The discovery of melatonin and its derivatives as antioxidants has stimulated a very large number of studies which have, virtually uniformly, documented the ability of these molecules to detoxify harmful reactants and reduce molecular damage. These observations have clear clinical implications given that numerous age-related diseases in humans have an important free radical component. Moreover, a major theory to explain the processes of aging invokes radicals and their derivatives as causative agents. These conditions, coupled with the loss of melatonin as organisms age, suggest that some diseases and some aspects of aging may be aggravated by the diminished melatonin levels in advanced age. Another corollary of this is that the administration of melatonin, which has an uncommonly low toxicity profile, could theoretically defer the progression of some diseases and possibly forestall signs of aging. Certainly, research in the next decade will help to define the role of melatonin in age-related diseases and in determining successful aging. While increasing life span will not necessarily be a goal of these investigative efforts, improving health and the quality of life in the aged should be an aim of this research.

A worldwide increase in the incidence of obesity indicates the unsuccessful battle against this disorder. Obesity and the associated health problems urgently require effective strategies of treatment. The new discovery that a substantial amount of functional brown adipose tissue (BAT) is retained in adult humans provides a potential target for treatment of human obesity. BAT is active metabolically and disposes of extra energy via generation of heat through uncoupling oxidative phosphorylation in mitochondria. The physiology of BAT is readily regulated by melatonin, which not only increases recruitment of brown adipocytes but also elevates their metabolic activity in mammals. It is speculated that the hypertrophic effect and functional activation of BAT induced by melatonin may likely apply to the human. Thus, melatonin, a naturally occurring substance with no reported toxicity, may serve as a novel approach for treatment of obesity. Conversely, because of the availability of artificial light sources, excessive light exposure after darkness onset in modern societies should be considered a potential contributory factor to human obesity as light at night dramatically reduces endogenous melatonin production. In the current article, the potential associations of melatonin, BAT, obesity and the medical implications are discussed.

Melatonin is a molecule present in a multitude of taxa and may be ubiquitous in organisms. It has been found in bacteria, unicellular eukaryotes, macroalgae, fungi, plants and animals. A primary biological function of melatonin in primitive unicellular organisms is in antioxidant defence to protect against toxic free radical damage. During evolution, melatonin has been adopted by multicellular organisms to perform many other biological functions. These functions likely include the chemical expression of darkness in vertebrates, environmental tolerance in fungi and plants, sexual signaling in birds and fish, seasonal reproductive regulation in photoperiodic mammals, and immunomodulation and anti-inflammatory activity in all vertebrates tested. Moreover, its waning production during aging may indicate senescence in terms of a bio-clock in many organisms. Conversely, high melatonin levels can serve as a signal of vitality and health. The multiple biological functions of melatonin can partially be attributed to its unconventional metabolism which is comprised of multi-enzymatic, pseudo-enzymatic and non-enzymatic pathways. As a result, several bioactive metabolites of melatonin are formed during its metabolism and some of the presumed biological functions of melatonin reported to date may, in fact, be mediated by these metabolites. The changing biological roles of melatonin seem to have evolved from its primary function as an antioxidant.

Melatonin (N-acetyl-5-methoxytryptamine) has been detected in a number of plant species. Indeed, there exists evidence that this classically-considered animal indole is actually both synthesized in and taken up by plants. Among the actions that melatonin may carry out in plant tissues, its role as an antioxidant or growth promoter is most strongly supported by the experimental evidence. Other suggested functional implications include the co-ordination of photoperiodic responses and regulation of plant reproductive physiology, defence of plant cells against apoptosis induced by harsh environmental conditions, its participation as a free radical scavenging agent and/or up-regulator of certain protective enzymes in the senescent process. This review presents a detailed summary of the investigations that have been performed to date in the plant melatonin (phytomelatonin) field. The purpose of this summary is to bring the reader up to date on what is known about melatonin in plants and to encourage plant scientists to investigate this novel research topic; this would certainly assist in solving the numerous questions that still remain regarding the role of melatonin in plants.

