| HOW TO STOP
AGING?
By Walter Pierpaoli, M.D., Ph.D.
[Ed. Dr. Pierpaoli is one of the world's leading neuroendocrine researchers
and it was his work that has made melatonin "common knowledge" throughout
the world. However, as you will read in this article, Dr. Pierpaoli's research
about melatonin goes far beyond its use just for sleep, jet-lag and as an antioxidant.
In-fact, Dr. Pierpaoli's ground-breaking work suggests that melatonin is a crucial
factor in the treatment for aging itself and these ideas formed the basis of his
lecture at the Second Monte Carlo Anti-Aging Conference (tapes now available).
We are therefore very pleased to print this article by Walter Pierpaoli, M.D.
of Chronolife in Switzerland].
Melatonin and the pineal gland:
The answer
to programmed neuroendocrine and immune aging, to its prevention and its reversal.
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 aging-accelerating effects of social distress, a large number of noxious
environmental agents, poisons, bacterial or viral diseases, that aging is by itself
a genetically programmed event for all species. In
homeotherms, (namely in warm-blooded vertebrates), we can in-fact 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 may never be able to
answer that question, but our curiosity concerns 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 its importance but
we forget for a while, the evolutionary significance of aging, and restrict our
attention to the nature of aging in order to delay, arrest or even reverse its
course. There is no time for academic exercises! I will
limit my article to the evaluation of the scientific "hard-facts" that
concern the known approaches to delaying aging in mammals : They are : Restricted
caloric diet
Exogenous administration of melatonin Over
the course of many years, we have progressively developed and analyzed the concept
and experimental data to underly our claim that aging, (similar to somatic growth
and fertility), is simply a pineal complex-driven neuroendocrine programme in
the brain, that leads to progressive derangement and de-synchronization of fundamental
neuroendocrine and hormonal regulation such as gonadal, thyroid, adrenal functions
etc. In other words, the aging conductor "the pineal"
delivers untimely and chaotic, haphazard messages and therefore the whole orchestra
gets deranged! 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 oxygen-dependent energy production inside the cells. We think that
the "programme of aging," similar to the "programme 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.
This is clearly exemplified in the course of aging by andropause and menopause.
However, in the course of our studies, other elements have appeared which are
in-fact a fundamental aspect of aging : the neuroendocrine-immune interactions
both during development of the immune system and during aging. The "discussion"
between the two systems is provided by the molecules to both the reproductive
functions and to the maintenance of an efficient and self-monitoring immune network. In
recent years, the discovery of transferrins as key agents for the maintenace of
"self" identity, has opened a new field for evaluation of the relevance
of "self" integrity and for interfering with the programme 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 in the cross-talk between the neuroendocrine and the immune
system, where we have identified some key elements which all contribute to an
efficient functioning of neuroendocrine and immune functions. We can now start
arguing about their role in the context of aging. However,
a restricted caloric diet (RCD) is the first historical approach to significantly
retard aging, so the question is: Has melatonin a relation to a low calorie diet?
In other words, does a low calorie diet modify melatonin and conversely does melatonin
mimic a restricted caloric diet? Is there a common denominator which will affect
the inherited longevity programme of each individual? Life
prolongation via a restricted calorie diet (RCD) Since the
first dramatic experimental evidence produced by McKay with rodents in 1934, an
immense amount of literature is now available which documents the different methods
used. All prove that a diminished calorie intake will significantly delay aging
and the many aging related diseases and their metabolic dysfunctions. However,
it took more than sixty years before the National Institute on Aging started to
evaluate whether or not a RCD applied to non-human primates would also retard
aging (sic!). There is now evidence that this is the case and many results begin
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 long ago in a rather neglected
publication, that the thymus does not deserve such a primary role for initiation
and progression of aging (Table 1). Removal of the thymus at different times after
birth in mice, did not significantly affect their life span (Table 2). However,
it became clear that the thymus was deeply involved in the ontogenetic programming
and maturation of the entire neuroendocrine system, and that 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
observations of the ability of mature lymphocytes to restore growth, immunity
and to prolong the life of dwarf mice, the idea evolved that a different hormonal
regulation could be responsible for the aging-postponing effects of a RCD. In
other words, 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 sexual functions of rodents maintained at
a RCD. We conducted some experiments in which we could demonstrate
that if mice are kept at 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 (Table 3). This data confirmed that the feeding
behaviour (at a time when the neuroendocrine system is still immature), permanenlty
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 permanent derangement of their mature neuroendocrine and metabolic
system and irreversible obesity. 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 however afflicts a small number of families and individuals. The
clear answers from many studies all indicate that a RCD produces juvenility-oriented
and permanent changes of neuroendocrine regulation and they are exactly the opposite
outcome of environmentally induced and aging-accelerating dietary obesity. If
endocrine and metabolic dysfunction are the expression of the programme of aging,
and if the pineal gland is a "life and aging clock", consequently we
must consider that a RCD affects mainly the pineal gland and its functional state.
