Other methods have given us contradictory and unclear results. Some preliminary results indicate that removal of the pineal gland in senescent animals may be beneficial. If this is true, it would confirm our concept that the pineal actively promotes aging when the "clock" of life has expired its genetically programmed cycle. A very extensive number of measurements must be carried out in order to evaluate the cause and the sequence of the derangements affecting immunological and neuroendocrine functions. It may be possible that pinealectomy at a young age does not affect the life span simply because compensatory mechanisms, (e.g. other sources of melatonin) adjust the body to the removal of the pineal. This could be completely different later in life or at the time of aging. The blunting or decrease of the night peak of melatonin in the course of aging could be only a signal of pineal aging and the initiation of active death signals. B) Pineal grafting in normal or pinealectomized, young, adult or older recipients. Experiments should be carried out in large groups of male or female mice and rats of different age, in order to evaluate if pineal grafting from a young or from an older donor into their thymus or under their kidney capsule would affect their aging. This approach would help understanding to what extent chronological aging of both the implanted pineal gland and of the grafted normal or pinealectomized young or old recipients, would delay aging and/or prolong their life span. C) Multiple and repeated pineal grafting into aging, intact or pinealectomized animals. Pinealectomized and normal, intact aging mice and rats should be implanted into the thymus with a pineal gland from young donors and transplantation of the young pineal from the young syngeneic donor should be repeated and a new gland grafted again into the thymus or under the kidney capsule of the same recipients about four-five months later. Grafting should be repeated again in case an aging-postponing effect is visible and measurable. This intervention could indicate if the limited duration of the aging-delaying effects of young-to-old pineal grafting depends on a progressive expiration, deterioration or aging of the intrinsic activity of the young, grafted pineal, which must be replaced with a new young pineal in order that the aging-delaying activity can be further prolonged. D) Seasonal variability of melatonin administration. It is of paramount relevance to evaluate the agingpostponing effects of nocturnal administration of melatonin to old mice and rats in relation to the season. This is particularly easy in rodents, whose life span is about two-three years and whose physiology (immunity, hormonal and reproductive functions) is profoundly influenced by the season, in spite of their maintenance under constantly artificial conditions of

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light and temperature. Experiments should be devised where the animals are maintained from birth under natural seasonal variations of light and temperature, in special and protected (low-stress) cages where natural cyclicity of environmental factors is much closer to the conditions of wild animals. We have observed a striking, aging-delaying effect of melatonin when given during four winter months (from November until February) to aging mice (unpublished). Although these effects may not be so relevant in man, their interpretation would be very useful for improving the beneficial activity of nocturnal melatonin administration in man. We just skimmed over the many, almost unlimited work which must be done before we can start to examine closely the mechanism of action of melatonin. It is in my view illusory the pretence to elaborate a "mechanism" until we have done the basic "dull" work which could clarify to us whether or not there is a centralized "aging and/or life clock" in the mammalian pineal gland which is amenable to a pharmacological or physiological modulation. What is aging? If we restrict our analysis to the vertebrates, and in particular to the mammalian species, we can clearly state that, notwithstanding the unforeseeable occurrence of traumatic accidents and the agingaccelerating effects of social distress, of a large number of noxious environmental agents and poisons, and bacterial or viral diseases, aging is by itself a genetically programmed event for all species. In homeotherms, namely in warm-blooded vertebrates, we can predict a lifespan which is closely dependent on their genetic background. The question arises: why has a specific lifespan been established for a species? We are not going to answer this evolutionary question. Our curiosity concerns only the nature and essence of the "programmed clock" for all mammalian species, and the common pattern which characterizes the decay of biological functions which, in all species, is called senescence. In other words, we do not deny the importance, but we forget for a while the evolutionary significance of aging, to confine our attention to the nature of aging in order to delay, arrest or even reverse its course. We have no time for academic exercises! I would here restrict further the discussion to the evaluation of the sheer scientific hard facts concerning the presently known approaches to aging delaying interventions in mammals: Restricted caloric diet. Exogenous administration of melatonin. Exogenous administration of melatonin and TRH. Over the course of many years, we have progressively developed and analyzed the concept

and the experimental data underlying our claim that aging, similarly to somatic growth and fertility, is simply a pineal complexdriven neuroendocrine programme in the brain leading to progressive derangement and de-synchronization of fundamental neuroendocrine, hormonal regulation such as gonadal, thyroid, adrenal functions and others. In other words, the aging orchestra director delivers untimely and chaotic, haphazard messages and the whole orchestra gets deranged! Therefore, there is a common denominator for all the typical somatic and functional deficits of aging and the metabolic decay and dissociation of basic cell activities such as the oxygendependent energy production inside the cells. We think that the "program of aging," similarly to the "program of growth" is basically dependent on the close synchronic and mutually dependent relationship between, first the developing and later the aging neuroendocrine and immune systems, clearly exemplified, in the course of aging, by andropause and menopause. However, in the course of our studies, other elements have appeared of which the fundamental aspects of aging are: the neuroendocrine-immune interactions both during ontogeny of the immune system and during aging. The "talk" between the two systems is based on the molecules which provide to both reproductive functions and to maintenance of an efficient and self-monitoring immune network. In recent years, the discovery of transferrins as key agents for the maintenance of "self" identity has opened a new field for evaluation of the relevance of "self" integrity and for interfering with the program of aging. In fact, one could speculate that aging is by itself the progressive extinction of the capacity to distinguish between "self" and "non-self," namely to maintain self-tolerance. This is typically shown in the emergence of autoimmune diseases and cancer, which is progressive with aging. Here we can find an important link between the cross-talk between the neuroendocrine and the immune system, in which we have identified some key elements which all contribute to an efficient functioning of neuroendocrine and immune functions. Life prolongation via a restricted calorie diet (RCD) Since the first dramatic experimental evidence produced by McKay with rodents

an immense amount of literature is now available which documents that the different methods used, all prove that a diminished calorie intake will significantly delay aging and the many aging related diseases and metabolic dysfunctions. However, it has taken ...the aging orchestra director over sixty years before delivers untimely and the National Institute on chaotic, haphazard Aging started to messages and the whole evaluate whether or not orchestra gets deranged! a RCD applied to non human primates would also retard aging (sic). There is now evidence that this is the case and many results start now to be available from this long-term trial. At the time when the thymus was considered to be, thanks to its basic developmental functions in ontogeny, a kind of "clock" for aging of the immune system, we demonstrated in a rather neglected publication, that in fact the thymus does not deserve such a primary role for initiation and progression of aging. Removal of the thymus at different times after birth in mice, did not significantly affect their life span. However, it became clear that the thymus was deeply involved in the ontogenetic programming and maturation of the entire neuroendocrine system, and those athymic nude mice suffered a kind of precocious senescence, which could be completely prevented by thymic implantation. In fact, thymus grafting resulted into a complete normalization of neuroendocrine functions. On the basis of those findings and the consequent "a diminished observations on the ability of mature calorie intake lymphocytes to restore growth, immunity will and to prolong the life of dwarf mice, the significantly idea evolved that the different hormonal delay aging"

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indicate that RCD produces juvenilityoriented and permanent changes of neuroendocrine regulation which are exactly the opposite outcome of environmentally induced and agingaccelerating dietary obesity. This hypothesis is documented later in the section concerning the anti-aging and obesitycuring effects of TRH.

"We can slow down aging, we can stop aging".

"It was shown that the combination of both melatonin and

TRH significantly enhance the anti-aging effects of melatonin"

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regulation would be responsible for the aging-postponing effects of a RCD. So we suggested that a decreased calorie intake would produce permanent changes in the central, hypothalamic-pituitary hormonal functions, thus maintaining the body at a more juvenile level of endocrine and metabolic regulation. This was particularly clear with regard to the sexual functions of rodents maintained on a RCD. We conducted some experiments to demonstrate that if mice are kept on a RCD for a few weeks after weaning, and then fed again ad libitum, they maintain in spite of this normal feeding a permanently different pattern of hormonal regulation. This data confirmed that the feeding behavior at a time when the neuroendocrine system is still immature, permanently affects maturation and function of the entire neuroendocrine system. This observation is of course very relevant with regard to the onset of obesity in overfed children and the consequent irreversible derangement of their mature neuroendocrine and metabolic system. This environmentally induced obesity which is now so dramatically evident in the affluent Western Society is of course different from mild or severe fattening of "normal" metabolic aging in humans. Also, this environmentally acquired dietary obesity is different from genetically inherited obesity, which afflicts a minor number of families and individuals. The clear answers from many studies all

If endocrine and metabolic dysfunctions are the expression of the programme of aging, and if the pineal gland is a "life and aging clock," consequently we must consider that RCD affects mainly the pineal gland and its functional state. This seems to be the case. In fact, it has been reported that a RCD maintains juvenile levels of melatonin both in rodents and in primates. In a collaborative project with Dr. George Roth and Mark Lane at the National Institute on Aging, Baltimore, USA, in which large groups of primates have been under RCD for several years, data are emerging that RCD very significantly maintains high levels of nocturnal melatonin in both male and female aging monkeys, comparable to the levels in young primates. Our conclusion is that a RCD, by setting the "neuroendocrine clock" at a more juvenile level, protects the pineal gland from aging and thus protects from aging the whole pineal-controlled hormonal, circadian and seasonal periodicity, whose progressive decay leads to aging. However, melatonin is only a signal from the pineal gland of an overall desynchronization of the whole neuroendocrine network leading to a progressive alteration of hormonal cyclicity and, consequently, of surveillance, immune functions. At the basis of this central, pinealdirected aging, lies TRH, a pineal peptide which is responsible for the agingpostponing effects of young-to-old pineal grafting (see below). The anti-aging molecule

melatonin

In spite of the vulgar defamatory campaign and plot against the anti-aging properties of melatonin, it is beyond any doubt that exogenous administration of melatonin to aging rodents postpones their aging and/or prolongs their life. Unfortunately, for mysterious or tactical reasons, those experiments have not been properly replicated while the deceptive behavior against melatonin anti-aging properties continues. Of course, melatonin served to indicate that the pineal gland is

