What I have here is an amazing little pill that can add decades--that's right, decades--to your life. Who among you wants to live for 120 years? Step right up . . ."

Even those street-corner medicine men of a century or so ago couldn't have dreamed up a miracle elixir like melatonin. For starters, it promises longevity--extra years of youthful vitality. Then it throws in some mighty impressive health benefits as part of the bargain: immune system enhancement, cancer protection, stress reduction, and sound sleep.

And guess what? This stuff is for real.

Bolstered by two Newsweek cover stories extolling its virtues, melatonin has become one hot hormone. Consumers are scarfing melatonin tablets by the billions, making the hormone one of the best-selling products of its kind. (It's cheap, too--about 10 cents a tablet.)

Most people take melatonin for its sleep-inducing effects. Granted, there's a lot to be said about the benefits of deep, restorative slumber. But the hormone offers so much more than just a trendy new cure for insomnia, especially in the anti-aging arena.

We know, for example, that melatonin is a potent--perhaps the most potent--scavenger of those marauding molecules known as free radicals. It thwarts the cellular degeneration that leads to heart disease, cancer, and other debilitating health problems.

Even more exciting for us Renewal-seekers is the discovery of melatonin's ability to reset the body's biological clock, which determines how quickly we age. This breakthrough prompted the following observation from Russell Reiter, Ph.D., a cellular biologist at the University of Texas Health Science Center at San Antonio and co-author with Jo Robinson of Melatonin: Your Body's Natural Wonder Drug: "I want to die young as late in life as possible, and I think this hormone could help."

Your Internal Alarm Clock

Manufacturing and secreting melatonin is the responsibility of the pineal gland, a sunflower seedsize structure located deep within your brain. The gland evolved from primitive eye tissue, and like a third eye, it monitors the day/night cycle and regulates your body's rhythms. When daylight reaches the pineal gland--traveling by way of the retinas and optic nerves in your eyes and the nerve cells in your brain--it shuts down production of melatonin. Darkness, on the other hand, stimulates production.

Blood levels of melatonin remain relatively low (around 10 picograms per milliliter) during waking hours. Then just before bedtime, between 9:00 and 10:00 p.m. for most people, the gland begins releasing melatonin into the bloodstream. By about 2:00 a.m., levels of the hormone peak at around 100 picograms per milliliter of blood. By about 7:00 or 8:00 a.m., levels return to their low daytime state. There they stay until nightfall, when the cycle begins all over again.

Although nighttime levels of melatonin run about 10 times higher than daytime levels, neither quantity is exactly humongous. A picogram is just one-trillionth of a gram, an amount that's invisible to the naked eye. Melatonin is so potent, though, that even microscopic specks of the stuff can send you to dreamland for hours.

Keeping Time for a Lifetime

Longevity researchers now believe that the pineal gland does more than regulate your 24-hour, sleep/wake clock. It may house your aging clock, the one that drives the aging process.

As you get older, the pineal gland produces less melatonin. A growing body of scientific literature strongly suggests--but has yet to prove--that restoring and maintaining optimum levels of melatonin turns back the aging clock. In this way, the hormone may extend life span.

Some of the most exciting research on this subject has been conducted by Walter Pierpaoli, M.D., Ph.D., an immunologist at the Biancalana-Masera Foundation for the Aged in Ancona, Italy. When Dr. Pierpaoli gave melatonin to old mice, the hormone reversed age-related shrinkage in the animals' thymus glands, which in turn revitalized the animals' immune systems. Intrigued by his findings, Dr. Pierpaoli teamed up with Vladimir A. Lesnikov of the Institute of Experimental Medicine in St. Petersburg, Russia, to transplant the pineal glands of young mice into old mice. The old mice were rejuvenated, their life spans extended by one-third.

Dr. Pierpaoli and Lesnikov then flip-flopped the experiment, transplanting the pineal glands of old mice into young mice. The results of the experiment flip-flopped as well: This time, the life spans of the young mice were shortened by one-third.

From these studies, Dr. Pierpaoli concluded that human aging begins in the pineal gland. He also demonstrated that melatonin could counterbalance the aging process. As he explains, "We should think of the pineal as the aging clock and melatonin as a means by which it translates its time-keeping pulses into body changes."