This seems to be the case. It has been reported that a RCD maintains juvenile
levels of melatonin in rodents. 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 a RCD for several years,
data is 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 (see reference 16). 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 de-synchronization of the whole neuroendocrine
network, leading to a progressive alteration of hormonal cyclicity and consequently,
of the surveillance of the immune functions. The anti-aging
molecule melatonin In spite of the political denigratory campaign
against the anti-aging properties of melatonin, it is beyond any doubt that exogenouse
administration of melatonin to aging rodents postpones their aging and/ or prolongs
their life (Figure 1). Unfortunately, for mysterious or tactical reasons, those
experiments have not been properly replicated, while the deceptive behaviour against
the anti-aging properties of melatonin continues. Of course, melatonin serves
to indicate that the pineal gland is directly involved in the aging process. Pineal
grafting experiments disclose a dramatic new approach for strategies to postpone
aging. Also, these fundamental experiments have not been replicated, although
they may soon, several years after their initial publication! The pineal grafting
experiments also serve to indicate that the pineal gland, via its links to the
entire neuroendocrine system, controls the "programme of aging" and
that in-fact an aging pineal can accelerate aging even in a normal young animal
carrying his own young pineal (Figure 2). These striking observations help to
understand that other key mechanisms and/or molecules must be operative for the
anti-aging and the aging-accelerating 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 peptides play
a basic role. That melatonin could significantly postpone aging
thanks to its anti-oxidative and hydroxyradical-scaveniging properties, (like
those of vitamin E or glutathione), is not supported either by logic or by any
serious in-vivo confirmation. It does not seem to me that the many receptor-mediated
effects of melatonin and the myriad of affinity binding mechanisms can explain
its anti-aging properties. The anti-stress, immunoprotecting effects of melatonin
show 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. But nocturnal melatonin supplements will not protect
from aging when the age of the animals is too advanced! This has now been proven
in another kind of placebo-controlled clinical trial, in which perimenopausal
women aged 42 to 62 years, have been treated with melatonin. 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 administration
starts rather early in life, in so-far as it protects the pineal from aging! This
observation is fundamental for the preventive 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 (which is a
rather energy consuming and complex two-phase enzymatic process). 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 emerging results in perimenopausal women. Melatonin
delays and reverses menopause in women
(Abstract from "Experimental Gerontology",
36, 297-310, 2001) Night levels of melatonin in mammals and
man decline progressively in the course of aging. Also, the function of the thyroid
gland and of sex glands (ovaries and testes) decline steadily, while on the contrary
in the hypophysis the production of gonadotropins (luteotropic hormone, LH and
follicle stimulating hormone, FSH) constantly increase. Those hormones regulate
the production of estrogens and progesterone in the ovaries and the menstrual
cycle and testosterone in the testes. The increase of LH and FSH is a clear-cut
aging signal for sexual and reproductive functions, both in males and in females
(i.e. menopause and andropause). Previous studies with laboratory
animals had shown that evening administration of melatonin in senescent animals,
as well as transplantation of a young pineal into old animals produces a true
reversal of sexual decay. This has been shown by measuring (in that part of the
brain that controls sexual organs and functions- the hippocampus), receptors which
regulate the synthesis of LH and FSH (gonadotropins) in the hypophysis (Figure
3). This remarkable evidence induced us to evaluate the effects of melatonin in
women from pre-menopausal and peri-menopausal age (from 42 to 52 years of age)
until menopause (from 52 to 62 years of age). The question was: is pineal melatonin,
whose blood levels decline in the course of aging in the sexual-reproductive tract
of women, responsible for, or directly connected with the onset of menopause?
