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A Tour of Melatonin

Melatonin—millions of people have been taking it, and health-food stores advertise it in their plate-glass windows. Is it as important as Drs. Pierpaoli and Regelson claimed in their bestselling book, "The Melatonin Miracle"?

My reply is maybe. This is a very important hormone. The more we learn, the more impressive it becomes. The six-million-dollar question is: Will replacement of deficient with melatonin increase your life span or quality of life? It does increase life span in mice. There are good reasons for thinking it might do something quite similar in people. But for a definitive answer, you'll just have to wait until 2050. The difficulty with doing longevity studies in humans is that people live so long.

That said, I'm now going to discuss whether melatonin does or doesn't add years to your life, it's most certainly going to improve it in ways that are well worth having, and, in combination with replacement of the other hormones, its value seems unquestionable. As you'll see, its usefulness as an enhancer of the immune system is very significant. That's a property we're seeing in replacement of all of the hormones lost with age. The last forty years of research has made it clear that relationships between the many endocrine glands and the immune system are unusually close. And let me put it quite bluntly—if I haven't done so already—when it comes to outfoxing death, a powerful, vigilant, ceaselessly active immune system is the master defender. Nothing except the beating of your heart and breathing of your lungs is more critical to your continued survival.

In addition to its immunological effects, melatonin deserves serious attention for its impressive potency as an antioxidant. I'm sure that most of you will have seen that term used again and again in magazine articles and news reports. Vitamins C and E are antioxidants. Beta carotene and selenium are antioxidants. The B-complex vitamins enhance antioxidant protection, as do copper, zinc, manganese, and many other antioxidants. Fruits and vegetables are filled with antioxidants. What these antioxidants are supposed to be protecting you from are molecules called free radicals. Each of the antioxidants will offer a slightly different approach to free radical protection.

Until the 1990s, this whole theory of free radical damage to the body and antioxidant protection was somewhat speculative. It has now entered the mainstream of medical knowledge, and it is widely conceded that free oxygen radicals play an extremely significant role in the aging process.

The antioxidant theory of aging was proposed four decades ago by Dr. Denham Harman. He had observed that radiation produced damage in the human body very similar to the effects of aging. What the radiation was doing was something that—thankfully at a slower rate—occurs in all our bodies as a normal consequence of simply living. You see, oxygen, which is the very basis of our form of life, without which we cannot live or produce energy, is also a potential bad guy—a two-edged sword.

In the normal process of cell metabolism, oxygen is used to burn or oxidize fuel from the food we eat in order to produce energy. As a by-product of this oxidative process, highly reactive and damaging forms of oxygen called free radicals are produced. When susceptible molecules in our cells encounter free radicals, they break apart and are otherwise damaged. If you ever took chemistry in high school, you'll remember that a molecule is composed of two or more atoms held together by electron bonds. The electrons are paired, with a balanced electrical charge to create a stable molecular structure. In the course of reacting with oxygen, molecules can lose an electron and become electrically unbalanced in such a way that they become so-called free radicals. Free radicals have an instantaneous and very strong desire is to combine with (oxidize) any other molecule in its vicinity. They can do this in a nanosecond, a billionth of a second, and the result in your body is damage to tissues, to cells, and to the very RNA and DNA in the nucleus of your cells that forms the genetic core program of life. Trillions of these free radical reactions are occurring in our bodies daily and without the protection of antioxidants—molecules that combine with free radicals in order to neutralize them—we would be in very deep trouble. In fact, we would be in much the same situation as a person who is exposed to a killing blast of nuclear radiation, which overwhelms all antioxidant defenses and creates widespread molecular destruction in the body.

Well, much of aging is an accumulation of free radical damage. And research has indicated that a long list of diseases from cancer and heart disease to Alzheimer's, Parkinson's, and arthritis are caused in part by free radical damage.

Thus the discovery of any important new antioxidant is of singular significance. Antioxidants make cells and molecules "bullet proof" against free radicals. Melatonin may be a particularly crucial addition to the antioxidant armory.

Apparently melatonin is one of the few powerful antioxidants that can pass through the blood-brain barrier, an anatomical feature designed to protect our brain from chemical or bacterial and toxic assault. Since our brain is much more subject to free radical molecular damage than any other part of our body, it theoretically could turn out that the significant portion of the aged population that shows a decline in brain function is experiencing the effects of declining levels of melatonin.

Various studies have shown that melatonin is one of—if not the most—vigorous antioxidant protector. But now, let's move from the molecular level to the larger picture; let's see just what a remarkable hormone melatonin is in the total scope of life.

MASTER OF THE STAGES OF LIFE

Melatonin is the major hormone produced by our pineal gland. The pineal is a tiny cone-shaped body buried deep within our brain. Cloaked in utter darkness, it is, nonetheless, connected to the retina of the eye and is sensitive to light. Indeed, the pineal is the master of our circadian rhythm, the whole process by which we are attuned to the cycles of day and night, light and dark. In animals the pineal, through its light sensitivity, controls the body's response to the seasons. Bears hibernate, birds migrate, and animals of all sorts mate during a restricted time of year. The pineal gland is a miraculous master controller of those cycles.

