Aging of the mammalian circadian timing system: changes in the central pacemaker and its regulation by photic and nonphotic signals

Abstract

Aging alters many aspects of endogenously regulated, 24-hour (circadian) rhythms, such as their amplitude, relationship to the ambient lighting cycle, and sensitivity to phase resetting signals. In order to elucidate the mechanisms responsible for these age-related changes, many studies have investigated age-related changes in the neural components of the circadian timing system, which include the hypothalamic suprachiasmatic nucleus (SCN), the site of the mammalian master circadian pacemaker, its afferent projections from the retina, thalamus, and midbrain raphe, and its efferent projections to the hypothalamus, thalamus and limbic system. Studies have shown that the SCN exhibits age-related changes in electrical activity rhythms in the absence of neurodegeneration. Also, aging selectively decreases SCN expression of the circadian clock genes, Clock and Bmal1, as well as vasoactive intestinal peptide. The latter participates in mediating light-induced phase resetting of the circadian pacemaker and the amplitude of the preovulatory luteinizing hormone surge, which are both attenuated by aging. Furthermore, by decreasing serotonin 5-HT7 receptors in the dorsal raphe, aging reduces one type of nonphotic input to the SCN. This review describes which aspects of circadian rhythm regulation exhibit changes during aging, as well as which mechanisms appear to be spared or remain to be explored.