Are we able to modify or eventually delay menopase by evening administration of
melatonin? Measurement of melatonin in saliva before the initiation
of the study allowed us to select women with nocturnal low basal levels of melatonin,
as well as women with medium night levels of melatonin and finally women with
high night levels of melatonin. This served to verify if the possible effects
of melatonin administration, depend only on a condition of individual endogenous
melatonin deficiency. Women were strictly divided into homogeneous
groups (melatonin or placebo) according to age and also to their endogenous levels
of nocturnal melatonin in the saliva. Before initiation, blood samples were taken
for measurement of hormones and all women answered questions in a questionnaire,
concerning mood, sleep, and all psychic problems and neurovegetative symptoms
typical of women' climacteric. Half of the selected women started taking 3mg of
highly pure melatonin while the other half took placebo, this was conducted with
the classic double-blind method (neither the physician nor the patient know if
the patient takes the active substance or not). After three and six months from
the initiation of the treatment, hormonal measurements were repeated and all women
answered again all the questions. The results obtained after
three and six months, (a period of time ethically acceptable for the administration
of placebo), have shown that: All women, in particular those
who had shown individual low night levels of melatonin in their saliva, had a
very remarkable improvement of latent and unsuspected conditions of low thyroid
function (hypothyroidism). In-fact, we observed a significant increase of the
active thyroid hormone triiodothyronin (T3) in all women independently from their
night levels of melatonin and to a minor extent of its precursor thyroxin (T4)
only in women with medium and low endogenous levels of melatonin (Table 4). The
effect of melatonin does not depend on pituitary TSH (thyrotropin stimulating
hormone) but on the direct effect of melatonin on the thyroid gland (conversion
of T4 into T3, the active hormone). In the course of six months,
evening administration of 3mg melatonin produced a clear-cut decrement in blood
of the pituitary hormone LH (which increases progressively in the course of aging).
This was most noticeable in the younger women (43 to 49 years of age). Therefore,
the recovery of pituitary function to a more juvenile pattern of regulation is
more pronounced and rapid in younger women (Figure 4a and 4b). This equaled to
an arrest and even a reversal of brain aging and restoration of reproductive functions
in the women taking evening melatonin As a confirmation of
a restoration of thyroid and sexual functions consequent to the evening use of
melatonin, seven women, at 2 and more years after onset of menopause (complete
interruption of the menstrual cycle), have now reacquired a normal and physiological
menstrual cyclicity. Finally, 96% of women who had taken melatonin,
declared a total disappearance of morning depression, which is typical in perimenopausal
and menopausel women. Our results demonstrate that a clear-cut,
cause-effect relationship exists between the function of the pineal gland and
night secretion of melatonin on one side, and aging of sexual functions on the
other side. The decline of synthesis and release of pineal melatonin during aging,
signals to us a central hypotlamaic alteration of the control of the juvenile
hormonal cyclicity and the progressive quenching of fertility in women. Our results
show that nocturnal administration of melatonin produces a recovery of thyroid
function (synthesis of T3 and T4) and pituitary (hypophysis) sensitivity to ovary
regulation (decrease of LH and FSH) in the direction of a remarkable recovery
of more juvenile sexual-reproductive functions. The effect of evening administration
of melatonin is more pronounced in younger women and in women with lower melatonin
levels in saliva (before initiation of oral melatonin treatment). Women
(and men), wake up! Who is afraid of melatonin? Since the publication
in New York in August 1995 of the American bestseller "The Melatonin Miracle"
(Simon and Schuster, 1995, authors W. Pierpaoli and W. Regelson with Carol Colman)
(Figure 5) which is now translated into 17 different languages, an oppressive
air of suspicion and conspirational silence descended in old Europe upon the word
"melatonin." This is only broken from time to time by isolated flashes
of light, which in-turn are immediately clouded by untimely and clumsy interventions
of the "insiders" of the press and television. In-fact, the simple and
clear scientific reality of the matter should not to be classed with day-to-day
"disposable products." It took millions of years for Mother Nature to
elaborate its logical strategy, which we are now really starting to perceive and
interpret. Few people read and try to learn and understand before opening their