Fending Off Free Radicals

Scientific understanding of melatonin has certainly come a long way since the hormone's discovery in the 1950s. Back then, cell biologists assumed that melatonin's sole function was the regulation of the sleep/wake (or diurnal) cycle. Today, of course, we know better.

With anti-aging medicine turning the spotlight on free radical biochemistry, melatonin has stolen the show because of its super-powerful antioxidant properties. Indeed, researchers have concluded that the pineal gland produces melatonin not only to induce sleep and regulate the body's hormonal systems but also to protect itself from free radical damage.

Of course, a properly fed body already has an ample supply of antioxidant nutrients, including vitamins A, C, and E, coenzyme Q₁₀, and the antioxidant phytochemicals. What can melatonin do that these other antioxidants cannot?

Back in chapter 24, I explained how each antioxidant nutrient specializes in servicing a particular area, or compartment, of the body. Well, melatonin is an exception to the rule. Its small molecular size allows the hormone to travel anywhere within the body--even to the brain. So it provides unequaled broad-spectrum protection against free radicals.

Melatonin is not only more versatile but also more potent than its fellow antioxidants. The hormone appears to have a far greater capacity for neutralizing free radicals than even the most powerful of the known naturally occurring antioxidants. "We've tested melatonin in every conceivable system that we can assemble," says Dr. Reiter. "It continues to perform as well as or better than any other antioxidant." This makes sense, biochemically speaking. It means the gland that regulates the aging process also produces the strongest defenders against free radical attack.

Because of its antioxidant properties, melatonin may play a leading role in the prevention and treatment of the chronic degenerative conditions caused by the cumulative effects of oxidative stress. (Oxidative stress, you'll recall, refers to the catastrophic cellular breakdown that occurs when free radicals overwhelm antioxidants.) Among the conditions linked to oxidative stress are Alzheimer's disease, atherosclerosis (hardening and clogging of the arteries), cancer, diabetes, multiple sclerosis, Parkinson's disease, and rheumatoid arthritis.

Rethinking Aging

As melatonin has gained fame, it has also revolutionized our understanding of the aging process. In chapter 1, I described how most anti-aging experts subscribe either to program theories or to damage theories. Program theorists maintain that we humans are genetically destined to die at a certain age. Damage theorists contend that the cellular wear-and-tear caused by free radicals speeds up the aging process and eventually kills us.

The boundaries between these two schools of thought became blurred when melatonin burst onto the scene. In their effort to explain how the hormone turns back the clock, experts on both sides have forged a new perspective on aging that combines both program and damage theories.

According to the researchers, melatonin protects the pineal gland--and the gland's preprogrammed aging clock--from free radical damage. But as with all other hormones, melatonin production declines with age. The resulting melatonin shortage leaves the pineal gland vulnerable to free radical attack. The combination of decreasing melatonin production and increasing free radical damage accelerates aging and precipitates physical and mental decline.

Restoring melatonin to optimum levels protects the pineal gland and its aging clock from free radical damage. This is how melatonin reduces oxidative stress and extends life span.

Turning Back the Clock

The body's melatonin production peaks while we're in our twenties, then begins a long and slow decline. The goal of melatonin replacement therapy is to reinstate the hormone levels of youth.

Scientists have yet to determine precisely how much melatonin is necessary to produce optimum anti-aging effects and prolong life. But given the intense research attention that melatonin--and natural hormone therapy in general--has been getting lately, I expect that we'll have some definitive answers within the next few years.

In the meantime, dosage recommendations can vary considerably. I have two friends--one a physician, the other a research scientist--who have published work on the subject of melatonin. One takes 1 milligram of the hormone nightly; the other, 30 milligrams nightly. Go figure.

So how much should you take? My advice is to stay within the range of 0.5 to 10 milligrams per day, even though the hormone has tested safe in much higher doses. If you're between ages 40 and 60, aim for the low end of the range (say, 0.5 to 3 milligrams). If you're over 60, you may want to take a tad more (2 to 6 milligrams). Within the appropriate range, try different doses until you find one that you feel comfortable with.

I usually don't recommend melatonin to people under 40 solely for its anti-aging benefits. Their bodies' production of the hormone has not yet dropped off all that dramatically.

