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1 Department of Neurobiology
and Physiology and Center for Circadian Biology and Medicine, Syrian
hamsters display age-related changes in the expression of circadian
rhythms and in responsiveness of the circadian system to photic and
nonphotic stimuli. This study characterized the effects of age on the
locomotor activity rhythm of middle-aged and old hamsters and evaluated
the effects of strengthening the entraining light signal. Compared with
young (4.5 mo) animals, middle-aged (11.25 mo) and old (16 mo) animals
displayed increased daily bouts of activity
(P < 0.001) and reduced total daily
activity and activity rhythm amplitude
(P < 0.05) in 14:10-h light-dark cycles. After the light intensity was increased from 300 to 1,500 lx
during the light cycle, middle-aged hamsters demonstrated decreased daily activity bouts (P < 0.05) and
increased total daily activity (P
aging; circadian activity rhythm
AGING IS ASSOCIATED with alterations in mammalian
circadian timing, including an overall increase in the lability of
circadian phase and a reduction in the amplitude and period length of
numerous endocrine, metabolic, and behavioral circadian rhythms in
various animal species including humans (for reviews see Refs. 3, 14, 20, 28). There is now considerable evidence from mammalian studies that
senescence is associated with alterations in the neural structure
thought to be primarily responsible for the generation of the circadian
oscillation, the suprachiasmatic nuclei (SCN) of the hypothalamus (16,
18, 19, 26). Recent findings in rodents suggest that aging has marked
effects on the response of the circadian pacemaker to the major stimuli
that can induce phase shifts in the clock or reinforce the amplitude of
the signal generated by the clock, namely the light-dark
(LD) cycle (15, 18, 30)
and the activity-rest cycle (12, 21, 22, 25).
In the Syrian hamster
(Mesocricetus
auratus), there are pronounced age-related changes in
the expression of circadian rhythms under both entrained and constant
or free-running conditions. Recent work in our laboratory suggests that
many of these changes in the locomotor activity rhythm are already
occurring by middle age (13-16 mo) in hamsters. For example,
middle-aged hamsters begin to display an advance in the phase angle of
entrainment, a loss of precision in the timing of activity onset (29),
and a diminished responsiveness to the phase-shifting effects of
triazolam, an activity-inducing stimulus (21, 22). These findings
suggest that age-related alterations in circadian rhythmicity are
occurring early in the aging process.
Old hamsters (>16 mo) demonstrate increasingly fragmented patterns of
activity, an advance in the phase angle of entrainment, a loss of
precision in the timing of daily activity onset, a significant shortening of the free-running activity period or tau ( Experiment 1
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
0.01) and activity rhythm amplitude (P 0.001) compared with controls maintained in 300 lx. The pattern of
changes in the activity rhythm of old experimental animals was similar
to trends observed in middle-aged experimental hamsters, although not
as robust. Thus age-related changes in the activity rhythm are
occurring by middle age in hamsters, and the provision of stronger
entraining signals may lead to more stable circadian organization.
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
) in constant darkness (4, 13, 15, 29), and a diminished responsiveness to the
phase-shifting effects of low-intensity light pulses (30) and stimuli
that induce changes in the activity-rest cycle (12, 21, 22). Witting
and colleagues (27) observed that, during entrainment to an LD cycle,
the amplitude of the activity rhythm of old rats could be increased by
increasing the light intensity. The investigators concluded that
age-related reductions in the amplitude of the circadian sleep-wake
rhythm could be partially compensated for by increasing the intensity
of daytime ambient illumination. The purposes of this study were to
1) characterize in more detail the
circadian locomotor rhythm in young, middle-aged, and old male Syrian
hamsters under entrained conditions and
2) examine circadian locomotor
activity in middle-aged and old hamsters when the intensity of the LD
cycle is increased fivefold.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
11 mo and <16 mo for
inclusion in the "middle-aged" group and animals 16 mo for
inclusion in the "old" group. Animals were individually housed in
cages equipped with running wheels and isolated in animal chambers in a
LD of 14 h of light to 10 h of dark (LD 14:10), where the light
intensity during the light phase was ~300 lx (40× optometer
photometer, United Detector Technology) measured at the cage floor.
Food and water were available ad libitum, and room temperature was
maintained at 22 ± 2°C. Animals were housed in these conditions
for 1 mo, after which locomotor activity data were analyzed for a
10-day period (days
30-40).
