Melatonin A Universal Guardian?

Written by ECCLES, BSc, Ph.D., MBBS, MRCP, Nyjon

The role of Melatonin in hormonal regulation and ageing has been described and reviewed in an elegant way by Pierpaoli in his book “The Key of Life” (2007). The fact remains that this molecule seems to be Universally conserved across animal but also plant species; this fact alone should draw attention to its likely universal importance.

It was named melatonin because of its ability in certain fish, reptiles and amphibians to lighten skin (Lerner et al. 1958).

5-methoxy-N-acetyltryptamine, is a hormone found in all living creatures from algae (Caniato et al, 2003) to humans, at levels that vary in a diurnal cycle. Since the rhythmic formation of melatonin has been demonstrated in unicellular organisms, invertebrates and vertebrates, it is hypothesized that this conserved molecule plays an important role in providing the clock and calendar information to all living organisms, including man. This large body of evidence permits the statement that melatonin is an (almost) ubiquitous substance. Ubiquity frequently indicates fundamental biological significance.

In higher animals, melatonin is produced by pinealocytes in the pineal gland (located in the brain) and also by the retina, lens and GI tract. It is naturally synthesized from the amino acid tryptophan (via synthesis of serotonin) by the enzyme 5-hydroxyindole-O-methyltransferase. Production of melatonin by the pineal gland is under the influence of the suprachiasmatic nucleus (SCN) of the hypothalamus which receives information from the retina about the daily pattern of light and darkness. It is secreted from the pineal gland at night, from where it diffuses into the cerebro-spinal fluid and the blood stream. It seems to be responsible for the synchrony of circadian rhythm, modulating sleep patterns with day and night. The activity of the enzyme N-acetyltransferase increases 30 to 70 times during the nocturnal hours and consequently the maximum levels of melatonin are found between 24.00 and 4.00 hours. By contrast, melatonin produced by the retina and the gastrointestinal (GI) tract acts as a paracrine hormone (local action).

The pineal gland, a small gland located at the base of the brain, was viewed by the ancient Greeks as the seat of the soul. The ability of light when applied at night (or the dark phase of the light-dark illumination cycle) to shut down the enzymatic machinery required for nocturnal melatonin production, with subsequent dramatic decline in melatonin levels, is common to all animal species studied thus far.

Melatonin is metabolized in the brain and the liver and excreted in the urine; it acts as a neurotransmitter and neuromodulator; it also plays a major role in interactions between the neuroendocrine and immune systems. It has a half life of 35 to 50 minutes. Many studies confirm that the normal peak level of melatonin in human serum is 10-200 picogram/ml (1). Also, serum melatonin levels in humans vary markedly with age, showing consistent circadian pulses until the mid 20’s, after which the pulses decline with age until the 60’s (Carlson, 1994; Brzezinski, 1997; Yu & Reiter, 1993; Foulkes et al, 1997; Olcese, 2000; Bartness & Goldman, 1989; Reiter, 1993; Humbert & Pevet, 1994).

There are some foods that contain small amounts of melatonin. Oats, sweet corn, and rice are the best sources of melatonin. However, to get the same amount of melatonin that is found in a supplement pill, you would need to eat about 20 bowls of oats. Ginger, tomatoes, bananas, and barley also contain small amounts of melatonin.
Melatonin in Plants (Phytomelatonin)

The August 2001 review in Journal of Pineal Research notes that plant research on melatonin is in its infancy and is hampered by the use of melatonin analysis methods for animals that are not suitable for plant tissue. Detection, destruction during extraction procedures (Pape & Luning, 2006), and environmental factors such as soil quality, temperature, and stress (De la Puerta et al, 2007) affect melatonin levels in plants and may be part of the reason for the difference in levels observed.

In 1995, it was detected in a variety of edible plants, and it is known that melatonin from plant foods is absorbed from the gastrointestinal tract and incorporated in the blood stream. This indoleamine also crosses the blood brain barrier and the placenta, being incorporated at the subcellular level. Melatonin has been detected and quantified in roots, shoots, leaves, fruits and seeds of a considerable variety of plant species. The levels of melatonin in plant organs vary considerably, from picograms to micrograms per gram of plant material. Generally, seeds and leaves present the highest level of melatonin and fruits the lowest. (Dubbels et al, 1995; Hattori et al, 1995; Burkhardt et al, 2001; Manchester et al. 2000; Balzer & Hardeland, 1996; Van Tassel et al. 2001).

