Anti-Aging Supplement Review and Update Part 3
By Ward Dean, MD
Melatonin is the principal hormone produced by the pineal gland, a tiny, pea-sized structure located in the base of the brain. Throughout the day the pineal gland monitors changing light levels and, sensing the approach of darkness, increases its output of melatonin. For this reason the primary secretion of melatonin occurs with nightfall, and nighttime melatonin levels are 10 times higher than daytime levels.1Although it is best known as a sleep-inducing hormone, melatonin also controls the timing and release of many other hormones and strongly influences our circadian bio-rhythms. Melatonin is one of the most potent antioxidants known, with a wide range of clinically beneficial effects.
Physiological or biochemical parameters that change with age, such as DHEA serum levels, are known as “biomarkers.” Biomarkers aid in determining biological age and health status. One of the major goals of anti-aging science is to restore as many biomarkers as possible to the most youthful levels possible. And since melatonin production drops like a rock as we get older, nighttime melatonin levels serve as one of the best biomarkers currently available (Fig. 1). 2-6
In fact, the age-related decline of melatonin levels is so dramatic that it has been proposed as an index of brain aging in humans.
Additionally, not only do absolute levels of melatonin decline sharply with age, but the timing of melatonin release also changes as we get older. As can be seen in Fig. 2, melatonin levels in young people begin to rise earlier in the evening, and peak sooner and higher than they do in older people.7 This decline in both the total output and the rhythmicity of melatonin is a major contributor to the disturbance of sleep patterns experienced by many older people.
Mechanisms of Action
One characteristic shared by many effective anti-aging substances is that they exhibit multiple mechanisms of action. Melatonin is no exception. In fact, melatonin simultaneously acts as 1) a hormone, 2) a hormone-receptor sensitizer, 3) a powerful antioxidant, 4) a mitochondrial resuscitator, 5) a neuroprotectant, and 6) an immune-enhancer.
Melatonin is one of the most potent antioxidants known. It has ubiquitous actions, both as a direct and indirect antioxidant and free radical scavenger. Besides directly detoxifying a variety of highly reactive molecules, melatonin also stimulates antioxidative enzymes. Additionally, one of the byproducts formed from melatonin’s interaction with free radicals, N1-acetyl-N2-formyl-5-methoxykynuramine, is itself a potent free radical scavenger that is at least as potent an antioxidant as melatonin itself. This ability to induce this “antioxidant cascade” serves to increase melatonin’s effectiveness for resisting oxidative damage.
Japanese scientists evaluated several indicators of free-radical activity in the brains of mice (Thiobarbituric acid-reactive substances [TBARS], protein carbonyls, and glutathione peroxidase [GPx] activity), and found that TBARS and protein carbonyls rose with age and GPx activity was decreased.8 When they administered melatonin (2 microg/ml) in the drinking water, they found that brain protein carbonyl content and brain TBARS decreased significantly (over 30 percent), and GPx activity increased (over 20 percent). The scientists concluded that melatonin reverses a number of age-related changes in brain tissue and reduces brain cell vulnerability to oxidation through its ability to scavenge oxygen free radicals and to stimulate antioxidant enzyme activity.