WHY DO W E AGE? deeply involved with the aging process. It suggested the pineal grafting experiments, which disclosed a dramatically new approach to aging postponing strategies. Also these fundamental experiments have not been replicated, although they may be now in course, several years after their initial publication. The pineal grafting experiments also served to indicate that the pineal gland, via its links to the entire neuroendocrine system, controls the "program of aging" and that an aging pineal can accelerate aging even in a normal young animal carrying his own young pineal. These striking observations helped to understand that other key mechanisms and/or molecules must be operative for the anti-aging and the agingaccelerating properties of pineal grafting. Whether or not the anti-aging and the pro-aging capacities of the young and old pineal gland depend on a unique mechanism, it is reasonably clear that pineal components, such as TRH, play a basic role. That melatonin could significantly postpone aging thanks to its anti-oxidative and hydroxyradical-scavenging properties, such as those of vitamin E or glutathione, is not supported either by logic or by any serious in vivo confirmation. It does not seem that the many receptormediated effects of melatonin and the myriad of affinity binding mechanisms can explain its anti-aging properties. The anti-stress, immunoenhancing effects of melatonin show in fact a rather slow "buffer" mechanism. This reinforces our hypothesis that melatonin does not by itself exerts the activities observed but rather protects the pineal gland from aging. Nocturnal melatonin supply will not protect from aging when the age of the animals is too advanced. This has now been proven in another kind of placebocontrolled clinical trial, in which perimenopausal women aged 40 to 60 years, have been treated with melatonin. Already after six months the evidence emerges that younger women are more susceptible than older women to the anti-aging properties of melatonin. This fact strongly supports the view that the beneficial and pineal-protecting effects of melatonin are more pronounced at a time when the pineal is still relatively young. This unexpected finding indicates that melatonin can exert a more pronounced anti-aging effect if the administrations start rather early in life, in so far it protects the pineal from aging. This observation is fundamental for the prophylactic use of melatonin in anti-aging interventions and strengthens the suggestion that the mechanism of action of melatonin cannot be attributed to a "hormonal" effect on specific receptors but rather to a relatively simple night saturation of melatonin content in the pineal gland, and consequent abrogation of night endogenous melatonin production. If this suggestion is true, it must be possible to drastically reduce or abrogate aging-dependent endocrine and metabolic dysfunctions by the administration of exogenous melatonin in the early, post-pubertal life of mammals, man included, as

hinted by the recent striking results in perimenopausal women treated with melatonin for six months. The anti-aging molecule hormone (TRH)

thyrotropin

releasing

A decade ago, in the course of studies on the stressprotective and antiviral effects on melatonin, the possibility was considered that melatonin may exert its effects through the thyroid gland, by enhancing synthesis or secretion of thyroid hormones, which are known to be potent immunoregulatory agents. When we analyzed the effects of TSH and also of TRH, we saw that TRH was perfectly able to mimic and even to increase the effects of melatonin. Further studies showed that the effect of TRH is obviously non-thyroidmediated. Also later studies demonstrated that a discrete lesion of the anterior hypothalamic area in mice, which produce electrolytic damage of the "thyrotropic area" which is known to contain high affinity receptors for TRH, resulted into a rapid involution of the thymus and a sharp decrease of peripheral lymphocytes, which could be restored with TRH treatment. Those early data disclosed the unsuspected role for TRH in the regulation of immunity and also a most remarkable effect of TRH in the restoration of normal levels of lipids in the blood of aging rodents. Those results suggested a key role for the tiny peptide TRH in the anti-aging effects of both melatonin and young-to-old pineal grafting. It was hypothesized that it is in fact the ubiquitous tripeptide TRH, highly concentrated in the pineal gland, which is responsible for the anti-aging effects of circadian administration of melatonin. In fact, the effects of TRH are by far more rapid than those of melatonin, in particular in the restoration of lipid levels. A posteriori, it seemed most obvious that TRH is in fact responsible for the effects of melatonin and pineal grafting. TRH is ubiquitous in nature and its mechanism may be linked to basic cells functions. Without entering into discussions about its mechanism, we studied the long-term effect of a combination of TRH and melatonin in old, aging mice, in order to see if both agents together are able to further delay aging and /or prolong life. It was shown that the combination of both melatonin and TRH significantly enhance the anti-aging effects of melatonin. It was also evident that the effect of the combination was not due to a chronic stimulation of thyroid hormone secretion. As hinted long ago, we can assert that TRH is in fact a main agent in the pineal gland, in the brain and in other cells, which possesses the unsuspected properties of a potent aging-reversing molecule. The metabolic effects of TRH in the normalization of cholesterol and triglycerides are amazing. We dispose now of a new natural and evolutionary ancient molecules for efficient anti-aging interventions. The mechanism for the rapid metabolic effects of TRH is unknown. We think that the reason for its old or acquired anti-aging or rather rejuvenating properties must be sought in the evolutionary history of

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WHY DO WE AGE? TRH a n d in its key role in basic metabolic pathways.

Conclusion Life from chaos: the haphazard patchwork of Nature for survival of the species. The cause of aging is simple: it is a program in the neuroendocrine system a n d it is independent from diseases. We a g e exactly the w a y we grow a n d stop growing. The program is genetic for man, dog, pig, mouse, but w e have the c a p a c i t y to learn how to change, not the genetic program, but the way a n d time of its expression. We c a n slow d o w n aging, we c a n stop aging. We c a n reverse aging a n d restore youth in so far no permanent d a m a g e of brain tissue has occurred. We will learn to see it in the course of the next few years, when the results of our c a p a c i t y of resetting the periodicity clock will be visible. Our way of resetting the central clock now is very primitive a n d empiric, but we shall learn progressively to be more knowledgeable a n d clever, more cautious a n d sophisticated, we shall use the ways of nature a n d the clever natural way: no jogging, no aerobic, no stretching, no fanatic dieting, simply with readjusting the body rhythms to those of the planetary system, namely the sun, the moon, the seasons, the day-night cyclicity. We age simply because we inadvertently lose the adaptation c a p a c i t y to be a n d to remain periodical a n d cyclical; w e de-regulate our neuroendocrine system a n d b e c o m e refractory to the laws of natural cyclicity.

Typical examples are menopause a n d andropause: they are indicators of loss of periodicity: lack of periodicity is death. When w e stop rotating around the sun, w e die. Our body becomes insensitive to the basic impulses a n d messages from the cosmos, w e desynchronize a n d b e c o m e cosmic dust, the way w e were for eons. Immortality is not a myth: it is simply a permanent re-adaptation to sun a n d lunar cyclicity. Now w e know to way to go a n d this aim we could achieve within a few years without the prejudice a n d arrogance of the "saviors." The amazing array of molecules in the living body makes any classification illusory a n d even extravagantly ridiculous. Every day new molecules are "discovered" a n d new functions for them are revealed in the scientific journals. The reductionistic a p p r o a c h to science, medicine a n d health care has created a true Babylonian communication barrier between researchers of different disciplines to the extent that intercommunication is totally barred. Apparently, we know almost everything but yet w e find daily something new. This situation does not accelerate knowledge; it only retards the most obvious interpretation of Nature's laws. For any scientist, it is even impossible to define himself a n d to indicate the direction he is going. Universities a n d schools have missed their aims a n d yet nobody seems to have noticed it! We g o on identifying thousands of new molecules in the body a n d in Nature,

Melatonin

much more than a good nights sleep.,. Melatonin has been shown to improve:

Longevity Sexual function Immunity Menopause Lipid/fat levels Hormone balance Macular degeneration

Walter Pierpaoli, M.D. is a pioneering research physician who introduced the concept of melatonin supplements to the world through his best selling book, The Melatonin Miracle. Dr. Pierpaoli's melatonin is the original, unique formula melatonin. This Swiss pharmaceutical grade Melatonin also contains Zinc and Selenium.

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yet w e cannot anymore link them into a logic framework for function. The fact is that logic a n d integrative knowledge requires nowadays such a huge integration of notions that, I a m sure, even Leonardo d a Vinci would be confused! Yet, in spite of this inextricable a n d hopeless lack of understanding of basic biological processes, we function! The miracle that w e function is in front of us a n d the regenerative c a p a c i t y of Nature is beyond imagination.

which has lost the c a p a c i t y to recognize a n d maintain itself in the hostile environment.

I a m convinced that w e are at the bottom of a hole. We possess an unbelievable amount of notions, yet w e fail to pose them in the right place: there may be not place for notions, only for concepts! The mechanistic a p p r o a c h to problems has only created a huge number of new questions without answering any of the already existing questions. In the medical research field, there is no cure or prevention for cancer a n d aging related degenerative diseases, there is no cure against many viruses. The so-called cure is often palliative a n d the stressful a n d overpopulated world creates new pathologies. We did not move a bit from 1940 as far as the understanding of biology a n d the laws regulating the body in the planetary system in which w e live a n d daily rotate. In this apparently rationalistic system, only the secretive laws of chaos may simplify our search for mental a n d body health a n d the balance of body a n d soul. I would start not from the Cosmos, but simply (and more modestly) from the planetary, solar system.

The progressive deterioration of the senses a n d also the loss of libido represent a passage from perception a n d also "The regenerative enjoyment capacity of Nature is of body's beyond imagination". sensorial capacities (odors, sounds, visual stimuli, sexual arousal a n d temperature changes) to a state of often unconscious a n d relentless d e c a y of self-consciousness towards total a c c e p t a n c e of the "laws of nature" a n d the programmed death. Although this view is evolutionarily understandable, its interpretation allows now to drastically deviate from its dogmatic, non scientific a n d deep-rooted social structure towards a limitless freedom for human kind.

The insensitive, inactive, feeble, fragile, erratic, shivering a n d apathetic "old man" is the living example of "something" between self a n d not-self, where the mind is the psychic counterpart of a degrading body

Why d o I worry about of my own aging? It is only a curiosity of life! It is simply to make more time available to escape the traps, not of Nature, but of mangenerated confusion.

References

and immunological capacity. II. Reconstitution of antibody production in hormonally deficient mice by somatotropic hormone, thyrotropic hormone and thyroxine. Immunology 16: 217-230, 1969. 11. Pierpaoli, W, Besedovsky, H.O. Role of the thymus in programming of neuroendocrine functions. Clin Exp Immunol 20: 323-338, 1975. 12. Pierpaoli, W„ Dall'Ara, A., Pedrinis, E„ Regelson, W. The pineal control of aging: the effects of melatonin and pineal grafting on the survival of older mice. Ann NY Acad Sci 621: 291-313, 1991. 13. Pierpaoli, W., Maestroni, G. Melatonin: a principal neuroimmunoregulatory and anti-stress hormone: its antiaging effects. Immunol Let 16: 355-362, 1987. 14. Pierpaoli, W., Regelson, W., Colman, C. The Melatonin Miracle. New York: Simon & Schuster, 1995. 15. Pierpaoli, W., Regelson, W. The pineal control of aging. The effect of melatonin and pineal grafting on aging mice. Proc Natl Acad Sci 91: 787-791, 1994. 16. Pierpaoli, W„ Sorkin, E. Relationship between thymus and hypophysis. Nature 215: 834-837, 1967. 17. Pierpaoli, W., Sorkin, E. Alterations of adrenal cortex and thyroid in mice with congenital absence of the thymus. Nature New Biology 238: 282-285, 1972. 18. Pierpaoli, W„ Sorkin, E. Hormones, thymus and lymphocyte functions. Experientia 28: 1385-1389, 1972. 19. Pierpaoli, W„ Yi, C.X. The pineal gland and melatonin: the aging clock? A concept and experimental evidence. In: Stress and the Aging Brain. Nappi, G., Martignoni, E., Genazzani, A.R., Petraglia, F., Eds., Aging Series, Vol. 37. New York: Raven Press, pp. 171-175, 1990. 20. Pierpaoli, W„ Yi, C.X., Dall'Ara, A. Aging-postponing effects of circadian melatonin: experimental evidence, significance and possible mechanisms. Int J Neuroscie 51:339-340, 1990. 21. Pierpaoli, W„ Yi, C.X. The involvement of pineal gland and melatonin in immunity and aging. I. Thymus-mediated, immunoreconstituting and antiviral activity of thyrotropin releasing hormone. J Neuroimmunol 27: 99-109, 1990.