The Immune System Stimulant

Melatonin can recharge an immune system undermined by age-related decline. As you get older, your thymus gland, spleen, and bone marrow--all key immune system players--begin to atrophy. In studies, all appear to recoup their former functionality with the help of melatonin replacement therapy.

Interestingly, scientists have discovered melatonin receptor sites on the surfaces of the thymus gland, spleen, and bone marrow cells. All of these tissues appear to be revived with added melatonin. What's more, the lymphocytes in bone marrow have melatonin receptor sites. Research has shown that melatonin reverses age-related declines in lymphocyte antibody production.

Melatonin also appears to protect lymphocytes against the effects of radiation. In one study, lymphocytes that were treated with melatonin sustained 70 percent less damage from ionizing radiation than those that were not treated. People who require diagnostic x-rays or who are undergoing radiation therapy may be able to protect their healthy tissues from radiation exposure by taking a dose of melatonin beforehand.

If the findings of several animal studies hold up for humans, melatonin may rejuvenate and protect the immune system in myriad other ways. Here's a sampling of what these studies have turned up so far.

• Mice given melatonin produced more antibodies when exposed to an antigen. (An antigen is any substance that induces an immune response.)

• Mice given melatonin produced more interferon and interleu-kin-2, potent immune system chemicals that protect against viral and bacterial infections.

• Mice given melatonin had twice as much immunity to an encephalitis virus as mice not given the hormone.

• Rats injected with melatonin before and after exposure to paraquat, a toxic herbicide, showed none of the devastating lung and liver damage experienced by unprotected rats.

Fighting Cancer on All Fronts

Given its immune-enhancing and antioxidant properties, melatonin has the makings of a natural cancer-fighter. Indeed, the hormone appears to inhibit development of the disease, though perhaps in some surprising ways.

For instance, melatonin may protect against breast cancer and other hormone-dependent cancers by regulating the release of estrogen. The longer a woman is exposed to estrogen over the course of her lifetime, the greater her risk of developing a hormone-dependent cancer. Factors that increase exposure include early onset of puberty, use of oral contraceptives, not bearing children, late onset of menopause, and non-natural estrogen replacement therapy.

Population studies have shown that women in countries with high breast cancer rates have low melatonin outputs. (Melatonin output is measured by the degree of calcification--that is, calcium salt deposits--in the pineal gland.) The opposite also holds true: Women in countries with low breast cancer rates have high melatonin outputs.

Breast cancer rates also tend to be high among women who've lost their vision. Scientists theorize that the women's pineal glands receive minimal light stimulation, which reduces their melatonin production.

Animal studies suggest that melatonin may block the formation of cancerous tumors. In one such study, cancer-prone mice received nightly doses of melatonin equivalent to human doses of one to three milligrams. After one year, only 23 percent of the hormone-treated mice had developed tumors, compared with 62 percent of untreated mice.

Beyond prevention, melatonin may someday prove useful as a cancer therapy. In test tube experiments, the hormone takes direct lethal action against breast cancer cells and impedes the growth of prostate cancer cells. Researchers have launched trials involving cancer patients to evaluate the hormone's effectiveness as a treatment.

Patients with a metastatic (spreading) form of lung cancer were given nightly 10-milligram doses of melatonin in a study conducted by Dr. Paoli Lissoni and his colleagues at Geraldo Hospital in Milan, Italy. The patients' one-year survival rate rose. Impressed with this result, the researchers then added melatonin to the interleukin-2 being given to patients with various types of cancer. (Interleukin-2 is often used as an anti-cancer drug to increase levels of T lymphocytes, immune cells that destroy cancer cells.) In the presence of melatonin, interleukin-2 was effective in a dramatically smaller dose--a godsend for the patients since the side effects of interleukin-2 can be horrendous.

Researchers have also used melatonin as a pretreatment for breast cancer cells. They found that the hormone increased by 100-fold the inhibitory effects of the breast cancer drug tamoxifen.

Number One for Slumber

As a sleep aid, melatonin works even better than synthetic sedatives such as barbiturates and benzodiazepenes. For starters, melatonin is effective in small doses and produces no side effects. Plus, the hormone preserves the normal architecture of sleep, including the timing and duration of dream phases characterized by rapid eye movement (REM).

