Melatonin Aging And The Circadian System

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Aging is associated with a number of changes in the morphology, physiology and biochemistry of the pineal gland resulting in a significant reduction of the nocturnal melatonin levels in rodents and humans alike (12,20,27). It has been hypothesized that the age-related disruption of this robust signal affects the integrity of circadian time structures and is a precursor of disease states (2,21). Recent studies indicate that decreased binding of melatonin to the SCN of old rats is correlated with disruption in overt circadian rhythmicity (43), whereas treatment with the melatonin agonist, S-20242, can partially reverse the age-related decrease in the amplitude of the circa-dian temperature rhythm (13). We have recently found that in some hamsters treatment with melatonin in the food increases the amplitude and cohesiveness of the rhythm of locomotor activity which often becomes fragmented and disorganized in old animals (Van Reeth, unpublished results). Further support for some linkage between melatonin and aging is the intriguing finding that increased longevity in rats after life-long food restriction is associated with improved pineal function and increased melatonin levels (20).

In addition to the possibility that a more robust melatonin signal somehow improves the integrity of the circadian clock system of old animals, the sleep-inducing effects of melatonin, while somewhat controversial (32) provide a second avenue for possible beneficial effects of melatonin in older humans. Disrupted sleep at an advanced age is a frequent complaint/problem in the elderly, which often takes the form of fragmentation of the periods of wake and sleep or a phase advance of the timing of sleep onset and offset (3). Thus any substance which enhances the overall temporal organization, causes phase shifts in circadian rhythmicity, and can act as a mild hypnotic would have the potential of enhancing the timing and duration of sleep. Since there is evidence that melatonin can have all of these effects, the possible anti-aging effects of melatonin could involve a number of different pathways.

The potential use of melatonin replacement for treating sleep-wake disorders in the elderly is a particularly attractive hypothesis since: 1) disturbed sleep becomes more prevalent with advanced age (3,6,19), 2) melatonin levels decline with age (39), and 3) melatonin levels are reported to be significantly lower in elderly insomniac patients than in age-matched controls (9). In a few studies using wrist activity as a marker of sustained sleep in elderly subjects complaining of insomnia, both low and high doses of melatonin were found to reduce motor activity at night (7,10,11,15). While such findings have raised the hope that melatonin treatment will be effective for improving sleep in the elderly, more rigorous studies involving polysomnographic sleep recordings are required before it can be concluded that melatonin is indeed an effective hypnotic for use in the elderly.

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