Stability of circadian timing with age in Syrian hamsters
FRED C. DAVIS AND N. VISWANATHAN
Department of Biology, Northeastern University, Boston, Massachusetts 02115
circadian rhythm; sleep; aging; activity/rest rhythm
AGE-RELATED CHANGES
in the regulation of human circadian rhythms are thought to contribute to age-related
changes in a variety of physiological and behavioral
functions, including the timing and quality of sleep and
the levels of hormones (2, 7, 9, 12, 31, 43). Consequently, age-related changes in circadian regulation
may contribute significantly to both the economic and
quality of life costs of human aging (20). For example,
disrupted sleep in individuals with dementing illness,
and its consequences for caregivers, is one of the
primary contributing factors in the need for long-term
institutional care (20, 29). Thus, for a variety of compelling reasons, there is considerable interest in the
causes and possible remedies for age-related changes in
daily rhythms.
A hypothesis held for many years primarily on the
basis of research in animals other than humans is that
the activity of the mammalian circadian pacemaker
within the suprachiasmatic nucleus (SCN) changes
during aging. In particular, it has been suggested that
the free running period and amplitude or output of the
pacemaker as well as its responsiveness to stimuli
change with age (1, 4, 5, 23, 25, 38, 46, 47). Evidence for
a change in free running period is based primarily on
studies of wheel-running activity rhythms in rodents
(18, 21, 22, 25, 27, 30, 36, 40, 46). In Syrian hamsters,
The costs of publication of this article were defrayed in part by the
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R960
free running period has been reported to shorten with
age (21, 22, 25, 27, 40, 46). Evidence for a shortening of
period with age has also been seen in humans (43), and
it has been suggested that a change in period might
contribute to early morning awakening (9), a complaint
more common among older people. Another hypothesis
concerning age-related changes in circadian rhythms is
that the amplitude of circadian oscillations and/or the
strength of output signals from the pacemaker decrease with age. Evidence for this is an age-related
decrease in the amplitudes of circadian rhythms in
both humans (7, 9) and other animals, including changes
in activity and sleep/wake rhythms (3, 17–19, 26, 32,
34, 36, 42, 44). In addition, rhythms expressed as
alternative states, such as activity and rest or sleep and
wakefulness, become more fragmented with age (19,
24, 26, 34, 36, 44), a change that could result from
reduced modulation of those functions by the circadian
pacemaker. Age-related changes in the expression of
rhythms within the SCN itself have also been reported
in rats and hamsters (16, 33, 41, 45).
The present study was undertaken to evaluate the
hypothesis that free running period shortens with age
in Syrian hamsters. The changes reported in previous
studies were small, and it is unclear to what extent
such changes would be of significance to the regulation
of circadian rhythms under entrained conditions. In
most, but not all (21), of the previous studies, different
age groups were represented by different hamsters. In
the present study we examined the relationship between age and free running period in individual hamsters by continuously measuring their wheel running
activity rhythms under constant conditions over their
entire lives. Other aspects of the activity rhythms that
might be related to amplitude, such as activity level
and the fragmentation of activity, were also measured.
By monitoring individual hamsters throughout their
lives it was also possible to determine whether there
was a correlation between the values of certain parameters and longevity.
METHODS
Male Syrian hamsters (Mesocricetus auratus, LVG) born in
the animal vivarium of Northeastern University were maintained on a 14:10-h light-dark cycle (LD 14:10, lights off at
2100, light intensity ,300 lx) until 8 wk of age. The hamsters
were then individually housed in cages equipped with running wheels and placed into constant dim light (,1 lx). Food
(5001, PMI Nutrition International, St. Louis, MO) and water
were available at all times. Wheel running activity was
recorded using the DataCol-3 data acquisition system (MiniMitter, Sunriver, OR). Counts of wheel revolutions were
stored in 10-min bins. The graphic display and analysis of
activity records were done with Circadia software (Behavioral Cybernetics, Cambridge, MA). Cages were changed
every 2 wk, and care was taken to examine the activity record
of each hamster before a change to avoid doing the change
0363-6119/98 $5.00 Copyright r 1998 the American Physiological Society
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Davis, Fred C., and N. Viswanathan. Stability of circadian timing with age in Syrian hamsters. Am. J. Physiol. 275
(Regulatory Integrative Comp. Physiol. 44): R960–R968,
1998.—The causes of age-related disruptions in the timing of
human sleep and wakefulness are not known but may include
changes in both the homeostatic and circadian regulation of
sleep. In Syrian hamsters the free running period of the
circadian activity/rest rhythm has been reported to shorten
with age. Although this has been observed under a variety of
experimental conditions, the changes have been small and
their consistency uncertain. In the present study, the wheel
running activity/rest rhythm was continuously measured in
male Syrian hamsters (Mesocricetus auratus) in dim constant
light (,1 lx) from 8 wk of age until death. Fifteen hamsters
survived to at least 90 wk (28%). The average free running
period of these hamsters did not change with age. In 18
hamsters that died between 50 and 88 wk, free running
period also did not change before death. In contrast to free
running period, other measures related to activity level
changed significantly with age and before death. Despite
changes in the expression of the activity/rest rhythm, the free
running period of the hamster circadian pacemaker remained
remarkably stable with age.
