Future Demands Concerning the Epigenetic Relevance of Melatonin and the Circadian System in Gerontology

Abstract

Melatonin is a highly pleiotropic regulator molecule that influences numerous functions in many cell types. Its actions comprise direct and circadian oscillator-mediated effects. The levels of circulating melatonin typically decline in the course of aging. Additionally,various aging-associated diseases further decrease melatonin concentrations. With regard to its remarkably broad spectrum of actions, control mechanisms upstream and downstream of melatonin should be investigated much more in detail with regard to the contribution of epigenetic modulation. The importance of epigenetic alterations has already become evident in the fields of both gerontology and chronobiology. Therefore, it seems necessary to fill the gaps concerning corresponding processes related to melatonin, especially under the aspects of physiologic malfunctions because of aging-associated decreases of melatonin. This review outlines the findings on melatonin's epigenetic actions, as obtained to date, and sets these results in correspondence to general knowledge and many specific findings concerning circadian rhythms. These considerations focus on DNA methylation and erasure of 5-methylcytosine, on histone modification, in particular, acetylation/deacetylation and methylation/demethylation, and on the manifold roles of noncoding RNAs, especially microRNAs. With regard to melatonin's spectrum of actions in the gerontological context, emphasis is given to its contribution to circadian oscillation amplitudes, to anti-inflammatory actions and to antioxidative protection.

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“…Its antioxidant actions, originally discovered by its radical scavenging properties [115,116], are meanwhile known to comprise numerous additional effects including the avoidance of free-radical formation and the detoxification of reactive intermediates by upregulating antioxidant enzymes [58,117,118] as well as contributions of protective melatonin metabolites [119][120][121]. Again, numerous epigenetic effects are highly likely to exist in the field of antioxidative actions of melatonin, although the actual knowledge is largely confined to the induction of antioxidant enzymes, the regulation of cyclooxygenase 2 and inducible NO synthase [14,15] as well as some other anti-inflammatory actions [11,52].…”