The Hindus referred to the pineal as "the third eye" and portrayed it as one of the seven chakras or centers of vital energy, which are arranged along the central axis of the body. Located at the apex of the head, it was thought by them to be the supreme or crown chakra and a source of bodily harmony. Rene Descartes, the seventeenth-century French philosopher, said the pineal was the seat of the soul (and found himself in theological hot water). In modern western medicine, however, the pineal was for a long time much neglected. Nobody knew what it did, and, until 1958, when Dr. Aaron Lerner, a Yale dermatologist, published an article in the Journal of the American Chemical Society, few people were aware that the hormone he dubbed melatonin even existed.

Now we know that our bodies would go haywire without melatonin, and the fact that pineal glands of the very old produce it in much-reduced quantities is a contributor to many of the health hazards of age.

Is the pineal actually the clock that regulates aging? Does it determine the stages of life? This is a hypothesis that now has much to support it. Certainly melatonin production has an impact on every stage of our life. Newborns produce very little of it. Then, at about three months of age—which is the stage of development when they start sleeping longer stretches at night and being more alert during the day—melatonin levels rise. From about the age of one, melatonin levels are more or less constant for a decade. Then, just before puberty, they go down sharply. Recent studies have demonstrated that this decline is the body's signal to the sex glands to set sexual maturation in motion. So clear is the signal meant to be, that a child who maintains unusually high levels of melatonin will experience a delay in the onset of pubescence. There have actually been rare cases, in which the melatonin level is so uncharacteristically high in adolescence that sexual maturation simply does not occur!

From adolescence to early middle age, melatonin levels more or less plateau. But somewhere around forty-five years of age, melatonin begins a steep decline, thus joining the ranks of the other declining hormones—estrogen, testosterone, DHEA, and human growth hormone. The endocrine hormones are essential for vital, energetic lives, but our bodies phase many of them out as the years advance.

By the time they're sixty, most people are producing less than half the melatonin they produced at twenty; by their late seventies, many people are producing hardly any melatonin at all. We know that the broken sleep patterns of many older men and women are a consequence of this deficit, but it also seems clear that the impairment of many of our most critical glands is also related to this shortage. The truth is that something vital is interrupted in people when the pineal gland's functioning declines. Our circadian rhythms (day-night cycles) are a crucial part of our nature and our relationship to the planet we live on and the sun we orbit. We are creatures of the light and the darkness, constructed for activity in daylight and rest at night.

Melatonin seems necessary for a restful night's sleep. Securely protected in the center of our heads, the pineal gland nonetheless knows all about light. When light reaches the retina of our eyes, the eye communicates the degree of light or dark to the pineal by a complicated pathway through the nervous system. Light inhibits the production of melatonin. Therefore, the hormone is mostly produced at night, starting around 11:00 P.M. and peaking between 2:00 and 3:00 A.M. This nocturnal production promotes sleepiness. In the last few years, insomniacs have been alerted to the drug-free benefits of melatonin, and travelers have discovered with relief that a simple melatonin tablet can sometimes relieve jet lag.

If melatonin is so important to our daily physical harmony and so reliably marks out the different stages of life, it wouldn't be at all surprising to find that it has some role to play in the final stage, the stage of our decline. In fact, when we reach our mid-forties, the pineal begins to undergo rapid aging, and the instrument of its action, melatonin, is progressively secreted at markedly lower levels.

Is melatonin a pro-longevity hormone? Would we be better off if our levels remained closer to what we had in youth?

MOUSE AMAZEMENT

It's time to take a look at what happens to animals when their melatonin levels go up or down.

Much of what we know is due to the very inventive research of scientists at the Center for Experimental Pathology in Locarno, Switzerland. Walter Pierpaoli, M.D., coauthor of last year's best-selling melatonin book, was one of the leading scientists in this field. In 1985 he and his colleagues decided to test the effect of administering melatonin to old mice. The first experiment involved healthy male mice nineteen months old. Since this breed lives to twenty-four months, this was roughly the equivalent of dealing with sixty-five-year-old humans. The mice were divided into two groups, with the first group receiving melatonin-laced drinking water and the second group regular tap water.

Dr. Pierpaoli assumed there would be improvements in immune function in the melatonin group. Even in 1985, good evidence existed for melatonin's ability to enhance the immune system. What actually occurred, however, was simply astonishing. The untreated mice, of course, quickly marched on into late old age. They lost muscle, developed bald patches in their fur, cataracts on their eyes, and all the other solemn indicators of their approaching end. They became increasingly inactive as their life force wound down.