AGE-RELATED CHANGES IN CIRCADIAN RHYTHMS
RESULTS
The average life span of Syrian hamsters with access
to individual running wheels and kept in constant dim
light was 72.03 wk 6 21.47 (6SD, n 5 58). Of the 58
hamsters from which activity was recorded, 15 survived to at least 90 wk of age; Fig. 1 shows the wheel
running activity records from five of these. Between 8
and 28 wk of age (the first 20 wk in dim light), the
average free running period (6SE) significantly lengthened (23.92 6 0.032 to 24.08 6 0.053 h, P , 0.01, n 5
15, paired t-test). This initial lengthening of period may
have been the result of decaying aftereffects following
entrainment to the 24-h light-dark cycle (28) or could
have been related to the regression and recrudescence
of the testes observed during this time. Paired testes
weights (g/100 g body wt) were 2.08 (n 5 4) at 8 wk, 1.04
(n 5 3) at 18 wk, 0.48 (n 5 2) at 22 wk, and 1.88 (n 5 3)
at 33 wk. Although elevated testosterone levels have
been reported to cause a shortening of period in mice
(10), testosterone levels were likely to have been falling
and then rising again while the period steadily lengthened during this first 20 wk in dim light. After 28 wk of age
and 20 wk in dim light, free running period appeared to
have stabilized. Measurements taken after 28 wk were
therefore used to evaluate subsequent age-related changes.
The average free-running period of the 15 hamsters
that survived to at least 90 wk did not change with age
(Fig. 2). Some of the individual hamsters showed a
shortening of period, some showed a lengthening,
whereas some showed no consistent change (Fig. 1). In
contrast to the average free running period, the average activity level, time active, intensity of activity, and
bout length all significantly decreased with age (Fig. 3).
Between 30 and 90 wk, these parameters decreased by
66, 43, 46, and 45%, respectively. The average number
of bouts only differed by 4% between 30 and 90 wk and
did not significantly change with age (Fig. 3). As
indicated by the average activity profiles in Fig. 4, the
decrease in activity level appeared to occur to a greater
extent near the beginning of the hamsters’ active time;
activity level at the time of the daily peak fell by ,75%.
Although the average free running period did not
change in the 15 animals that survived to 90 wk, this
could have been because these animals were unusually
healthy. To examine the possibility that period changed
as animals approached death, free running period was
measured relative to death regardless of when this
occurred in hamsters that died between 50 and 88 wk of
age (n 5 18). As shown in Fig. 5, there was no change in
the average period before death. However, average
activity level, time active, intensity of activity, bout
number, and bout length all decreased significantly in
the 1 wk before death (Fig. 6). Examples of the records
from two of these hamsters are shown in Fig. 7.
Because activity level, time active, intensity of activity, bout number, and bout length changed with age
and/or as death approached, we examined whether any
of these parameters assessed at an age (50 wk) before
the average age of death were correlated with longevity.
Only one parameter, time active, showed a significant
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during the hamster’s late subjective day. Unpublished observations indicated that a cage change at this time could cause
a phase shift and/or a change in free running period.
