Age-Related Changes in the Circadian System Unmasked by Constant Conditions
2015
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.
Significance statement: It is becoming increasingly evident that aging impacts the neural activity rhythms in the central circadian clock in the SCN. However, evidence for age-related disruption of circadian oscillations of clock genes in the SCN has been equivocal. Our data indicate that, at the population level, aging lengthens the free-running period and attenuates the amplitude of population-based PER2::LUC rhythms in the SCN. At the single-cell level, aging lengthens the period and reduces the synchrony of single-cell oscillations without reducing their amplitude. These findings were observed in mice housed in prolonged conditions of constant darkness. These data suggest that light-dark cycles mask the effects of aging on SCN cellular clocks and that aging may increase the vulnerability of the SCN circadian ensemble.
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