mouth, particularly newsmen and reporters. They must produce an inexhaustible
supply of exciting news daily, while Mother Nature, fortunately for us, does not
measure time or regard fashions. As my mother, a woman of central Italy, used
to say : "They open their mouth and give out breath!" (She was referring
to politicians and their mental and personal deficiencies). The
basic question is : "Why do we age?" The answer is so simple to the
point, that it sounds provocative and strange, and for many of my colleagues outrageous,
as did the straightforward observation of Galileo to the Fathers of the Catholic
Church in the Vatican: "And yet (the earth) it moves!" We age in a way
similar to that in which we grow! But then, what is melatonin needed for? It inhibits
aging. Why? Simply because it prevents aging of the remarkable "switchyard"
in the pineal gland (which truly is not a typical gland!). Nocturnal administration
of melatonin prevents the pineal from deteriorating, from decaying into a heap
of scrap, and thus from becoming unsuitable to deliver the precise signals which
regulate the natural rhythms of day and night. These precise messages keep us
constantly synchronized through the hormonal system with the environment in which
we live. If and when we stray from this natural pathway, we develop diseases and
age more rapidly. The so-called reality of the world in which we live escapes
our sensorial and psychological consciousness, simply because we are an integral
part of it! We navigate in a dimension whose nature and boundaries we ignore.
Our only reference marks are the rhythms scanned by day, night and the seasons.
It would be like asking a fish to describe air, or a bird to say what life in
the water looks like. But is melatonin a true hormone? No!
Can it induce damage? No! Melatonin is produced and secreted by different tissues
and organs, but during night-time only by the pineal gland. Even at huge dosages
and for very long periods, melatonin is totally harmless. Well documented data
for this exists, but it is never mentioned ! However, a few milligrams (3mg) of
melatonin suffices to put the pineal at "night rest" and thus to protect
the pineal, our hormonal switchboard center, from aging! If the pineal does not
age, we cannot possibly age, or at least the aging process will never again be
as we have seen and experienced it until now. Why do I address
women? I wish to speak to women because they are more adaptable
and flexible and thus rightly live longer. They read more and are able to ponder
what they hear and read. They are the vehicles of family, peace and serenity,
the true basis of our daily life. They have endured the dominance of men for millennia
and can thus better help destroy a world of ignorance, lies and egoism. For this
reason, two years ago we started a long, expensive, wearisome and unannounced
investigation under the guidance of Dr. Giulio Bellipanni and his co-worker Pierluigi
Bianchi at the Menopause Center of the Madonna delle Grazie Clinic in Velletri,
near Rome. Using accepted strict scientific criteria we aimed at answering the
most obvious and urgent question concerning the aging of women : What is menopause?
Can it be prevented, delayed or modified? If melatonin is able to decelerate or
even to stop aging, what more suitable model is there than menopause? We now have
the answer, and it is extremely convincing. Our findings have
been elaborated and have recently been published. Nocturnal melatonin alone can
deeply modify the hormonal and psychosomatic conditions in the perimenopausal
years, which can extend from 40 to 60 years of age. Here we only mention what
is published in an official scientific journal, to inform all women about it in
order to alleviate the countless problems they face daily in family and society.
Menopause is simply the end of the hormonal "fertility program" of women,
but this program is perfectly amenable to modification. It is not true that "the
ovaries are depleted!" They simply atrophy according to their "genetic
program." But the expression of that program is purely hormonal, and we can
restore the juvenile hormonal control of the ovaries. Certainly the juvenility
and health of women are linked to the maintenance of a juvenile hormonal status,
which can be supported with nocturnal melatonin administration. In perimenopausal
women, melatonin in the most striking fashion, reconstitutes the juvenile hormonal
conditions and produces a rapid regression of all the neurovegetative and psychic
alterations of menopause, in particular the states of nervousness, anxiety and
depression. In addition, we can now address the issue of an impressive combination
of melatonin with zinc. Zinc is a basic mineral in the body and essential for
the function of over 200 enzymes that are fundamental for the respiration of all
cells in the body. The combination of melatonin and zinc dramatically accelerates
the effects of melatonin and boosts a depressed immunity. This is all documented.
