The first (and only) single gene mutation in a mammalian circadian system has recently been discovered in the golden hamster, this mutation alters the period of the circadian clock (the endogenous period under free- running conditions is reduced from the normal 24 hrs to about 20 hrs) and the response of the clock to the phase shifting effects of light and activity-inducing stimuli. These effects on the circadian clock are associated with ,.about a 50% decrease in the lifespan of the mutant hamsters. The overall objectives of the proposed studies are to determine 1) if decreased longevity in tau mutant hamsters is due to genetic or environmental factors, 2) if age-related changes in the circadian clock system occur at an earlier age in tau mutant animals, 3) what effect the tau mutation has on the timing of age-related changes in the circadian clock system, and 4) if longevity is reduced in the tau mutant animal because of the mutation's effects on the circadian clock itself. To reach these objectives, the circadian rhythm of locomotor activity 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 mammals. In one series of experiments, male and female wild-type and tau mutant hamsters will be exposed to either constant light (LL) or light-dark (LD) cycles in the two circadian ranges (i.e. 20 or 24-hr LD cycles) to determine if the decreased lifespan in the mutant animals is due to an intrinsic genetic effect on longevity or to the inability of the circadian clock of mutant animals to entrain normally to the standard 24-hr light cycle. In a second series of experiments, the effects of age on 1) the period of the clock, 2) the phase relationship of the activity rhythm to entraining light-dark cycles, 3) the rate of reentrainment following phase shifts in the light-dark cycle, and 4) the response of the circadian clock to light pulses or to a variety of activity-inducing stimuli will be determined in wild-type and tau mutant hamsters. The results of these studies will establish whether a mutation in the circadian system has an effect on normal age-related changes in the circadian clock system, as well as whether such changes occur at an earlier age in the mutant hamsters that corresponds in time with the decreased lifespan of the animals. In a third series of experiments, the effects of destruction of the circadian clock in the SCN on longevity will be established in order to determine if changes in the clock itself are responsible for the reduced lifespan of the mutant animals. A final series of experiments involving the transplantation of fetal SCN tissue from both wild-type and mutant hamsters to animals of the same or different genotype will be carried out to determine the role of transplanted SCN tissue in the restoration of circadian function in old hamsters. In view of the central role played by the circadian clock in the regulation of diverse biological systems, age-related changes in the clock can be expected to have a major impact on the health of the organism. A variety of circadian abnormalities have been found in elderly humans, including those suffering from Alzheimer's disease and disturbances of the sleep-wake cycle. Studies on how circadian mutations affect age-related changes in the circadian clock and whether circadian disturbances induced by mutations affect aging itself, may provide new information on the underlying physiological bases for age-related dysfunction within the circadian system and how altered clock function may contribute to the aging process.
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