Melatonin in Healthy Aging and Longevity

Abstract

Melatonin is a regulator of the circadian multioscillator system. It transmits the information ‘darkness’, contributes to internal and external alignment of rhythms and, presumably via sirtuin-1, to high amplitudes. During normal aging, both the circadian system and melatonin secretion deteriorate. These processes are aggravated by several diseases and disorders of different etiology, most strongly under conditions of neurodegeneration, especially Alzheimer’s disease. Preclinically, melatonin counteracts alterations that may contribute to the acceleration of aging. It supports mitochondrial electron flux, enhances intramitochondrial protection against free oxygen and nitrogen radicals, reduces the duration of permeability transition and attenuates free radical formation. In nontumor cells, it acts as an antiapoptotic agent and may prevent excessive peripheral mitophagy. Numerous preclinical studies have documented a remarkable neuroprotective potential. Despite encouraging results, the translation of findings to the human is sometimes problematic, e.g., because of the different association of melatonin with rest or activity in nocturnally active rodents and in man. These differences extend to the tractability of metabolic syndrome and diabetes type 2, because of the preferred times of food intake. An overexpressed risk allele of the melatonin receptor gene MTNR1B decreases glucose tolerance in humans. Insulin resistance is also of high interest to neuroinflammation. With regard to both pro- and antiinflammatory actions, the role of melatonin in human inflammaging remains to be clarified. Life extension by melatonin was only preclinically demonstrated and remained, in rodents, rather modest. In man, melatonin’s value should be sought in supporting healthy aging, which may have indirect effects on lifespan.