The answer to our queries is clear, simple and strictly scientific. Nocturnal
administration of melatonin can resynchronize the entire hormonal system and,
by protecting the pineal from aging, can maintain the juvenility of the pineal
and its capacity to synthesize other very remarkable molecules. We found another
of these molecules 12 years ago, but it must be studied in more detail before
being used. At the present time only melatonin is available, which according to
our studies is better if taken with zinc. This is all published in excellent scientific
journals. Nothing I have stated is casual or extemporized! Enough
of trivial reservations regarding jet-lag and sleep, together with threats of
"hormonal side-effects" : Melatonin is, as I said recently in a BBC
interview in London, a "gift of God" and can harm only those who do
not take it! People (especially women), are now able to appreciate what hormonal
and metabolic aging means and thus also prevent it. Others, let them wait to have
"youth genes" inserted! At present, 3 milligrams of melatonin and zinc
is sufficient for me and all those dear to me before switching off the light and
sinking into refreshing sleep Who is right? We shall see in a few years! [Ed-
As can be gleened from Dr. Pierpaoli's excellent and provocative article- he is
passionate about Melatonin and his work (and rightly so). Dr. Pierpaoli also become
annoyed at the low quality of melatonin on the market and has since devised his
own formula. This version is "more" than just melatonin and contains
"other" natural substances that work synergistically. We were all staggered
at IAS to find that it is far more potent than any other form of melatonin we've
used! The new form is called TI-MElatonin® and details of it are outlined
below]. TI-MElatonin®: Biological effects and scientific
information TI-MElatonin® expresses the best imaginable
melatonin preparation available on the world-market and is now available as a
food additive and dietary supplement to anybody wanting to take advantage of the
extraordinary scientific observations of Dr. Walter Pierpaoli and his co-workers. The
basic experimental findings of 35 years of research, resulted in the discovery
of the undeniable existence of a programmed "Aging Clock" in the pineal
gland complex of the brain. We have investigated the possible
mechanisms and also the molecules which presumably cooperate and synergize with
melatonin in the regulation and re-synchronization of the fundamental immunological
and hormonal functions, (which are normally lost or deranged in the course of
aging). In recent studies and long-term experiments with old rodents it has been
observed that zinc can completely correct aging-dependent immunodepression and
several other hormonal and metabolic alterations typical of aging. It has been
found that the low zinc levels in aging animals can be restored to normal values
with nocturnal administration of melatonin or transplantation of the pineal gland
from young animals into older animals6-9. Zinc is an essential component of more
than 200 enzymes and one of the most relevant trace elements in the body8,9. It
is therefore clear that additional zinc must be supplemented daily to the body
of an aging organism with a low zinc balance, in-order that melatonin can better
exert its anti-aging activities on the entire neuroendocrine and immune systems!
This important and novel scientific observation of the powerful anti-aging and
immonoenhancing activity of the combination of zinc and melatonin has now resulted
into the development of TI-MElatonin®. Furthermore, selenium
is a fundamental trace element of the body and possesses powerful anti-cancer
effects. But modern agriculture and alimentary habits have dramatically decreased
the daily input of selenium from the diet. Selenium is essential for the enzymatic
reaction responsible for the synthesis of glutathione, a powerful physiological
molecule which constantly protects the body from oxidative damage. A lack of selenium
will thus result in a loss of the detoxification capacity of the body, immunodepression
and onset of degenerative diseases and cancer10. This is the reason why TI-MElatonin®
combines, (in a unique synergistic combination), the three fundamental anti-aging
molecules of melatonin, zinc and selenium. Whilst melatonin plays the master role
for reactivation and restoration of its natural night peak to juvenile levels,
(this resulting into normalization of all measurable immunological and endocrine
functions in the course of aging), the positive age-postponing, metabolic and
immunological effects of TI-MElatonin® can be measured easily by anybody with
a normal periodic check-up! These restoring metabolic changes will become progressively
more visible and remarkable over the course of years, after initiation of the
treatment with TI-MElatonin®. Further studies are now in
progress and they will allow us to progressively add more elements suitable to
further improve and accelerate the rejuvenizing effects of nocturnal melatonin.