1. Edmunds, L.N. Jr. Clocked cell cycles clocks: implications towards chronopharmacology and aging. In: Aging and Biological Rhythms. Samis, H.V., Capobianco, S., Eds., New York: Plenum Publishing Company, pp. 125-184, 1978. 2. Fabris, N., Pierpaoli, W., Sorkin, E. Hormones and the immunological capacity. IV. Restorative effects of developmental hormones or lymphocytes on the immunodeficiency syndrome of the dwarf mice. Clin Exp Immunol 9: 227-240, 1971. 3. Lesnikov, V.A., Pierpaoli, W. Pineal cross-transplantation (old-to-young and vice-versa) as evidence for an endogenous "aging clock". Ann NY Acad Sci 719: 456-460, 1994. 7. Maestroni.G., Pierpaoli, W. Pharmacological control of the hormonally mediated immune response. In: Psychoneuro immunology. Ader, R., Ed., New York: Academic Press, pp. 405-428, 1981. 4. Pierpaoli, W. Changes of the hormonal status in young mice by restricted caloric diet. Relation to lifespan extension. Preliminary results. Experientia 33: 1612-1613,1977. 5. Pierpaoli, W. Integrated phylogenetic and ontogenetic evolution of neuroendocrine and identity-defense, immune functions. In: Psychoneuroimmunology. Ader, R., Ed., New York: Academic Press, pp. 575-606, 1981. 6. Pierpaoli, W. Pineal grafting and melatonin induce immunocompetence in nude (athymic) mice. Int J Neurosci 68: 141-153, 1992. 7. Pierpaoli, W. The pineal gland: a circadian or seasonal aging clock? Aging 3: 99-101, 1991. 8. Pierpaoli, W. The pineal aging clock. Evidence, models and an approach to agingdelaying strategies. In: Aging, Immunity and Infection. Powers, D.D., Morley, J.E., Coe, R.M., Eds., New York: Springer, pp. 166-175, 1994. 9. Pierpaoli, W. The pineal gland as ontogenetic scanner of reproduction, immunity and aging. Ann NY Acad Sci 741: 46-49, 1994. 10. Pierpaoli, W., Baroni, C., Fabris, N., Sorkin, E. Hormones

November 2006 i a m

letters Q : . I've had a measurement confirming that there is 53 micrograms/ liter of mercury in my blood. Since then I've taken intravenous therapies and I'm currently waiting on a hair analysis result. I'd like to know is it safe to also take "Beyond Chelation Improved" (BCI) to assist in a complete detox? By the way, the condition was caused from 6 oz. tuna every day for 18 months! A: Indeed it can be used in unison. BCI is a complete daily nutritional therapy containing vitamins, oils, minerals and chelation. The chelation part is actually made up of Dr. Gordon's Essential Daily Defense (EDD) which contains the "metal" removing part of the equation with ingredients such as allicin from garlic, EDTA from vinegar and malic acid from apples etc. Considering your position it may be worth taking extra EDD which can be purchased seperately, (note there are 3 capsules in each sachet of BCI). On top of that we could suggest vitamin C, particularly as Beyond C which also contains MSM, betaine, ribose and bioperine, the upshot of which is improved uptake of nutrients, lowered inflammation and reduced cardiovascular biomarkers such as homocysteine. According to Thomas E. Levy, M.D. book; Vitamin C, infectious diseases and toxins, high doses of C has many chelating properties. It is also worth noting that DMSA can also be taken orally, in Dr. Gordon's product Heavy Detox it is contained along with efficacious amounts of selenium. As you may know, selenium binds to mercury making it inactive. Dr. Gordon recommends 1 capsule of Heavy Detox for each 50 lbs. bodyweight for persons with a known mercury condition, this can be cycled 1-month on, 1-month off. Finally, there is evidence that some mercury gets reabsorbed in the gut whilst traveling through under a detox program. To try and avoid this, a high fiber diet is recommended, this helps to flush out the undesired toxins. Once again, to complete his comprehensive

iam

November 2006

Tuga is one of the best known causes of mercury contamination

detox range, Dr. Gordon has developed a product called Beyond Fiber. This powder can be easily added to cereals/ food etc. I think your message is clear about the problems of heavy metal contamination in foods today. Although Tuna is one of the best known causes of mercury contamination- your experience has made it clear how easily this can be obtained. In fact please take a look at Dr. Brian Halvorsen's article in this issue of the November 2006 Antiaging Magazine to see what he recommends for his patients to help excrete their mercury. Q: I've been reading your articles about carnosine. I was especially intrigued regarding a low or high daily dose. One thing that stood out to me was that: "some of the benefits of carnosine are derived AFTER carnosine has been degraded by carnisinases to produce histidine and alanine. Therefore some of the benefits may be due to these amino acids, particularly histidine." What I like to ask, if the above is true, doesn't then make sense to take, beside carnosine, also the amino acids, histidine and alanine too? I didn't see anything mentioned about that. What is your opinion of this? A: We asked carnosine expert Marios Kyriazis, M.D. who stated; "it's a good point, but I think it may be overkill. Carnosine has other benefits in its own right, and its actions are not dependant on alanine etc. alone. Plus it is also probably also cheaper to use carnosine than alanine and histidine supplements separately." I think I would add that it is best (unless one wants to be the guinea pig) to stick to the clinical based evidence when

choosing a supplement or a regime, in this respect carnosine is better understood than the other two. At the end of the day, in antiaging medicine if one reads and absorbs everything it can become almost impossible to know when to stop! Therefore start simply to quantify the evidence basis for your own needs first. Q: I was placed on Prozac in 1980 and was on it for approx. 8 years. Then my doctor suggested I change to paroxetine. I did so and have been fine, but I have put on a tremendous amount of weight even though I eat very healthily and live a healthy life. My question is- have these drugs caused this situation? A: The answer is a likely yes. Both of these drugs are SSRIs, that is to say "selective serotonin reuptake inhibitors" and a well known and accepted side-effect for them is weight gain, (and perversely also anorexia). Other popular side-effects are anxiety, restlessness, nervousness, insomnia, drowsiness, fatigue; headache, tremor, dizziness, seizures, hallucinations, confusion, agitation, mania and sexual dysfunction. However there are other methods of improving serotonin levels to overcome depression (which is the most common reason why SSRIs are prescribed). Two of the best are the precursors of serotonin themselves, those being the one found through diet- the essential aminoacid Ltryptophan and its more potent cousin 5HTP (5-hydroxy-tryptophan). Studies with 5HTP have found it to be as effective as Prozac but with fewer side effects. However any switch of antidepression drugs needs to be done carefully and slowly and best performed under the care of a physician. Please note that there is an article in this Antiaging Magazine (November 2006) regarding natural methods such as the tryptophans to help alleviate depression. Send your questions, letters & comments to: editor@antiaging-magazine.com

c a l e n d a r of e v e n t s

in the n e w s Funding for antiaging medicine research Peter A. Thiel, cofounder and former CEO of the online payments system PayPal, has announced his pledge of $3.5 Million to support scientific research into the alleviation and eventual reversal of the debilities caused by aging, to be conducted under the auspices of the Methuselah Foundation, a charity cofounded and Chaired by Dr. Aubrey de Grey. Mr. Thiel commented "Rapid advances in biological science foretell of a treasure trove of discoveries this century, including dramatically improved health and longevity for all. I'm backing Dr. de Grey, because I believe that his revolutionary approach to aging research will accelerate this process, allowing many people alive today to enjoy radically longer and healthier lives for themselves and their loved ones. Mr. Thiel will donate a total of $500,000 over the next three years to fund pilot research projects intended to deliver early stage validation of the "SENS" approach to combating the debilitation caused by aging. Additionally, from now until the end of 2009, Mr. Thiel promises to match every Dollar donated to the Methuselah Foundation for SENS research with a 50 cent matching contribution from himself, up to a maximum of $3 Million of matching funds. Dr. de Grey said "I am extremely grateful to Peter for his bold and visionary initiative. I have been working with leading biologists and biochemists around the world in identifying promising research projects, and with this generous donation we will go to work straightaway." Low testosterone and death link A new study, published in the Aug. 14/28 issue of the Archives of Internal Medicine indicates that persons over 40 with a low testosterone count have an increased risk of death. Seattle based researchers have stated that older men with relatively low testosterone had an 88% increased risk of death compared with men with normal testosterone levels. "It's a really an unusual finding and we need to work the exact mechanism out," said Dr. Molly M. Shores of the Veterans Administration Puget Sound Health Care System and University of Washington. Seattle. It's well known that as men age, their testosterone levels gradually decline, by the age of 30 on average testosterone levels decrease by about 1.5% per year. Low testosterone levels can result in decreased muscle mass and bone density, insulin resistance and low sex drive, as well as less energy, more irritability and feelings of depression. The study in question examined 858 men over the age of 40 to see if low testosterone levels were

associated with an increased risk of death. Among them, 19% had low testosterone levels, 28% had equivocal testosterone levels (e.g. their tests revealed an equal number of low and normal levels) and 53% had normal levels. Dr. Shores concluded; "low testosterone in older men was associated with an increased risk for mortality." During the 4 years of follow-up, 20.1% of men with normal testosterone levels died compared with 24.6% of men with equivocal levels and 34.9% of men with low testosterone levels. As testosterone levels can be affected by illness, surgery and other medical problems the researchers excluded men who had died within the first year of follow-up, however those with low testosterone levels were still 68% more likely to die compare to men with normal levels of the hormone. The research team stressed that "it's not yet clear whether low testosterone helps to cause illness and death, for example it may be that men who are ill have a low testosterone level, and then they have a higher death rate. It has been noted that this study confirmed earlier data from the Massachusetts Male Aging Study, although the threshold Dr. Shores used to define low testosterone were lower indicating that people with really low testosterone levels are at risk. A new smart pill can be stomached An electronic capsule that has been described as a mini-laboratory has won federal approval. The new technology gives physicians another way to diagnose a patient's stomach condition. The wireless device, about the size of a large vitamin pill, travels down the gastrointestinal tract collecting data and transmitting it to a receiver worn on the patient's belt or around the neck. Once the capsule is excreted from the body, the patient brings the receiver back to the doctor, who downloads the data to a computer. By the way, there's no need to retrieve the capsule itself - it's disposable! On its journey the smart-pill measures pH, pressure in the stomach, intestines and bowel. The approval of the $500 device is designed to diagnose a condition known as gastroparesis, which causes the stomach to empty slowly. Until recently the method for diagnosing gastroparesis was a "nuclear medicine test" where a patient eats a meal accompanied with a small amount of radioactive material. The patient has to stay at the hospital for several hours while a scanner monitors the amount of radioactivity in the stomach. The new device is expected to bring significant improvement and comfort of use to those suffering the symptoms of gastroparesis- which affects up to 50% of diabetics, as well as those suffering from Parkinson's disease, not forgetting the runof-the-mill conditions of nausea, vomiting, abdominal pain and bloating.