Anyone of any age who suffers from insomnia can benefit from melatonin. The hormone is especially appropriate for older people. These folks may have trouble getting a good night's sleep because their pineal glands have cut production of melatonin.

You needn't be a floor-pacing, sheep-counting, hard-core insomniac to benefit from melatonin. For people like me, who sleep okay but not always as soundly as possible, the hormone can encourage deeper, more restorative slumber. You feel much more refreshed the next day.

Melatonin supplements facilitate sleep by raising blood concentrations of the hormone from daytime levels of 10 picograms per milliliter to nighttime levels of 100 picograms per milliliter. The supplement dose required to achieve this increase varies from one person to the next. "Normal" doses range from 0.3 to 6.0 milligrams, although in my experience, some stubborn cases of insomnia have required doses as high as 20 milligrams. Your best bet is to begin at the lower end of the range--say, 1 to 3 milligrams--and gradually increase your dose until you find what works for you.

The type of insomnia you have determines the time you should take melatonin for maximum effect. For instance, if you have trouble falling asleep but no problem staying asleep, take regular melatonin a half-hour before bedtime. If you fall asleep easily but then sleep shallowly or even wake up in the wee hours of the morning (between 2:00 and 5:00 a.m.), you may get better results from taking timed-release melatonin right at bedtime.

Some people have both types of insomnia. If you're one of them, you may want to experiment with a combination of regular and timed-release melatonin supplements.

When you first start taking melatonin, you may feel vaguely disoriented or fuzzy-headed for the first few hours after you wake up. This sensation should go away after a few nights of melatonin use. If it persists, you likely need to cut back your dose.

Trouble-Free Time Travel

The Spanish king Alfonso the Wise (122184) once said, "Had I been present at the Creation, I would have given some helpful hints." Now I don't know what he may have had in mind. But I'd cast my vote for a body better suited to travel across time zones.

We humans are not designed for rapid transit from one spot on the globe to another. It leaves us with the familiar symptoms of jet lag: fatigue, insomnia, irritability, and poor concentration. Nothing terribly serious--but enough to spoil travel plans, whether for business or for pleasure.

Crossing time zones catches your pineal gland off guard. The gland expects the sun to set at more or less the same time every day. When you change time zones, it continues secreting melatonin on the same schedule as if you were back home. Since melatonin controls so many of the body's internal cycles, the body is thrown into temporary turmoil. Left to its own devices, the pineal gland requires a few days to reset its 24-hour clock to the new time zone.

Until melatonin supplements came along, the only real recourse against jet lag was to tough it out until the pineal gland made the necessary adjustments. The more time zones crossed, the greater the discombobulation, and the longer the pineal gland needed to acclimate.

I am very sensitive to jet lag. Before melatonin supplements came along, I'd arrive at my destination and wander around like a zombie for a couple of days. I had to allow extra time in my travel schedules to recover from my flights.

If you're prone to jet lag, melatonin supplements can help reset your pineal gland when you travel from one time zone to another. My advice: The first night that you're in the new time zone, take a dose of melatonin at bedtime. The size of the dose is not set in stone. Try different amounts until you determine what works best for you. Some experts recommend taking one milligram of melatonin for each time zone that you cross. When I travel to the East Coast from my home in northern California, I add five milligrams to my regular nightly dose of melatonin. I take this larger dose at bedtime on my first night in my destination city.

Is there any advantage to starting melatonin supplementation a few days before you travel? No. In fact, researchers found that people who took melatonin ahead of time actually experienced more severe jet lag symptoms. They felt even worse than people who took placebos.

Maximizing Melatonin's Benefits

The title of this chapter asks whether melatonin is a "medical megamarvel" or "magnificent myth." Based on the information presented here, I'd say that the hormone lands squarely in the former category. Of course, much research remains to be done to determine whether melatonin actually lives up to expectations.

Right now, one absolute certainty about melatonin is its safety. When researchers attempted to determine the lethal dose of melatonin for 50 percent of a group of mice (the LD-50, in scientific speak), they couldn't do it. Not a single mouse succumbed, no matter how much of the hormone it was given. (As an animal rights advocate, I can say that I like this kind of experiment.) The mice were, however, very well rested.

