Ray Sahelian MDWouldn’t it be great if science discovered supplements that could prolong our life span? Perhaps that time is not far away. Perhaps that time is now. Perhaps melatonin is one of these supplements.
Span Extension in Animals
In my introduction, I discussed the experiment by Maestroni and colleagues, published in 1988, that found an average 20% increase in longevity in middle-aged, male mice when they were given melatonin in their nightly drinking water. The researchers state, “To our surprise, chronic, nightly administration of melatonin resulted in a progressive, striking improvement of the general state of the mice and, most important, in a remarkable prolongation of their life. In fact, starting at 5 months from the initiation of melatonin administration, the body weight of the untreated mice still surviving started to decrease rapidly, and also astonishing differences in the fur and in the general conditions of the 2 groups (vigor, activity, posture) became increasingly evident. Melatonin treatment preserved completely optimal pelage (fur) conditions.”
A similar experiment on middle-aged, male mice, done in 1991 by Pierpaoli and colleagues, also found a 20% increase in life span.
What would melatonin do in the young? To find out, Pierpaoli and colleagues gave melatonin every night to young, female mice (strain C3H/He) starting at age 12 months until death. (There are various strains of laboratory mice and the effect of a particular substance may be different on each strain. That’s why it’s important to mention which one.) The average life span in this strain of mice is about 24 months. The age of 12 months (pre-menopause) would correspond roughly to age 35 in humans. To the surprise of everyone, melatonin shortened life span by 6%. A high rate of ovarian cancer occurred in these young mice. Apparently there are cells in the ovaries in this strain that overgrow when stimulated by melatonin, causing tumors. Another strain of young, female mice (NZB) was also given melatonin nightly starting at age 12 months, and they lived longer than the untreated group. A third group of NZB strain female mice was given melatonin at 5 months of age (Pierpaoli, 1994). They also lived longer than those not on melatonin. Obviously, different mouse strains respond to melatonin differently.
It is possible that if the mice who developed ovarian cancer had been given a lower dose of melatonin, they may have fared better. Based purely on a weight ratio, the amount of melatonin given the mice was many times the dose a human would normally use at night for sleep.
How did melatonin affect female mice who already had reached menopause? In one study, when 18 month old post-menopausal mice (strain C57BL/6) were given melatonin nightly, ovarian cancer was not detected. They lived 20% longer than those who were not given melatonin.
How can we interpret these animal studies in order to make practical recommendations for us humans? First, we have to realize that rodents and humans may respond differently to the same medicine. We have seen that even different strains of mice respond differently. We know by experience, however, in countless other studies and with various other medicines that there is often a similarity between the effects of a substance on rodents and that on humans. We should also consider the possibility that while one person may benefit from a medicine, another may be harmed. Just as there are differences in response between different strains of mice, there may be differences in response between different human beings.
In order for us to know what melatonin will do in humans when given for a lifetime, we would need to follow hundreds or thousands of people. Multiple groups would be needed to try different dosages. Such a comprehensive study is not under way at this time. Even if it were, the results would not be available until well into the 21st Century. What shall we do in the meantime?
Different scientists familiar with these studies may recommend different courses of action. One scientist may caution, “Let’s wait a few more years.” Another may advocate, “If we wait, we’ll have to wait decades. I’m 65 now and I’m having trouble sleeping at night. Melatonin provides me with great sleep. In addition it could extend my life span.” Who will eventually be proved right? No one can be sure at this time.
There are additional studies that support the role of melatonin and the pineal gland in life extension. It has been known for decades that when rodents have their pineal glands removed, they die sooner (Malm, 1959). When the pineal glands of 4 month old mice were transplanted into 18-month-old mice, the older mice lived longer and aging symptoms were postponed (Lesnikov, 1994). When young mice receive the pineal gland from older mice, they die sooner.
The pineal gland releases substances other than just melatonin that play a role in longevity. One such example is epithalamin, which, together with other pineal gland extracts, has produced life extension in mice (Anisimov, 1994).
How Can Melatonin Extend Life Span?
The pineal gland communicates with every cell of the body through its primary hormone, melatonin. Most hormones need a receptor on the cell membrane before they can enter the cell. Not so for melatonin. As the pineal gland releases melatonin, it quickly goes into the local bloodstream and then into general circulation. From there, melatonin finds its way to every body fluid and tissue. Melatonin has the unusual capacity to easily permeate tissues and enter practically every cell of the body. When melatonin enters the cells, it goes into every compartment, including the nucleus. Researchers speculate that the amount of melatonin reaching the DNA of each cell informs that cell as to which proteins to make. The November 1994 Journal of Biological Chemistry reported that researchers Becker-Andre and colleagues found a specific receptor for melatonin right in the nucleus of cells. They conclude, “A nuclear signaling pathway for melatonin may contribute to some of the diverse and profound effects of this hormone.”