Because Syrian hamsters maintained in short photoperiods or in constant darkness undergo gonadal regression and
spontaneous recrudescence over ,25 wk (14) and because
endocrine changes could affect free running period and activity level (10, 14), the reproductive status of hamsters was
assessed. The testis and body weights of an initial group of
four hamsters from the experimental pool were measured at 8
wk of age. Subsequently, hamsters from the experimental
conditions were randomly selected and killed at 18 (n 5 3), 22
(n 5 2), and 33 (n 5 3) wk of age to obtain body and testis
weights. Whether the testes initially regressed and subsequently recrudesced or were maintained fully functional by
the dim constant light, it was expected that at some age
reproductive status would stabilize.
Measurements for the assessment of age-related changes
were taken from 4-wk blocks of continuous data with midpoints at 30, 50, and 70 wk of age and from 2- to 4-wk blocks at
90 wk of age from hamsters that lived until at least 90 wk of
age (n 5 15). In addition, to determine whether changes
occurred before death, regardless of the age when this
occurred, measurements from 2- to 3-wk blocks were compared just before death (2–3 wk) and at 3 and 6 mo before
death in hamsters that lived for at least 50 wk but died before
88 wk (n 5 18). Correlations between longevity and various
rhythm parameters were examined with the use of measurements obtained at 50 wk of age (n 5 33) from all of the
hamsters that lived to at least 50 wk.
Estimates of free running period with a resolution of 65
min were made using the x2 periodogram (32) and further
estimated to a resolution of 62.5 min by adjusting the folding
period of the actogram and visually identifying the period
that produced the best vertical alignment of the activity and
rest times. Activity level was calculated as the average
number of wheel revolutions per day. The time active was
taken as the percentage of 10-min bins that contained at least
two activity counts, and the intensity of activity was taken as
the average number of wheel revolutions per 10-min bin (with
activity). The number and length of activity bouts were also
determined. An activity bout was any continuous series of
10-min bins (including only a single bin) that contained at
least two activity counts. Average bout length was the total
number of 10-min bins of activity divided by the total number
of bouts. Although the number of bouts may be considered a
measure of the extent to which activity is fragmented (more
bouts indicating more fragmentation), the number of bouts
could decrease although activity is becoming more fragmented if the total amount of activity has also decreased. A
better measure of fragmentation may be bout number normalized for the total amount of activity, for example bout number
divided by total activity. Average bout length is simply the
inverse of this number and is therefore considered to represent a measure of fragmentation. A smaller average bout
length would be seen when, for example, the same total time
active is broken into a greater number of bouts (i.e., is more
fragmented). Whether a significant change in a particular
measurement occurred with age was evaluated with a onefactor, repeated-measures ANOVA.
Averaged activity profiles were also compared at 30 and 90
wk of age. For a particular hamster and age, the activity
record was folded at the hamster’s circadian period and the
average count in each 10-min bin was calculated. These
averages were then averaged across animals to determine the
average profile at each age.
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R962
AGE-RELATED CHANGES IN CIRCADIAN RHYTHMS
correlation with longevity (Fig. 8). Even in this case, if
it were not for low values in three hamsters that died
soon after the measurement age, the correlation would
not be significant. The correlation coefficients and P
values for activity level, intensity of activity, bout
number, and bout length were r 5 0.150, 0.206, 0.289,
and 20.014 and P 5 0.407, 0.253, 0.103, and 0.941,
respectively.
DISCUSSION
Fig. 2. Average free running period at different ages for 15 hamsters
that lived to at least 90 wk of age. Beginning with 30 wk of age the
averages were 24.07, 24.13, 24.10, and 24.09 h. Vertical lines indicate
SEs (P . 0.05, ANOVA).
The present study tested the hypothesis that the free
running period of the hamster circadian activity/rest
rhythm changes with age. Free running period was
continuously measured from individual hamsters that
had been bred in our facility under a stable 14:10-h
light-dark cycle until the time they entered dim light at
8 wk of age. The reproductive status of the population
was monitored so that changes in period could be
assessed after reproductive state stabilized (after the
first 20 wk in dim light). During the first 20 wk in dim
light it is also likely that any aftereffects of the prior
entrainment had decayed. The hamsters were not
disturbed in any way during the study except for cage
changing and the replenishment of food and water. As
noted, cage changing was timed for each hamster so as
to minimize the possibility of effects on the free running
activity rhythm. The results demonstrate that from 28
to 92 wk of age, the average free running period of the
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Fig. 1. Double-plotted wheel running activity records of
5 hamsters recorded continuously in dim constant light
from 8 wk of age until death. Measurements were taken
at the ages indicated on right (30, 50, 70, and 90 wk of
age). These hamsters were among the 15 that contributed data to Figs. 1 and 3.
