ALTERED RHYTHMS IN AGING--MECHANISMS AND RESTORATION OF FUNCTION

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In the golden hamster, there are pronounced age-related changes in the expression of circadian rhythm under both entrained and free-running conditions, as well as in the response of the circadian clock system to a variety of photic and non-photic stimuli. Studies performed during the previous grant period have provided important observations in three areas pertaining to the development of such age-related alterations, their underlying mechanisms and possible approaches for corrective strategies. The proposed studies will build on these findings to 1) determine the chronology of the development of various age-related changes in the circadian clock system, 2) to determine the physiological mechanisms underlying age-related changes in the circadian clock system and 3) to test the efficacy of specific countermeasures to reverse or attenuate the effects of aging on circadian rhythmicity. In particular, various hypotheses will be tested regarding the role of serotonin and neuropeptide Y, as well as the influence of the pineal gland and its hormone melatonin, in age-related changes in the circadian system. Countermeasures involving treatment with melatonin or altering the strength of the entraining light- dark cycle will be employed to test the hypothesis that age-related changes in the circadian system can be attenuated, delayed or reversed. Throughout the proposed studies, the effects of aging on the expression of five different rhythms (i.e., wheel-running behavior, total locomotor activity, drinking behavior, body temperature and circulating melatonin levels), and on the ability of the circadian pacemaker to be phase shifted by either photic or non-photic stimuli, will be determined in hamsters. It is anticipated that the elucidation of the physiological basis for age- related changes in circadian function, and of the mechanisms which underlie the efficacy of various corrective strategies, will lead to new insights into the regulation and organization of circadian rhythmicity and of its interaction with environmental stimuli. These studies are also expected to lead to new clinical approaches for treating, preventing or delaying disturbances of circadian rhythms and sleep in older human populations.