Melatoni Extra2
Melatoni Extra2
21, 2010
Review Article
Introduction
Melatonin is a somewhat mysterious substance. In animals, melatonin is secreted from the pineal gland during the night. It acts as a hormone, functioning as a circadian mediator for time information over the course of each day, and is also able to eliminate free radicals (reactive oxygen species). Melatonin also exists in higher plants (edible plants), and is inadvertently obtained from daily meals 1,2). This substance was isolated by chance from the pineal gland, an endocrine organ, and is therefore named a hormone. Regarding the effect of melatonin in inducing synchronization of circadian rhythms, which is generally regarded as a sleep-promoting effect, melatonin administration lowers deep body temperatures not only in those with rhythm disorders but also in healthy individuals, from children to elderly people 3); shortens the time required to fall asleep; and improves sleep 4). In addition, melatonin functions as an antioxidative substance (Review: Reiter, 2000) 5) and acts on bone metabolism 6). Melatonin thus has a variety of activities. In a rat model, melatonin inhibited age-related visceral adiposity 7). These findings may indicate that in addition to meals and physical exercise, sleep is deeply involved in metabolic syndrome, which has become of increasing concern in recent years. In the Current Concept Session Melatonin at the 9th Scientific Meeting of the Japanese Society of Anti-Aging Medicine in 2009, three speakers presented basic data and their interpretations and applications in clinical settings from the viewpoints of brain functions, sleep medicine, and reproductive functions, namely Melatonin and Brain Functions by Kazuyoshi Tsutsui, Sleep Medicine and Melatonin by Masako Okawa, and Melatonin and Reproductive Functions by Bunpei Ishizuka. This Session was co-held with the Society of Anti-Aging Endocrinology. In the future, we intend to introduce new basic and clinical research studies on melatonin and propose a lifestyle that will not decrease but rather lead to an increase in melatonin.
Anti-Aging Medicine 7 (7) : 85-91, 2010 (c) Japanese Society of Anti-Aging Medicine
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cerebrospinal fluid, saliva, aqueous humor of the anterior chamber, follicular fluid, and breast milk. Melatonin receptors are distributed over a variety of tissues and organs, and accordingly, the time information based on melatonin concentration is transmitted to tissues throughout the entire body. The presence of melatonin receptors has so far been confirmed in the brain (including the SCN), spinal cord, pituitary gland, retina, spleen, thymus, adrenal gland, liver, kidney, heart, lungs, testes, ovaries, blood vessels, lymphocytes, and osteoblasts 11,12). It is therefore assumed that in addition to the melatonin-related synchronization of the circadian clock at the SCN, synchronization with sleep phase may occur at the entire body level, bringing better rest to the body.
study performed by the Anti-Aging Medical Research Center, Doshisha University, demonstrated that when the quality of sleep was upgraded by the use of comfortable bedding, oxidative stress disorders as evaluated by an indicator of urinary 8-hydroxydeoxyguanosine (8-OHdG) were improved 18). This may be explained by the exertion of an antioxidative effect resulting from increased melatonin secretion.
Antioxidative Effect
Melatonin has an antioxidative effect 5). The first mechanism of this effect is to function as a free-radical scavenging antioxidant that removes hydroxy radicals (HO) 13), peroxyl radicals 14), and in addition extremely highly toxic peroxynitrite 15). Melatonin also inhibits lipid peroxidation and blocks the production of isoprostanes 16). The second mechanism of action is to activate endogenous enzymes that scavenge free-radicals. Administration of melatonin to pregnant rats increased the activities of superoxide dismutase (SOD) or glutathione peroxidase in fetal brain tissues 17). Melatonin has its own antioxidative effect and also intensifies the activity of endogenous antioxidative enzymes, which together exert a powerful antioxidative effect. Considering that melatonin is secreted during the nighttime and passes through the blood-brain barrier, it may play a preventive role against oxidation disorders of cerebral nerve cells during nocturnal sleep. A clinical
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The circadian change in spontaneous locomotor activity was analyzed in relation to 7-hydroxypregnenolone synthesis and melatonin secretion 23,24). Quail is active during the daytime: the amount of spontaneous locomotor activity is circadian, being high during the light period and low during the dark period. Melatonin is secreted during the dark period and inhibits the synthesis of 7 -hydroxypregnenolone: the amount of spontaneous locomotor activity in quail decreases during the dark period. In newts, a nocturnal animal, melatonin secreted during the dark period accelerates the synthesis of 7-hydroxypregnenolone, which increases the amount of spontaneous locomotor activity during the dark period. It is thus evident that the regulation of 7 -hydroxypregnenolone synthesis by melatonin plays a central role in the circadian rhythms of animal activity.
may reduce intracellular cAMP via Gi-proteins, and control the activity of cAMP sensitive phosphotyrosine phosphatase, accelerating phosphorylation of insulin receptors 25). Administration of melatonin to an experimental rat model of diabetes improved blood levels of neutral fat, free fatty acid, and total cholesterol, and in addition reduced TNF- 50% 29). On the other hand, pinealectomy increased insulin resistance and induced hyperinsulinemia, accelerating disease progression in type 2 diabetic rats 30). These animal data indicate that melatonin improves insulin resistance. Long-term administration of melatonin to humans and experimental animals reduces blood and liver cholesterol and LDL-cholesterol levels 31). These effects are remarkably noted in experimental animal models of hypercholesterolemia, middle-aged and older animals, and experimental animal models of diabetes, but rarely noted in young healthy rats. Treatment of peri- and postmenopausal women with melatonin increased HDL-cholesterol 32). Overall, melatonin may favorably affect lipid metabolism.