NOVEMBER 2006 Date: November 3-5, 2006 Name: International Congress of Antiaging Medicine Place: Madrid, Spain Contact: www.semal.ono.com Date: November 10-12, 2006 Name: Clinical Applications for Age Management Medicine Place: Las Vegas, Nevada, USA Contact: www.aainaoptions.org DECEMBER 2006 Date: December 7-10, 2006 Name: International Anti-Aging Congress Place: Las Vegas, Nevada, USA Contact: www.worldhealth.net MARCH 2007 Date: March 1-2, 2007 Name: Conference on Antiaging Place: Bangkok, Thailand Contact: www.bumrunarad.com/antiaainq/20Q7 Date: March 22-24, 2007 Name: Antiaging World Congress Place: Monte Carlo, Monaco Contact: www.world2007.org APRIL 2007 Date: April 29-1 May, 2007 Name: Society of Antiaging & Aesthetic Medicine Place: Kuala Lumpur, Malaysia Contact: www.saamm.com MAY 2007 Date: May 4-6, 2007 Name: Antiaging Medicine Congress Place: Bucharest, Romania Contact: www.theantiaging.ro

If you organize or attend an event that you think will be of interest to our readers please contact: editor@antiaging-magazine.com

Correction In the September 2006 issue of the Antiaging Magazine we published an article by David Jay Brown about Dr. Hoffman and hydergine. He wishes to make it clear that Dr. Hoffman's use of hydergine is 'periodic' and not 'regular' as stated in the article and that we hope this correction makes that clear.

November 2006 i a m

DENTISTRY AND YOUR HEALTH We welcome part two of Dr. Brian Halvorsen's article in which he continues on from his first submission- in that he described the issues of dentistry, aging and health, specifically the problems associated with the accumulation of heavy metals such as mercury. Here in part two he offers his constructive advice on how to remove those metals, advice based on many years of helping his own patients

overcome

their personal health issues.

iam

DENTISTRY & YOUR HEALTH n westernised societies our life expectancy has been extending for the last 50 years, however if we examine the quality of life as we grow older, it becomes apparent that all is not well. For example, 50% of the North American population over the age of 80 have clinical Alzheimer's, and this figure does not include all the other neurodegenerative diseases such as dementias and Parkinson's etc!

brain. This is because large areas of the brain have little blood supply. The circulatory system is the main physiological mechanism for the body to carry heavy metals to sites where they can be excreted. This is a similar situation with lead. Lead besides the brain, tends to accumulate in the bones of the body. Again these sites have a poor blood supply compared to organs such as heart, liver and kidneys.

A hundred years ago the elderly were revered for their accumulative wisdom, especially in a community or tribal environment, not so today. For the older we get, the greater the body burden becomes. This combined with an aging (declining) immune system means we are less able to cope. I sincerely believe that a major causative factor in this age degeneration is the accumulation of toxic metals in our bodies, particularly mercury and lead which are both powerful neurotoxins.

Sadly, mercury is extremely toxic to nerve tissues and my personal opinion is that this situation is grossly unfair! Mercury can be easily absorbed and assimilated into our bodies relatively The advice given by Dr. Brian Halvorsen to his

Within the dental profession the 'amalgam' debate has raged for more than 150 years. However, there can be no arguments that in an increasingly toxic environment, any increase of mercury from amalgam fillings (50% mercury, 50% silver) will add to the body burden. A body burden can be defined as how much the immune system has to work to maintain health at a cellular level (e.g. homeostasis). Many toxins that we ingest remain in the body for a comparatively short time. However this is not the case with heavy metals such as mercury (Hg) and lead (Pb) because they are retained for lengthy periodssometimes indefinitely. For example, mercury has a 20 year half life in the

1000 times

pathways in the body.

patients to improve their diet and reduce their

8. Consume members of the onion and garlic

intake of toxins/ heavy metals:

family regularly. These vegetables are rich in sulfur compounds to increase liver sulfation,

'Modern man' has been exposed to these toxic elements for many years, [Ed.- evidence exists that we have 1000 times the lead levels of our preindustrialized relatives]. So it is not surprising that we are seeing so many negative health effects on our ageing population.

"we have

easily but alas it is difficult to remove. My analogy is it is like having your best white suit splashed with dirty grease, it's easy to do, but not easy to clean.

1. Eat organically grown produce wherever

which is used to back up the glutathione detox

possible in order to avoid consuming mercury

system.

through fungicides and pesticides.

9. Eat lots of selenium rich foods (seeds and

2. Avoid eating large amounts of tuna and

nuts- particularly walnuts) because selenium is

swordfish which may contain unacceptable

required to bind to mercury and inactivate it.

levels of mercury. Instead stick mainly to deep-

The 7 tips above can help regulate phase I

water fish such as cod, haddock and sole. For

and II enzyme activity levels, responsible for

omega-3 fatty acids consume the smaller oily

mercury removal and to help support healthy

fish such as sardines and mackerel.

liver enzyme activity.

The 2 tips above are designed to help limit the

10. Reduce the intake of hydrogenated fats

daily intake of mercury.

that are often found in margarine, cookies and

3. Eat at least 5 portions of organic fresh fruit

sweet snacks. Instead eat plenty of

and vegetables each day. Choose a variety of

polyunsaturated fats found in borage seeds,

colors for their antioxidant pigments and

olive oil, hemp seeds, sunflower seeds, grape

carotenoids.

seeds, sesame seeds and avocados. Also cut

4. Consume plenty of vegetables from the

down the consumption of saturated fats, e.g.

Brassica family, e.g. Brussel sprouts, broccoli,

those found in sausages, burgers and tinned

cauliflower and cabbages etc. These foods

meats. Plus avoid "trans" fats- those found in

increase the activity of the phase-ll

crisps, chips and food fried in polyunsaturated

glutathione-S-transferase system which helps

fats.

detoxify heavy metals.

11. Avoid artificial flavors, colors and

5. Eat plenty of foods containing soluble fiber,

preservatives.

particularly pectin, which binds to toxins and

12. Avoid caffeine- it is a potent diuretic.

draws them from the body. Good fiber foods

13. Stop smoking and avoid smoky

include natural grains, brown rice, oatmeal,

atmospheres.

millet, corn and flax seeds; note that these

14. Avoid polluted regions.

also contain good levels of B vitamins which

15. Drink plenty of hydrating fluids, e.g. spring,

act as cofactors for liver enzyme systems.

mineral or filtered water and herbal teas.

6. Do not consume refined sugars which drive

These last 6 tips will reduce the total load on

mercury into the cell rather than allowing it to

the liver, paramount to allow maximum

exit the body through its natural route- the

detoxification of mercury to take place.

bowel. Eat fresh fruit instead.

NB: Modifications can be made to this program

7. Drink less beer, spirits and white wine. Red

to suit the individual- to achieve the maximum

wines contain potent antioxidants so the

benefit most people will benefit from the advice

occasional glass is acceptable but remember

of a well-trained nutritional therapist.

that alcohol inhibits the natural detoxification

the lead levels

of our pre-industrialized

relatives" November 2006

j a m

DENTISTRY & YOUR HEALTH Just washing with water will not suffice, so specialised cleaning agents are required which will chelate the grease and free it from the cloth. I will discuss later both nutritional and supplemental ways to chelate mercury and lead from the body, so it's not all bad news!

If you have amalgam fillings the level of mercury in your body will increase with age, but there are other sources of mercury including fish and seafood which will increase your body burdens; (please see my first article for more details). There are numerous studies that identify symptoms of micro-mercurism varying widely from mental confusion, short term memory loss, 'brain fog,' tiredness, anxiety, depression, hormonal imbalances, speech disorders, insomnia and neuro degenerative diseases such as Alzheimer's. All of these are associated with age related declining mental health, so as mercury is a very powerful neurotoxin, could this be why aging is associated with declining mental capabilities? For sure, pathological links between mercury and Alzheimer's have been clearly demonstrated by scientists such as Boyd-Hayley.

Prevention Terrible dementias such as Alzheimer's and Parkinson's put a massive strain not only on the sufferer and their family and friends, but also on general society. Yet much of this could be preventable and I would like to outline some measures that will help minimise the likelihood of the

"If you have amalgam 26

i a m

November 2006

onset of these diseases. Modern society creates 4 basic stresses. These can be broadly summarised: • Environmental: In the form of ingested, airborne and waterborne pollution. • Physical: A lack of exercise reduces the excretion of toxins via sweat etc. • Psychological: Negative stress has been shown to chemically damage brain cells and make the individual more liable to diseases such as Alzheimer's. • Nutritional: Poor nutrition inhibits repair mechanisms, but there are substances we can ingest that help to eradicate toxins. All of the above are interrelated. Trying to do any in isolation is not advantageous, e.g. trying to think positively when your brain is poisoned is stressful. Having a sporty lifestyle but eatingjunk food or living in an industrialised city, or near freeways etc., all exacerbate the factors leading to increase of toxins in the body.

Nutrition The corner stone to any health issues is sound nutrition- we all know the saying- 'you are what you eat.' But what many people don't know is that by targeting food which have antioxidant and chelating properties that heavy metals can be proactively reduced from the body. You can see from figure 1 the dietary, nutrient and general health recommendations that I offer to my patients and my colleagues (i.e. fellow dentists who after all are in a uniquely toxic situation due to their occupation).

I believe the toxicity of mercury and lead makes heavy metals the body's number 1 enemy. When combined, lead makes mercury a hundred times more toxic. So we cannot only be

fillings the level of mercury

interested in mercury detoxification but other heavy metals such as lead too. So whilst the correct organic diet/ lifestyle goes a long way to help prevent long-term disease processes from occurring, I sincerely believe that a proactive detoxification and chelation supplement program is essential for anyone who has had amalgam fillings. Where do we draw the line? It's not that long ago when gasoline was leaded so most of us have already been exposed to that. Who has had inoculations, vaccines or eye drops containing the preservative Thimerosal? (This is essentially mercury). As our nest becomes more and more poisoned there are many of the opinion that a detox and chelation program is for everyone (sic). As for myself, I have taken supplements for over 20 years in order to try to protect myself from excess mercury exposure, (an occupational hazard as a dentist). I believe my well researched methods have been partially successful, but now having met Dr. Garry Gordon I have followed his advice and tried his specially formulated Beyond Chelation Improved® (BCI) system with startling results. Furthermore, many of my 'mercury patients' have also noticed big improvements in their mental and physical well being on this program. The BCI program is essentially a 3 part system. 1. The Beyond Chelation Improved® has all the synergistic supplements included to make it idiot proof, i.e. each daily sachet contains 9 pills, each of which provide a comprehensive and balanced nutrition which is needed to biochemically compliment the active chelators, i.e. EDTA and allicin- which are also included. 2. Beyond C ® is a pure L-ascorbic acid which is also combined with antiinflammatory MSM, energy enhancing ribose and homocysteine lowering

in your body will increase

with

age"

betaine. Beyond C carries the chelated toxins to the sites for elimination from the body- which are primarily through the kidneys and the lower bowel. 3. Beyond Fiber速. As heavy metals are mainly excreted through the large intestine, if the lower bowel is sluggish or does not contain enough fiber to absorb the diffusion through the gut wall- then the toxins and toxic metals can be reabsorbed and re-circulated elsewhere in the body. Beyond Fiber consists of rice husk bran, EDTA and Jerusalem artichoke. From my personal experience Beyond Fiber has been instrumental in improving all aspects of my personal health, both mentally and physically. We have added it to this program to ensure that all the mercury unbound from cells is then excreted out through the gut. A useful 4th edition is the Beyond Clean速 EDTA bath salts. These help to remove heavy metals from the skin and are particularly useful after intense exercise or a sauna to trap and remove the toxins from the skin. Plus this is the easiest approach, after all everyone enjoys a soak in the tub and the salts are simply added to the water beforehand.