One theory proposes that during infancy and childhood there is a high level of melatonin reaching every cell. This high level lets the cells know that the organism is young. Proteins necessary for growth and repair are manufactured. The amount of melatonin released each night is lessened in adults and reduced even more in old age. Therefore, as we advance in years, less melatonin reaches the DNA in our cells. Some researchers (Kloeden, 1993) think the pineal gland functions as a centralized clock to coordinate genes switching on and off.
This decline of melatonin levels may inform all cells of the body’s age— i.e., it’s time to call it quits, call a lawyer, write a living will, and put the first down payment on a cemetery plot (or cryonics arrangements for futurists). Melatonin supplementation could trick the DNA into thinking, “Maybe I miscalculated. I must be younger than I thought.”
We should not think of melatonin as the only influence on aging. In a complex organism such as the human body there are countless factors influencing the aging process. The pineal gland is only one of these factors, albeit an important one.
Some of the ways melatonin could prolong life span include its ability to enhance the immune system, regulate hormonal levels, and act as an antioxidant. There’s also an interesting correlation between diet and melatonin. Food restriction in rodents causes an increase in melatonin production (Stokkan, 1991). Food restriction also leads to their life extension. It is too early to tell whether the increase in melatonin due to food restriction causes this longevity (Huether, 1994).
A Powerful Antioxidant
Many diseases are now believed to be caused or aggravated by free radicals. A free radical is any molecule with an unpaired electron restlessly going around ravaging and harming other molecules— like a hyperactive child swirling around a playpen breaking toys. Free radicals are formed as the end result of burning glucose and other energy molecules within our cells. When we drive a car, we burn gasoline as fuel. The leftovers are spewed out through the tail pipe of the exhaust system. When food is broken down and then metabolized, it similarly creates byproducts. These free radicals are some of the harmful molecules that are left over. They include molecules called hydroxyl (OH•), superoxide (O2• –), and hydrogen peroxide (H2O2). Hydroxyl radicals are thought to be the most damaging (Reiter, 1994).
In the past few years researchers have found that melatonin possesses unique properties as a free radical neutralizer. Melatonin is not only able to trap free radicals such as superoxide anions, but is also very efficient at preventing damage from hydroxyl radicals. Melatonin has been found to be the most potent neutralizer of hydroxyl radicals ever detected. It stops damage immediately and is more effective as an antioxidant than even vitamins C and E (Hardeland, 1993). It also stimulates the enzyme glutathione peroxidase, which converts destructive hydrogen peroxide, H2O2, to safe water, H2O (Reiter, 1993). Researchers in France have also confirmed melatonin’s antioxidant abilities (Pierrefiche, 1993).
Many antioxidant vitamins and nutrients lack the capacity to enter cells and organelles as easily as does melatonin. Melatonin has the advantage of being able to freely enter and permeate all parts of a cell. In a study of DNA damage induced by safrole, a cancer promoting agent, melatonin protected the DNA almost entirely from free radical damage (Tan, 1994). This occurred even though melatonin was given at 1/1000 the dose of the carcinogen. Melatonin also has been found to bind to chromatin within the nucleus of a cell, thus indicating that it may have direct on-site protection of DNA. As discussed earlier, melatonin levels decrease as we age. Researchers speculate that lower melatonin levels may not be able to protect brain cells (neurons) from normal wear and tear. Furthermore, the activity of some brain enzymes, such as MAO-B, monoamine oxidase type B, can increase with age, leading to more breakdown of neurotransmitters and more free radical production. The failure of neurons and the decline of neurotransmitters may then accelerate, leading to dementia, Alzheimer’s disease, Parkinson’s disease, and other degenerative mental illnesses. As Hardeland and associates concluded in their 1993 article, “Melatonin promises to become a powerful pharmacological agent with its unique properties as a nontoxic, highly effective radical scavenger which provides protection eventually from neurodegeneration as well as from the mutagenic and carcinogenic actions of hydroxyl radicals.” In other words, melatonin, taken as a supplement, could slow down the aging process and decrease the incidences of brain damage and cancer.
Russell J. Reiter, a highly respected pineal gland researcher at the University of Texas Health Science Center in San Antonio, concluded in a 1994 article published in the Annals of the New York Academy of Sciences, “Melatonin may prove to be the most important free radical scavenger discovered to date.”
Diseases that may be caused or aggravated by free radical damage include atherosclerosis (blockages in arteries), emphysema, cataracts, Parkinson’s, Lou Gehrig’s, other neurological diseases, and some forms of cancer.
Enhancing Immunity
A complicated interaction between our immune system, hormones, and nervous system allows our bodies to adapt to the external world and prevents us from coming down with infections. The pineal gland is intimately involved in regulating these systems. Receptors for melatonin have been found in lymphoid organs such as the thymus and spleen (Poon, 1994) and on white blood cells (Lopez-Gonzalez, 1993).
