Melatonin as a Chronobiotic and Cytoprotector in Non-communicable Diseases: More than an Antioxidant

A circadian disruption, manifested by disturbed sleep and low-grade inflammation, is commonly seen in noncommunicable diseases (NCDs). Cardiovascular, respiratory and renal disorders, diabetes and the metabolic syndrome, cancer, and neurodegenerative diseases are among the most common NCDs prevalent in today's 24-h/7 days Society. The decline in plasma melatonin, which is a conserved phylogenetic molecule across all known aerobic creatures, is a constant feature in NCDs. The daily evening melatonin surge synchronizes both the central pacemaker located in the hypothalamic suprachiasmatic nuclei (SCN) and myriads of cellular clocks in the periphery ("chronobiotic effect"). Melatonin is the prototypical endogenous chronobiotic agent. Several meta-analyses and consensus studies support the use of melatonin to treat sleep/wake cycle disturbances associated with NCDs. Melatonin also has cytoprotective properties, acting primarily not only as an antioxidant by buffering free radicals, but also by regulating inflammation, down-regulating pro-inflammatory cytokines, suppressing low-grade inflammation, and preventing insulin resistance, among other effects. Melatonin's phylogenetic conservation is explained by its versatility of effects. In animal models of NCDs, melatonin treatment prevents a wide range of low-inflammation-linked alterations. As a result, the therapeutic efficacy of melatonin as a chronobiotic/cytoprotective drug has been proposed. Sirtuins 1 and 3 are at the heart of melatonin's chronobiotic and cytoprotective function, acting as accessory components or downstream elements of circadian oscillators and exhibiting properties such as mitochondrial protection. Allometric calculations based on animal research show that melatonin's cytoprotective benefits may require high doses in humans (in the 100 mg/day range). If melatonin is expected to improve health in NCDs, the low doses currently used in clinical trials (i.e., 2-10 mg) are unlikely to be beneficial. Multicentre double-blind studies are required to determine the potential utility of melatonin in health promotion. Moreover, melatonin dosage and levels used should be re-evaluated based on preclinical research information.