In related research in India, similar studies were conducted with melatonin on the brain, liver, spleen and kidney tissues of mice. Old mice were supplemented with melatonin (0.10 mg/kg body weight per day) for three months; evaluations were then made on lipid peroxidation, reduced glutathione (GSH), glutathione disulphide (GSSG), glutathione peroxidase (GPx) and serum phosphatase activity. Melatonin significantly inhibited the age-induced declines in GSH, GPx and alkaline phosphatase activity, causing the scientists to conclude that low-dose chronic administration of melatonin acts as an anti-aging agent.9
In addition to its profound antioxidant properties, melatonin also stimulates electron transport and ATP production in the inner-mitochondrial membrane, thereby acting as a potent mitochondrial resuscitator.10
Scientists at UC Irvine fed melatonin to adult mice for six months to determine its effects on age-associated changes in brain-mitochondrial-electron-transport- chain-enzyme activities. They discovered that while cytochrome c oxidase (Complex IV) activity decreases with age, supplementation with melatonin effectively restored activity to the levels of young animals.11
Japanese scientists also tested the effect of long-term melatonin administration (2 mcg/ml of drinking water) on mitochondrial activity.12 They evaluated a number of age-related parameters of mitochondrial activity in the livers of these mice (Respiratory Control Index [RCI], adenosine-5-diphosphate [ADP]/O ratio, State 3 respiration and dinitrophenol [DNP]-dependent uncoupled respiration and complex I and IV). They found that activities were all improved by melatonin. The scientists concluded that age-related reductions in mitochondrial function in mice are improved by melatonin, and that “melatonin is beneficial during aging, as it reduces the age-related deteriorative oxidative changes in mitochondria and other portions of the cell.”
Melatonin’s beneficial effects on mitochondrial homeostasis may explain its protective properties for a number of degenerative conditions, including aging, Parkinson’s disease, Alzheimer’s disease, epilepsy, sepsis and other injuries such as ischemia-reperfusion. A common feature in these diseases is mitochondrial damage due to oxidative stress, which leads to decreased mitochondrial efficiency and ATP production, and, as a consequence, increased free-radical generation. In sum, melatonin directly scavenges a variety of toxic oxygen- and nitrogen-based reactants, stimulates antioxidative enzymes, and increases the efficiency of the electron-transport chain (thereby limiting electron leakage and free radical generation, and enhancing ATP synthesis). Via these actions, melatonin preserves the integrity of the mitochondria and helps to maintain cell functions and survival.12
Cytokines are proteins that act as important modulators of the immune system. Many cytokines demonstrate age- related changes—especially interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha)—both of which rise with age. When old mice were treated with melatonin (200 ppm) for six weeks, basal levels of these inflammatory cytokines were reduced to values normally found in the young animals. The researchers concluded, “these findings reflect a trend in melatonin-treated aged mice, to more closely approximate the status of younger mice.”14
A common problem for older people is that they don’t experience the same quality of restorative sleep that they did in their youth. This problem is characterized by difficulty in falling asleep at night, inability to sleep soundly throughout the night, and difficulty in returning to sleep once it has been interrupted. Naturally this lack of quality sleep leads to daytime fatigue, irritability, memory problems and depression. One of the major causes of age-related sleep disturbances is a reduction in the amount, and alteration in the timing, of melatonin production by the pineal. Supplementation with melatonin has often been shown to ameliorate these disturbances in the sleep-wake rhythm.15-18
Another cause of sleep disturbance, and one unique to older men, is benign prostatic hypertrophy (BPH). Men with BPH have to get up and urinate repeatedly throughout the night in response to the pressure exerted on the bladder by an enlarged prostate gland. Physicians in the United Kingdom evaluated the effects of melatonin on nocturia (night-time urination) in men with BPH.20
Using a bedtime dosage of 2 mg melatonin for four weeks, the physicians found that, although melatonin treatment did not improve the BPH itself, it did result in an improvement in the “nocturia response rate” and improvement in “nocturia related bother” (i.e., they were less troubled by their BPH at night).
Jet lag occurs when our biologic clock becomes “desynchronized.” This condition is caused by drastic changes in the sleep-wake cycle, such as when crossing multiple time zones during east-west (or even worse, west-east) travel, or when performing shift work with rotating shifts (like physicians and nurses, law enforcement officers, management trainees for 24-hour business, soldiers under battle-alert conditions, etc). Jet lag is characterized by fatigue, early awakening or insomnia, headaches, fuzzy thinking, irritability, constipation, and reduced immunity. It may take as much as one day for each time zone crossed in order to fully recover. Older people have an even tougher time adjusting to these changes than younger people.