But the "programme of aging" can be slowed down now to a more acceptable
rate with regular nocturnal use of TI-MElatonin®. TI-MElatonin®:
Composition of active components in each tablet Melatonin (N-acetyl-5-methoxytryptamine),
3mg, synthetic, certified purity: (99.9 % (HPLC), Zinc-orotate x 2H2O, 50mg corresponding
to 8.7mg zinc. Selenium, 50mcg, from sodium selenite pentahydrate. TI-MElatonin®
is produced in Switzerland in compliance with the severe international rules of
Good Manufacturing Practise (GMP) and under licence of Swiss Health Authorities. Contraindications
and general suggestions TI-MElatonin® should not be given
to healthy children, pregnant women and lactating mothers unless specifically
prescribed by a physician. There is no evidence that TI-MElatonin® could adversely
influence the effects and activity of estrogens. On the contrary, melatonin increases
the density of estrogen receptors in sensitive target tissues (mammary gland,
womb, ovaries, etc.) and greatly improves their actions. There are no contraindications
for dietary supplements containing melatonin, zinc and selenium. No ascertained,
life-threatening, acute or moderate, short- or long-term side-effects have been
scientifically demonstrated or reported. Melatonin must be
taken late in the evening at bedtime in order to mimic and restore the physiological
night peak, which normally declines progressively during the course of aging.
As mentioned in the literature reported above, the progressive abrogation of melatonin
night-cyclicity during aging is considered to be a basic signal expressing the
extinction of the most fundamental regulatory system in the body. This brain "clock"
is genetically and evolutionary linked to the sun, the planetary system and the
obvious dependence of our health from daily and nocturnal, rhythmic cyclicity.
Every person expresses their own genetically inherited nocturnal peak of melatonin,
with very large individual variability. However, in the majority of the population,
the night elevation of melatonin declines and most of us become "flat"
after 80 years of age. This is a basic aging message from the "clock"11. The
dosage of melatonin is still rather empyrical and based on animal and human studies.
The blood night level generated by 3mg by far exceeds the normal night levels
of healthy young persons. However, melatonin is rapidly metabolized and excreted
by the kidneys with no consequences. Use of beta-blockers in
the evening may abrogate the night peak of melatonin. If they must be taken, it
may be necessary to take them in the morning or to increase the dosage of melatonin.
Circadian, night melatonin seems to produce a resynchronization of the entire
neuroendocrine system and will certainly improve metabolic and hormonal functions,
including blood pressure, cholesterol levels, thyroid, gonadal and adrenal functions.
These effects can be easily evaluated with a routine check-up. Melatonin will
counteract the negative side-effects of corticosteroids and of di-stressful agents,
thus protecting the immune system. Melatonin does not induce sleep but facilitates
its onset and produces a sleep pattern which is typical of children or young persons.
It greatly improves the quality of sleep and its restoring physical and psychological
effects, with a clear improvement of morning mood and body muscle strength. Melatonin
is not a drug and it is not itself a cure for any disease! Melatonin is ubiquitous
in nature, cells, plants, animals, tissues and any living organism. Milk, vegetables,
cereals, rice, meat, etc., contain variable amounts of melatonin. Synthetic melatonin
could be theoretically replaced by alimentary melatonin in the daily food, but
its replacement would be problematic and difficult to achieve for everybody. Melatonin
produced by the pineal gland seems to be responsible for the night peak, while
melatonin produced by the gut and the retina does not seem to affect the nocturnal
levels. It is thus evident that the night peak of melatonin initiates a sequence
of positive effects with a cascade of events which maintain the body systems synchronized
with the physiological cyclicity of hormones and cells. This night "signal"
is essential for the maintenance of immunity and the "surveillance"
against the onset of tumors. Therefore melatonin is a fundamental element for
prevention of aging-related diseases, including cancer, autoimmune and cardiovascular
diseases. Melatonin cannot be considered a classical "hormone," although
it is so-named. It does not possess any of the qualities of the classical hormones
like growth hormone, cortisol, estrogens, thyroid hormones etc. It is rather a
chemical mediator whose mechanism is still unknown. It modulates and controls
the synthesis and secretion of all hormones within a circadian and seasonal periodicity
and variability. It has been given at a huge dosage of grams daily for prolonged
periods, and to 1500 women at the daily dosage of 300mg for years with no observed
late side-effects and consequences. The administration of melatonin to restore
the physiological adaptation of the body to circadian and seasonal periodicity
is only the beginning of a new medicine based on the concept that nobody can escape
the established laws of Nature within the solar-planetary system, in which man
developed as a mammalian species. We must be able to restore and correct the derangements
of this adaptation system and maintain it in its original juvenile conditions.