Meanwhile, the mice on melatonin were not getting older but apparently younger. Their fur had become thick and shiny, their eyes were clear, their muscles firm, and in activity and energy they resembled far younger mice. Moreover, they went on living. The untreated mice began to die at around twenty-four months. The melatonin mice survived an extra six months, the equivalent in human terms of living past a hundred.

According to Dr. Pierpaoli, the mice showed one other remarkable quality: Not only did the treated mice live longer, they remained healthy, disease-free, and relatively vigorous until virtually the end of their lives. Tests indicated that their immune function was similar to young mice, and their thyroid function, which generally shows signs of decline in older animals, also remained youthful. One last indicator spelled youthfulness. The melatonin mice remained sexually active until almost the end of their very long lives. Do centenarians pursue the opposite sex? They do if they're melatonin-treated mice.

For mice, here was the fountain of youth. Melatonin had shown itself capable of rejuvenating at least three systems: the endocrine, the immune, and the reproductive. Consequently it extended life. The theory that the pineal gland might in some way be a major regulator of the body's overall, age-related functioning had definitely received support. And, of course, such a wide range of benefits had done far more than increase longevity. These mice had lived again in the happy vigor of youth.

Dr. Pierpaoli's team decided to take their research one step further and actually transfer young pineal glands into old mice. Surgically it was too difficult to put these glands into the mice's brains as replacements for their old pineal glands, so they implanted them in the thymus, the immune-system gland lying behind the breastbone. Since the thymus is fed by the same nerves as the pineal, this seemed a logical location.

The results were interesting. The old mice did live three months longer than their untreated brethren, but this was only half the increase in longevity brought about by the simple ingestion of melatonin. It occurred to Dr. Pierpaoli that this might be because the animals still retained their old pineals. If the pineal is the regulator, the controller of the aging clock, the conductor of the symphony of glands that permits life, then it seemed probable that two pineal glands, one old and one young would produce discordance in the music. The final demonstration of the pineal gland's potency was still ahead.

In the early 1990s, techniques of microsurgery finally made it possible to conduct pineal transplantations within the brain of the mouse. That's more difficult than one can easily imagine, since the pineal is extremely small—pea-sized in a human, microscopic in a mouse. Nonetheless, surgery was successfully done on groups of four-month-old and eighteen-month-old mice. Each old mouse was given the pineal of a young mouse, and each young mouse an old pineal.

The results were as bizarre as anything dreamed up in Frankenstein's lab. After several months of adjustment, it became obvious that the "young" mice were rapidly aging, while the "old" mice had become young again. The two groups rapidly passed each other moving in opposite directions. The young mice, decrepit before their time, all died in middle age. The rejuvenated older mice lived to thirty-three months, the equivalent in human terms of 105 years. Although Pierpaoli and Regelson do not ask the question in their book, I cannot help wondering what would have happened if, some months before the little rodents' eventual demise, they had taken the old mice, removed their second pineal glands, and given them yet a third pineal gland-yet another young one. Would they have been rejuvenated a second time? Would they have begun again, fur glossy, sex drive restored, and added yet another six or seven months to their record-breaking lifespan? How many times could such a step be taken? What are the limits of longevity, if the pineal should prove to be its crucial element?

Can we extrapolate these fairly earth-shattering achievements in mouse medicine to human beings? Should we order the champagne and send out the invitations for our hundredth-birthday parties now? Although I'm firmly convinced that some of you readers have an good likelihood of reaching a hundred or more, I wouldn't plan the celebration simply on the basis of melatonin. As I'll be showing you in the pages to come, this is a powerful hormone. But no one knows if it will do for human longevity what it has done for our little rodent friends. People are a great deal more complex than mice, they live a great deal longer, and the pattern of their aging is necessarily different from that of a mouse. If it turns out that folks who take supplemental melatonin from middle age on are able to increase their life span by 25 percent, then we will all have good cause for celebration. Let's look now at the unquestioned benefits of melatonin.

SMART IMMUNITY

Whether or not the pineal gland turns out to be the body's aging clock, there is very little doubt that its hormone, melatonin, does a magnificent job of priming your immune system.

The immune system is one of the most "intelligent" enterprises in the human body. Specifically, it knows who we are and what is and what isn't us. That's much more difficult than you might, at first blush, think it to be. The living cells of your body have tremendous similarities to all the other living organisms in the world around us. We live in symbiosis with an enormous number of bacteria. They enter our mouths and our noses, they prosper on the surface of our skin, they inhabit the interior world of our intestines. Some of them are beneficial, some alien but relatively benign, and many of them harmful or disastrously malignant. Before the age of antibiotics, infections were one of the leading causes of death. But antibiotics are simply an extra defense that we employ when our natural defenses are on the verge of being overwhelmed. Our first line of defense is our immune system, which we already have within us.