For my patients who are in a higher risk category I also use a potent selenium and DMSA product called Heavy Detox速 which is swallowed before bedtime on an empty stomach and EZ Defense速 gums which are simply chewed after each meal before being thrown away. Fundamentally what I can report is that every one of my colleagues and my patients who have used the simple 3-part BCI system has reported an improvement in their physical and mental energy, as well as a significant loss of weight.

To give you some examples, here are some of the comments I have received: "Within days of being on the program I feel better, with more energy- and my lethargy has gone. What's in this stuff? I can't believe these improvements could happen in such a short time." AC "This is the best combination of supplements I've ever used, after several weeks my friends and family

have been commenting on my healthy appearance and indeed performance!" APM Even my accountant is on my program. He phoned me a week later and I thought he wanted to discuss my books, but instead he wanted to thank me for getting him onto the program because he too was "feeling like a million Dollars" (his words).

Conclusion I want to say that I so believe in the chelation program that I am committed to writing my new book; the heavy metal diet. I wouldn't have considered this challenging feat a few years ago, but since adopting this program-l too have far more energy and focus, not only to perform in my practice but also for enjoying my life.

[Ed.- Thank you Dr. Halvorsen for your enthusiasm and your commitment to spreading the word about body burdens. Let us remember that no matter what we are "into" whether that is exercise, nutrition, bioidentical hormones or even stem cell therapy, everything works better after detoxification and chelation].

heavy metal* The accumulation of heavy metals in the human body poses a significant health risk, leading to a wide array of symptoms, including anemia, learning difficulties, reduced intelligence, behavioral and cognitive changes, tremor, gingivitis, hypertension, irritability, cancer, depression, memory loss, fatigue, headaches, gout, chronic renal failure, male infertility, possibly multiple sclerosis and even Alzheimer's disease. Heavy Detox is specially formulated for those who require detoxification of heavy metals, particularly mercury. Heavy Detox supports the body's natural detoxification procedures for the elimination of toxic heavy metals. Specially formulated by renowned expert on Chelation, Dr. Garry F. Gordon M.D., DO, M.D. (H)

To order Heavy Detox from IAS call:

-866-800-4677

For more information: w w w . a n t i a g i n g - s y s t e m s . c o m November 2006 a m

steps to

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detoxification A p r o g r a m designed by world r e n o w n e d chelation e x p e r t G a r r y G o r d o n , M . D . Studies tell us just how much we have introduced all kinds o f toxic chemicals

Beyond Chelation Improved (BCI) does everything a familiar multi-vitamin does, but it also includes unique ingredients that offer protection against toxic elements including heavy metals like lead and mercury. These toxic elements are found in everyday life and are impossible to avoid. A unique compound in BCI bonds to these elements and prevents them for being absorbed into the body.

into the environment. Through industrialization, agribusiness and the burning o f fossil fuels our land, air and water has been contaminated to one degree or

another. To accumulate these toxins into our own bodies does not mean we have to be handling dangerous chemicals in the sense

For the first time, virtually everyone can take enough vitamin C (3-5 grams 1-3 times daily) to really experience the benefits. Beyond C has L-ascorbic acid (the most active part of vitamin C ) along with GMS ribose technology that enables fast uptake of vitamin C, avoiding the stomach problems previously associated with large doses of vitamin C.

that a scientist, an engineer, a mechanic, a farmer or even a gardener may. In the every day course o f our lives, simply breathing, eating, drinking and cleaning ourselves enables us to accumulate toxins.

200g Powder $39.99

Chelation is the process o f removing heavy metals from the bloodstream, which if allowed to accumulate can place "burdens" upon the body. For example, chelation

People are aware that "high fiber" diets are a good thing, but most are unaware of the differences in the quality of fibers. Beyond Fiber is a product that contains the best form of fiber, the rice bran husk (the bit that is normally thrown away!). Not only does it taste good when taken in a "power drink" but can also be added to morning cereals, or sprinkled over deserts or fruits etc.

therapy is the only way to treat lead poisoning. But lead is not the only metal cleansed from the body through chelation, others include mercury, cadmium, aluminium, arsenic, fluoride and chlorine.

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This first part of a two part article looks at the role of bioidentical substances in alleviating depression and improving that feel good factor, an essential part of enjoying life

BIO-IDENTICAL MOOD ENHANCERS

to the full.

epression affects millions worldwide, regardless of nationality, race, socioeconomic status, age or gender. Insufficient activity of key neurotransmitters, such as the monoamines serotonin, norepinephrine, and dopamine, is the leading theory of depression held by neurobiologists today.

Yet despite the wide array of pharmaceuticals currently available â&#x20AC;&#x201D; monoamine oxidase inhibitors (MAOI's), tricyclic antidepressants (TCA's), and selective serotonin reuptake inhibitors (SSRI's) â&#x20AC;&#x201D; depression remains difficult to treat. In fact, conventional antidepressants are BY LESLIE FARER November 2006

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BIO-IDENTICAL MOOD ENHANCERS ineffective in an estimated 10% to 30% of depression cases. (1) These socalled "xenobiotic" (foreign to the body) compounds also carry the risk of troublesome and potentially dangerous side effects and delayed onset of action. The good news is that a sizable body of clinical data has established the efficacy of certain physiologically occurring compounds in treating this disease. Conventional drugs manipulate brain chemistry in a roundabout way because instead of boosting neurotransmitter synthesis, they increase synaptic serotonin levels by hindering usual enzymatic degradation (MAOI's), or preventing customary reuptake following nerve transmission (SSRI's and TCA's). "Bio-identical" agents (exact replicates of substances occurring naturally in the body), on the other hand, directly correct chemical deficiencies by providing raw materials that spark key metabolic processes leading to neurotransmitter production, thus restoring proper brain chemistry. In addition, they display a quicker onset of action, higher safety level (lower toxicity) and fewer side effects. This article describes a few of these neurotherapeutic substances clinically indicated to combat depression.

donor in a broad array of cellular reactions involving proteins, phospholipids, DNA and neurotransmitter synthesis (3,4) and as a precursor molecule to both the aminopropylation (4,5) and transulfuration (4,6) pathways, leading to the production of polyamines and glutathione. In order for these pathways to function efficiently, an adequate physiological supply of SAMe is essential; illness and aging may deplete the body's stores of this crucial biochemical. Dozens of clinical studies performed since the 1970's have demonstrated SAMe's mood-lifting properties. When compared to conventional antidepressants, SAMe has been shown to be as effective as TCA's (such as imipramine and chlorimipramine), with fewer side effects and faster onset of action. (4,7,8) When taken in combination with TCA's, SAMe was shown to potentiate and hasten their effect. (8,9) Perhaps it is the stimulatory effect of SAMe on monoamine neurotransmitters, or its role in phospholipid methylation, or both, which underlies its antidepressant effect. In addition to relieving symptoms in otherwise healthy people, SAMe has also been shown to ease depression in those suffering from AIDS (10) and Parkinson's (11). Besides depression, SAMe's therapeutic value in treating Alzheimer's (4), liver disease (4,12), and osteoarthritis (4,13) has been demonstrated.

S-Adenosylmethionine (SAMe) SAMe is a metabolite present in all living cells, formed from the amino acid methionine and adenosine triphosphate (ATP), the major energy source necessary for cellular reactions. Since its discovery in 1952, SAMe's biochemical actions and therapeutic potential have been extensively investigated. This amino acid derivative plays an integral role in three important mechanisms â&#x20AC;&#x201D; as a methyl (CH3)

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November 2006

SAMe is an unstable compound; however, stable salts (such as the butanedisulfonate and toluenesulfonate forms) have been developed. SAMe is available as enteric-coated tablets (and as an injectable), the dosage for tablets is typically 400 - 1600 mg daily in divided doses, on an empty stomach; if gastrointestinal problems occur, increase dosage slowly and take with food. Include a daily B-complex supplement or multi-vitamin with folic acid, B6 and B12

L-Tryptophan (LT) LT is an amino acid precursor to serotonin, one of the monoamine neurotransmitters implicated in depression. Data suggest that lack of this essential amino acid in the diet can potentially cause or exacerbate depression in some people. (14, 15) LT is present in foods in relatively small quantities and must compete with five other amino acids for entry into the brain via a transport molecule (i.e., a biochemical "vehicle" that "carries" amino acids across the blood-brain barrier). Getting adequate LT into the grey matter is a challenge, considering that as little as one percent of dietary LT may actually enter the brain (16). Although it is possible to increase LT levels through a carefully devised nutritional strategy, it would be extremely difficult, or nearly impossible, to reach or maintain adequate therapeutic levels (gram quantities) through diet alone. Supplemental LT has been used since the 1970's for its purported antidepressive effects. However, it's difficult to draw firm conclusions on its efficacy due to the mixed outcomes punctuating the medical literature, which perhaps stem from poor or inconsistent study design. Even so, LT may be of therapeutic value for those with mild or moderate depression. (17) It seems that more unequivocal results have been obtained when LT is used as an adjunct to conventional antidepressants. In one such study, when 20 mg of fluoxetine (Prozac?) was administered with two grams of LT to a group of depressive patients over eight weeks, positive effects were seen sooner compared to a group that took fluoxetine and placebo. (Interestingly, slow wave sleep, which was decreased in the fluoxetine /placebo group, was maintained in the fluoxetine/LT patients.) (18) In 1989, a single batch of tainted LT caused an epidemic of eosinophiliamyalgia syndrome (EMS), which resulted in its removal from the U.S. market by the FDA. The EMS-induced fatalities and illnesses were attributed

BIO-IDENTICAL MOOD ENHANCERS not to any toxicity on the part of the supplement itself, but to contamination during the manufacture of this particular batch. Dosage: One to three grams with a carbohydrate snack or on an empty stomach; do not consume with protein foods.