These metabolic conditions can be perfectly measured and maintained under balance,
not with a cumbersome and complex hormonal supplementation (e.g. testosterone,
growth hormone, pregnenolone, etc.), but with a correction of the central regulatory
system located in the "pineal complex" (pineal gland and the many anatomical
and functional connections in the brain and the neuroendocrine-immune systems). TI-MElatonin®
is perfectly suitable to re-synchronize all neuroendocrine functions. TI-MElatonin®
contains basic elements which will synergize in order to obtain more rapid effects
and to compensate the loss of fundamental minerals, due to a wrong diet or to
aging. The beneficial effects of melatonin in the normalization of zinc levels
have been scientifically proven and constitute a basic tool for maintenance of
hormonal and immune functions and to restore these functions during aging. Common
agents which antagonize synthesis and secretion of melatonin Alcohol,
corticosteroids, beta-blockers (especially in the evening), caffeine, nicotine
and many chemical substances with pharmacological activity can antagonize the
synthesis and secretion of Melatonin. But melatonin does not itself antagonize
the activity of any drug and can be used in combination with any medical drug
and pharmaceutical speciality. Nocturnal melatonin will in-fact improve the effectiveness
and activity of drugs as a consequence of its synchronizing properties on the
entire neuroendocrine and immune systems. TI-MElatonin®:
Suggested daily dosages as a dietary supplement Between 40
and 50 years of age: 1.5mg to 3mg at bedtime (peremptorily at the same hour, with
half an hour tolerance). After 50 years until 75 years of age: 3mg at bedtime-
as above. From 75 years of age: 3-6mg at bedtime- as above. Although
not mandatory, it is indicated to take TI-MElatonin® for 5 months in summer
(May-June-July-August-September) and for 5 months in winter (November-December-January-February-March).
TI-MElatonin® can be safely taken without intervals after 50 years of age,
in the presence of chronic, degenerative diseases and cancer, or as a protective
agent under stressful conditions (night-work, exposition to poisons and noxious
agents, time-zone travel etc.). It is strongly recommended
to take TI-MElatonin® for periods of weeks before and after surgical interventions
to ameliorate general conditions (mood, immunity, etc.) and to accelerate immunological
reconstitution, wound healing, tissue regeneration and recovery from anesthesia
toxicity after the operation. For jet-lag we suggest taking
3mg of TI-MElatonin® for four to five days at 10-11 PM, local time, on arrival
at the place of destination and to repeat the same procedure after returning to
the original place of departure. Key-words (42) Aging,
andropause, anti-oxidant, autoimmunity, biorhythms, brain ischemia, cancer, cholesterol,
cholitis, coronary and cardiovascular diseases, depression, dietary supplement,
eye diseases, fertility, heart infarction, hepatitis, humour, hypertension, immunity,
insomnia, jetlag, libido, medical food, melatonin, menopause, multiple sclerosis,
natural molecules, nervosity, osteoporosis, parkinson, pineal gland, prostata,
selenium, senescence, sex power, sleep, stress, surgery, thyroid diseases, ti-melatonin,
Walter Pierpaoli, zinc. References
1. Pierpaoli, W. and Regelson W.
with Carol Colman, "The Melatonin Miracle", Simon & Schuster, New
York, 1995.
