Aging of the circadian system in zebrafish and the effects of melatonin on sleep and cognitive performance.

Aging is a complex process involving intracellular changes and, notably, modifications in intercellular communications, required for coordinated responses to internal and external events. One of the potential reasons for such changes is an age-dependent failure of the integrating systems, including the circadian clock. Here we demonstrate that aging in a diurnal vertebrate, zebrafish (Danio rerio), is associated with major but selective circadian alterations. By 3-5 years of age, zebrafish have reduced amplitude and increased fragmentation of entrained circadian rhythms of activity, with fast desynchronization of the rhythms in the absence of environmental time cues. Aging in zebrafish is also associated with a reduction in the overall duration of nighttime sleep, followed by lower activity levels and a higher arousal threshold during the day. The production of the principal circadian hormone, melatonin, progressively declines during zebrafish aging. However, the ability of melatonin to acutely promote sleep and entrain circadian rhythms of activity remains robust until at least 4-5 years of age, consistent with the preserved levels of mRNA expression for melatonin receptors. Aged zebrafish have altered expression of the circadian genes zBmal1 and zPer1 but not zClock1. A lack of circadian time cues alters cognitive performance in aged more than in young zebrafish and this can be partially attenuated by daily melatonin administration. The advantages of zebrafish as a diurnal, small, prolific and genetically well-characterized vertebrate model provide new opportunities to clarify the intrinsic circadian factors involved in human aging and promote the search for prophylactic and treatment strategies.