Experiment 2
In the second experiment (conducted 8 mo later), we evaluated the effect of increasing the strength of the entraining photic stimulus on the circadian locomotor activity rhythm of middle-aged (12.5 mo) and old (19 mo) Syrian hamsters. The hamsters were obtained from the cohort of animals (originally the young and middle-aged hamsters) used in experiment 1 of this study. The animals were matched by age and visual inspection of the locomotor activity patterns (e.g., time of activity onset, activity
, number of daily activity
bouts), divided into control and experimental groups (middle-aged
hamsters: 7 control, 10 experimental; old hamsters: 7 control, 6 experimental), and maintained in LD 14:10 with a light intensity equal
to 300 lx. Control hamsters remained in these lighting conditions for
12 wk. Experimental hamsters were maintained in 300 lx for 6 wk during
the baseline or period
1, after which the light intensity was
increased to 1,500 lx (i.e., during the light phase of the LD cycle)
for 6 wk during period 2. To determine if alterations in the
circadian locomotor activity rhythm after exposure to a bright-light
stimulus were sustained after the entraining agent was removed, animals
were released into constant darkness (DD) for 2 wk, and the
free-running activity , total daily activity, and activity rhythm
amplitude were evaluated during the first week.
Analysis of Locomotor Activity
The locomotor activity rhythm was recorded in all animals by monitoring running wheel behavior via computer using the Chronobiology Kit (Stanford Software Systems) for data collection. Activity was recorded as the number of wheel revolutions, and data were logged into the computer in 1-min bins. Wheel running in rodents occurs in a series of temporal clusters, or activity bouts, with varying duration separated by intervals of inactivity. Using software developed in our laboratory (11), we quantified the degree of rhythm fragmentation of animals at different ages by analyzing the number of discrete bouts of activity performed each day. Daily activity bouts identified with this computerized method were characterized by time of onset and offset, total duration, and total number of wheel revolutions.Other parameters of the locomotor activity rhythm evaluated across age
groups included the phase angle of entrainment to the LD cycle
[the difference between the time of lights-out (onset of
darkness) and the time of activity onset] and the duration of the
active period or activity (measured from activity onset to offset).
Activity onset was defined as the first 5-min bin where activity
equaled 10% of the maximum daily activity and was sustained for at
least another 10 min during the following 30-min epoch. Activity offset
was defined as the last 5-min bin where activity equaled 10% of the
maximum daily activity. Also, we examined the 24-h locomotor activity
rhythm profile and amplitude (the maximum intensity of daily activity
in revolutions/min), the phase of the daily activity peak (in
relationship to the time of lights-out), and the phase of the maximum
bout of daily activity (greatest number of wheel revolutions performed
in a single bout of activity).
Statistical Analysis
A one-way analysis of variance (ANOVA) was used in experiment 1 to examine mean differences in parameters of circadian activity among young, middle-aged, and old hamsters, and Tukey post hoc comparisons were used to examine differences between specific age groups. When data were not normally distributed, the nonparametric Kruskal-Wallis multiple-comparison z-test was used to analyze group differences with a Bonferonni post hoc test. Summary statistics have been reported as the mean ± SE, and P < 0.05 was considered significant. In experiment 2 the variable of interest was the change in circadian locomotor activity parameters in control and experimental animals between the first and second time periods. Therefore, the difference between period 1 and period 2 was calculated for each group, and Student's t-tests were used to evaluate between-group differences.| |
RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Experiment 1: Comparison of Young, Middle-Aged, and Old Hamsters
Age-related alterations in activity consolidation and the daily volume of activity were observed. Compared with young animals, middle-aged hamsters demonstrated a significant increase in the number of activity bouts per day (ANOVA; P < 0.05; Fig. 1A), whereas both middle-aged and old animals displayed a significant reduction in the total number of daily wheel revolutions (Kruskal-Wallis; P < 0.05; Fig. 1B).
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An examination of the overall 24-h pattern of activity (Fig.
2,
A-C)
revealed an age-related decline in rhythm amplitude. Compared with
young animals, middle-aged and old hamsters displayed a significant
decline in the maximum intensity of daily activity (ANOVA;
P < 0.05). Middle-aged and
old hamsters also demonstrated significant delays in the phase of the
time when peak activity occurred each day (Kruskall-Wallis;
P < 0.05; Fig.
2D) and in the phase of the time at
which they initiated the largest bout of daily activity
(Kruskall-Wallis; P < 0.05; Fig.