Melatonin is believed to enhance the immune system. Mice given melatonin had an increased response of immune globulins to antigens (Maestroni, 1988, Caroleo, 1994). The researchers speculate that vaccines may be more effective when given at the same time as melatonin supplements. Even when mice were given cortisol, a substance which depresses the immune system, additional melatonin counteracted the detrimental effects of the cortisol (Maestroni, 1986).
Melatonin counteracts the effects of stress on the immune system. When mice are restrained, their antibody production drops, the weight of their thymus gland decreases, and their resistance to viruses lessens. Evening administration of melatonin buffered them against the effects of stress (Maestroni, 1988). Many of the harmful effects on the immune system by stress are closely related to signs and symptoms of aging. In the elderly, the thymus gland shrinks and immunity is lowered. Since aging is associated with lower melatonin levels, melatonin replacement may have a role in improving immunity. The elderly are particularly susceptible to pneumonia, flu, and other infections.
Recent studies indicate that melatonin may restore the function of the thymus gland. The thymus gland is involved with the production and maturation of T lymphocytes. Melatonin stimulates the production of T lymphocytes in those who have a poorly functioning immune system (Maestroni, 1993). The mineral zinc is also thought to improve the functioning of the thymus gland. Melatonin is believed to facilitate the interaction of zinc with the thymus gland, allowing another pathway of immune enhancement (Mocchegiani, 1994).
Sze and colleagues found that giving mice melatonin for 2 weeks induced production of powerful virus and bacteria fighting substances such as interferon and interleukin-2.
We all know how great it feels the day after 8 hours of uninterrupted slumber. We feel younger, more energetic, almost forgetting that there is such a thing as “tired.” For the elderly who have low melatonin levels, and toss and turn all night, supplementation could provide that refreshing rest so critical to well-being. In an article published in the November/December, 1994, issue of Psychosomatic Medicine, Michael Irwin, MD, and colleagues, at the San Diego Veterans Affairs Medical Center, studied 23 healthy men, ages 22 to 61. All spent 4 nights in a sleep laboratory. On the third night, volunteers were denied sleep between the hours of 3 am and 7 am. The majority of the subjects had substantially reduced activity of their white blood cells, specifically natural killer (NK) cells. NK cells help protect us from viruses and the abnormal growth of cancer cells.
In brief, melatonin seems to improve the functioning of the immune system, at least in mice, by restoring the thymus gland, increasing interferon production, enhancing antibody production, and enhancing anti-tumor factors (Caroleo, 1994). With time we are likely to find that melatonin also influences countless other components of the immune system. Whether these benefits will be found in humans is still not established.
To Take it (Regularly), or Not to Take: That is the Question
I know a number of individuals, including pineal gland researchers, who have started taking melatonin nightly at doses ranging from 0.1 mg to 10 mg. They do not necessarily take melatonin for sleep, but for its potential health and longevity benefits. Some organizations involved in seeking ways for life extension are recommending that their members use melatonin regularly.
Before we embrace melatonin as the latest age-reversing miracle and swallow megadoses every night, let’s consider these points:
1) There are countless differences between rodents and humans. For one, mice are nocturnal animals— they are active and alert during the night, even though they produce melatonin at night. (For another, they rarely complain of nightmares or depression.)
2) We have little clue on how to extrapolate the life-prolongation doses of melatonin in mice to what would be the right dose in humans. Assuming melatonin does extend human lifespan, is our optimal dose 100mg? 10 mg? 1mg? 0.1mg? or even less? Is it best to take it nightly, every other night, once a week? Would there be a different result with the time-release pills than with the sublinguals?
3) Are there dosage differences between men and women? What are the best doses for different age groups?
4) Could long-term melatonin supplementation have a negative impact on our hormonal system? Could it interfere with our pancreas releasing insulin? our thyroid gland making thyroxine? our adrenal glands making cortisol? etc., etc.? Or, could it help our organs stay young?
5) Since melatonin stimulates the immune system, including lymphocytes, could long-term supplementation lead to uncontrolled multiplication of these cells leading to lymphomas?
6) Are there other substances besides melatonin produced by the pineal gland— such as epithalamin and peptides— that influence longevity? Would melatonin supplementation interfere with their production? Or maybe help?
These are some of our present uncertainties. Anyone who states that they are certain melatonin will increase life span in humans is making a claim that cannot be supported by the currently available scientific data. At this point the continuous use of melatonin for longevity purposes is a gamble. Having said this, and knowing that melatonin levels decline with aging, I feel it is possible that in the future, if we find melatonin supplements can actually make us healthier, physicians may use low doses as a replacement hormone just as we now replace estrogen in postmenopausal women. We could call this MRT (melatonin replacement therapy).
We don’t know for certain the long-term effects of continuous melatonin use in humans— positive or negative. Then again, we don’t know for certain the long-term (10-50 year) effects, or ideal dosages, of many common medicines or supplements, including aspirin and vitamins. However, we do know how melatonin has been used in the short term to help people, as we’ll see in Chapter 6. But first, let’s look at some practical matters involving dosage and timing.
Maryon Stewart
Jim Strohecker
Tom Ferguson MD
