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Age-Related Changes in the Circadian System Unmasked by Constant Conditions(1,2,3).

Nakamura TJ, Nakamura W, Tokuda IT, Ishikawa T, Kudo T, Colwell CS, Block GD - eNeuro (2015)

Bottom Line: Circadian timing systems, like most physiological processes, cannot escape the effects of aging.With age, humans experience decreased duration and quality of sleep.These data suggest that aging degrades the SCN circadian ensemble, but that recurrent LD cycles mask these effects.

View Article: PubMed Central - HTML - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Effects of aging on PER2::LUC rhythms in SCN explants from mice maintained in DD. A, Representative double-plotted actograms of wheel-running activity in young and aged PER2::LUC mice maintained in DD. Asterisks indicate the timing of the killing of the animals. B, Typical examples of PER2::LUC rhythms of SCN explants from mice maintained in DD for 10 d, as measured by PMT. C, Phase map of peak PER2::LUC rhythms in the SCN. Each point represents the average peak of PER2::LUC rhythms in each cycle, plotted relative to the circadian time prior to the killing of the animals. D, Amplitude of PER2::LUC rhythms in the SCN. The amplitude of each oscillation was determined as the sum of the absolute value of the lowest and highest points (counts). Data are shown as the mean ± SD. n = 5 per group. *p < 0.05, **p < 0.01 for young vs. aged animals (Bonferroni post hoc comparison).
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Figure 2: Effects of aging on PER2::LUC rhythms in SCN explants from mice maintained in DD. A, Representative double-plotted actograms of wheel-running activity in young and aged PER2::LUC mice maintained in DD. Asterisks indicate the timing of the killing of the animals. B, Typical examples of PER2::LUC rhythms of SCN explants from mice maintained in DD for 10 d, as measured by PMT. C, Phase map of peak PER2::LUC rhythms in the SCN. Each point represents the average peak of PER2::LUC rhythms in each cycle, plotted relative to the circadian time prior to the killing of the animals. D, Amplitude of PER2::LUC rhythms in the SCN. The amplitude of each oscillation was determined as the sum of the absolute value of the lowest and highest points (counts). Data are shown as the mean ± SD. n = 5 per group. *p < 0.05, **p < 0.01 for young vs. aged animals (Bonferroni post hoc comparison).

Mentions: Next, we recorded bioluminescence rhythms in SCN explants from mice maintained in DD (Fig. 2). The wheel-running activity of young and aged mice in DD was monitored for 10 d, and the mice were then killed in the dark at CT10-11 (Fig. 2A). Both young and aged SCNs clearly showed circadian rhythms of PER2::LUC expression (Fig. 2B). Two-way repeated-measures ANOVA showed an interaction between age and cycle in the peak phases (Fig. 2C, Table 1; p < 0.001c). The phase differences gradually increased up to the fifth cycle [peak phase (CT); 16.13 ± 1.24 and 18.03 ± 0.63 for the first cycle (p < 0.05g); 17.53 ± 1.77 and 20.13 ± 1.40 for the second cycle (p < 0.05h); 18.43 ± 2.34 and 22.33 ± 2.68 for the third cycle (p < 0.05i); 19.50 ± 2.89 and 24.80 ± 2.31 for the fourth cycle (p < 0.05j); 19.7 ± 2.67 and 33.23 ± 6.36 for the fifth cycle (p < 0.01k) in young and aged SCNs (n = 5 per group), respectively; Fig. 2C, Table 2]. As indicated by the delayed peaks, the free-running period of PER2::LUC rhythm in aged SCNs was significantly longer than in young SCNs. Moreover, the amplitude was decreased by the aging; two-way repeated-measures ANOVA revealed a significant interaction between age and cycle in the amplitude data (Fig. 2D, Table 1; p < 0.001d). Significant differences between young and aged groups were detected in the second to the fifth cycle [normalized amplitude (first cycle set to 1.00); 0.60 ± 0.12 and 0.35 ± 0.07 for the second cycle (p < 0.01l); 0.39 ± 0.10 and 0.18 ± 0.06 for the third cycle (p < 0.01m); 0.25 ± 0.07 and 0.10 ± 0.03 for the fourth cycle (p < 0.01n); 0.15 ± 0.06 and 0.05 ± 0.02 for the fifth cycle (p < 0.01°) in young and aged SCNs (n = 5 per group), respectively; Fig. 2D, Table 2].