2E). Young hamsters typically
displayed peak activity and the largest bout of activity within the
first hour after lights-out. No significant differences were observed
in either the phase angle of entrainment or activity among age
groups. To evaluate within-group variability in activity parameters,
indexes of variability were determined for each age group and were
statistically compared using ANOVA (see Table
1). The results suggest a trend toward
increasing within-group variability with advancing age, particularly in
total daily locomotor activity and the time of the major bout of daily activity. Taken together, these
results suggest that most of the age-related changes in the circadian
locomotor activity rhythm have already occurred by middle age in
hamsters.
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Experiment 2: Effects of Increased Light Intensity
In the second experiment, the strength of the photic entraining stimulus was increased to evaluate the possibility of attenuating or reversing age-related changes in the circadian locomotor activity rhythm of middle-aged (12.5 mo) and old (19 mo) hamsters. An initial comparison of control and experimental hamsters revealed that the groups were similar and not statistically different on any of the parameters evaluated in this study. Hamsters were maintained in period 1 (light intensity: all hamsters = 300 lx) and period 2 (light intensity: controls = 300 lx, experimentals = 1,500 lx) for 6 wk each, and data from the last 3 wk in each condition were analyzed. As in experiment 1, indexes of variability for activity variables were determined for each age group, and changes in variability from period 1 to period 2 were statistically compared. No significant differences in within-group variability were noted for either middle-aged or old hamsters.Degree of rhythm fragmentation. Middle-aged hamsters displayed significant between-group differences in the magnitude of change from period 1 to period 2 in the mean number of daily activity bouts (P = 0.042; Fig. 3A). Control hamsters demonstrated an increase in rhythm fragmentation from period 1 to period 2, whereas experimental hamsters displayed a decline in the number of daily activity bouts after exposure to 1,500 lx. Old hamsters did not display significant between-group differences in the number of daily activity bouts (Fig. 3B).
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Twenty-four-hour locomotor activity rhythm profile and amplitude. Middle-aged hamsters displayed significant between-group differences in the magnitude of change from period 1 to period 2 in total daily activity (P = 0.01; Fig. 4A) and activity rhythm amplitude (P = 0.001; Fig. 5, A-D, and Fig. 6, A and B). Control hamsters demonstrated a decline in the volume of total daily activity and activity rhythm amplitude from period 1 to period 2. In contrast, experimental hamsters displayed an increase in total daily activity and activity rhythm amplitude after exposure to 1,500 lx.
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Although there were no significant between-group differences among old hamsters in total daily activity (Fig. 4B), the pattern or trend of changes observed in old experimental animals was similar to trends observed in the activity rhythm of middle-aged experimental hamsters. Activity rhythm amplitude was the only variable in which significant (P = 0.039) between-group differences in the magnitude of change were observed. Four of six old experimental animals demonstrated an increase in activity rhythm amplitude after exposure to the bright-light entraining stimulus, in contrast to the reduction in rhythm amplitude observed in the control group during period 2 (Fig. 5, E-H, and Fig. 6, C and D).
Circadian phase. Middle-aged hamsters
displayed significant between-group differences in the magnitude of
change from period 1 to
period
2 in the phase of the maximum bout of
daily activity (P = 0.008; Fig.
7A).
Control hamsters demonstrated a phase delay in the time at which they
initiated the largest bout of daily activity from
period
1 to
period
2. In contrast, after exposure to
1,500 lx, experimental hamsters displayed little if any change in the
time at which they initiated the largest bout of daily activity. No
between-group differences were observed among middle-aged animals in
the phase angle of entrainment, activity , or the phase of the daily
activity peak between periods
1 and
2.
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Increasing the light intensity to 1,500 lx during the light phase of
the LD cycle did not result in significant changes in the circadian
phase of the locomotor activity rhythm of old hamsters. No significant
between-group differences were observed in old animals in the phase of
the maximum bout of daily activity (Fig. 7B), the phase angle of entrainment,
activity , or the phase of the daily activity peak between
periods
1 and
2.
Circadian locomotor activity in
DD. To determine if alterations in the
circadian locomotor activity rhythm after exposure to a bright-light
stimulus were sustained after the entraining agent was removed, animals
were released into DD for 2 wk, and the free-running activity period
(), total daily activity, and activity rhythm amplitude were
evaluated. Although there were no significant differences between
middle-aged control and experimental groups in the free-running
activity , significant between-group differences were noted in the
magnitude of change in activity rhythm amplitude
(P = 0.001; Fig.
8A) and
total daily activity (P = 0.007; Fig.
8B) during the first week in DD.