Melatonin taken in the evening (in the new time zone) rapidly resets the biological clock, and almost totally alleviates (or prevents) the symptoms of jet lag. The ability of melatonin to alleviate jet lag was demonstrated in a study of 17 subjects flying from San Francisco to London (eight time zones away). Eight subjects each took 5 mg of
melatonin, while nine subjects took a placebo. Those who took melatonin suffered almost no symptoms from jet lag (Fig. 3).19 For jet lag prevention and treatment, I recommend a dosage of one mg for each time zone crossed, in addition to any dose a person normally takes. Usually, this high dose needs to be taken for only one or two
Melatonin has been shown to have significant anti-cancer properties in cellular (in vitro), animal, and human studies. For example, scientists in China found that melatonin significantly inhibited the growth of hepatocarcinoma (liver cancer) cells by inducing apoptosis (“cell suicide”) and by extending the length of the cell cycle (i.e., reducing the speed of replication) of the tumor cells.21 Melatonin has also been shown to inhibit the growth of mammary tumors in animals.22
A number of human clinical studies have incorporated melatonin in the treatment of cancer — both as a single agent, and in combination with other therapies. Melatonin is usually taken in a dose of 20 mg at bedtime when used as adjunctive therapy for cancer, although dosages as high as 40 mg nightly have been used. Melatonin appears to enhance the efficacy of other forms of cancer treatment, reduces adverse side effects of the other treatments, increases survival and improves the patients’ quality of life.23
Melatonin has also been shown to protect mammalian cells from the destructive effects of ionizing radiation. Clinical reports indicate that melatonin administration, in combination with traditional radiotherapy, results in a reduction of radiation-induced adverse effects in the treatment of human cancers. Melatonin has also been proposed as a means of protecting individuals from radiation terrorism.24
Italian scientists proposed that the decline in melatonin levels is the signal that triggers the onset of menopause.25 In studies on perimenopausal and menopausal women from 42 to 62 years of age, Bellipanni and colleagues found that melatonin administered at bedtime for six months resulted in increased thyroid hormone levels, and a suppression of LH (a hormone that rises with age) in women under 50. In addition, they reported that melatonin resulted in a general improvement of mood, a significant mitigation of depression, restoration of pituitary and thyroid functions, and a trend towards a more juvenile pattern of hormonal regulation.
Stimulates Growth Hormone
One of the inevitable consequences of growing older is the age-related drop in production of Growth Hormone (GH) (Fig. 4). A number of human studies have shown that melatonin can significantly stimulate the release of growth hormone. Italian scientists discovered that oral doses of 10 mg of melatonin caused an increase in basal GH release while enhancing GH responsiveness to GHRH.26 When the dose of melatonin was increased to 12 mg orally, serum GH levels jumped fivefold.27And in England scientists demonstrated that a single dose of oral melatonin (5 mg) enhanced exercise-induced GH secretion, as well as IGFBP-1.28
Life-Extension and Anti-Aging Studies
Two of the earliest lifespan studies with melatonin were conducted by Drs. Georges Maestroni and Walter Pierpaoli.29,30 They gave melatonin to mice, administering a dose of 10 mcg/ml each evening in the drinking water. At the start of the study the mice were already at the relatively advanced age of 575 days. The treated mice not only exhibited a 20 percent increase in maximum lifespan (Fig. 5), but they also exhibited many signs of younger mice, including more lustrous fur, greater vigor, more activity and better posture. The second study in a different strain of mouse produced similar results (Fig. 6).
Dr. Vladimir Anisimov—an associate of Prof. Vladimir Dilman (originator of the neuroendocrine theory of aging) — has also extensively researched
the effects of melatonin on lifespan. In one recent study, Anisimov and his colleagues gave melatonin to female mice (20 mg/l in drinking water) for five days every month, beginning at the age of six months.31 They found that melatonin inhibited free-radical processes in serum, brain, and liver; slowed down the age-related switching-off of estrous function (in essence, delayed “menopause”); and increased the lifespan. On the negative side, they also reported that treatment with melatonin increased the incidence of tumors.
