Effects of age on circadian rhythms are similar in wild-type and heterozygous Clock mutant mice

Abstract

The amplitudes of many circadian rhythms, at the behavioral, physiological, cellular, and biochemical levels, decrease with advanced age. Previous studies suggest that the amplitude of the central circadian pacemaker is decreased in old animals. Recently, it has been reported that expression of several circadian clock genes, including Clock, is lower in the master circadian pacemaker of old rodents. To test the hypothesis that decreased activity of a circadian clock gene renders animals more susceptible to the effects of aging, we analyzed the circadian rhythm of locomotor activity in young and old wild-type and heterozygous Clock mutant mice. We found that the effects of age and the Clock mutation were additive. These results indicate that age-related changes in circadian rhythmicity occur equally in wild-type and heterozygous Clock mutants, suggesting that the Clock mutation does not render mice more susceptible to the effects of age on the circadian pacemaker.

Figure 1

Representative activity records from young (top) and old (bottom) wild-type and Clock mutant mice. Data from wild-type mice are on the left, and data from age-matched Clock/+ mice are on the right. The phase shifts near the bottom of each record are the result of a 6-h light pulse delivered at CT 17.

Figure 2

Effects of age on various parameters of the circadian timing systems of wild-type and Clock mutant mice. Compared to young mice, old mice had significantly more bouts of activity per day (A), lower relative FFT power in the circadian range (B), fewer wheel revolutions per day (C). Age did not affect free-running period in constant darkness (D) or the magnitude of the light-induced phase shift (E). Clock mutant mice had significantly lower relative FFT power (B) and running wheel activity (C). The Clock mutation also led to a significantly longer free-running period (D) and larger phase shifts to a 6-h light pulse delivered at CT 17 (E). Open bars: wild-type mice. Dark bars: Clock heterozygotes.

Figure 3

The expression of mPer1 was significantly lower in the SCN of Clock mutant mice at CT 6. (A) Autoradiograms of hypothalami from representative young and old wild-type and Clock mutant mice. (B) mPer1 signal in the SCN of animals from each group. Age did not significantly affect mPer1 expression.

Figure 4

The Clock mutation significantly decreased expression of mPer2 in the SCN at CT 6. (A) Autoradiograms of hypothalami from representative young and old wild-type and Clock mutant mice. (B) mPer2 signal in the SCN of animals from each group. There was no effect of age on the mPer2 expression.