This brief review summarizes new findings related to the reported beneficial effects of melatonin on reproductive physiology beyond its now well-known role in determining the sexual status in both long-day and short-day seasonally breeding mammals. Of particular note are those reproductive processes that have been shown to benefit from the ability of melatonin to function in the reduction of oxidative stress. In the few species that have been tested, brightly colored secondary sexual characteristics that serve as a sexual attractant reportedly are enhanced by melatonin administration. This is of potential importance inasmuch as the brightness of ornamental pigmentation is also associated with animals that are of the highest genetic quality. Free radical damage is commonplace during pregnancy and has negative effects on the mother, placenta, and fetus. Because of its ability to readily pass through the placenta, melatonin easily protects the fetus from oxidative damage, as well as the maternal tissues and placenta. Examples of conditions in which oxidative and nitrosative stress can be extensive during pregnancy include preeclampsia and damage resulting from anoxia or hypoxia that is followed by reflow of oxygenated blood into the tissue. Given the uncommonly low toxicity of melatonin, clinical trials are warranted to document the protection by melatonin against pathophysiological states of the reproductive system in which free radical damage is known to occur. Finally, the beneficial effects of melatonin in improving the outcomes of in vitro fertilization and embryo transfer should be further tested and exploited. The information in this article has applicability to human and veterinary medicine.

The role of melatonin in the mediation of apoptotic events has recently gained attention, especially after recent studies have reported that melatonin exerts antiapoptotic actions in normal cells but may activate proapoptotic pathways in some tumor cells. Here, we have evaluated the effect of melatonin on apoptosis in the human leukemia cell line HL-60. Melatonin treatment (1 mm) induced a significant increase in caspase-3 and -9 activities. The effect of melatonin on the activation of caspases was time dependent, reaching a maximum after 12 hr of stimulation, and then decreasing to a minimum after 72 hr. Treatment with melatonin also evoked mitochondrial membrane depolarization and permeability transition pore induction, which caused loss of mitochondrial staining by calcein, and increased cell death by apoptosis/necrosis as demonstrated by propidium iodide positive-staining of cells after 72 hr of stimulation. In addition, the exposure of cells to melatonin resulted in an activation and association of the proapoptotic proteins Bax and Bid, as well as promoting detectable increases in the expression of both proteins. We conclude that melatonin has proapoptotic and/or oncostatic effects in the human myeloid cell line HL-60.

Tryptophan, serotonin, and melatonin, present in Jerte Valley cherries, participate in sleep regulation and exhibit antioxidant properties. The effect of the intake of seven different Jerte Valley cherry cultivars on the sleep-wake cycle, 6-sulfatoxymelatonin levels, and urinary total antioxidant capacity in middle-aged and elderly participants was evaluated. Volunteers were subjected to actigraphic monitoring to record and display the temporal patterns of their nocturnal activity and rest. 6-sulfatoxymelatonin and total antioxidant capacity were quantified by enzyme-linked immunosorbent assay and colorimetric assay kits, respectively. The intake of each of the cherry cultivars produced beneficial effects on actual sleep time, total nocturnal activity, assumed sleep, and immobility. Also, there were significant increases in 6-sulfatoxymelatonin levels and total antioxidant capacity in urine after the intake of each cultivar. These findings suggested that the intake of Jerte Valley cherries exerted positive effect on sleep and may be seen as a potential nutraceutical tool to counteract oxidation.

The experimental data obtained from both human and rodent studies suggest that melatonin may have utility in the treatment of several cardiovascular conditions. In particular, melatonin's use in reducing the severity of essential hypertension should be more widely considered. In rodent studies melatonin has been shown to be highly effective in limiting abnormal cardiac physiology and the loss of critical heart tissue resulting from ischemia/reperfusion injury. Melatonin may also be useful in reducing cardiac hypertrophy in some situations and thereby limiting the frequency of heart failure. Finally, some conventional drugs currently in use have cardiotoxicity as a side-effect. Based on studies in rodents, melatonin, due to its multiple anti-oxidative actions, is highly effective in abrogating drug-mediated damage to the heart. Taken together, the findings from human and animal studies support the consideration of melatonin as a cardioprotective agent.