title: Age-Related Changes in the Circadian System Unmasked by Constant Conditions
abstract: Circadian timing systems, like most physiological processes, cannot escape the effects of aging. With age, humans experience decreased duration and quality of sleep. Aged mice exhibit decreased amplitude and increased fragmentation of the activity rhythm, and lengthened circadian free-running period in both light-dark (LD) and constant dark (DD) conditions. Several studies have shown that aging impacts neural activity rhythms in the central circadian clock in the suprachiasmatic nucleus (SCN). However, evidence for age-related disruption of circadian oscillations of clock genes in the SCN has been equivocal. We hypothesized that daily exposure to LD cycles masks the full impact of aging on molecular rhythms in the SCN. We performed ex vivo bioluminescent imaging of cultured SCN slices of young and aged PER2::luciferase knock-in (PER2::LUC) mice housed under LD or prolonged DD conditions. Under LD conditions, the amplitude of PER2::LUC rhythms differed only slightly between SCN explants from young and aged animals; under DD conditions, the PER2::LUC rhythms of aged animals showed markedly lower amplitudes and longer circadian periods than those of young animals. Recordings of PER2::LUC rhythms in individual SCN cells using an electron multiplying charge-coupled device camera revealed that aged SCN cells showed longer circadian periods and that the rhythms of individual cells rapidly became desynchronized. These data suggest that aging degrades the SCN circadian ensemble, but that recurrent LD cycles mask these effects. We propose that these changes reflect a decline in pacemaker robustness that could increase vulnerability to environmental challenges, and partly explain age-related sleep and circadian disturbances.
authors.affiliation: Department of Life Sciences, School of Agriculture, Meiji University , Kanagawa, Kawasaki 214-8571, Japan ; Faculty of Pharmaceutical Sciences, Teikyo Heisei University , Tokyo 164-8530, Japan ; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles , Los Angeles, California 90024-1759.
authors.forename: Takahiro J
authors.initials: TJ
authors.lastname: Nakamura
authors.affiliation: Laboratory of Oral Chronobiology, Graduate School of Dentistry, Osaka University, Suita , Osaka 565-0871, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nakamura
authors.affiliation: Department of Mechanical Engineering, Ritsumeikan University , Shiga, Kusatsu 525-8577, Japan.
authors.forename: Isao T
authors.initials: IT
authors.lastname: Tokuda
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo Heisei University , Tokyo 164-8530, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles , Los Angeles, California 90024-1759.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kudo
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles , Los Angeles, California 90024-1759.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Colwell
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles , Los Angeles, California 90024-1759.
authors.forename: Gene D
authors.initials: GD
authors.lastname: Block
keywords: PER2::luciferase; aging; imaging; suprachiasmatic nucleus