In a study involving humans, a whopping 6,000 milligrams of melatonin--that's 1,000 times the average effective dose--failed to produce more than occasional stomach upset or mild foggy-headedness when taken every night for a month. Even 250 milligrams of melatonin, administered intravenously on a nightly basis, caused no short-term or long-term toxic reaction. Gram for gram, ordinary table salt is more toxic than melatonin.

I've been taking melatonin for several years now. I've prescribed it to hundreds of patients as well. Not once have I heard of a person having an adverse reaction to the hormone.

There are a few rules of thumb for using melatonin effectively. First, always take the hormone just before bedtime. If you take it earlier in the day, it can disrupt your sleep/wake cycle, which you definitely don't want.

How close the dose is to bedtime really depends on you. Earlier in the chapter, I made specific recommendations for insomnia and jet lag. In general, people seem to feel that melatonin works best when taken a half-hour before bedtime. Some folks extend that window to one or even two hours to achieve the desired effects. (If you work at night, take melatonin at your regular bedtime, whenever that is.)

Second, if you have a serious illness of any kind--especially leukemia, lymphoma (cancer of the lymph tissue), an autoimmune disorder (in which immune cells attack healthy tissues), or major depression--you should consult a doctor before beginning melatonin supplementation. The same rule applies if you're taking any prescription medication, particularly an immune-suppressing drug such as prednisone or cyclosporine. Melatonin is not recommended for anyone on antidepressant medication, especially serotonin reuptake inhibitors such as paroxetine (Paxil), fluoxetine (Prozac), and sertraline (Zoloft) and monoamine oxidase inhibitors.

Third, if you're a woman who is pregnant or nursing, absolutely do not take melatonin.

Only Natural, Please

The magic of melatonin is that it achieves its anti-aging effects without poisoning any of the body's organs and systems in the process. The hormone fosters internal harmony rather than undermining it, as so many prescription and over-the-counter drugs do. With melatonin, there is no toxicity, no risk of dependency or overdose, no adverse reaction.

Melatonin supplementation underscores the ultimate wisdom of using "friendly molecules" to the greatest extent possible in the treatment and prevention of disease. There are two types of friendly molecules: the one that your cells make, and the one that comes from the foods you eat. (Remember, the structure and dose must be identical.) When your biochemical machinery--genes, enzymes, and cell membranes and receptor sites--encounters friendly molecules, it accepts them without question. It knows that these substances belong.

When taken in the appropriate physiologic dose (that is, the dose that matches the amount produced by the body), a natural hormone such as melatonin is incapable of causing a toxic reaction. The same cannot be said of synthetic hormones, drugs, and other unfriendly molecules. When your cells encounter these frauds, they go into alarm/damage control/detoxification mode--the metabolic equivalent of dialing 911. This puts your body through a tremendous amount of stress. And stress accelerates aging.

Finding Hope in a Hormone

As an anti-aging strategy, melatonin replacement therapy works because it targets causes of age-related decline rather than merely masking symptoms. The road to longevity must be paved with nontoxic, health-enhancing therapies like melatonin and other natural hormones.

In their groundbreaking best-seller The Melatonin Miracle, Dr. Pierpaoli and William Regelson, M.D., eloquently summarize this point
of view:

"We want you to understand that 'senescence,' the downward spiral that is now the hallmark of aging, is not inevitable and that aging is neither irresistible nor irreversible. It is possible to retain our strength, sexual vigor, and love of life for all of our decades.

"The miracle of melatonin is not just that it can extend your life and preserve your health and vigor. The true miracle of melatonin is the wider impact that it will have on our generation and on generations to come. We are embarking on an adventure together. We are the first generation to have the power to prevent the disease and the debility that have come to typify 'normal' aging. For the first time, we have the power to preserve our youthfulness and to stay vital and vigorous for our entire lives. For the first time, not only are we able to prevent the physical decline associated with aging but we're actually able to slow down and even reverse the aging process itself. This is truly the melatonin miracle."

Amen.

*

The sex hormones, estrogen, progesterone, and testosterone are probably the best known of the anti-aging hormones. They're also probably the most controversial. The next chapter sorts through all of the conflicting information to help you decide whether any of these hormones is right for you.