Melatonin and circadian oscillators in aging--a dynamic approach to the multiply connected players.

From the perspective of systems biology, melatonin is relevant to aging in multiple ways. As a highly pleiotropic agent, it acts as a modulator and protectant of mitochondrial electron flux, a potent antioxidant that supports the redox balance and prevents excessive free radical formation, a coregulator of metabolic sensing and antagonist of insulin resistance, an immune modulator, a physiological hypnotic and, importantly, an orchestrating chronobiotic. It entrains central and peripheral circadian clocks and is required for some high-amplitude rhythms. The circadian system, which controls countless functions, is composed of many cellular oscillators that involve various accessory clock proteins, some of which are modulated by melatonin, e.g. sirtuin 1, AMP-dependent protein kinase, and protein kinase Cα. Aging and age-related diseases are associated with losses in melatonin secretion and rhythm amplitudes. The dynamic properties of aging processes deserve particular attention. This concerns especially two vicious cycles, one of peroxynitrite formation driven by inflammation or overexcitation, another one of inflammaging driven by the senescence-associated secretory phenotype, and additionally the loss of dynamics in a deteriorating circadian multioscillator system.