5-Hydroxytyptophan (5-HTP) 5-HTP, a metabolite of LT, is the immediate precursor to serotonin.* This amino acid analog is commercially produced by extraction from the seeds of the African plant, Griffonia simplicifolia. Unlike LT, 5-HTP easily crosses the blood-brain barrier — it does not require the presence of a transport molecule or compete with other amino acids to enter the brain. As much as 70% is absorbed into the bloodstream from an oral dose. (16) Like LT, 5-HTP acts primarily by increasing levels of serotonin within the central nervous system, with the added benefit of augmenting levels of other neurochemicals too, including melatonin, dopamine, norepinephrine and beta-endorphin. (16) Antidepressant effects and positive clinical outcomes appear to be more consistent with 5-HTP than with LT. (19, 20)

metabolized to other products, including the sleep and circadian rhythm hormone, melatonin; a naturally occurring compound we discussed earlier, SAMe, is required for this conversion, underscoring its diverse physiological roles.] When compared to conventional antidepressants, 5-HTP was shown to be as effective as the SSRI fluvoxamine (21) and the TCA imipramine, (22) with fewer side effects and a faster onset of action (within one to two weeks vs. four or more weeks) (23, 24). And, like LT, 5HTP has been successfully used in conjunction with MAOI's and TCA's to enhance their therapeutic effect. (25, 26) Medical experts differ over whether 5HTP should be taken with a drug known as a decarboxylase inhibitor (such as carbidopa) to prevent the metabolism of 5-HTP to serotonin in the bloodstream before it reaches its target destination, the brain. Proponents of co-administration of carbidopa (27) argue that if the conversion takes place in the blood, negligible serotonin will enter the brain, due to the neurotransmitter's limited access across the blood-brain barrier; others question the need for such an agent, pointing to successful clinical outcomes using 5-HTP alone (16).

One author undertook the task of attempting to statistically analyze the results of 15 heterogeneous studies evaluating the efficacy of 5-HTP in depression, performed from 1972 to 1991. These investigations varied as far as type of depression, study design (open trial or double-blind vs. placebo), dosage, and duration of treatment, and thus were not suitable for a standard meta-analysis. Nonetheless, the researcher tallied the results and took a grand total: out of 511 patients, 285 showed improvement with 5-HTP (56%); when only the double-blind studies (8 out of the 15 studies) were considered, 94 out of 161 patients demonstrated amelioration of symptoms (58%). (16) [*An interesting biochemical aside — serotonin can be subsequently

Dosage: 50 to 100 mg, two times per day. Some people may experience mild nausea, so start with 50-mg doses, take with meals and increase slowly as needed.

Nicotinamide Adenine Dinucleotide (NADH) NADH is the coenzyme, or active, form of Vitamin B3 (known as niacin, niacinamide, or nicotinic acid). It is a large and structurally complex molecule that exists both in its oxidized (NAD+) and reduced or electron-rich (NADH) form. NAD+/NADH plays a critical role in each of the three major cellular energy pathways that generate ATP, the highenergy intermediate necessary to all

cellular processes (which we discussed earlier in relation to SAMe). NADH is also involved in neurotransmitter production. The name Birkmayer has long been associated with NADH — it belongs to two physicians of the Birkmayer Institute in Vienna, Austria who have performed groundbreaking research into the metabolic role of the B3 coenzyme in disease states, and have developed a patented stabilized form. In several fascinating studies performed by the Birkmayers, successful outcomes were obtained by treating Parkinson's patients with NADH. It was found that the patients' reduction of symptoms was related to the coenzyme's influence on endogenous dopamine production. (28, 29) (The synthesis of dopamine is impaired with the disease.) In the course of this research, the Birkmeyers observed another interesting phenomenon — the Parkinson's patients' improvement was also accompanied by a decline in disease-related depressive symptoms. This finding spurred the researchers to conduct further studies on NADH's effect on various types of depression. In 205 patients treated with the coenzyme (administered orally, intramuscularly, or intravenously), 93% demonstrated improvement, establishing NADH as a neurotherapeutic agent with the "potential capacity to stimulate the biosynthesis of L-Dopa (a precursor to dopamine), dopamine and norepinephrine." (30) NADH has also been shown to be effective in treating such diverse

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BIO-IDENTICAL MOOD ENHANCERS I I I I ]n|

conditions as Alzheimer's (31), chronic fatigue syndrome (32), and even jet lag (33). The double role of NADH in the energy production pathways and neuro-transmitter synthesis make it an intriguing subject of medical research and a novel and versatile therapeutic agent. Dosage: A typical dose is 5-10 mg taken in the morning on an empty stomach (at least 30 minutes before breakfast); some people may find a larger dose of 10-20 mg more effective.

Conclusion These effective, relatively non-toxic and naturally occurring raw materials for neurotransmitter production are an ideal first course of action in treating many (except the most severe) cases of depression. When necessary, they may also be used as adjuncts to conventional pharmaceuticals to enhance their action and speed their onset. In the next article, we'll cover a few more of these fascinating substances, including acetyl-l-carnitine, DHEA, omega-3 fatty acids and others. Caution: If you are currently taking an antidepressant, do not stop or alter treatment without a physician's supervision. The natural antidepressants described here may

interact with conventional drugs. If you are not taking medications and would like to try one of these supplements, it would be prudent to inform your physician, and then take one at a time for a course of four to eight weeks to determine its effect. Please note that S-adenosylmethionine, L-tryptophan and 5-hydroxtryptophan (and St. John's Wort, which is a natural, but not bioidentical agent, and is not covered here) act on the serotinergic system, and if taken together could, potentially, dangerously elevate levels of the neurotransmitter (a condition known as serotonin syndrome, characterized by hypertension, flushing, dizziness, disorientation, and muscle twitching (2)). Dosages listed should be used as guidelines only; consult your health-care professional if you wish to exceed these recommendations.

I N C R E A S E S E R O T O N I N LEVELS L-Tryptophan

L-Tryptophan's uses include alleviating depression, alcohol withdrawal and aiding weight loss. This product is the German pharmaceutical grade LTryptophan

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This supplement brand 5HTP has many similar uses compared to L-Tryptophan, such as the assistance of sleep and alleviation of age related mental depression.

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For more information, or to place an order for L-Tryptophan or 5-HTP go to:

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November 2006

References

major depressive disorder: antidepressant and hypnotic effects. J Psychiatry Neurosci. 2000 Sep;25(4):337-46.

1. Perret G, Hilleret H, Widmer JR, Bovier P. L-tryptophan plasma levels in treatment resistant depressive states. Rev Med Suisse Romande. 2000 Feb;120(2):153-7. 2. Turner EH, Loftis JM, Blackwell AD. Serotonin a la carte: supplementation with the serotonin precursor 5hydroxytryptophan. Pharmacol Ther. 2006 Mar;109(3):325-38.

19. van Praag HM. Management of depression with serotonin precursors. Biol Psychiatry. 1981; 16: 291-310.

3. Lee ES, Charlton CG. l-Methyl-4-phenyl-pyridinium increases S-adenosyl-L-methionine dependent phospholipid methylation. Pharmacol Biochem Behav. 2001 Sep;70(l):105-14. 4. Bottiglieri T. S-Adenosyl-L-methionine (SAMe): from the bench to the bedside —molecular basis of a pleiotrophic molecule. Am J Clin Nutr. 2002 Nov;76(5):1151S-7S. 5. Genedani S, Saltini S, Benelli A, Filaferro M, Bertolini A. Influence of SAMe on the modifications of brain polyamine levels in an animal model of depression. Neuroreport. 2001 Dec 21;12(18):3939-42. 6. Gigliozzi A, Romeo R, Fraioli F, et al. Effect of S-adenosyl-Lmethionine and dilinoleoylphosphatidylcholine on liver lipid composition and ethanol hepatotoxicity in isolated perfused rat liver. Dig Dis Sci. 1998 0ct;43(10):2211-22. 7. Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol Scand Suppl. 1994;154:7-14. 8. Mischoulon D, Fava M. Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr. 2002 Nov;76(5):1158S-61S. 9. Berlanga C, Ortega-Soto HA, Ontiveros M, Senties H. Efficacy of S-adenosyl-L-methionine in speeding the onset of action of imipramine. Psychiatry Res. 1992 Dec;44(3):257-62. 10. Shippy RA, Mendez D, Jones K, Cergnul I, Karpiak SE. Sadenosylmethionine (SAM-e) for the treatment of depression in people living with HIV/AIDS. BMC Psychiatry. 2004 Nov 11;4:38. 11. Di Rocco A, Rogers JD, Brown R, Werner P, Bottiglieri T. SAdenosyl-Methionine improves depression in patients with Parkinson's disease in an open-label clinical trial. Mov Disord. 2000 Nov;15(6):1225-9. 12. Lieber CS. S-adenosyl-L-methionine: its role in the treatment of liver disorders. Am J Clin Nutr. 2002 Nov;76(5):1183S-7S. 13. Hardy ML, Coulter I, Morton SC, et al. S-adenosyl-Lmethionine for treatment of depression, osteoarthritis, and liver disease. Evid Rep Technol Assess (Summ). 2003 Aug;(64):l-3. 14. Moreno FA, Gelenberg AJ, Heninger GR, et al. Tryptophan depletion and depressive vulnerability. Biol Psychiatry. 1999 Aug 15;46(4):498-505. 15. Booij L, van der Does AJ, Haffmans PM, Spinhoven P, McNally RJ. Acute tryptophan depletion as a model of depressive relapse: behavioral specificity and ethical considerations. Br J Psychiatry. 2005 Aug; 187:148-54. 16. Birdsall TC. 5-Hydroxytryptophan: a clinically-effective serotonin precursor. Altern Med Rev. 1998 Aug;3(4):271-80. 17. Meyers S. Use of neurotransmitter precursors for treatment of depression. Altern Med Rev. 2000 Feb;5(l):64-71. 18. Levitan RD, Shen JH, Jindal R, Driver HS, Kennedy SH, Shapiro CM. Preliminary randomized double-blind placebocontrolled trial of tryptophan combined with fluoxetine to treat

