Reciprocal interactions between circadian clocks and aging

Abstract

Virtually, all biological processes in the body are modulated by an internal circadian clock which optimizes physiological and behavioral performance according to the changing demands of the external 24-h world. This circadian clock undergoes a number of age-related changes, at both the physiological and molecular levels. While these changes have been considered to be part of the normal aging process, there is increasing evidence that disruptions to the circadian system can substantially impact upon aging and these impacts will have clear health implications. Here we review the current data of how both the physiological and core molecular clocks change with age and how feedback from external cues may modulate the aging of the circadian system.

Fig. 1

Simplified representation of the mammalian molecular clock. The core clock genes constitute a transcriptional feedback loop which maintains a period of approximately 24 h. Note that CLOCK and BMAL1 regulate the expression of two Per genes (Per1 and Per2) and two Cry genes (Cry1 and Cry2). A more detailed review of the molecular clock can be found in Mohawk et al.

Fig. 2

Activity profiles of young and aged mice demonstrate the breakdown of the circadian system with age. a Double-plotted actograms of four different mouse strains at 3 and 18 months of age. These activity profiles demonstrate that mice show a number of age-related changes including reduced activity, reduced circadian amplitude, and lengthened circadian period. Figure reproduced from Banks et al. . b Circadian rhythm of sleep behavior in 3- and 18-month-old mice. Older mice show poor rhythmicity and reduced amplitude in their rhythms. Figure adapted from Banks et al.

Fig. 3

Loss of SCN electrical rhythms is due to the contribution of disruptions to various components of intra-SCN communication. Age-related changes in the electrical membrane properties, synaptic connectivity, GABAergic function, and expression of neuropeptides of SCN neurons all contribute to a loss of synchronization of the SCN network. This is reflected by an age-related loss of the amplitude of electrical rhythms of the SCN