Control hamsters demonstrated an increase in activity rhythm amplitude,
coupled with a slight decline in total daily activity. In contrast,
experimental animals displayed a decline in activity rhythm amplitude
and the volume of daily activity. Old hamsters did not display
significant between-group differences in the free-running activity ,
the activity rhythm amplitude, or total daily activity.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Results from this study indicate that prominent age-related changes in the circadian activity rhythm are already occurring by middle-age in Syrian hamsters. Previous findings in our laboratory demonstrating that by 13-16 mo of age hamsters are already beginning to display an advance in the phase angle of entrainment, a loss of precision in the timing of activity onset (29), and a loss of responsiveness to the phase-shifting effects of activity-inducing stimuli (21, 22), provide further evidence that the age-related alterations of circadian rhythmicity are apparent early during the aging process. Similar findings have been reported in middle-aged rats in which significant reductions in the amplitude and stability of the circadian activity (6, 8) and body temperature (8) rhythms were observed.
Age-related alterations in circadian rhythms may be at least partially due to a decrease in responsiveness to synchronizing environmental stimuli. In advanced age, the circadian clock of Syrian hamsters becomes less sensitive to the phase-shifting effects of low-intensity light pulses (30) and unresponsive to the phase-shifting effects of stimuli that induce changes in the activity-rest cycle (12, 21, 22). Aging is also associated with a reduction in light-induced gene expression in the SCN of rats and hamsters (7, 18, 30, 31). Such age-related alterations in circadian sensitivity to photic and activity-inducing stimuli may reflect a weakened coupling between oscillators that make up the circadian system (5). Diminished circadian sensitivity to low-intensity light could reflect deterioration of input mechanisms to the clock. For example, there may be a decline in the number and/or sensitivity (i.e., stimulation threshold) of photoreceptors in the retina, or there may be alterations in retinal pathways to the SCN. Compared with young hamsters, old hamsters display an ~20-fold increase in threshold sensitivity to light. That is, thresholds for both the phase-shifting effects of light on the circadian locomotor activity rhythm and the photic induction of Fos in the SCN are shifted toward higher light intensities (30). Retinal degeneration and/or the presence of cataracts in old animals could reduce photic input to the SCN. However, it is unlikely that changes in retinal transmittance alone could account for a change of this magnitude, because old hamsters (18 mo) only demonstrate a 10-20% reduction in light transmission through the retina compared with young controls (Zhang and Turek, unpublished observations).
Previous work by Witting and colleagues (27) suggested that the amplitude of the sleep-wake rhythm in old rats could be augmented during entrainment to an LD cycle by increasing the strength of the entraining photic stimulus. Whereas at a given light intensity (ranging from 3.5 to 445 lx) the amplitude of the sleep-wake rhythm was lower in old than in young rats, the amplitude of old rats exposed to the brightest light was comparable to those of young rats under the dimmest light intensity. The investigators concluded that age-related reductions in the amplitude of the circadian sleep-wake rhythm could be partially compensated for by increasing the intensity of daytime ambient illumination. However, it was not clear if the effects of the bright LD cycles on the rhythm amplitude reported by these investigators were due to the masking effects of light (27).
Results from the present study indicate that increasing the strength of the entraining LD cycle can significantly increase total daily wheel running activity and activity rhythm amplitude, thus attenuating at least some of the effects of aging on the circadian locomotor rhythm, particularly in middle-aged hamsters. Furthermore, we evaluated circadian locomotor activity rhythms after removal of the bright-light entraining signal. The increase in the daily volume of activity and the activity rhythm amplitude exhibited by experimental hamsters under bright LD was not sustained once the animals were released into DD. One possible explanation is that the bright-light stimulus provided aging hamsters with a stronger entraining signal that led to a more coherent profile of the overall 24-h activity pattern, but did not fundamentally alter underlying circadian organization. Therefore, removal of the photic entraining stimulus resulted in the animal's return to activity patterns reflective of its endogenous circadian timing system. Alternatively, the masking effects of the bright LD cycle might have led to the expression of a more coherent circadian activity pattern, or the bright-light entraining stimulus may have suppressed locomotor activity during the light phase, leading to a subsequent decline in activity feedback signals to the clock. Although the mechanism by which increased light intensity modifies age-related changes in the activity rhythm remains unknown, our results indicate that providing aging hamsters with a stronger entraining photic signal can lead to a more stable circadian organization. Although the bright photic stimulus of 1,500 lx was used in experimental conditions in this study, lower levels of light intensity may be just as effective in enhancing the stability of the circadian system. Future studies could involve evaluating the effect of lower light intensities on circadian rhythms in aging animals, starting from a lower baseline (e.g., 50 lx) and conducting a dose-response study to light at 100, 200, and 400 lx.