2. Pierpaoli, W. The pineal gland: a circadian or a seasonal aging
clock? Aging 3: 99-101, 1991.
3. Pierpaoli, W. Dall'Ara, A, Pedrinis, E. and
Regelson, W. The pineal control of aging. The effects of melatonin and pineal
grafting on the survival of older mice. Second Stromboli Conference on Aging and
Cancer, June 1990. Ann. N.Y. Acad. Sci. 621: 291-313, 1991.
4. Pierpaoli,
W., and Lesnikov, V.A. The pineal aging clock. Evidence, models, mechanisms, interventions.
The Aging Clock. Third Stromboli Conference on Aging and Cancer, June 1993. Ann.
N.Y. Acad. Sci. 719: 461-473, 1994.
5. Pierpaoli, W. and Regelson, W. Pineal
control of aging: effect of melatonin and pineal grafting on aging mice. Proc.
Natl. Acad. Sci. USA, 94: 787-791, 1994.
6. Mocchegiani, E., Bulian, D., Santarelli,
L., Tibaldi, A., Muzzioli, M., Pierpaoli, W. and Fabris, N. The immuno-reconstituting
effect of melatonin or pineal grafting and its relation to zinc pool in aging
mice. J. Neuroimmunol. 53: 189-201, 1994.
7. Mocchegiani, E., Bulian, D.,
Santarelli, L., Tibaldi, A., Muzzioli, M., Lesnikov, V., Pierpaoli, W. and Fabris,
N. The zinc pool is involved in the immunoreconstituting effect of melatonin in
pinealectomized mice. J. Pharmac. & Exp. Therap. 277: 1200-1208, 1996.
8. Mocchegiani, E., Bulian, D., Santarelli, L., Tibaldi, A., Pierpaoli, W. and
Fabris, N. The zinc-melatonin interrelationship. A working hypothesis. The Aging
Clock. Third Stromboli Conference on Aging and Cancer, June 1993. Ann. N.Y. Acad.
Sci. 719: 298-307. 1994.
9. Fabris, N. Neuroendocrine-immune aging: an integrative
view on the role of zinc. The Aging Clock. Third Stromboli Conference on Aging
and Cancer, June 1993. Ann. N.Y. Acad. Sci. 719: 353-368, 1994.
10. Meister,
A. and Anderson, M.E. Glutathione. Ann. Rev. Biochem. 52: 711-760, 1983.
11.
Pierpaoli, W. and Lesnikov, V.A. Theoretical considerations on the nature of the
pineal "aging clock". Gerontology 43: 20-25, 1997.
12. Bellipanni,
G., Bianchi. P, Pierpaoli, W., Bulian, D. and Ilyia, E. Effects of melatonin in
perimenopausal and menopausal women. A randomized and placebo controlled study.
Exp. Gerontol. 36, 297-310, 2001.
13. Pierpaoli W, The Biological Basis of
Aging and Aging Reversal: Clinical Evidence, Second Monte Carlo Anti-Aging Conference,
June 23-24, 2001.
14. Bulian, D. and Pierpaoli, W. The pineal gland and cancer.
I. Pinealectomy corrects congenital hormonal dysfunctions and prolongs life of
cancer-prone C3H/He mice. J. Neuroimmunol. 108: 131-135, 2000.
15. Pierpaoli,
W. and Bulian, D. The pineal aging and death program. I. Grafting of old pineals
in young mice accelerates their aging. J. Anti-Aging Med. 4: 31-37, 2001.
16. Roth, G.E., Lesnikov, V., Lesnikova, M., Ingram, D.K. and Lane, M. Dietary
caloric restriction prevents the age-related decline in plasma melatonin levels
of Rhesus monkeys. J. Clin. Endocrinol. Metab. 86: 3292-3295, 2001.
DISCLAIMER:
ALL INFORMATION IS EDUCATIONAL AND PROVIDED UNDER IAS TERMS AND CONDITIONS. IT
DOES NOT, AND SHOULD NOT, REPLACE THE ADVICE OF YOUR PHYSICIAN.
Last Updated:
Wednesday, February 20, 2002
© 2002 International Antiaging Systems
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