AGE-RELATED CHANGES IN CIRCADIAN RHYTHMS
R963
wheel running activity rhythm does not change (Fig. 2).
In addition, hamsters that died between 50 and 88 wk
of age showed no change in the average free running
period before death (Fig. 4). The lack of a change in the
average free running period could result from the
absence of any change within individuals or from
changes in individuals in opposite directions. In the
present study, the first of these appears to be most
applicable (Fig. 1): 12 of 15 hamsters showed no
systematic change in period, defined as a change in the
same direction over the last three measurement intervals. Two hamsters showed a consistent shortening,
whereas one showed a lengthening. In addition, the
coefficients of variation for 30 and 90 wk of age (0.0086
and 0.0121) were not significantly different, indicating
that there had not been an increase in the differences
among hamsters with age.
Five previous studies of age-related changes in Syrian hamster activity rhythms reported a shortening of
the average free running period (21, 25, 27, 40, 46). The
changes observed ranged from ,0.23 h between 3 and
16 mo of age (21) to 0.05 h between 3 and 19 mo of age
(25). One of the studies reported no significant change
between 10.5 and 21 mo of age (46). All of these
previous studies differed from the present study in
some way that could account for the different results. In
some cases, the different age groups were represented
by different hamsters, possibly with different histories.
Also in those studies, the hamsters had been recently
transferred from a light-dark cycle to either constant
darkness or dim constant light rather than free running for an extended time. It is possible that agerelated differences in the aftereffects of a previous
entraining cycle could influence free running period. In
addition, because the hamsters were transferred from a
light-dark cycle, the reproductive status of the hamsters in those studies was not known. Although there is
no evidence in the present study of any specific effect of
Fig. 3. Average activity level (P , 0.0001), intensity of activity (P ,
0.0001), time active (P , 0.0001), bout number (P . 0.05), and bout
length (P , 0.0001) for 15 hamsters that lived to at least 90 wk of age.
Vertical lines indicate SEs. See METHODS for more descriptions of the
measurements.
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Fig. 4. Activity profiles for 15 hamsters at 30 (heavy line) and 90
(thin line) wk of age. Activity is the average number of counts per
10-min bin.
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AGE-RELATED CHANGES IN CIRCADIAN RHYTHMS
gonadal regression and regrowth on free running period and age-related differences in the photoperiodic
response have not been reported, such differences
might exist and in some way influence free running
period.
The previous study that is most similar to the design
of the present study is that of Morin (21), in which
individual hamsters were continuously monitored from
3 to 16 mo of age. These hamsters were blinded, and,
similar to those of the present study, had probably
undergone gonadal regression and regrowth early in
the study. That study began with 15 hamsters, but the
number of hamsters representing the older ages was
unclear. A shortening of ,0.23 h was observed in that
study, and this result was supported by several other
groups of hamsters, also blinded when young but
recorded for shorter durations at various ages. Again,
there is no evidence that enucleation affects free running period (11), but it is possible that it in some way
exacerbates an age-related change. A shortening of free
running period with age was observed in the rhythms
restored by SCN grafts in SCN-lesioned hamsters,
supporting the possibility that under some conditions
free running period shortens with age (40).
A survey of the previous studies showing an agerelated change in free running period suggests that the
critical parameter in determining the magnitude of any
such change is the average free running period of the
young hamsters. In the previous studies showing the
greatest shortening of period, the young hamsters
showed the longest average free running period (24.2–
24.3 h) (21, 27), whereas in the previous studies
showing the smallest change (25), as well as in the
present study, the average free running period of the
young hamsters was shorter (24.0–24.1 h). Consequently, in all of the aging studies the average free
Fig. 6. Average activity level (P , 0.0001), intensity of activity (P ,
0.0001), time active (P , 0.0001), bout number (P , 0.0001), and bout
length (P , 0.001) for 18 hamsters at 6 and 3 mo and 2 wk before
death. Vertical lines indicate SEs. See METHODS for more descriptions
of the measurements.