At any time in human history, death would have come upon us rather quickly if it were not for the incomparable sophistication with which our immune system defends us. Confronted daily with thousands of different bacterial intruders, it knows what's us and what isn't us-what to attack and what to leave alone. Our immune system can't attack everything that's not us, of course. If it did, how would we eat food?

Thus, our immune system is a system of identification possessing the power of discrimination and judgment, as well as providing a murderously effective team of killer cells. It is the intelligence corps that identifies the enemy, the general who decides whether to attack, and the army that takes out the tough guys as needed. Of the hormones discussed on this website, three—DHEA, human growth hormone, and melatonin—have demonstrated a capacity to significantly upgrade our immune system as it ages. Just as these three hormones seem to give us the strength and energy we had when young, so they give back to our immune system the organizing intelligence and aggressive vigor that was natural to it in our youth.

How big is the immune difference between young and old? Well, the odds of a teenager dying of cancer are about 1 in 25,000. The likelihood that an infectious disease other than AIDS will bring his young life to a close is about 1 in 2,000,000. Once you're over seventy, however, you have about a l-in-8 chance of dying of cancer and a l-in-30 chance of dying of an infectious disease.

If you're planning to live in good health and for a long time, the place to start is your immune system.

Melatonin has earned its spurs in a host of medical studies conducted since the mid-1980s. We shouldn’t be surprised, for it is the only substance apart from human growth hormone that has shown evidence of being able to regenerate the thymus gland, the original seat of immune system function. The thymus's virtual disappearance with age has a highly damaging effect on immunity. Back in the 1970s, the pineal research team in Locarno, Switzerland, demonstrated that the thymus glands of even young animals would begin to shrivel up if the pineal gland was removed. That was pretty telling evidence of a connection that nobody had suspected until then. And that connection has held up, for in the experiment we just discussed in which young pineals were put into old mice and old pineals into young ones, the thymus glands of the young mice soon began to wither and the thymus glands of the old mice grew and regenerated.

The experiment in which old mice had melatonin added to their drinking water also offered telling evidence. The thymus glands of those mice increased in size and began more actively producing T-cell lymphocytes, called the killer cells of the immune system-they kill ineffective microorganisms and destroy cancer cells. Let's quickly look at three other examples of enhanced immune function brought about by melatonin.

Melatonin: Enhancing Survival

Interestingly enough, a double-blind study conducted by Virginia Utermohlen at Cornell University demonstrated that melatonin is even capable of enhancing the immune response of young adults. Ten male college students were given either 20 mg of melatonin or a placebo for a week. When the study was being conducted a virus was going around the campus, and many of the men participating had a cold. Those receiving melatonin produced 250 percent more salivary IgA, an immune antibody protein that helps protect against colds and upper respiratory infections.

Two mouse studies showed vastly increased resistance to severe infection after melatonin was administered. In one, the mice were given a sublethal dose of encephalomyocarditis virus. This was usually not enough to kill mice, but the researchers went further and stressed the mice by confining them for several hours a day in tubes perforated with air holes. Immune function declined correspondingly. Half the mice were then given melatonin, and the researchers sat back to see what happened. The untreated mice fared very badly—in the end, only 6 percent of them survived. But by the end of the study, 82 percent of the melatonin-treated mice had overcome the combination of physical and mental stress they had been exposed to and were still alive.

In the other mouse study, a mixed group of young and old mice were injected with encephalitis-A virus that causes an often fatal brain infection—again accompanied by stress confinement. Half of each age group were then given melatonin. Of the untreated mice, only 6 percent of the young and none of the old survived. Of the treated mice, 39 percent of the young and 56 percent of the old survived, an interesting and rare advantage for the old that has not yet been explained.

The Army of Immunity

These various research demonstrations are all well and good, but how does melatonin support immune function? The most promising finding was made in 1995, when scientists discovered that melatonin links up with a type of immune cell known as the T-helper cell, which aids in the action of antibodies. In fact, it turns out that there are melatonin receptor sites on the surfaces of those cells. Our body is so precisely designed that all cells have receptors that are specifically crafted to receive the molecules that are going to visit them.

Imagine a space ship fitting precisely into the mother ship's landing dock. If T-helper cells have landing docks for melatonin, that means melatonin was always intended to go there and presumably was always intended to influence the immune system—a highly significant finding. And, if both melatonin production and T-helper cells decline with age—and they do—then, considering melatonin's demonstrated effects on immune function, it's pretty certain this isn't coincidental.

The T-helper cells are one particular form of the T-cells that are most important to our immune system. These T-cells actually originate in our bone marrow, but then they migrate to our thymus gland for their higher education. One T-cell will learn that it must respond to the herpes virus, another recognizes and attacks tuberculosis, a third goes after one particular upper respiratory infection. Every T-cell is trained to be a specialist, and, after graduation, they go forth prepared to fight and die for you. There are billions of T-cells in your body right now, on the lookout for their designated enemies.