Melatonin is found in many fruits and vegetables. Grapes, red wine, tomatoes, olive oil, rice, beer, nuts and seeds have significant levels of the compound. Phytomelatonin has the same chemical structure as that produced by the human body. Some herbs (medicinal or not) present high levels of melatonin, in the order of micrograms/g dry weight, as is the case of Hypericum perforatum (St. John’s wort), Tanacetum parthenium (feverfew) and some Chinese medicinal herbs.( Murch et al, 1997; Chen et al, 2003; Murch et al, 2004; Simopoulos et al, 2005). Melatonin was found in most of the 108 medicinal herbs commonly used in traditional Chinese medicine. In 64 herbs, its amount was above 10 ng g-1 DW, in 34 above 100 ng g-1 DW and in 10 above 1,000 ng g-1 DW (Chen et al. 2003). It was very interesting that the highest melatonin concentrations were observed in the herbs used to retard aging and to treat diseases which associate with free radicals (e.g. neurological disorders) (Chen et al. 2003).

Melatonin is synthesized from trytophan, which is also a precusor to the important plant hormone, auxin. Melatonin may eventually become recognized as a plant hormone after its role in plants has been further researched. However, the exact role of melatonin in plants remains to be elucidated. Experimental data indicate a role similar to the auxin molecule (Hernandez-Ruiz, Cano, & Arnao, 2004, 2005) and a protective effect in germ cells has been proposed (Manchester et al., 2000). The high concentration of melatonin detected in seeds presumably provides antioxidative defense in a dormant and more or less dry system, in which enzymes are poorly effective and cannot be up-regulated. Melatonin may protect lipids stored in seeds against peroxidation, thus increasing seeds viability and vigor (Van Tassel and O’Neil 2001; Manchester et al. 2000). Generally, as it was mentioned before, the physiological concentrations of melatonin in the seeds studied were very high, for example, in white and black mustard seeds it was 129 and 189 ng g-1, respectively. This level of melatonin is much higher than the known physiological concentrations in the blood of many vertebrates.

As in animals, the amount of melatonin is higher in young, reproductive plant tissues and falls down during senescence.

According to new Italian research ( Iriti et al, 2010), melatonin has been identified in the key parts of the Mediterranean diet including grapes, wine, olive oil, tomatoes and beer. French, Spanish and Italian wines, especially reds, have all been shown to have levels much higher than other alcoholic drinks, such as whisky, gin, vodka and rum. The melatonin is thought to come directly from grapes. Melatonin was also found in olive oil, especially extra virgin, and in purslane, a commonly used salad ingredient in the region. The melatonin levels in the case of the extra virgin olive oil samples were roughly almost double those of both the refined olive and sunflower oil samples. Research also shows that consuming melatonin-rich food and drink leads to increased levels of the hormone in the blood. And in laboratory animals, melatonin levels increased threefold after eating walnuts.

One study, as yet unpublished, cited by the Italian team showed that blood levels of the hormone increased by 20 per cent one hour after drinking a 100ml glass of red wine. Does this partly explain why so many people can relax with a glass of wine? The well-established pharmaconutritional properties of this fruit may be due not only to the presence of polyphenolic nutrients, such as Resveratrol, anthocyanins and proanthocyanidins, but also to the powerful antioxidant activity of melatonin.

There is a correlation between dietary vegetable intake and blood levels of melatonin (Reiter, Manchester, & Tan, 2005; Reiter et al., 2001), demonstrating that this molecule is well absorbed and it readily raises blood plasma concentration of melatonin (Nagata, Nagao, Shibuya, Kashiki, & Shimizu, 2005; Reiter et al., 2001). One might postulate that the proven protective health benefits reported for fruits and vegetables against a broad range of diseases including cancer, heart disease and stroke (see Eccles, 2010) may be contributed to by their mealtonin content. Recent studies have demonstrated that dietary combinations of phytochemicals show enhancing health benefits by additive and synergistic effects (Jacobs & Steffen, 2003; Liu,2004).