In a followup study with another strain of mice, Dr. Anisimov and his colleagues administered melatonin (2 or 20 mg/l in drinking water) for five consecutive days every month, beginning at three months of age.32 Again melatonin was found to slow down the age-related switching-off of estrous function. And while melatonin failed to influence the mean lifespan in this study, it did increase the lifespan of the last 10 percent of the survivors in comparison to controls. Importantly, treatment with the low dose melatonin (2 mg/l) actually decreased tumor incidence (almost twofold), whereas the higher doses (20 mg/l) had no effect on tumor incidence. Because of their conflicting results, Anisimov and colleagues cautioned against melatonin as a “geroprotector” for long-term use. However, I disagree with their conclusions.
Despite the increase in tumors in the first study, the melatonin paradoxically resulted in an increased mean and maximum lifespan compared to the control group—so the “tumorigenic effect” was overcome by the anti-aging and life-extending benefits. In fact, in the second study there was no increase in tumors on the high-dose melatonin, and there was a decrease in tumor incidence with the low-dose. Thus, it is likely that the species of mouse used in these studies had a unique, “idiosyncratic” response to melatonin.
Another organism that has repeatedly been shown to respond to the life-extending effects of melatonin is the lowly fruit fly, Drosophila melanogaster. 33,34 The most recent study to confirm these results was conducted by scientists in Venezuela. When they added melatonin to the nutrition medium at a concentration of 100 mcg/ml, they again measured a significant increase in the flies’ lifespan. Melatonin increased the maximum lifespan of the melatonin-fed flies by 33 percent, and the www. lifespan by 13 percent, lending further support to the anti-aging reputation of melatonin.35
Melatonin is one of the best-studied and most effective anti-aging nutrients available today. Melatonin has also been shown to confer a host of beneficial effects in humans, including enhancing immune system function, improving sleep onset, duration and quality, and stimulating the release of GH. In addition to its proven ability to restore melatonin levels to youthful levels in humans, researchers have repeatedly demonstrated melatonin’s unique ability to extend maximum lifespan in a number of species of organisms.
While I believe that melatonin is fine for occasional use by younger people, I do not recommend its use on a regular basis by those under age 35. For those over 35, I recommend a dose that will help one get to sleep (usually in the range of 3 to 6 mg, more or less), yet not cause grogginess upon awakening. For jet lag, I recommend 1 mg per time zone crossed, in addition to one’s usual nightly dose (i.e., for someone who normally takes three mg, who travels across five time zones, the dose would be 8 mg taken at bedtime in the destination time zone).
For those suffering from cancer, I recommend that a dose of 20 to 40 mg be taken in a single dose at night. Regarding melatonin safety, Walter Pierpaoli once told me that “melatonin is so safe, you can take it by the pound.”
Criteria for Selecting Anti-Aging Nutrients for This Series
For this series of articles reviewing top anti-aging nutrients, Ward Dean, MD, has selected substances based on several criteria:The mechanism by which the substance is believed to act. Most substances discussed are involved in one or more theories of aging (i.e., antioxidants/free radical theory; cross linkage inhibitors/cross linkage theory; hormone receptor sensitizers/neuroendocrine theory, etc).
- The health-enhancing effect of the substance.
- Whether the substance has shown the capability to reverse or restore a biomarker to a more youthful state.
- Has the substance demonstrated the ability to extend the maximum lifespan of one or more experimental organisms?
- Practical considerations: An individual’s “pill capacity”—how many capsules/ tablets is a person willing to take? Cost and availability—for example, some substances are beyond the reach of many people due to high cost or other impediments (i.e., legal issues, availability, requirement for a prescription, etc.).
Based on these criteria, the series of articles presents what Dr. Dean considers to be the most effective anti-aging/life extending substances readily available today. The substances featured are presented in no particular order. The first article in the series focused on DHEA, published in the June 2004 issue; part 2, on CoQ10, appeared in July.