Your body has two main varieties of lymphocytes: T-killer cells and T-helper cells. The T-helper cells are the commanding officers in this army. Once a bacterial or viral enemy is spotted, the T-helper cells signal for the troops. Chemical messages transmitted by substances called cytokines tell the body which T-cells are needed, and, in a matter of hours or days, millions of exact copies of the specialized T-killer cells that target that particular invader are produced and directed to the site of infection, where they go into battle. Since most of us live fairly long lives, you can be confident that your T-cell army has won thousands of victories.

If melatonin supports the T-helper cells, then we have at least a partial explanation for its unquestionable capacity to enhance our immune system. Since it also appears to regenerate the thymus, our immune system's original powerhouse, it may work synergistically with human growth hormone to keep us disease free as we age. Certainly these are convincing scientific explanations for the increases in immunity that both hormones have separately produced. When we get to devising a comprehensive plan of hormonal supplementation, we'll ask ourselves what is the likely result of combining so many powerful substances.

THE CANCER CONNECTION

As I pointed out earlier, modern medical science has arrived rather firmly at the conclusion that cancer is in large part a disease caused by failure of the immune system. This is, of course, the reason why it is, by and large, a disease of aging. Breast cancer has become fearfully common in our society, and many people have read magazine articles and listened to media discussions of the principal risk factors. Having no children, having the first child late in life, not breast-feeding, having relatives with breast cancer, early menstruation, late menopause—the list is long. But the factor that correlates most strongly with a woman's likelihood of contracting the disease is her age. And this simple, unavoidable risk is actually at the very top of the list for most other cancers as well.

Thus it seems probable that the best way (other than dying young) not to get cancer is to keep your immune system as much like that of a young person as you possibly can. I believe that following the suggestions in this book will allow most of us to do just that—if not forever, then at least until we reach our nineties. Remember that in the normal process of aging, without replacement of deficient hormones, the immune system declines dramatically in our seventies.

Melatonin is bound to be important in this struggle. If, indeed, the pineal gland proves to be our aging clock, then it may be the most important of all. For the moment, however, let's look at some of the very suggestive research that has been carried out on the relationship between melatonin and cancer.

First, I'd like to recall the experiences of one isolated physician, Dr. Kenneth Starr. In 1963, just five years after melatonin had been identified, Dr. Starr gave large intravenous doses of it to a young man with a tumor in his leg that had spread to his lymph nodes. The treatment resulted in a complete remission. Starr had successes with a number of other cancer patients, but being an "unimportant" physician in private practice, without access to the academic major medical journals, his work was soon forgotten.

He was actually not the first pioneer. As far back as the early 1900s, there have been doctors who thought that some unknown substance in the pineal gland blocked cancer growth. A number of these physicians gave ground-up pineal glands to cancer patients and, anecdotally, reported positive responses.

There was no real follow-up to these early successes. It is easy to blame the cancer researchers, but it probably wouldn't be fair. They have pursued cancer cures up and down thousands of blind alleys, and science is complicated. Now, however, melatonin's time has arrived.

In 1980 an American scientist named Lawrence Tamarkin injected rats with a potent carcinogen that stimulates the growth of breast tumors. He then administered a daily dose of melatonin to some of the rodents. After ninety days, 50 percent of the untreated rats had breast tumors. Not one of the melatonin-treated animals had developed a tumor. Tamarkin then stopped giving melatonin, and eventually 20 percent of the melatonin group developed tumors as well.

Naturally one wonders if results like this could occur in the human female.

Breast Cancer and Melatonin

One of the leading investigators in this field is David Blask, M.D., Ph.D., working out of the Mary Imogene Bassett Research Institute in Cooperstown, New York. In 1986 Blask attempted to inhibit the growth of a virulent strain of breast cancer cells called MCF- 7 cells. Cell lines like this are grown in a tissue culture from the actual tumor cells removed from a breast-cancer patient.

Blask and his team set up two groups of the MCF-7 cells, one receiving melatonin, the other not. The dosage of melatonin used was extremely large, a hundred times that found in the human bloodstream. To their disappointment, the growth of the cancer cells was not inhibited in the slightest. No matter how often they repeated the experiment, the result was the same.

At this stage, Blask might have abandoned the attempt, but it suddenly occurred to him to try a lesser dose. The normal practice in oncology research is to look for a maximum impact on cancer cells by giving a maximum dose. There is some logic to this when chemotherapy is being used, since chemotherapeutic agents are essentially chemical poisons not naturally present in the human body. Melatonin, however, is always naturally present, and when Blask began to dose his MCF-7 cells with melatonin at levels approximating the concentration normally present in the young human body, the results were dramatic. The growth of the breast cancer cells was blocked by 75 percent.

Continued experimentation showed that the window of effectiveness was quite narrow. Concentrations of melatonin that were too much below or too far above the amount normally present in a healthy human body were equally ineffective.