Old hamsters did not demonstrate the same robust response to the bright photic entraining stimulus; however, the pattern or trend of changes observed in old experimental animals was similar to trends observed in the activity rhythm of middle-aged experimental hamsters. Visual impairments in old hamsters could reduce photic input to the SCN and coupled with a decline in daily wheel running activity may have played a role in minimizing the effects of bright light on the circadian responsiveness of old animals. Physiological changes that accompany aging, such as a decline in the animal's physical ability and/or a decline in motivation to use the wheel, may have contributed to a reduction in locomotor activity in the old hamsters. Measurement of the animal's general activity in the cage may more accurately reflect the activity patterns of old rodents and will be a consideration in future studies. The possibility remains that, if age-related changes in the circadian system are already occurring by middle age, it may be more difficult to attenuate or reverse a process that is already well established by old age.
Age-related changes in circadian timing have been well-documented in rodents; however, findings in humans remain controversial. Human aging is associated with an overall increase in the lability of circadian phase and a reduction in the amplitude and period length of numerous endocrine, metabolic, and behavioral circadian rhythms (for reviews see Refs. 3, 14, 20). Human senescence is often associated with reduced exposure to bright light, social cues, and physical activity, particularly among institutionalized elderly. Visual impairments in the elderly, as well as limitations in physical mobility also contribute to diminished visual cues and limited exposure to bright outdoor light (1). Recent studies now indicate that timed bright-light exposure can normalize the phase of the body temperature rhythm and enhance alertness, mood, and performance in institutionalized elderly (2, 10). Furthermore, new data suggest that long-term fitness training in healthy elderly males can lead to a significant reduction in the fragmentation of the rest-activity rhythm (24). In subjects with Alzheimer's disease, there is clearly a deterioration in the amplitude and stability of the circadian activity rhythm (17), and current findings indicate that exposing demented subjects who are not visually impaired to indirect bright light increases the stability of the rest-activity rhythm (23). In contrast to the findings in institutionalized elderly, Monk (9) studied healthy elderly men living at home and found no significant differences in either the amplitude or period of the body temperature rhythm between these subjects and young healthy male controls (9). Such findings suggest that age-related changes in circadian rhythms may vary among individuals, and an individual's health coupled with the environment in which they live and their level of interaction with that environment may play a critical role in maintaining the stability of the circadian system.
Perspectives
Descriptive studies have provided clear evidence that rhythms change with age; however, little is known about the underlying factors contributing to these changes. The present results show that most changes in the circadian locomotor activity rhythm are already occurring by middle age in hamsters. Daily exposure of middle-aged animals to a bright photic-entraining stimulus attenuates age-related declines in activity rhythm consolidation, volume, and amplitude, while having little effect on the activity rhythm of old hamsters. Thus attempts to reverse or attenuate changes associated with aging may be more effective if treatment is initiated earlier rather than later, and the provision of stronger entraining signals may be a valuable component in leading to a more stable circadian organization. Findings with elderly humans also indicate that age-related changes in circadian rhythms can be attenuated or reversed by increasing the strength of the external zeitgeber. Evaluating circadian marker rhythms such as the sleep-wake, body temperature, melatonin, and growth hormone rhythms in humans during midlife could lead to the early identification of individuals who are already beginning to demonstrate age-related alterations in circadian stability and organization. Providing such individuals with stronger entraining signals could delay or attenuate temporal disorganization that occurs in at least some individuals in advanced age.| |
ACKNOWLEDGEMENTS |
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We thank Dr. Teresa Horton and Dr. Kathryn Scarbrough for assistance in the preparation of this manuscript. We also thank Dr. Plamen Penev for writing the computer program used for the analysis of locomotor activity bouts.
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FOOTNOTES |
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This research was supported by National Institutes of Health Grants PO1-AG-11412, RO1-HD-AG-10870, RO1-AG-09297, and NRO6954.
Address for reprint requests: S. Labyak, Sleep and Chronobiology Lab, E. P. Bradley Hospital, 1011 Veterans Memorial Parkway, E. Providence, RI 02915.
Received 2 May 1997; accepted in final form 2 December 1997.
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Abstract
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Discussion
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). No. of activity bouts per day
(A) and total daily activity counts
(B) over a 10-day period.
a Significant
(P 