1. Touitou Y. Human aging and melatonin. Clinical relevance. Exp Gerontol 2001 Jul;36(7):1083-1100.
2. Iguchi H., Kato K.J., Ibayashi H. Age dependent reduction in serum melatonin concentrations in healthy human subjects. J Clin Endocrinol Metab 1982 55:27-29.
3. Beck Friis J., Von Rosen D., Kjellman B.F., et al. Melatonin in relation to body measures, sex, age, season and the use of drugs in patients with major affective disorders and healthy subjects. Psychoneuroendocrinology 1984 9:261-278.
4. Waldhauser F., Weiszenbacher G., Tatzer E., et al. Alterations in nocturnal serum melatonin levels in humans with growth and aging. J Clin Endocrinol Metab 1988 66:648-652.
5. Reiter R. The pineal gland and melatonin in relation to aging: A summary of the theories and of the data. Experimental Endocrinology 1995 30 (3-4):199-212.
6. Zhao Z.Y., Xie Y., Fu Y.R., Bogdan A., Touitou Y. Aging and the circadian rhythm of melatonin: a cross-sectional study of Chinese subjects 30-110 yr of age. Chronobiol Int 2002 Nov;19(6):1171-82.
7. Nair N.P.V., Hariharasubramanian N., Pilapil C., Isaac I., Thavundayil J.X. Plasma melatonin—An index of brain aging in humans? Biol Psychiatry 1986 21:141-150.
8. Okatani Y., Wakatsuki A., Reiter R.J., Miyahara Y. Melatonin reduces oxidative damage of neural lipids and proteins in senescence-accelerated mouse. Neurobiol Aging 2002 Jul-Aug;23(4):639-44.
9. Manda K., Bhatia A.L. Melatonin-induced reduction in age-related accumulation of oxidative damage in mice. Biogerontology 2003 4(3):133-9.
10. Reiter R.J., Tan D.X., Manchester L.C., El-Sawi M.R. Melatonin reduces oxidant damage and promotes mitochondrial respiration: implications for aging. Ann N Y Acad Sci 2002 Apr;959:238-50.
11. Sharman E.H., Bondy S.C. Effects of age and dietary antioxidants on cerebral electron transport chain activity. Neurobiol Aging 2001 Jul-Aug;22(4):629-34.
12. Okatani Y,. Wakatsuki A., Reiter RJ, Miyahara Y. Hepatic mitochondrial dysfunction in senescence-accelerated mice: correction by long-term, orally administered physiological levels of melatonin. J Pineal Res 2002b Oct;33(3):127-33.
13. Leon J., Acuna-Castroviejo D., Sainz R.M., Mayo J.C., Tan D.X., Reiter R.J. Melatonin and mitochondrial function. Life Sci 2004 Jul 2;75(7):765-90.
14. Sharman K.G., Sharman E.H., Yang E., Bondy S.C. Dietary melatonin selectively reverses age-related changes in cortical cytokine mRNA levels, and their responses to an inflammatory stimulus. Neurobiol Aging 2002 Jul-Aug;23(4):633-8.
15. Van Someren E.J. Circadian and sleep disturbances in the elderly. Exp Gerontol 2000 Dec;35(9-10):1229-37.
16. Pandi-Perumal S.R., Seils L.K., Kayumov L., Ralph M.R., Lowe A., Moller H., Swaab D.F. Senescence, sleep, and circadian rhythms. Ageing Res Rev 2002 Jun;1(3):559-604.
17. Pawlikowski M., Kolomecka M., Wojtczak A., Karasek M. Effects of six months melatonin treatment on sleep quality and serum concentrations of estradiol, cortisol,
dehydroepiandrosterone sulfate, and somatomedin C in elderly women. Neuroendocrinol Lett 2002 Apr;23 Suppl 1:17-9.
18. Skene D.J., Swaab D.F. Melatonin rhythmicity: effect of age and Alzheimer’s disease. Exp Gerontol 2003 Jan-Feb;38(1-2):199-206.
