Although a variety of stimuli have been identified which can alter the circadian clock system of young animals, little is known about how aging alters the response of the clock to external and internal environmental stimuli. Preliminary data in the golden hamster demonstrate that the response of the circadian clock system to the primary external environmental synchronizing agent, light, is dramatically altered in old age (i.e. > 18 months of age). In addition, with advanced age the circadian clock in this species appears to become unresponsive to feedback signals about the activity-rest state. The overall objectives of the proposed studies are, 1) to determine in detail how the response of the circadian clock system to light or changes in the activity-rest state is altered in old age, and 2) to determine the physiological basis for age- related changes in the response of the circadian clock to environmental stimuli. To examine the effects of aging on the response of the circadian system to various stimuli, the circadian rhythm of locomotor activity in golden hamsters will be used as a marker rhythm for the state of the circadian clock located in the suprachiasmatic nucleus (SCN) that underlies most behavioral and physiological rhythms in this species. With respect to age- related changes in the response of the clock to light, a series of experiments will be carried out to determine 1) the extent to which aging alters both the phase-shifting and entraining effects of light, and 2) whether age-related alterations in the response to light are due to changes in the reception of photic information or to changes at the level of the SCN. Whether age-related changes in the response of the clock to light are associated with an alteration in light-induced protein synthesis within the SCN will also be determined. With respect to age-related changes in the response of the clock to signals about the activity-rest state, a series of experiments will be carried out to determine 1) if the circadian clock of old animals is completely insensitive to the phase shifting effects of various stimuli that induce acute changes in the activity state, as well as phase shifts in the circadian clock of young animals, and 2) the age at which the circadian clock becomes totally or partially insensitive to the phase-shifting effects of feedback signals about the activity-rest state of the animal. In view of recent findings indicating that norepinephrine may be involved in mediating the effects of stimulated activity on the circadian clock, a series of experiments will be carried out to determine if age-related changes in central noradrenergic activity underlie the loss of responsiveness to such stimuli with advanced age, and whether the response of the circadian clock to such stimuli can be restored by increasing central adrenergic activity in old animals. In addition to providing new insight into how the response of the circadian clock system to external and internal stimuli is altered with age, these findings may lead to new clinical approaches for treating disorders in the elderly that are associated with a disruption of circadian rhythmicity.
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