Table taken from: Russel J. Reiter and Dan-Xian Tan. 2002. Melatonin: An antioxidant in edible plant.
Ann. N. Y. Acad. Sci. 957: 341-344. (Table 1)

Although the exact function of melatonin in plants is not well defined, it is hypothesised that it probably functions as a night signal, coordinating responses to diurnal and photoperiodic environmental cues. Melatonin was observed to be elevated in alpine and mediterranean plants exposed to strong UV irradiation, a finding amenable to the interpretation that melatonin’s antioxidant properties can antagonize damage caused by light-induced oxidants (Hardeland and Pandi-Perumal 2005; Afreen et al. 2006). In ripe tomato fruit, the level of melatonin is much higher than that in green ones. It may be connected with protection of fruit against high free radical generation during ripening (Dubbels et al. 1995).

The list of the potential functions of melatonin in humans continues to extend far beyond the sleep and jet lag correction that remain the most popular associations in the minds of those who have at least some knowledge of the molecule.

Its role in regulating hormonal systems such as thyroid and adrenal as well as the female sex hormone axis are reviewed elsewhere as are the apparent age-reversing effects; at least in animals. Recent research has concluded that melatonin supplementation in perimenopausal women produces a highly significant improvement in Thyroid function and gonadotropin levels, as well as restoring fertility and menstruation, delaying the onset of menopause (Bellipanni et al, 2001) and preventing the depression associated with the menopause (Bellipanni et al, 2005).

In animals and humans, it has been identified as a remarkable molecule signaling not only the time of day or year, but also promoting immunomodulatory and cytoprotective properties. Several characteristics of melatonin such as its direct, non-receptor-mediated free radical scavenging activity—distinguish it from a classic hormone (Tan et al. 2003).Many biological effects of melatonin are produced through activation of melatonin receptors (Boutin et al, 2005) while others are due to its role as a pervasive and extremely powerful antioxidant (Hardeland, 2005) with a particular role in the protection of nuclear and mitochondrial DNA (Reiter et al, 2001).

Since melatonin at low concentrations is soluble in both water and lipids (fats), it may be a hydrophilic and hydrophobic antioxidant. This fact together with melatonin’s small size makes it particularly able to migrate easily between cell compartments in order to protect them against excessive ROS. It can easily cross cell membranes and the blood-brain barrier (Hardeland, 2005). Its antioxidant activity seems to function via a number of means: (1) as a direct free radical scavenger, (2) by stimulating antioxidant enzymes, (3) by stimulating the synthesis of glutathione, (4) by its ability to augment the activities of other antioxidants (5) by protection of antioxidant enzymes from oxidative damage (6) by increasing the efficiency of mitochondrial electron transport chain thereby lowering electron leakage and thus reducing free radical generation (Tan et al. 2002; Kladna et al.

2003; Rodriguez et al. 2004; Leon et al. 2005). Melatonin induces synthesis of endogenous antioxidants such as superoxide dismutase (SOD).I t directly detoxifies the hydroxyl radical (OH), hydrogen peroxide, nitric oxide, peroxynitrite anion, peroxynitrous acid, and hypochlorous acid. Unlike other antioxidants, melatonin does not undergo redox cycling, the ability of a molecule to undergo reduction and oxidation repeatedly. The melatonin molecule presenting no pro-oxidative effects, while melatonin-intermediate products show antioxidant properties and an important synergistic action with other antioxidants, such as ascorbic acid, glutathione, etc. Melatonin is reported to be five times more powerful in fact than vitamin C and twice as strong as vitamin E. Because melatonin, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals it has been referred to as a terminal (or suicidal) antioxidant (Tan et al , 2000). In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer (Karbownik et al, 2001).

It seems that exposure to Electromagnetic fields (EMFs) inhibits the nocturnal synthesis of melatonin, perhaps thereby increasing the risk of cancer. Melatonin´s radioprotective qualities have been reported and reviewed (Vijayalaxmi et al, 2004). There may be reduced levels of melatonin in people with cancer. Women with breast cancer have only a tenth of normal melatonin levels (Schernhammer & Hankinson,2005). While it is clear that melatonin interacts with the immune system (Carrillo-Vico et al, 2005; Arushanian & Beier, 2002) the details of this interaction are unclear. Over-illumination can create significant reduction in melatonin production. Reduced melatonin production has been proposed as a likely factor in the significantly higher cancer rates in night workers (Schernhammer et al, 2004), the effect of modern lighting practice on endogenous melatonin has been proposed as a contributory factor to the larger overall incidence of some cancers in the developed world (Pauley, 2004).

There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete, clinical trials. Melatonin has been shown to reduce tissue damage in rats due to ischemia in both the brain ( Lee et al, 2007) and the heart (Dominguez-Rodriguez et al, 2006); however, this has not been tested in humans. Several clinical studies indicate that supplementation with melatonin is an effective preventative treatment for migraines and cluster headaches (Dodick & Capobianco, 2001; Gagnier, 2001). Melatonin has been shown to be effective in treating one form of depression, Seasonal Affective Disorder (Hardeland, 2005) .Melatonin is involved in the regulation of body weight, and may be helpful in treating obesity (especially when combined with calcium) (Barrenetxe et al, 2004). One remarkable clinical study with melatonin has demonstrated stabilisation and reversal of Age related macular degenration using a dosage of 3mg (Changxian et al, 2005).

The list of actions described in the literature goes on. Melatonin has been shown to increase the average life span of mice by 20% in some studies (Ward Dean MD et al, 1993; Anisimov et al, 2003; Oaknin-Bendahan et al, 2003). Cross transplantation of old pineal glands into young mice (accelerated aging) and young pineal glands into old mice (decelerated aging) has provided evidence for a critical role of the pineal gland in senescence (Lesnikov & Pierpaoli ,1994; Pierpaoli & Regelson , 1993; Pierpaoli & Bulian 2001, 2005).

Because mice have a 2 year lifespan the effect of melatonin on ageing and longevity is easier to study than in humans. Long-term effects in humans remain to be clarified. However, some of the recent work emerging from Russia on pineal peptides and melatonin suggests that there may indeed be a rejuvenating and tissue preserving action in humans (Anisimov et al, 2001; Khavinson & Morozov,2003). Moreover, this work suggests that melatonin and other pineal peptides seem to play a crucial gene protective role. This may explain why as melatonin levels diminish in the fourth decade that cells are more likely to become unregulated and degenerative and why risk of almost all disease increases with ageing. I have reported that melatonin is found very commonly in plants and fruit and vegetables and that increased blood levels of melatonin are detected after eating such foods. It is interesting to postulate therefore, that a general lack of intake of phyto-melatonin in conjunction with other phytonutrients due to inadequate fruit and vegetable intake, especially in Western cultures (where it is estimated that the proportion of the general population eating 5 or more fruit and vegetable portions a day is in the order of 10%), offers another fascinating perspective on disease occurrence and a further explanation of why all the major diseases seem to be less common in people in various populations that have a greater intake of phytonutrients.

In the USA melatonin was released into the general health supplement market in 1993. Whereas in Britain you cannot buy melatonin over the counter (OTC). Melatonin is practically nontoxic and exhibits almost no short-term side effects. Melatonin derived from animal sources may be contaminated with viral material; synthetic melatonin can be taken to avoid this risk (Melatonin Information from No studies have been conducted yet to determine whether there are any long-term side effects. Furthermore, exogenous melatonin normally does not affect the endogenous melatonin profile in the short or medium-term, merely advancing the phase of endogenous melatonin production in time.

Knowing what we do know about melatonin and its apparent lack of reported detrimental effects in the face of a multitude of possible benefits, not least the potential of slowing the biological ageing clock, it would seem to be a sensible thing to supplement this important universal regulator into our preventative health, well-being and anti-ageing programs.

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Vijayalaxmi, Affiliations · Department of Radiation Oncology, The University of Texas Health Science Center, San Antonio, Texas, USA · Reprint requests to: Vijayalaxmi, Ph.D., Department of Radiation Oncology, The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Tel: (210) 616-5648 end_of_the_skype_highlighting; Fax: (210) 949-5085 · Reiter, RJ, Affiliations · Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA · Tan, D, Affiliations · Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA · Herman, TS Affiliations ·Department of Radiation Oncology, The University of Texas Health Science Center, San Antonio, Texas, USA Thomas, CR (2004). Melatonin as a radioprotective agent: a review. International Journal of Radiation Oncology , 59,(3) , 639-653,

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