Significant in itself, this research becomes still more telling if one remembers a study conducted at the National Institutes of Health (NIH) in 1978. NIH scientists discovered that there was a direct statistical correlation between the incidence of breast cancer and the rate of pineal calcification as detected by X-rays of the skull. As the pineal gland ages, it frequently develops calcium deposits, a problem found in many organs of the body. This calcification stiffens a gland or organ and interferes with its activity. Not everyone's pineal calcifies, however, and there are national differences. Countries—such as the United States—with a high rate of pineal calcification have high breast cancer rates. Countries with low rates of pineal calcification—Japan is an example—have low levels of breast cancer. As you might expect, pineal calcification is associated with low levels of melatonin. If, as Blask's research indicates, melatonin has a direct inhibitory effect on breast cancer cells, the circle is complete.

Can We Beat Breast Cancer with Melatonin?

I think it's very possible that melatonin supplementation will at least help in the prevention of breast cancer. But, for the hundreds of thousands of women who already have it, this approach may be too late.

In 1992, continuing with his work on breast cancer cells, David Blask decided to add melatonin to the already well established anti-breast-cancer drug, tamoxifen. Tamoxifen binds with estrogen receptors and inhibits their effects on cell growth. Since more than 60 percent of breast tumors are estrogen-sensitive, many women with established cancer improve on tamoxifen. However, the drug is by no means free of side-effects and, in most cases, the initial positive effects begin to diminish with time. Blask hoped that adding melatonin would enable a lower dose of tamoxifen to be given while simultaneously enhancing the drug's effectiveness. This approach succeeded beyond his wildest dreams; when melatonin was used, the potency of tamoxifen was increased one hundred times.

Paolo Lissoni, a neuroimmunologist from San Gerardo Hospital in Monza, Italy, was sufficiently impressed with Blask's work to try the technique on fourteen women with advanced metastatic breast cancer who were not responding to treatment. All the women had been treated with tamoxifen before the study began and had either not responded or, after initial good effects, had begun to show diminished responses.

The women were receiving 20 mg of tamoxifen in the daytime and another 20 mg at night. In a 1995 article in the British Journal of Cancer, Lissoni reported an impressive series of results. Four of the women had a 50 percent or greater reduction in the size of their tumors. Eight other women had no further increase in tumor size. And only two failed to respond to treatment.

Blask has been unable to get approval in the United States to try his therapy on humans, but, in a recent animal study, has been able to show significant improvement in mice given tamoxifen and melatonin in combination.

And in Prostate Cancer?

The male half of the population may enjoy equal cancer-fighting benefits from melatonin. In 1993 Dr. Christian Bartsch of the University of Tubingen in Germany reported that men with prostate cancer shared many accompanying hormonal abnormalities: low thyroid levels, low prolactin levels (prolactin stimulates the immune system), and high FSH levels (indicating low testicular activity). But what they most conspicuously showed was an utterly strange pattern of melatonin production. Instead of peaking at 2 or 3 A.M., their melatonin levels increased and decreased at unusual times, both in the afternoon and at night. Something was out of order in their pineal glands.

Prostate cancer is the most common form of cancer in men and second only to lung cancer in mortality. This year, 40,000 men, give or take a few, will die of it. Dr. David Blask has now followed up his breast cancer research by incubating human prostate cancer cells in melatonin. This resulted in a 50 percent inhibition of growth. Blask intends to proceed with further research in animals.

He is not alone. A study carried out by researchers at the University of Texas Medical School found that melatonin reduced the growth rate of prostatic tumors in rats by 50 percent. Such a result in men would certainly represent a sizable prolongation of life.

It remains to be seen whether melatonin's suspected influence over other hormonal systems is part of the reason for its benefits in both prostate and breast cancer. Both cancers, after all, are subject to hormonal stimulation. Estrogen and prolactin may stimulate established breast cancer, once it has formed, and testosterone can stimulate established prostate cancer. Both cancers can be arrested in their early stages but are much more dangerous once they've metastasized. And people who have either of these cancers tend to have unusually low levels of melatonin. But at this stage, we are merely speculating. It may turn out that all cancers are sensitive to melatonin therapy.

Dr. Lissoni Again

Another piece of the melatonin-cancer puzzle is offered by that indefatigable Italian researcher, Dr. Paolo Lissoni. He has been tireless in pursuing the melatonin connection. In 1990, reasoning that the body calls on all parts of the immune system, not simply melatonin, to fight cancer, he decided to combine melatonin with interleukin-2. IL-2 is a natural part of our immune system, a signaling molecule that fosters immune cell growth. For many years, it has been one of the most investigated immunological approaches to fighting cancer, but there is a severe drawback. Given in doses high enough to inhibit a cancer, it is quite toxic, and patients could die from side effects.

Lissoni wondered whether melatonin would reduce the toxicity effect. This proved to be the case. Equally significant, melatonin combined with IL-2 proved to be a great deal more effective than IL-2 alone. Lissoni and his team took eighty late stage cancer patients, put half on IL-2 and half on IL-2 plus melatonin. One year after the start of treatment, 46 percent of the patients in the IL-2 plus melatonin group were still alive versus only 15 percent of the patients in the IL-2 alone groUp.15

In 1994 Lissoni decided to try the combined melatonin-IL-2 therapy against one of the deadliest of all malignancies—late stage lung cancer. He ran his new combination therapy in a head-to-head competition with the combination of cisplatin and etoposide, a standard chemotherapeutic treatment for advanced lung cancer. At the end of the first year, 45 percent of those receiving melatonin/IL-2 were still alive, compared with only 19 percent of those on chemotherapy. The melatonin group also experienced fewer side effects.

I think there's little doubt that melatonin should be vigorously researched as an anti-cancer agent in the future. Unfortunately, the patent has long since expired on melatonin, and medical research is very expensive. So there is no source of research funds to investigate this promising therapy.

Here, we are only peripherally concerned with cancer therapies. What impresses me about melatonin is the evidence that far from being just an effective natural sleeping potion, it is, as well, an essential part of the harmony of the human body. Like human growth hormone and DHEA, it resurrects something we cannot live for very long without: a vigorous and actively functioning immune system.

THE SLEEP KING

If hormone replacement with age continues to demonstrate such a gratifying ability to halt the inexorable decline of immunity, we may someday find ourselves entering a different world.

Melatonin’s capacity to aid in sleep enhancement is not disputed by even the most skeptical critics of this hormone's new-found celebrity. Since life without a good night's sleep is deprived living, this is one quality of the pineal's hormone well worth celebrating. How we sleep is controlled by our circadian cycle, the day-night cycle that synchronizes our hormone production, hunger, moods, body temperature, energy level, and, of course, sleep-wake patterns. This cycle runs twenty-four hours in length, roughly similar to our twenty-four-hour day, and it can change with age.

In fact, disturbances of the circadian cycle that affect the ability to get a good night's sleep are very common among older people. Not only do the elderly produce relatively low amounts of melatonin—the sleep messenger—they very commonly produce it out of phase. The most frequent old-age sleep disorder results when an individual starts producing melatonin too early in the evening and then stops producing it too early in the morning. Older folks with this problem have a tendency to fall asleep soon after dinner and then wake early, sometimes in the middle of the night, well before sunrise. Moreover, the quality of the sleep they get is often poor.

Consider, for a moment, what a good night's sleep is designed to do for you.

THE STAGES OF SLEEP

Sleep researchers, who have been vigorously delving into the mysteries of the kingdom of Nod, divide sleep into five separate stages: stages I, II, III, and IV, and REM sleep (rapid-eye-movement sleep)-the stage when you dream. As you dream, your eyes dart rapidly back and forth, as if you were following the action of your own private, interior movies-thus the name.

Stage I is the shallow sleep with which you begin a sleep cycle. Stage II is a little deeper, and is followed by Stages III and IV, which are really deep, non-dreaming (NREM) sleep. This deep sleep is generally regarded as the most restful sleep and probably does most to rejuvenate our energies for the coming day. In these stages, breathing is regular and slow, blood pressure goes down, and muscular movement is quite minimal. This is called delta sleep—even our brains slow down and brain waves, if recorded on EEG machines, show large, slow, smooth waves.

Because this deep sleep is so necessary to the replenishment and healing of our body, our sleep cycles pack as much of it in as possible during the early stages of rest, just in case our night's sleep is destined to be a short one. The cycles of sleep consist of sixty to one hundred minutes of NREM sleep followed by a significantly shorter period of dream sleep. As the night progresses, the NREM segments become somewhat shorter and the REM sleep longer. There are usually five to six cycles a night.

Older people seem to have a harder time staying in the deepest levels of NREM sleep. Since the body is believed to be carrying out a good deal of quiet repair and regeneration during those stages, this is unfortunate. Equally crippling, however, would be disruption of the REM dream stage.

Without it, our mental functions deteriorate radically. Memory falters, learning becomes almost impossible, and psychological disorders occur. Sleep researchers believe that dreaming allows us to assimilate and cope with the various experiences we have had during our waking hours. Apparently our dreams allow us to clean up superfluous data and file away important information.

Without sufficient sleep, therefore, we are both physically exhausted and mentally somewhat dysfunctional. Tens of millions of people attempt to address these problems by taking sleeping pills, and more than a third of the folks taking those prescription drugs are over sixty-five. Unfortunately, all the effective sleep-inducing drugs so far discovered disrupt normal sleep cycles and eventually make the problem worse. Benzodiazepines (which include Dalmane, Halcion, Valium, Ativan, and Xanax) are among the worst offenders. Studies have shown that several months of benzodiazepine use can virtually abolish Stage III and IV sleep.

