Melatonin in the Context of Circadian Oscillator Genes and Signaling Polymorphisms

Melatonin is a highly pleiotropic regulator molecule that acts almost everywhere in a mammalian body. Because of this diversity of actions, decreases in its level by aging or diseases have numerous health implications. Melatonin has synchronizing properties in the circadian system, at the hypothalamic master clock and, presumably, other oscillators, too. Different forms of circadian dysfunction exist that can be caused by mutations in circadian oscillator genes, epigenetic changes in their expression or neurodegenerative processes. Circadian malfunction has been observed in circadian rhythms sleep disorders as well as in mood disorders with circadian etiology, such as bipolar disorder, seasonal affective disorder and sub forms of major depression. In these cases, re-entrainment of rhythms by melatonin is an option of treatment. Melatonin also influences the expression of sirtuin 1. In aging tissues, it upregulates sirtuin 1, which is known to enhance circadian amplitudes, an effect that should improve the functioning of the circadian system. However, in profoundly dysregulated oscillators of tumor cells, melatonin suppresses sirtuin 1 expression and inhibits proliferation. Polymorphisms have been detected in genes of melatonin synthesis and melatonin receptors. These may lead to forms of melatonergic dysfunction. An allele of the melatonin receptor 2 has been shown to act in a prodiabetic way by becoming overexpressed in midlife, with the consequence of suppressing insulin secretion in pancreatic β cells.

Author(s): Hardeland R

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