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Fig. 5. Average free running period of 18 hamsters at 6 and 3 mo and
at 2 wk before death. Vertical lines indicate SEs (P . 0.05). Age at
death ranged between 51 and 87 wk.
AGE-RELATED CHANGES IN CIRCADIAN RHYTHMS
R965
Fig. 7. Segments of the activity records from 2 hamsters that contributed
to the data of Fig. 5. Both hamsters
died at the end of the third segment.
Hamster in A died at 60 wk of age and
one in B died at 71 wk of age. At right, 6
mo, 3 mo, and 2 wk are times before
death.
Fig. 8. Correlation between activity time (percent of 10-min bins
with activity) at 50 wk of age and longevity (r 5 0.373, P 5 0.032, n 5
33). Other measurements were not significantly correlated with
longevity (see RESULTS ).
ence between young and old hamsters really has much
to do with age.
Morin (21) reported that free running period was not
different between young and old hamsters kept in
bright constant light and suggested that light might
affect period more in older hamsters, thereby masking
a shortening of period. Although our hamsters were
kept in constant light, the intensity was low (,1 lx), low
enough to cause gonadal regression, and older hamsters and mice have been found to be less sensitive to
the acute effects of light on circadian rhythms (1, 47). In
addition, the average periods in our study were generally shorter than those observed by Morin (21) for
hamsters in constant light or for blinded hamsters,
suggesting no lengthening effect of constant light on
the free running periods of our hamsters.
An important conclusion from the present results
and the above discussion is that free running period
may shorten slightly with age in hamsters under some
circumstances but that this change is neither sufficiently consistent nor sufficiently robust to pursue as
either a consequence of degenerative changes within
the SCN or as an explanation for age-related changes in
other phenomena such as age-related changes in sleep/
wake patterns. The constancy of period over a hamster’s lifetime is, in fact, remarkable; in the present
study, free running period changed (regardless of direction) an average of only 8 min. Although there is
evidence that activity can feed back to influence free
running period (13), average period did not change with
age despite a 66% decrease in activity level. Recent
evidence in humans in which the intrinsic period of the
body temperature rhythm was examined under a forced
desynchrony protocol also indicates that the free running period is essentially identical in younger and
healthy older men (8). In mice, the evidence for an
age-related change in free running period appears
stronger than that in hamsters. Two studies have
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running period of older hamsters is similar, whereas
the average period of younger hamsters is variable. It
could be that there is some lower limit on how short a
period can become and if the period begins too close to
that value it cannot change. This hypothesis is not,
however, supported by the present results; there was no
correlation between initial period and the size or direction of changes in period. For example, one hamster
with one of the longest initial periods (24.33 h) showed
a longer period by the end of the study (24.62 h),
whereas one with one of the shortest initial periods
(23.79 h) showed a shorter period by the end of the
study (23.62 h). Because in some studies, such as the
current study, young hamsters express what is in other
studies the average free running period of older hamsters, it is unclear whether previously observed differ-
R966
AGE-RELATED CHANGES IN CIRCADIAN RHYTHMS
continued to be expressed by even the oldest hamsters.
In only a few cases where activity fell dramatically
before death did circadian rhythmicity become unclear.
Activity decreased with age primarily at the time of
peak activity, resulting in a decrease in the amplitude
of the wheel running activity rhythm. A similar change
has also been reported in mice and rats (18, 24, 26, 34,
36, 42, 44). In the present study, there was not an
accompanying increase in activity during the normal
time of inactivity; activity expressed during rest time
was negligible in both young and old hamsters. Thus
the reduced amplitude of the activity rhythm could
have resulted from a decrease in the drive or signal for
activity across the circadian cycle rather than from a
change in amplitude of a rhythm in such drive. A
change in the average level or drive for activity could
result from a change in regulation by the circadian
pacemaker but could also result from a change more
proximate to the expression of activity. For example, in
SCN-lesioned young or old hamsters, both with grafts
containing young SCN, a difference in the level of
activity present before the lesions and before receiving
the grafts persists, although somewhat reduced (40).
