Melatonin as a Chronobiotic and Cytoprotector in Healthy Aging

Abstract

A circadian alteration, as shown by a disturbed sleep and a low-degree inflammation, i.e., “inflammaging,” are two common disruptions oftenly seen in aging. Their aggravation contributes substantially to the etiology of non-communicable diseases (NCDs) like cardiovascular, respiratory and renal disorders, diabetes and the metabolic syndrome, cancer, and neurodegenerative diseases, of a high incidence in the elder population. A common observation in aging is a decline in plasma melatonin, a chemical with extraordinary phylogenetic conservation found in all known aerobic creatures. Every day, the melatonin surge in the late afternoon/early evening synchronizes both the central circadian pacemaker in the hypothalamic suprachiasmatic nuclei and a slew of peripheral cellular clocks (“chronobiotic effect”). Indeed, melatonin is the prototype of the endogenous family of chronobiotic agents. Several meta-analyses and consensus studies back melatonin treatment for sleep/wake cycle disturbance associated with NCDs in the elderly. Melatonin exerts also a cytoprotective action, buffering free radicals and reversing inflammaging by down-regulating pro-inflammatory cytokines, suppressing low-grade inflammation, and preventing insulin resistance, among other effects. Such a versatile activity explains melatonin´s conservation in phylogeny. Melatonin treatment of aged animals prevents a wide range of senescence-related alterations. Circulating melatonin levels are consistently reduced in NCDs. As a result, melatonin's therapeutic efficacy as a chronobiotic/cytoprotective drug that promotes healthy aging should be explored. Sirtuins 1 and 3 are at the heart of melatonin’s chronobiotic and cytoprotective function in healthy aging, with properties such as aging suppressors and mitochondrial protection, as well as accessory components or downstream elements of circadian oscillators. However, allometric calculations based on animal research reveal that the cytoprotective benefits of melatonin require greater doses (in the 100 mg/day range) to become visible. If melatonin is predicted to be successful in improving health, particularly in the elderly, the modest amounts frequently utilized clinically (i.e., 2–10 mg) are unlikely to be beneficial. To examine and further investigate the potential and utility of melatonin in healthy aging, multicenter double-blind studies are required. The melatonin levels employed should be re-evaluated considering preclinical research available.