Adapted from Reference No. 27 (Nishida S. Effect of melatonin on glucose and lipid metabolism. Modern Physician 27: 1127-1130, 2007.)
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More recently, newly discovered functions of melatonin involvement in regulation of bone metabolism have been reported. A joint study performed by the Department of Biology, Tokyo Medical and Dental University, and the Marine Laboratory, Kanazawa University, used fish scales as an experimental bone model and found that melatonin inhibits the activity of osteoclasts 35). Subsequently, the study group reported that melatonin derivatives enhanced bone mineral density and bone strength in ovariectomized rats (an experimental model of post-menopausal osteoporosis) and in rats fed with low-calcium feed 6). In addition, administration of melatonin to growing mice increased bone mineral density and bone mass, to which a reduction of RANKL-mediated osteoclast formation was reported to contribute 36). In ovariectomized rats with fewer osteoblasts and more osteoclasts, melatonin treatment returned the numbers of both osteoblasts and osteoclasts to the control levels 37). The presence of melatonin receptors was proven in osteoblasts derived from human jaw bones and ilia, and melatonin accelerated the proliferative differentiation of osteoblasts and increased collagen production 38). On the basis of comprehensive evaluation of the above findings, it is expected that melatonin may prevent osteoporosis and accelerate fracture healing (bone regeneration).
Relation to Cancer
It is generally accepted that breast and endometrial carcinomas occur less frequently in the blind than in the nonhandicapped. This may be because the absence of light stimulation on the retina keeps blood melatonin at high levels 45,46). In addition, experimental studies have demonstrated the anti-tumor effects of melatonin in different types of tissues. Melatonin inhibited the formation of azoxymethane-induced aberrant crypt foci in rat colon 47). Although treatment of LNCaP cells derived from the prostate with dihydrotestosterone increased PSA production, melatonin inhibited this increase 48) and induced apoptosis of LNCaP cells 49). Melatonin receptor 1a might be a tumor suppressor gene and it has been demonstrated that melatonin inhibits oral squamous-cell carcinoma via this receptor 50). In an estrogen-positive uterine body cancer cell line, melatonin significantly intensified the anti-tumor effect of paclitaxel 51), which is mediated by the melatonin receptor 1a and involves expression of the estrogen receptor. In breast cancer cells, melatonin inhibited the expression of estrogen-responsive cancer-related genes 52). It is expected that combined use of melatonin in a variety of anticancer therapies may bring additional efficacy.
significantly increased and sleep was improved 57). Furthermore, a 4-year follow-up study demonstrated that in the group of subjects in whom melatonin secretion decreased, sleep was improved by melatonin treatment. Among patients with circadian rhythm sleep disorders, 30 with delayed sleep phase syndrome (DSPS) and 16 with non-24-hour sleep-wake syndrome (non-24h) received melatonin treatment. A total of 17 patients (12 with DSPS and 5 with non-24h) responded to melatonin, showing normalization of the time required to fall asleep and wake; and the duration of sleep became adequate 58). Those who responded to melatonin had a shorter duration of sleep and had developed the clinical symptoms at an older age than those who did not respond to the treatment. In light of the above studies, melatonin may affect sleep homeostasis or the clock system related to biological rhythms, as it acts on the autonomous nerve system and endocrine system to affect the sleep regulating system. Its application to medical use has been expanded.
Conclusion
Age-related changes in hormone secretion include somatopause, which is the decline in secretion of the growth hormone/IGF-I system; adrenopause, which is the decline in DHEA (-s) level; and menopause/andropause, which is the decline in secretion of sex hormones 74). Since melatonin secretion by the pineal gland substantially decreases with aging, we would like to propose the term pinealpause to characterize this condition. In the elderly, endocrine diseases are characterized by the fact that reduced secretion of a single hormone alone among the above does not cause symptoms, but rather that declining levels of multiple hormones induce composite symptoms. Deepening our understanding of interactions among hormones from the viewpoint of Anti-Aging Medicine is important to the realization of hormone replacement therapies. Hormone replacement therapy has two main aspects: to replenish a hormone that is diminishing, and to promote health. How much a given hormone will be replenished should not be determined according to a one-size-fits-all criterion but needs to be adequately quantified on the basis of an individuals morphometry, intensity of activity, desired lifestyle patterns, and blood hormone levels. For melatonin, however, no methods have been established to make an accurate measurement of its secretion. The key to understanding how to administer these hormones safely and effectively while minimizing adverse events and achieving maximum benefit first depends on the accumulation of data from many medical institutions over a long period of time.
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