20. Byerley WF, Judd LL, Reimherr FW, Grosser Bl. 5Hydroxytryptophan: a review of its antidepressant efficacy and adverse effects. J Clin Psychopharmacol.1987; 7: 127-37. 21. Poldinger W, Calanchini B, Schwarz W. A functionaldimensional approach to depression: serotonin deficiency as a target syndrome in a comparison of 5-hydroxytryptophan and fluvoxamine. Psychopathology. 1991;24(2):53-81. 22. Angst J, Woggon B, Schoepf J. The treatment of depression with L-5-hydroxytryptophan versus imipramine. Results of two open and one double-blind study. Arch Psychiatr Nervenkr. 1977 Oct ll;224(2):175-86. 23. Takahashi S, Kondo H, Kato N. Effect of 1-5hydroxytryptophan on brain monoamine metabolism and evaluation of its clinical effect in depressed patients. J Psychiatr Res. 1975 Nov; 12(3): 177-87. 24. Nakajima T, Kudo Y, Kaneko Z. Clinical evaluation of 5hydroxy-L-tryptophan as an antidepressant drug. Folia Psychiatr Neurol Jpn. 1978;32(2):223-30. 25. Alino JJ, Gutierrez JL, Iglesias ML. 5-Hydroxytryptophan (5HTP) and a MAOI (nialamide) in the treatment of depressions: a double-blind controlled study. Int Pharmacopsychiatry. 1976; 11: 8 - 1 5 . 26. Nardini M, De Stefano R, lannuccelli M, Borghesi R, Battistini N. Treatment of depression with L-5hydroxytryptophan combined with chlorimipramine, a doubleblind study. Int J Clin Pharmacol Res. 1983; 3: 2 3 9 - 5 0 . 27. Mendlewicz J, Youdim MB. Antidepressant potentiation of 5-hydroxytryptophan by L-deprenil in affective illness. J Affect Disord. 1980 Jun;2(2):137-46. 28. Birkmayer JG, Vrecko C, Vole D, Birkmayer W. Nicotinamide adenine dinucleotide (NADH) — a new therapeutic approach to Parkinson's disease. Comparison of oral and parenteral application. Acta Neurol Scand Suppl. 1993;146:32-5. 29. Birkmayer GJ, Birkmayer W. Stimulation of endogenous Ldopa biosynthesis — a new principle for the therapy of Parkinson's disease. The clinical effect of nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotidephosphate (NADPH). Acta Neurol Scand Suppl. 1989;126:183-7. 30. Birkmayer GJ, Birkmayer W. The coenzyme nicotinamide adenine dinucleotide (NADH) as biological anti-depressive agent. New Trends Clin Neuropharmacol. 1992; 6: 75-86. 31. Demarin V, Podobnik SS, Storga-Tomic D, Kay G. Treatment of Alzheimer's disease with stabilized oral nicotinamide adenine dinucleotide: a randomized, double-blind study. Drugs Exp Clin Res. 2004;30(l):27-33. 32. Forsyth LM, Preuss HG, MacDowell AL, Chiazze L Jr, Birkmayer GD, Bellanti JA. Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome. Ann Allergy Asthma Immunol. 1999 Feb;82(2): 185-91. 33. Birkmayer GD, Kay GG, Vurre E. Stabilized NADH (ENADA) improves jet lag-induced cognitive performance deficit. Wien Med Wochenschr. 2002;152(17-18):450-4.02 Nov;76(5):1151S-7S.

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Pharmacology

Focus an

Synonyms: Cl-871; Pyrrolidone Acetamide; UCB-6215 Chemical Name: 2-(2-Oxopyrrolidin-lyl)acetamide. Molecular Formula: C6H10N202. Molecular Weight: 142.2 CAS Registry: 7491-74-9

Description Piracetam remains the world's best selling Nootropic (means "acting on the mind") drug. Initial interest was sparked for its use in the treatment of senile dementias. Despite having some effect in this area, piracetam is noted for its role in the treatment of age-related mental decline. Piracetam is able to prevent and correct memory losses due to old age, it sharpens the memory, relieves boredom and improves clarity and attention to detail. Its entry into the market place caused a great stir as an effective Nootropic with few side effects and no toxicity. Recently great interest has been aroused in Piracetam and its ability to help treat Down's syndrome. In trials, piracetam has increased the life span on animals. However, the most usual comment with Piracetam use is; "I feel as though the fog has lifted."

Action

Our focus section takes a direct look at some of the most important supplements available today. It is designed to be a straight-to-detail section for those who want to get to the core of its uses immediately. This issue focuses on ANTIAGING

Piracetam and is taken from the IAS Antiaging Medicine Reference book. It contains over 100 similar descriptions of different key nutrients, hormones and medicines being used in antiaging medicine today. Just $69.95 including P&P get your copy today by calling 1-866-800-4677 iaifl

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Piracetam is a derivative of the amino acid GABA, however, there is no evidence to suggest that Piracetam operates through the GABA pathway. Piracetam acts upon acetylcholine helping to restore this vital neurotransmitter's levels. It is also a muscarinic agonist, increasing muscarinic receptor sensitivity. These receptor sites are also known to deteriorate with age and Piracetam helps to support them, thus acting in an anti-aging manner. Piracetam is also known to increase the density of AMPA neuronal receptors. Piracetam acts upon the nerve cells to bring about important metabolic modifications, which in turn results in greater receptiveness and increased use of chemical energy by these cells. Piracetam is also known to improve communication across the corpus callosum, which has been tested in dichotic listening examinations.

Indications i. ii. iii. iv.

Age-related mental decline. Environmental toxins. Down's syndrome. Altitude sickness.

Life e x t e n s i o n .

vi.

Alertness and concentration.

vii.

Memory.

viii.

Well being.

ix.

Ideas (intelligence).

Contraindications T h e r e are no k n o w n c o n t r a i n d i c a t i o n s to P i r a c e t a m other t h a n hypersensitivity to the product. Patients with renal disorders should use Piracetam with caution.

Side effects Side effects at lower doses are very u n c o m m o n , this may be b e c a u s e Piracetam has an L D 5 0 higher t h a n salt! Side effects can include nausea, dizziness and headache. Even at higher doses P i r a c e t a m is m e r c i f u l l y f r e e o f s i d e effects.

Dosage A d u l t s a t h i g h e r d o s e s initially t a k e P i r a c e t a m f o r t h e f i r s t m o n t h . T y p i c a l l y it's 2400mg taken morning and afternoon. After that period d o s e s are r e d u c e d to 1200mg morning and afternoon. S o m e patients e m p l o y doses as high as 8 6 0 0 m g p e r d a y , b u t t h i s is u n u s u a l a n d n o t r e c o m m e n d e d if s t a r t i n g o u t . B e a r in mind the comments made under "cautions."

Cautions

1981. 3. Buresova 0: Bures J: "Piracetam Induced facilitation of interhemispheric transfer of visual information in rats" Psychopharmacologia V46 P93-102 1976. 4. Bylinsky G: "Medicines next marvel, the Memory Pill" Fortune Jan 20 p 68-72 1986.

of mental performance" ACTAN Psychiatrica Scandinavia" V54 p 150-160 1976. 17. Mondadori C: "Effects of Oxiracetam on learning and memory in animals" Clinical Neuropharmacology V9 Supplement 13 p27-37 1986 (New York Raven Press). 18. Nickerson V: Wothius 0: "Effects of the acquisition enhancing drug Piracetam on rat cerebral energy" Biochemical Pharmacology V25 P2241-2244 1976.

5. Chase CH: "A new chemotherapeutic investigation, Piracetam's effect on dyslexia" Annals of dyslexia V34 p29-48 1984. 6. Corners CK: "Piracetam and event related potentials in dyslexic children" Psychopharmacology V5 p2720278 1985. 7. Diamond S: Browers E: "Increase in the power of human memory in normal man with the use of drugs" Psychopharmacology V49 p307-309 1976. 8. Dilanni M: "The effects of Piracetam in children with dyslexia" Journal of clinical psychopharmacology" V5 p272-278, 1985. 9. Donaldson T: "Therapies to improve memory" Anti-Aging News No 4 pl3-21 1984. 10. Ferris SH: "Combination of Choline and Piracetam in the treatment of senile dementia" Psychopharmacology Bulletin V18 p94-98 1982. 11. Friedman E: "Clinical response to Choline plus Piracetam in Senile Dementia" The New England Journal of Medicine No 24 304 p 1490-1491 1981. 12. Giurgea CE: "The Nootropic approach to the pharmacology of the integrative activity of the brain" Conditional Reflex V8 No 2 p l 0 8 - 1 1 5 1973. 13. Giurgea CE: "Nootropic drugs" Progress in Neuropsychopharmacology V I p235-247 1977. 14. giurgea CE: "Nootropic drugs" Progress in Neuropsychopharmacology V I p235-247 1977.

19. Parducz A: "Depletion of synaptic vesicle lipids in stimulated cholinergic nerve terminals" Alzheimer's disease: Advances in basic research and therapies. Thirs meeting of the international group of treatment disorders of the aging. Zurich Switzerland p217-126 1984. 20. Pearson D: Shaw S: "Durk Pearson's and Sandy Shaws newsletter" Oct 1988 V I No 8 p65. 21. Pellegata R: "Cyclic Gaba Gabob Analogues" 6th International meeting of Society for neurochemistry, Copenhagen Aug. 21-26 1977. 22. Perlton R: Pelton T: "Mind food and smart pills" New York Double Day 1989. 23. Pepeu G: L Spignoli G: "Neurochemical actions of Nootropic drugs" Advances in Neurology V51 Alzheimer's disease New York Raven Press 1990. 24. Pilch H: "Piracetam elevates muscarinic cholinergic receptor density in the frontal cortex of the aged" Psychopharmacology 94 p74-78 1988. 25. Poschel B: "New Pharmacologic perspectives on Nootropic drugs" Handbook of Psychopharmacology p l l - 1 8 p24-25 1988. 26. Stegink A: "The clinical use of Piracetam, a new Nootropic drug" Arzbeimittelforschung V22 No 6 P975-977 1972.

15. Kent S "Piracetam increase brain energy" Anti-Aging News V2 No 10 p65-69 1981. 16. Mindus P: "Piracetam induced improvement

27. South J "Reviewing the Smart Drugs" AntiAging Bulletin, Volume 3 Issue 4, January 1998, International Anti-Aging Systems.

CETAM

P i r a c e t a m is s y n e r g i s t i c w i t h o t h e r Nootropic drugs, products containing choline, Ergoloid Mesylates, a m p h e t a m i n e s a n d caffeine etc. W h e n

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inverted curve.

U C B a n d is t h e w o r l d s b e s t s e l l i n g s o - c a l l e d s m a r t d r u g . It h e l p s w i t h l e a r n i n g and a p p e a r s t o ?

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References 1. Anderson K: Anderson L: "Orphan Drugs" Los Angeles The Body Press 1983 p.163. 2. Bartus RT: "Profound Effects of combining Choline and Piracetam on memory enhancement in aged rats". Neurobiology of Aging V2 p l 0 5 - l l l

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i f The continuing interview

development of Can-C eye-drops

The only version proven to help reverse eye-disorders

Whilst at the September 2 0 0 6 London Antiageing Conference, w e took the opportunity to interview Dr. Mark Babizayev. Dr. Babizayev is the M o s c o w based lead researcher behind Innovative Vision Products- the organisation responsible for developing the remarkable nacetylcarnosine eye-drops (CanC) that have shown clinical efficacy in reversing conditions of cataract. AAM: "Thank you Dr. Babizayev for taking some time out of your busy schedule here at the London Antiageing Conference. How was your lecture about n-acetylcarnosine (NAC) eye-drops and their role in reversing cataracts received?" MB: "It was received very well Phil with a lot of interest. But it is always a surprise to me that since Innovative Vision Products (IVP) have developed these drops in 2001 and the fact that we have published our results in several prominent medical journals, that I still meet so many people, doctors included- who do not know about or indeed understand our technology!" AAM: "I know that it does take many years for any new development to reach the mainstream, whether that is the medical professional or the general public through the mass media. For example, Prozac速 was patented in 1977 after I O-years of research, yet it did not become known to the vast majority of people until the late 80's. Perhaps that is what we have to expect from the current set-up- a period of at least 20-years for new medical breakthroughs to become regular practice! That was always our intention behind the Antiaging Magazine- to help reduce that gap of knowledge to practice for our readers." MB: "I think the Antiaging Magazine is helping, we have always been grateful that you were one of the first to appreciate and recognize the significance of our eye-drops."