If you have a sleep problem, what you need is a solution that reinforces rather than disrupts the normal patterns of sleep—and melatonin does just that.

What Melatonin Does

Richard Wurtman, M.D., a researcher at MIT, conducted a series of studies over ten years that demonstrated quite conclusively that even fractions of a milligram of melatonin can enhance sleep. His first studies used 240 milligrams—a huge dose by today's standards—and his subjects did, indeed, sleep—like rocks—and usually woke up feeling pretty groggy. Eventually Wurtman determined that as little as 0.3 milligrams would significantly decrease the amount of time a volunteer needed to fall asleep.

The effective dose seems to vary widely from person to person, however. In my practice, an occasional elderly patient has taken up to 30 with no side effects. Others have found that one mg or less is adequate and that more might cause drowsiness the next day.

When you take a melatonin tablet, your pulse rate declines, your body temperature drops, and you feel more tranquil and drowsy. The gates of sleep begin to open. A recent study conducted at the Technion Medical School in Haifa, Israel, showed that men and women between the ages of sixty-eight and eighty who took melatonin cut the time they required to fall asleep by more than half (from forty minutes to fifteen), as well as reporting a more refreshing sleep.

If you have a problem sleeping, I recommend that you start with between 1 and 3 mg of melatonin at your desired sleep time. Try the smaller dose first: it may be enough. Your goal is to get a solid night's sleep and wake up refreshed.

MELATONIN FOR LIFE?

Melatonin declines and so do we. Direct connection? Nobody knows for sure, but the evidence assembled so far—even though it's mostly the product of animal studies—is certainly interesting.

At the moment, my recommendation for people over forty-five is that they modestly supplement their bodies with melatonin at bed time. There is certainly no evidence of any kind to show that it can harm you. Thousands of people have taken it in clinical trials. Even when doses as high as several thousand milligrams were given daily for a month, there was no apparent toxicity. And that dose is thousands of times greater than what you'd take to maintain a youthful level of melatonin.

It would be better, of course, if there had been large-scale double-blind studies conducted over years that would have the capacity to accurately identify both benefits and negative effects. Having said that, we come back to the basic thesis here: What may or may not happen if you take megadoses of a hormone is inherently unpredictable, but what will happen if you take doses that approximate your own body's natural youthful levels is probably quite predictable. After all, this is what your body has been accustomed to for decades.

Therefore, with melatonin as with other hormones, I recommend for my patients amounts that best approximate nature's original plan. When you are in your twenties, your melatonin blood level is at its adult peak of approximately 125 picograms/ml. The level falls off very gradually, and, then in the mid-forties, a more dramatic decline begins. By the time you're eighty, you will likely be at half or less your youthful peak.

LONGEVITY OR JUST BETTER HEALTH?

We've already described a fairly comprehensive listing of potential health benefits produced by melatonin. What I'm sure you'd like to know as much as I would is whether melatonin will radically restructure the body's aging clock and perhaps make it possible for us to live longer than the usual maximum of eighty to ninety years. I suppose the proper answer is that you and I and all the millions of other people who are taking melatonin now are guinea pigs in a great longevity experiment.

Doctors Regelson and Pierpaoli in their best-selling book, The Melatonin Miracle, have suggested that melatonin does reset the clock. In fact, the essence of their theory is that by taking a replacement dose of melatonin we essentially fool our bodies into thinking we're younger than we are. They have speculated that the pineal gland is the timer for aging.

The pineal gland begins to break down in our middle years. It shrinks, it loses many of its pinealocytes, the cells that produce melatonin and other compounds, and the system that transmits light signals from the retinas of the eyes to the pineal also begins to show wear and tear. As less melatonin and other pineal hormones are produced, it could well be that the body starts losing its ability to adjust to its environment. The loss of proper circadian rhythm appears to be related to the loss of many different kinds of essential metabolic adjustments. (For instance, older people have more difficulty adapting to extremes of heat and cold.)

Regelson and Pierpaoli's theory is that the slowing of melatonin production is a major signal to all the other hormone systems to begin slowing down. In effect, diminished melatonin is a message to self-destruct. The other glands, obedient to the pineal clock, then secrete less of their own critical hormones, and the process that we call aging proceeds on its less than merry way. Regelson and Pierpaoli cite the astonishing mouse studies that we described above as evidence for this thesis.

Those studies are, of course, also evidence for the far more pleasing idea that supplemental melatonin can cause the pineal gland to age more slowly and that most of the other crucial hormonal systems will follow suit, thus effectively slowing aging throughout the body. Such a theory is potent but unproven stuff. But there's no harm that I can see in whistling optimistically as we take our melatonin tablets. This hormone is a mighty antioxidant, a vigorous enhancer of our immune system, and a cancer fighter, and promotes a good night's sleep.

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Copyright © 2012 Elmer M. Cranton, M.D., all rights reserved

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