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N-acetyl-5-methoxytryptamine (melatonin) is a product of tryptophan metabolism highly preserved throughout phylogeny, which in humans, as well as in different other animal species, is synthesized in the pineal gland as a neurohormone and released in blood and cerebrospinal fluid to exert regulatory roles on seasonal and circadian rhythms. In the pineal gland, serotonin is converted in to melatonin through a two-step enzymatic process involving N acetylation followed by O-methylation. Melatonin production was demonstrated also in extrapineal organs and tissues such as the gastrointestinal tract, retina and lens, skin, immune and hematopoietic cells, some reproductive organs, and endocrine glands. In all these organs and tissues, the rhythm and extent of melatonin synthesis vary from those in the pineal gland. Even the most abundant peripheral sources of melatonin (such as the retina) seem to provide a limited contribution to systemic levels of this hormone, due to sustained local catabolism. Thus, it is believed that these sources may contribute to explaining local levels and melatonin-dependent effects that might be in part or completely independent from darkness and other aspects related to chronobiology. These include the role of melatonin as intracrine, autocrine, and/or paracrine factor in key homeostatic functions such as the control of energy metabolism, physiological growth, differentiation, and responsiveness to stress stimuli.

Melatonin is a natural occurring compound with well-known antioxidant properties. In the last decade a new effect of melatonin on mitochondrial homeostasis has been discovered and, although the exact molecular mechanism for this effect remains unknown, it may explain, at least in part, the protective properties found for the indoleamine in degenerative conditions such as aging as well as Parkinson’s disease, Alzheimer’s disease, epilepsy, sepsis and other injuries such as ischemia-reperfusion. Melatonin is able of directly scavenging a variety of toxic oxygen and nitrogen-based reactants, stimulates antioxidative enzymes, increases the efficiency of the electron transport chain thereby limiting electron leakage and free radical generation, and promotes ATP synthesis. Via these actions, melatonin preserves the integrity of the mitochondria and helps to maintain cell functions and survival.

The study of plasma melatonin among subjects of different age groups reveals a consistent decrease as aging progresses. With some exceptions the decline of melatonin with age has been repeatedly reported. The melatonin day/night rhythm has been found altered with phase advance in the elderly as compared to young women. Great variations in the amplitude of nocturnal melatonin secretions are found among individuals suggesting that some individuals produce significantly less melatonin during lifetime than others; this may have an impact in terms of aging. The loss of amplitude of melatonin rhythm in the advanced age is both an indication as well as a cause of age-related disturbances in the circadian pacemaker leading to chronobiological disorders. This is accompanied by a general deterioration of cognitive, psychological and social functioning as well as by sleep disturbances.