An interview with Mark Babizayev, Ph.D. 36

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November 2006

AAM: "Please remind our readers about the problems of cataracts." MB: "Cataract is the leading cause

interview of blindness and accounts for about 42% of all such cases worldwide, remember this is in-spite of the availability of surgical treatment. Today we have the appalling situation where more than 17 million people around the world are blind because of cataract and 28,000 new cases are reported everyday. In developing countries, there are simply not a sufficient number of surgeons to perform cataract operations. Furthermore, cataract surgery is the most commonly performed surgical procedure in people over 65-years of age. 43% of all visits to ophthalmologists by Medicare patients in the US are directly associated with cataract. Meanwhile, approximately 25% of the populations over 65 (and about 50% over 80) have a serious loss of vision due to cataract. Since it is this population that is most susceptible to lens opacification and as this section of the population is expected to increase dramatically in the coming years, so we can expect the numbers of individuals with cataract is also set to explode!" AAM: "So was this your inspiration to develop an eye-drop that could help reverse and prevent cataracts?" MB: "Yes it was and 1 feel that it is rather appropriate that as Russia gave the world the technology for rapid eyesurgery for lens removal that we have now used Russian technology and knowhow again, only this time we have moved on to the possibility of reversing cataract development in-situ with eyedrops, which in many cases means without the need for surgery." AAM: "Please be so kind as to remind us of the results you have obtained with your eye-drops in humans." MB: "Our patients were given 1% nacetylcarnosine eye-drops or a placebo and were tested for their glare sensitivity, visual acuity and gross transmissivity of their lenses. These results were compared at baseline and at 6-month follow-up

examinations for 2-years. When compared with placebo, 41.5% of the eyes treated with NAC eye-drops presented a significant improvement in visual acuity of 7% to 100% and 88.9% of the eyes ranged a 27% to 100% improvement in glare sensitivity. Topographic studies demonstrated less density and corresponding areas of opacification in posterior subcapsular and cortical morphological regions of the lens. The total study period was over 24 months and it revealed that the beneficial effect of NAC eye-drops is sustainable. Image analytical readings of lenses indicated that no cases resulted in a worsening of visual acuity for the NACtreated group of patients, and in most of the patients drug tolerance was good. Statistical analysis revealed significant differences between 6 and 24 months as an overall cumulative and positive change of the characteristics of cataracts in the NAC-treated group, when compared to the control group- plus remember that in the placebo group we saw a worsening of their sight over 2years. Thus, we have therefore proposed that our synthesized NAC eye drops are effective and physiologically acceptable for non-surgical treatment of age-related and senile cataracts." AAM: "Were there any side-effects noted in the human trials?" MB: "For most of the patients treated, drug tolerance was good and no sideeffects were specifically associated with the application of 1% NAC eye-drops. What is more, no recurrence of cataract development occurred during the period of NAC application. In rare cases persons with a poor Ph balance, there are some instances of stinging, although this tends to be mild and passes. However this is normally indicative of their poor Ph balance and this stinging effect would be likely to occur with any eye-drops they placcd into their eyes because our eye-drops are formulated to have a neutral Ph of 7. The only other times there have been issues have been in

persons who wear contact lenses and have a build up of lactic acid because of them. In these cases the solution is easy, it is to simply remove the contacts, wash the eyes with cold water and allow to dry, then place the NAC eye-drops into the eye and finally to wait 15-minutes before reapplying the contacts." AAM: "Have you drawn any conclusions as to why NAC is able to treat cataract so successfully? Is NAC breaking existing cross-links of proteins as well as inhibiting them? Or are there other forces at work here?" MB: "NAC eye-drops when applied lead to a diminishing of light-scattering units in the lens, probably by prevention of the oxidative modification of crystallins and utilization of lipid peroxides that promote lens opacities. Most known biological antioxidants that can prevent oxidative damage to biological molecules show some specificity in their mechanism of action, and so they can provide only one type of protection. Nacetylcarnosine may exert its antioxidant properties by removing high reactive peroxide compounds from the lipid phase of the lens, i.e. the fiber cellular membranes. We assume the advantage of NAC is as a universal antioxidant, which relates to its ability to give efficient protection against lipid peroxidation, both in the lipid phase of biological membranes and in the aqueous environment. We maintain the hypothesis that NAC assists the proprietary lens antioxidant systems including glutathione, and the enzymatic antioxidant systems of the lens, to provide their operation most effectively. Glutathione in conjunction with glutathione related systems, like glutathione reductase, can partially reduce the S-S bonds in the cross-linked lens proteins. We also agree that NAC can prevent and reverse the cross-linking of the lens proteins, including crystallins induced by lipid hydroperoxides and their secondary breakdown molecular products, like aldehydes. This

Treatment of human cataract with the eye drops of 1% n-acetylcarnosine eyedrops for a period of 5 months. The left image shows the appearance of cataract which resembles a bat in its form. The right image shows that this opacity has disappeared after the cited period after treatment with n-acetylcarnosine is completed. The lens has become clearer. November 2006 i a m

interview mechanism can be prominent to reverse and prevent lens opacification that is related to the glycation reactions o f the lens proteins, and as you know, they are also associated with complications o f diabetes." A A M : "I appreciate that your work has focused on the treatment o f patients with cataract, but do you envisage that N A C may also have a role to help prevent cataract?" M B : " O h yes! We usually pursue the following therapeutical strategy for the treatment o f human cataracts with N A C . Firstly, we expect to obtain the maximal effect o f improvement o f visual acuity within the first 3 to 5 months o f therapy, and then the clinical strategy is to maintain the received visual outcome for a lasting period. In this connection, N A C does indeed help to prevent human cataracts." A A M : " W h a t kind o f dosages are we talking about?" M B : "There is no need to exceed 2-drops twice daily into the eye. We do recommend that the drops are used for a period o f 3 months and ideally 5-months, although some patients may notice benefits as early as 1 -month." A A M : "1 also understand that you have acquired the proprietary process o f producing a high-purity N A C for eyedrop use. Did you find that normal production o f N A C was in some way inferior?" M B : "There are many carnosines with little or abandoned biological activities. This strongly varies with the content o f transition metals in the peptide moiety, admixtures o f hydrazine and other impurities dependent to the type o f obtention and synthesis. We have developed the important c G M P manufacturing process for our approved eye-drops which demonstrates its extraordinary biological anti-cataract activity in humans. We have provided the chemical-functional correlation o f the N A C properties and ensured the clinical anti-cataract efficacy o f the product for human lenses. But i f N A C is extremely pure this also abandons the antioxidant and biological activities o f the peptide product! We keep secret our know-how on the processing and permanent biological and analytical controls, in order to manufacture the effective anticataract N A C bulk material. This technology has been envisaged after extensive studies and cooperation with a Japanese pharmaceutical facility."

j a m

November 2006

A A M : " H a v e you protected your invention?" M B : "Yes our application o f N A C for the treatment o f cataracts has been protected by the pending patents by our groupwhich we believe will be enforceable in 2007. Unfortunately before then a number o f companies have attempted to duplicate our eye-drops. However we have studied some o f their samples and found that their source o f the active Nacetylcarnosine has a higher value melting point demonstrating that their source is not racemized. In another words they are not using the necessary form o f the dipeptide. Furthermore, there are discrepancies in the N M R spectra o f their products, which most probably indicate the presence o f deleterious impurities." "I would like to add that our formula improves the effectiveness o f our special pure N A C by providing a longer bioadhesion to the mucous corneal layer, this is achieved with the lubricant carboxymethylcellulose and is why this is also mentioned in our patients. Other lubricants are not so effective and we note that these are being used by the generic copies." A A M : " S o what can that mean to someone w h o uses the incorrect eyedrops?" M B : "Essentially it means that they will be using an eye-drop that does not conform to our studies, even i f it appears that the formula is similar. We can stand by the efficacy and safety o f our product due to our long research and trials in animal and h u m a n eyes, whereas the generic copies are attempting to m i m i c our published research without understanding the crucial points o f our technology, nor do they have the proven efficacy or safety o f our product." A A M : " H o w are you trying to overcome this confusion in the marketplace so that the user is aware o f the difference and can obtain an original eye-drop developed by I V P ? " M B : "They should enquire as to whether the eye-drop is approved and patented by IVP: this information must be printed on the box. O u r original brand name is CanC." A A M : " W o u l d it appear that the Can-C eye-drops may be effective in other disorders?" M B : " W e are investigating the potential for other eye-disorders, our early results are promising that we can affect the progress of; presbyopia, open-angle

primary glaucoma- particularly in combination with beta-blockers, corneal disorders, computer vision syndrome, eyestrain, ocular inflammation, blurred vision, dry eye syndrome, retinal diseases, vitreous opacities and lesions, complications o f diabetes mellitus and other systemic diseases. In particular I would like to raise a point concerning diabetes." A A M : "Please tell us about the complications o f diabetes and cataracts." M B : "Diabetics are especially prone to cataracts because o f oxidative stress in the eye. Although cataracts can be surgically removed, in diabetics this can be an extremely risky procedure, since cataract removal causes suction on the retinas, which may completely pull away diabetic retinas already weakened by retinopathy. Also, macular detachment can more readily occur because o f suction in diabetic cataract removal than in otherwise healthy patients. Further, the trauma o f cataract surgery promotes retinopathic neovascularization, which can lead to rapid worsening o f retinopathy, and can also cause neovascularization to spread even to the surface o f the eye, where it cannot be removed. All o f these possible sideeffects make the risk for blindness extremely high for diabetics having cataract surgery, and those with retinas already loose from retinopathy may face a choice between going blind from retinopathy, which cannot be treated because cataracts prevent safe intervention with the laser; or from retinal detachment or neovascular overgrowth caused by cataract removal; or from the untreated cataracts themselves." A A M : " S o do you believe that your eyedrops can assist to help prevent surgical intervention?" M B : "Yes, these natural eye-drops have been clinically proven to treat cataracts, which mean not only to prevent cataracts from developing in the first place, but also to reduce cataracts once they are established. O u r n-acetylcarnosine eyedrops have been proved safe and effective in countless studies published over the past 14 years in peer-reviewed medical journals o f the highest caliber." A A M : "Congratulations Dr. Babizayev, we wish you luck with your progress on spreading the word about the cataract reversing eye-drops- including your NDA." M B : "Thank y o u . "

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