The present results are consistent with, but do not
provide strong evidence for, an age-related change in
the amplitude of the pacemaker. Other evidence, however, does support such a change. For example, in mice
(44), rats (19, 26), and hamsters (24), old animals have
been found to be awake less or to be less active at night
and more awake or more active during the day than
young animals. In addition, rhythms within the SCN
itself show reduced amplitude in older rats and hamsters (16, 33, 41, 45) and in hamsters SCN grafts can
regulate activity in intact older hosts, suggesting a
deficit in the output of the host’s SCN (15). In addition,
other rhythms have been reported to show reduced
amplitude with age in rodents (2, 3, 6, 19, 32).
The fragmentation of sleep with advancing age is a
common observation in humans as well as in some
animal studies (2, 3, 44). The relationship between the
fragmentation of sleep and the changes in wheel running activity examined here and elsewhere is unclear.
Age-related changes in the systems underlying sleep
and arousal may occur independently but with the
same general consequence of a decreased ability to
maintain a particular behavioral state. In addition, a
change in one may directly affect the other (44). Alternatively, or in addition, age-related changes in the fragmentation and amplitudes of sleep and activity rhythms
(as well as in other rhythms) may have a common
origin in age-related changes of the underlying circadian pacemaker. Evidence in rats suggests that changes
at the level of the SCN can precede changes in overt
rhythms (33). It is remarkable that despite the changes
that occur in the expression of circadian rhythms with
age, the timing function of the circadian pacemaker,
reflected in its free running period, changes so little, if
at all, with age.
The authors are grateful for encouragement from Charles Czeisler
and for comments during the course of the work from the Scientific
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demonstrated significant age-related lengthening of
the average period of ,0.3 and 0.5 h (30, 36).
In contrast to free running period, other aspects of
the wheel running activity rest rhythm changed with
age and before death, regardless of when death occurred. In particular, the total level of activity (wheel
revolutions), the amount of time active (percent of
10-min bins with activity), the intensity of activity
(wheel revolutions/10-min bin), and average bout length
all significantly decreased. An age-related change in
activity level is a particularly consistent observation
across studies (18, 24, 34, 36). The active phase of the
circadian cycle, alpha, was similar in older and younger
hamsters (Fig. 4), so that the time spent in wheel
running activity by older hamsters, although less than
that of young hamsters, remained spread over about
the same number of circadian hours. It appears that
with aging (but not when death is imminent) a total
decrease in activity occurs more at the expense of
running intensity and bout length than at the expense
of bout number. Just before death bout number also
significantly falls.
It is difficult to make a strong case for an increase in
the fragmentation of activity with age when the total
number of bouts does not increase or spread out over a
broader range of circadian times. However, except at
the oldest age, there was a tendency for bout number to
increase and, despite a dramatic decrease in activity
level, activity remained spread out over approximately
the same circadian phase and was represented by a
similar number of smaller bouts in old hamsters. In
this sense, then, activity was more fragmented. Furthermore, an age-related increase in the number of activity
bouts has been reported in recent studies in hamsters
and mice (18, 24, 34, 36). On the other hand, at least in
the present study, it appears that most of the change in
activity occurred near activity onset (Fig. 4) and it is
therefore possible that the shortening of average bout
length resulted primarily from a shortening of the first
(and usually the largest) activity bout. Thus most of the
observed change in average bout length could have
resulted from a change in the size of a single bout each
circadian cycle with little additional fragmentation
elsewhere.
Although parameters related to the level, amount,
and intensity of activity changed with age and before
death, there was no indication that the values of such
parameters were predictors of longevity unless the
parameters happened to be measured within ,2 wk of
a hamster’s death. Thus it does not appear as though it
is possible to predict the longevity of hamsters based on
observations of the wheel running activity rhythm at
an age well before death.
Morin (21) assessed by subjective criteria the quality
of wheel running activity rhythms in Syrian hamsters
at different times before their deaths and found little
evidence of change except in the last 5 days. Although
activity level decreased and fragmentation increased
with age in the present study, clear circadian rhythms
AGE-RELATED CHANGES IN CIRCADIAN RHYTHMS
Advisory Committee of the National Institute on Aging Program
Project Grant that supported this work (Grant P01-AG09975 to C.
Czeisler, Brigham and Women’s Hospital, Boston, MA).
Address for reprint requests: F. C. Davis, Dept. of Biology, 414
Mugar Life Sciences Bldg., Northeastern Univ., Boston, MA 02115.
Received 12 February 1998; accepted in final form 11 June 1998.
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