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by Jeanne F. Duffy INTRODUCTION
Relevant current problems and economic, social, personal consequences of the problems. Numerous studies have found that specific sleep complaints are reported by many older people. In fact, when Foley et al. compared their results from surveying over 9,000 older persons to results from 3 other survey studies, there was a consistent percentage of older persons reporting early morning awakening (about 15%) and difficulty maintaining sleep (about 30%) (30). These four studies included both urban and rural respondents and were carried out over a 20-year time span (see Figure 1). Others have found higher percentages of the older population reporting sleep complaints, with one third of respondents reporting that they wake up too early in the morning several times per week, and up to 40% of respondents complaining of occasional problems sleeping (47,49,63). While many of these sleep complaints are associated with health problems, even healthy older individuals report sleep complaints (30). Daytime sleepiness is also common in the elderly (11,34,48,69) and has been found to correlate with measures of sleep disturbance (10). This high percentage of sleep complaints among older persons is associated with an age-related increase in the use of sleep medications (4,80). Furthermore, it has been suggested that age-related sleep disturbances are associated with increased mortality and with increased nursing home placement (66). BACKGROUND
In humans, postmortem studies have revealed that the human brain contains the same key structural elements of the circadian timing system as have been identified in other mammals (33,45,59,75,83). It is well-established that the suprachiasmatic nucleus (SCN) of the hypothalamus acts as the central pacemaker for circadian rhythms in a wide array of physiologic and behavioral measures (27,36,39,50,58,60,70,71,76,81). Light from the environment is transmitted to the SCN via the retinohypothalamic tract (RHT) (58,61,62,75).
In the absence of periodic time cues from the environment, humans continue to behave in a periodic
manner (1,52,79). Studies carried out under such conditions have revealed that the timing and
organization of sleep, alertness, and performance vary with circadian phase.
The circadian pacemaker has been shown to be a major determinant of the timing of sleep and sleep structure in human subjects. The duration of the daily sleep episode, the timing of sleep, and the distribution of REM sleep vary with circadian phase (12,17,18,82). Furthermore, recent studies have revealed that high sleep efficiency can only be maintained when there is a unique phase-relationship between the timing of the sleep episode and circadian phase (20,21). This phase-relationship is such that even a small change in the relative timing between the daily sleep episode and circadian phase can have large impact on ability to consolidate sleep throughout the night.
The phase relationship between the timing of sleep and circadian rhythms is also important for the
regulation of daytime alertness and performance. Alertness and performance are regulated by both the
output of the circadian pacemaker and the length of time awake, and in young men awake for durations of
18 hours, the contribution these two processes was found to be approximately equal (22). Those
studies also demonstrated that the effects of wake duration on alertness depended on circadian phase,
and that there was a unique phase relationship between the circadian timing system and the timing of
sleep at which stable levels of alertness could be maintained throughout the waking day, such that
under entrained conditions circadian timing system opposes the wake-dependent deterioration of
alertness and performance (20,22,40,42).
A commonly reported feature of aging is the change in the timing of activity, bedtime, and awakening to earlier hours (34,47,49,51,53,57,85,86). During sleep, there is an increase in the number and duration of waking episodes after sleep onset, a reduction of stage 3-4 (SWS) sleep, and a flattening of REM distribution throughout the night (2,4-6,19,28,29,32,37,41,53,67-69, 72,87,88).
These changes in sleep and sleep timing are associated with increased complaints of early morning
awakening and difficulty maintaining sleep(30,47,49,63), and have been hypothesized to be related to
changes in circadian rhythms with age.
Age-related changes in sleep timing are associated with advances in the timing of circadian rhythms, including rhythms of activity, body temperature, performance, cortisol, and the timing of REM sleep(28,29,41,44,55,56,73,77,78,84,87,89). The earlier phase of circadian rhythms has been shown to persist even when activity, posture, and food intake are held constant so as to control for age-related differences in the timing of behavior (13,15,16). While it has been hypothesized that the age-related phase advance of these rhythms is a consequence of a change of the intrinsic period of the circadian pacemaker with age, a recent series of studies found that the intrinsic period of the core body temperature, plasma melatonin, and plasma cortisol rhythms of healthy older subjects is not significantly different from that found in young men (14), suggesting that an age-related shortening of intrinsic period is unlikely to account for the advanced circadian phase seen in older subjects. Age-related changes in the response of the circadian system to light have also been reported in both animal and human studies, and an age-related change in the phase-response curve (PRC) to light could also explain the observed age-related change in circadian phase. A reduced phase-delay and/or an increased phase-advance portion of the PRC could produce the age-related advance of circadian phase. Older humans have more trouble adapting to actual or simulated shift work (7), and older humans have also been reported to have more difficulty adjusting to time zone changes (35,54). Other animal studies have shown that the size of phase-shifts to light may be different in older animals at particular circadian phases (74). However, preliminary findings from a study in which young and older subjects were administered 3-cycles of 5-hour exposure to bright indoor light do not support the hypothesis of an age-related change in the shape of the PRC (43).
The amplitude of some circadian rhythms, particularly that of core body temperature and plasma
melatonin secretion, has been reported to be reduced with age. However, not all investigators have
found reduced amplitudes with increasing age, and the functional significance of the reported reduction
in amplitude remains to be determined.
Misalignment between the sleep-wake cycle and the timing of circadian rhythms has been shown to occur in some clinical conditions, and may contribute to the age-related sleep complaints discussed above. In patients with delayed sleep phase syndrome, which is most prevalent in young subjects, there is a longer interval between the circadian temperature phase and habitual waketime than was observed in a group of healthy controls (65). In healthy young subjects, sleep onset insomnia can be induced by scheduling the subjects to a slightly shorter than 24-hour day, a schedule associated with a change in the relationship between the timing of the sleep/wake cycle and circadian phase (31,64). Furthermore, in healthy young subjects, a reduction in sleep efficiency can be induced by exposure to morning light, which is associated with a change in the phase of the circadian temperature rhythm relative to sleep(8). In older subjects with sleep maintenance insomnia, it was reported that exposure to evening bright light, which changed the phase of the circadian temperature rhythm relative to sleep timing, alleviated the sleep maintenance insomnia (9). These studies suggest that the relative timing of sleep with respect to circadian phase may underlie the high incidence of early-morning awakening in the elderly. Recent studies using the forced desynchrony technique, in which sleep and wake episodes are scheduled to occur at all circadian phases, have revealed that the circadian drive for wakefulness is strongest in the evening hours in both young and older subjects, and that the overall shape of the circadian rhythm of early morning awakening is similar in both groups. However, those same studies also revealed that older subjects report more difficulty maintaining sleep when it is scheduled at abnormal circadian phases than do young subjects. Furthermore those data demonstrate that there is a narrower window within the circadian cycle during which older subjects report the ability to maintain sleep than there is for young subjects (23-25). Analysis of objective sleep data from the same forced desynchrony studies have confirmed the findings from these subjective reports (24). These findings from forced desynchrony studies are also supported by two recent studies of simulated jet-lag and shift-work in middle-aged subjects (7,54). These data imply that even small age-related changes in the timing of circadian phase relative to the timing of the sleep-wake cycle may have substantial effects on sleep disruption in older individuals. It has also recently been reported that there is a shorter interval between the timing of habitual awakening on self-selected schedules and the phase of the circadian rhythm of core body temperature in older subjects as compared to young subjects (26). Not only did the healthy normal older subjects wake at an earlier clock hour and an earlier phase within the circadian cycle than did the young subjects, the variability in the older population between the timing of sleep and circadian rhythms was much greater. Taken together, these recent findings suggest that age-related changes in the relative timing between sleep and circadian rhythms may underlie the observed age-related increase in difficulty maintaining sleep and early-morning awakening. FUTURE NEEDS
Prevalence of chronic sleep disturbances in older populations. Adapted from Foley, et al., 1995 (30). Light bars: percentage of surveyed population reporting early morning awakening; dark bars: percentage of surveyed population reporting difficulty maintaining sleep. Results from these four studies, carried out over nearly two decades, and in differing geographic areas (including urban and rural areas) are remarkably consistent, finding that approximately 15% of older persons surveyed report early morning awakening, and approximately 30% report difficulty maintaining sleep. References 1. Aschoff, J. and R. Wever. Spontanperiodik des Menschen bei Ausschluss aller Zeitgeber. Die Naturwissenschaften 49: 337-342, 1962. 2. Bixler, E. O., A. Kales, J. A. Jacoby, C. R. Soldatos, and A. Vela-Bueno. Nocturnal sleep and wakefulness: effects of age and sex in normal sleepers. Int. J. Neurosci. 23: 33-42, 1984. 3. Bixler, E. O., A. Kales, C. R. Soldatos, J. D. Kales, and S. Healey. 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