19. Arendt J., Aldhous M., Marks V. Alleviation of jet lag by melatonin: Preliminary results of controlled double blind trial. Br Med J 1986 May 3;292(6529):1170.
20. Drake M.J., Mills I.W., Noble J.G. Melatonin pharmacotherapy for nocturia in men with benign prostatic enlargement. J Urol 2004 Mar;171(3):1199-202.
21. Qin L., Wang X., Duan Q., Chen B., He S. Inhibitory effect of melatonin on the growth of H22 hepatocarcinoma cells by inducing apoptosis. J Huazhong Univ Sci Technolog Med Sci 2004 24(1):19-21,31.
22. Carranza-Lira S., Garcia Lopez F. Melatonin and climactery. Med Sci Monit 2000 Nov-Dec;6(6):1209-12.
23. Lissoni P. Melatonin and cancer treatment, in: Melatonin in the Promotion of Health by R.W. Watson, CRC , Boca Raton, 1999 pp.175-190.
24. Vijayalaxmi, Reiter R.J., Tan D.X., Herman T.S., Thomas C.R. Jr. Melatonin as a radioprotective agent: a review. Int J Radiat Oncol Biol Phys 2004 Jul 1;59(3):639-53.
25. Bellipanni G., Bianchi P., Pierpaoli W., Bulian D., Ilyia E. Effects of melatonin in perimenopausal and menopausal women: a randomized and placebo controlled study. Exp Gerontol 2001 Feb;36(2):297-310.
26. Valcavi R, Zini M, Maestroni GJ, Conti A, Portioli I. Melatonin stimulates growth hormone secretion through pathways other than the growth hormone-releasing hormone. Clin Endocrinol (Oxf) 1993 Aug;39(2):193-9
27. Coiro V., Volpi R., Capretti L., Giuliani N., Caffarri G., Colla R., Marchesi C., Chiodera P. Different effects of naloxone on the growth hormone response to melatonin and pyridostigmine in normal men. Metabolism 1998 Jul;47(7):814-6.
28. Forsling M.L., Wheeler M.J., Williams A.J. The effect of melatonin administration on pituitary hormone secretion in man. Clin Endocriol (Oxf) 1999 51(5):637-642.
29. Maestroni G.H.M., Conti A., Pierpaoli W. Pineal melatonin, its fundamental role in aging and cancer, in: Neuroimmunomodulation: Interventions in Aging and Cancer. Annals of the NY Academy of Sciences 1988 521:140-148.
30. Maestroni G.H.M., Conti A., and Pierpaoli W. Melatonin, stress and the immune system. Pineal Research Reviews 1989 7:203-26.
31. Anisimov V.N., Zavarzina N.Y., Xabezhinski M.A., et al. Melatonin increases both life span and tumor incidence in female CBA mice, J Gerontology Biological Sciences 2001 56A, B311-B323.
32. Anisimov V.N., Alimova I.N., Baturin D.A., Popovich I.G., Zabezhinski M.A., Rosenfeld S.V., Manton K.G., Semenchenko A.V., Yashin A.I. Dose-dependent effect of melatonin on life span and spontaneous tumor incidence in female SHR mice. Exp Gerontol 2003 Apr;38(4):449-61.
33. Anisimov V.N., Mylnikov S.V., Oparina T.I., Khavinson V.K. Effect of melatonin and pineal peptide preparation epithalamin on life span and free radical oxidation in Drosophila melanogaster. Mech Ageing Dev 1997 Aug;97(2):81-91.
34. Izmaylov D.M., Obukhova L.K. Geroprotector effectiveness of melatonin: investigation of lifespan of Drosophila melanogaster. Mech Ageing Dev 1999 Jan 15;106(3):233-40.
35. Bonilla E., Medina-Leendertz S., Diaz, S. Extension of life span and stress resistance of Drosophila melanogaster by long-term supplementation with melatonin. Exp Gerontol 2002 37:7629-638.
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