Age-Related Changes in the Circadian System Unmasked by Constant Conditions(1,2,3).

Nakamura TJ, Nakamura W, Tokuda IT, Ishikawa T, Kudo T, Colwell CS, Block GD - eNeuro (2015)

Effects of aging on PER2::LUC rhythms in SCN explants from mice maintained in DD. A, Representative double-plotted actograms of wheel-running activity in young and aged PER2::LUC mice maintained in DD. Asterisks indicate the timing of the killing of the animals. B, Typical examples of PER2::LUC rhythms of SCN explants from mice maintained in DD for 10 d, as measured by PMT. C, Phase map of peak PER2::LUC rhythms in the SCN. Each point represents the average peak of PER2::LUC rhythms in each cycle, plotted relative to the circadian time prior to the killing of the animals. D, Amplitude of PER2::LUC rhythms in the SCN. The amplitude of each oscillation was determined as the sum of the absolute value of the lowest and highest points (counts). Data are shown as the mean ± SD. n = 5 per group. *p < 0.05, **p < 0.01 for young vs. aged animals (Bonferroni post hoc comparison).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4596014&req=5

Figure 2: Effects of aging on PER2::LUC rhythms in SCN explants from mice maintained in DD. A, Representative double-plotted actograms of wheel-running activity in young and aged PER2::LUC mice maintained in DD. Asterisks indicate the timing of the killing of the animals. B, Typical examples of PER2::LUC rhythms of SCN explants from mice maintained in DD for 10 d, as measured by PMT. C, Phase map of peak PER2::LUC rhythms in the SCN. Each point represents the average peak of PER2::LUC rhythms in each cycle, plotted relative to the circadian time prior to the killing of the animals. D, Amplitude of PER2::LUC rhythms in the SCN. The amplitude of each oscillation was determined as the sum of the absolute value of the lowest and highest points (counts). Data are shown as the mean ± SD. n = 5 per group. *p < 0.05, **p < 0.01 for young vs. aged animals (Bonferroni post hoc comparison).
Mentions: Next, we recorded bioluminescence rhythms in SCN explants from mice maintained in DD (Fig. 2). The wheel-running activity of young and aged mice in DD was monitored for 10 d, and the mice were then killed in the dark at CT10-11 (Fig. 2A). Both young and aged SCNs clearly showed circadian rhythms of PER2::LUC expression (Fig. 2B). Two-way repeated-measures ANOVA showed an interaction between age and cycle in the peak phases (Fig. 2C, Table 1; p < 0.001c). The phase differences gradually increased up to the fifth cycle [peak phase (CT); 16.13 ± 1.24 and 18.03 ± 0.63 for the first cycle (p < 0.05g); 17.53 ± 1.77 and 20.13 ± 1.40 for the second cycle (p < 0.05h); 18.43 ± 2.34 and 22.33 ± 2.68 for the third cycle (p < 0.05i); 19.50 ± 2.89 and 24.80 ± 2.31 for the fourth cycle (p < 0.05j); 19.7 ± 2.67 and 33.23 ± 6.36 for the fifth cycle (p < 0.01k) in young and aged SCNs (n = 5 per group), respectively; Fig. 2C, Table 2]. As indicated by the delayed peaks, the free-running period of PER2::LUC rhythm in aged SCNs was significantly longer than in young SCNs. Moreover, the amplitude was decreased by the aging; two-way repeated-measures ANOVA revealed a significant interaction between age and cycle in the amplitude data (Fig. 2D, Table 1; p < 0.001d). Significant differences between young and aged groups were detected in the second to the fifth cycle [normalized amplitude (first cycle set to 1.00); 0.60 ± 0.12 and 0.35 ± 0.07 for the second cycle (p < 0.01l); 0.39 ± 0.10 and 0.18 ± 0.06 for the third cycle (p < 0.01m); 0.25 ± 0.07 and 0.10 ± 0.03 for the fourth cycle (p < 0.01n); 0.15 ± 0.06 and 0.05 ± 0.02 for the fifth cycle (p < 0.01°) in young and aged SCNs (n = 5 per group), respectively; Fig. 2D, Table 2].

Bottom Line: Circadian timing systems, like most physiological processes, cannot escape the effects of aging.With age, humans experience decreased duration and quality of sleep.These data suggest that aging degrades the SCN circadian ensemble, but that recurrent LD cycles mask these effects.

View Article: PubMed Central - HTML - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus