Contribution of circadian physiology and sleep homeostasis to age-related changes in human sleep

The circadian pacemaker and sleep homeostasis play pivotal roles in vigilance state control. It has been hypothesized that age-related changes in the human circadian pacemaker, as well as sleep homeostatic mechanisms, contribute to the hallmarks of age-related changes in sleep, that is, earlier wake time and reduced sleep consolidation. Assessments of circadian parameters in healthy young (∼20-30 years old) and older people (∼65-75 years old)—in the absence of the confounding effects of sleep, changes in posture, and light exposure—have demonstrated that an earlier wake time in older people is accompanied by about a 1h advance of the rhythms of core body temperature and melatonin. In addition, older people wake up at an earlier circadian phase of the body temperature and plasma melatonin rhythm. The amplitude of the endogenous circadian component of the core body temperature rhythm assessed during constant routine and forced desynchrony protocols is reduced by 20-30% in older people. Recent assessments of the intrinsic period of the human circadian pacemaker in the absence of the confounding effects of light revealed no age-related reduction of this parameter in both sighted and blind individuals. Wake maintenance and sleep initiation are not markedly affected by age except that sleep latencies are longer in older people when sleep initiation is attempted in the early morning. In contrast, major age-related reductions in the consolidation and duration of sleep occur at all circadian phases. Sleep of older people is particularly disrupted when scheduled on the rising limb of the temperature rhythm, indicating that the sleep of older people is more susceptible to arousal signals genernpated by the circadian pacemaker. Sleep-homeostatic mechanisms, as assayed by the sleep-deprivation-induced increase of EEG slow-wave activity (SWA), are operative in older people, although during both baseline sleep and recovery sleep SWA in older people remains at lower levels. The internal circadian phase advance of awakening, as well as the age-related reduction in sleep consolidation, appears related to an age-related reduction in the promotion of sleep by the circadian pacemaker during the biological night in combination with a reduced homeostatic pressure for sleep. Early morning light exposure associated with this advance of awakening in older people could reinforce the advanced circadian phase. Quantification of the interaction between sleep homeostasis and circadian rhythmicity contributes to understanding age-related changes in sleep timing and quality. (Chronobiology International, 17(3), 285-311, 2000)     

Age-related changes in the circadian and homeostatic regulation of human sleep

The reduction of electroencephalographic (EEG) slow-wave activity (SWA) (EEG power density between 0.75-4.5 Hz) and spindle frequency activity, together with an increase in involuntary awakenings during sleep, represent the hallmarks of human sleep alterations with age. It has been assumed that this decrease in non-rapid eye movement (NREM) sleep consolidation reflects an age-related attenuation of the sleep homeostatic drive. To test this hypothesis, we measured sleep EEG characteristics (i.e., SWA, sleep spindles) in healthy older volunteers in response to high (sleep deprivation protocol) and low sleep pressure (nap protocol) conditions. Despite the fact that the older volunteers had impaired sleep consolidation and reduced SWA levels, their relative SWA response to both high and low sleep pressure conditions was similar to that of younger persons. Only in frontal brain regions did we find an age-related diminished SWA response to high sleep pressure. On the other hand, we have clear evidence that the circadian regulation of sleep during the 40 h nap protocol was changed such that the circadian arousal signal in the evening was weaker in the older study participants. More sleep occurred during the wake maintenance zone, and subjective sleepiness ratings in the late afternoon and evening were higher than in younger participants. In addition, we found a diminished melatonin secretion and a reduced circadian modulation of REM sleep and spindle frequency-the latter was phase-advanced relative to the circadian melatonin profile. Therefore, we favor the hypothesis that age-related changes in sleep are due to weaker circadian regulation of sleep and wakefulness. Our data suggest that manipulations of the circadian timing system, rather than the sleep homeostat, may offer a potential strategy to alleviate age-related decrements in sleep and daytime alertness levels.     

Are age differences in sleep due to phase differences in the output of the circadian timing system?

Our aim was to evaluate whether age-related changes in the phase of the output of the circadian timing system (CTS) can explain age differences in habitual bedtime/wake time and in sleep consolidation parameters. Analyses focused on a group of healthy elderly people (older than 70 years) with no sleep problems and with similar subjective sleep quality as a young control group. The 2-week sleep diary data and 24h laboratory temperature recordings were examined for 70 subjects (22 young men [YM], 19 old men [OM], 29 old women [OW]). Polysomnographic (PSG) sleep data recorded during temperature data acquisition were also available for 62 subjects. These analyses made use of our recently developed technique to demask temperature rhythm data. As expected, compared to the young subjects, older subjects showed earlier habitual bedtime and wake time, more disturbed sleep, and a tendency for an earlier minimum of the circadian temperature rhythm. Despite sleep consolidation differences, the groups showed very similar habitual phase-angle differences (interval between the time occurrence of the fitted temperature minimum and habitual wake time). Both elderly and young subjects woke up on average 3h after the temperature minimum. After controlling for the effects of age group, habitual bedtime and wake time were related to clock time phase of the circadian temperature rhythm, with an earlier phase associated with earlier habitual bedtime and wake time. None of the sleep consolidation parameters were linked to the temperature phase angle. In conclusion, sleep consolidation changes associated with healthy aging do not appear to be related to changes in the phase-angle difference between the output signal from the CTS and sleep.     

Age‐related Changes in the Circadian and Homeostatic Regulation of Human Sleep

The reduction of electroencephalographic (EEG) slow‐wave activity (SWA) (EEG power density between 0.75–4.5 Hz) and spindle frequency activity, together with an increase in involuntary awakenings during sleep, represent the hallmarks of human sleep alterations with age. It has been assumed that this decrease in non‐rapid eye movement (NREM) sleep consolidation reflects an age‐related attenuation of the sleep homeostatic drive. To test this hypothesis, we measured sleep EEG characteristics (i.e., SWA, sleep spindles) in healthy older volunteers in response to high (sleep deprivation protocol) and low sleep pressure (nap protocol) conditions. Despite the fact that the older volunteers had impaired sleep consolidation and reduced SWA levels, their relative SWA response to both high and low sleep pressure conditions was similar to that of younger persons. Only in frontal brain regions did we find an age‐related diminished SWA response to high sleep pressure. On the other hand, we have clear evidence that the circadian regulation of sleep during the 40 h nap protocol was changed such that the circadian arousal signal in the evening was weaker in the older study participants. More sleep occurred during the wake maintenance zone, and subjective sleepiness ratings in the late afternoon and evening were higher than in younger participants. In addition, we found a diminished melatonin secretion and a reduced circadian modulation of REM sleep and spindle frequency—the latter was phase‐advanced relative to the circadian melatonin profile. Therefore, we favor the hypothesis that age‐related changes in sleep are due to weaker circadian regulation of sleep and wakefulness. Our data suggest that manipulations of the circadian timing system, rather than the sleep homeostat, may offer a potential strategy to alleviate age‐related decrements in sleep and daytime alertness levels.     

Loss of circadian organization of sleep and wakefulness during hibernation

We investigated circadian and homeostatic regulation of nonrapid eye movement (NREM) sleep in golden-mantled ground squirrels during euthermic intervals between torpor bouts. Slow-wave activity (SWA; 1-4 Hz) and sigma activity (10-15 Hz) represent the two dominant electroencephalographic (EEG) frequency components of NREM sleep. EEG sigma activity has a strong circadian component in addition to a sleep homeostatic component, whereas SWA mainly reflects sleep homeostasis [Dijk DJ and Czeisler CA. J Neurosci 15: 3526-3538, 1995; Dijk DJ, Shanahan TL, Duffy JF, Ronda JM, and Czeisler CA. J Physiol (Lond) 505: 851-858, 1997]. Animals maintained under constant conditions continued to display circadian rhythms in both sigma activity and brain temperature throughout euthermic intervals, whereas sleep and wakefulness showed no circadian organization. Instead, sleep and wakefulness were distributed according to a 6-h ultradian rhythm. SWA, NREM sleep bout length, and sigma activity responded homeostatically to the ultradian sleep-wake pattern. We suggest that the loss of sleep-wake consolidation in ground squirrels during the hibernation season may be related to the greatly decreased locomotor activity during the hibernation season and may be necessary for maintenance of multiday torpor bouts characteristic of hibernating species.     

The use of melatonin for the treatment of insomnia

The pineal product melatonin is involved in the regulation of the sleep/wake cycle in humans. In blind individuals and in people travelling through time zones, melatonin rhythms are sometimes unsynchronized with the diel cycle, and nocturnal sleep may be disturbed. Low or distorted melatonin rhythms have repeatedly been reported in middle aged and elderly insomniacs. Melatonin administration effectively synchronized the sleep wake cycle in blind individuals and in subjects suffering from jet lag and advanced sleep onset in subjects suffering from delayed sleep phase syndrome. In elderly insomniacs, melatonin replacement therapy significantly decreased sleep latency, and/or increased sleep efficiency and decreased wake time after sleep onset. In addition, melatonin substitution facilitated benzodiazepine discontinuation in chronic users. These data show an association between melatonin rhythm disturbances and difficulties to promote or maintain sleep at night. Specific melatonin formulations may be useful to treat circadian-rhythm-related sleep disorders and age-related insomnia.     

The benefits of four weeks of melatonin treatment on circadian patterns in resistance-trained athletes

Exercise can induce circadian phase shifts depending on the duration, intensity and frequency. These modifications are of special meaning in athletes during training and competition. Melatonin, which is produced by the pineal gland in a circadian manner, behaves as an endogenous rhythms synchronizer, and it is used as a supplement to promote resynchronization of altered circadian rhythms. In this study, we tested the effect of melatonin administration on the circadian system in athletes. Two groups of athletes were treated with 100?mg?day^?1 of melatonin or placebo 30?min before bed for four weeks. Daily rhythm of salivary melatonin was measured before and after melatonin administration. Moreover, circadian variables, including wrist temperature (WT), motor activity and body position rhythmicity, were recorded during seven days before and seven days after melatonin or placebo treatment with the aid of specific sensors placed in the wrist and arm of each athlete. Before treatment, the athletes showed a phase-shift delay of the melatonin circadian rhythm, with an acrophase at 05:00?h. Exercise induced a phase advance of the melatonin rhythm, restoring its acrophase accordingly to the chronotype of the athletes. Melatonin, but not placebo treatment, changed daily waveforms of WT, activity and position. These changes included a one-hour phase advance in the WT rhythm before bedtime, with a longer nocturnal steady state and a smaller reduction when arising at morning than the placebo group. Melatonin, but not placebo, also reduced the nocturnal activity and the activity and position during lunch/nap time. Together, these data reflect the beneficial effect of melatonin to modulate the circadian components of the sleep–wake cycle, improving sleep efficiency.     

Melatonin rhythms in delayed sleep phase syndrome

The aim of this study was to compare circadian and sleep characteristics between patients with delayed sleep phase syndrome (DSPS) and healthy controls. The authors studied 8 DSPS patients and 15 normal controls. Serum melatonin concentration was assessed every hour for 24 h under dim light conditions. The sleep phase and the melatonin rhythm in DSPS patients were significantly delayed compared to those in normal controls. Sleep length was significantly greater in DSPS patients compared to that in controls, but the duration of melatonin secretion did not differ between the two groups. The final awakening, relative to melatonin onset, melatonin midpoint, and melatonin offset, was significantly longer in DSPS patients than in controls. By contrast, the timing of sleep onset relative to melatonin rhythm did not differ between the two groups. The authors found a significant positive correlation between sleep phase markers and melatonin phase markers in DSPS. They postulate that a delayed circadian pacemaker may be responsible for delayed sleep phase syndrome. The alteration of phase angle between melatonin rhythm and sleep phase suggested that not only the delay of the circadian clock but also a functional disturbance of the sleep-wake mechanism underlies DSPS.     

An endogenous circadian rhythm in sleep inertia results in greatest cognitive impairment upon awakening during the biological night

Sleep inertia is the impaired cognitive performance immediately upon awakening, which decays over tens of minutes. This phenomenon has relevance to people who need to make important decisions soon after awakening, such as on-call emergency workers. Such awakenings can occur at varied times of day or night, so the objective of the study was to determine whether or not the magnitude of sleep inertia varies according to the phase of the endogenous circadian cycle. Twelve adults (mean, 24 years; 7 men) with no medical disorders other than mild asthma were studied. Following 2 baseline days and nights, subjects underwent a forced desynchrony protocol composed of seven 28-h sleep/wake cycles, while maintaining a sleep/wakefulness ratio of 1:2 throughout. Subjects were awakened by a standardized auditory stimulus 3 times each sleep period for sleep inertia assessments. The magnitude of sleep inertia was quantified as the change in cognitive performance (number of correct additions in a 2-min serial addition test) across the first 20 min of wakefulness. Circadian phase was estimated from core body temperature (fitted temperature minimum assigned 0 degrees ). Data were segregated according to: (1) circadian phase (60 degrees bins); (2) sleep stage; and (3) 3rd of the night after which awakenings occurred (i.e., tertiary 1, 2, or 3). To control for any effect of sleep stage, the circadian rhythm of sleep inertia was initially assessed following awakenings from Stage 2 (62% of awakening occurred from this stage; n = 110). This revealed a significant circadian rhythm in the sleep inertia of cognitive performance (p = 0.007), which was 3.6 times larger during the biological night (circadian bin 300 degrees , approximately 2300-0300 h in these subjects) than during the biological day (bin 180 degrees , approximately 1500-1900 h). The circadian rhythm in sleep inertia was still present when awakenings from all sleep stages were included (p = 0.004), and this rhythm could not be explained by changes in underlying sleep drive prior to awakening (changes in sleep efficiency across circadian phase or across the tertiaries), or by the proportion of the varied sleep stages prior to awakenings. This robust endogenous circadian rhythm in sleep inertia may have important implications for people who need to be alert soon after awakening.     

Are modifications of melatonin circadian rhythm in the middle years of life related to habitual patterns of light exposure?

The mechanisms underlying age-related changes in the signal from the biological clock have yet to be determined. The authors sought to determine if the phase advance of circadian melatonin rhythm during the middle years of life is related to different patterns of habitual light exposure. Forty-one healthy subjects between the ages of 22 and 58 y were studied. Habitual light exposure was measured by a wrist monitor for 7 days. Participants underwent a 25-h constant routine. They provided saliva samples every 30 min, and melatonin concentration was determined by radioimmunoassay to assess salivary dim light melatonin onset (S-DLMO(1.3)). Aging was associated with earlier S-DLMO(1.3). Increasing age was not related to the time spent at different light intensities. However, it was associated with lower percentage of light exposure during the night (between 0200-0400, 0600-0700, and 2300-2400 h) and with higher percentage of light exposure in the morning (between 0800-1100 h). Earlier S-DLMO(1.3) was associated with lower percentage of light exposure early on in the night (between 2200-0000, 0000-0100, and 0200-0300 h) as well as in the afternoon (between 1500-1600 h) and with higher percentage of light exposure in the morning (between 0800-1100 h). When the effects of age were controlled, there was no significant relationship between S-DLMO(1.3) and percentages of light exposure. Yet increasing age was associated with earlier S-DLMO(1.3) regardless of light exposure patterns. Earlier habitual wake time explained the earlier light exposure patterns of older subjects. Both habitual wake time and age contributed to the prediction of S-DLMO(1.3). The results suggest a phase advance of circadian rhythms in the middle years of life. Whereas a clear change in habitual light exposure patterns was associated with aging and with shifts in S-DLMO(1.3), it did not explain entirely the age-related advance of melatonin circadian phase.     

Expression of clock genes in human peripheral blood mononuclear cells throughout the sleep/wake and circadian cycles

The rhythmic expression of circadian clock genes in the neurons of the suprachiasmatic nucleus (SCN) underlies the manifestation of endogenous circadian rhythmicity in behavior and physiology. Recent evidence demonstrating rhythmic clock gene expression in non-SCN tissues suggests that functional clocks exist outside the central circadian pacemaker of the brain. In this investigation, the nature of an oscillator in peripheral blood mononuclear cells (PBMCs) is evaluated by assessing clock gene expression throughout both a typical sleep/wake cycle (LD) and during a constant routine (CR). Six healthy men and women aged (mean±SEM) 23.7±1.6 yrs participated in this five-day investigation in temporal isolation. Core body temperature and plasma melatonin concentration were measured as markers of the central circadian pacemaker. The expression of HPER1, HPER2, and HBMAL1 was quantified in PBMCs sampled throughout an uninterrupted 72 h period. The core body temperature minimum and the midpoint of melatonin concentration measured during the CR occurred 2:17±0:20 and 3:24 ±0:09 h before habitual awakening, respectively, and were well aligned to the sleep/wake cycle. HPER1 and HPER2 expression in PBMCs demonstrated significant circadian rhythmicity that peaked early after wake-time and was comparable under LD and CR conditions. HBMAL1 expression was more variable, and peaked in the middle of the wake period under LD conditions and during the habitual sleep period under CR conditions. For the first time, bi-hourly sampling over three consecutive days is used to compare clock gene expression in a human peripheral oscillator under different sleep/wake conditions.     

Persistence of sleep-temperature coupling after suprachiasmatic nuclei lesions in rats

The suprachiasmatic nucleus (SCN) regulates the circadian rhythms of body temperature (T(b)) and vigilance states in mammals. We studied rats in which circadian rhythmicity was abolished after SCN lesions (SCNx rats) to investigate the association between the ultradian rhythms of sleep-wake states and brain temperature (T(br)), which are exposed after lesions. Ultradian rhythms of T(br) (mean period: 3.6 h) and sleep were closely associated in SCNx rats. Within each ultradian cycle, nonrapid eye movement (NREM) sleep was initiated 5 +/- 1 min after T(br) peaks, after which temperature continued a slow decline (0.02 +/- 0.006 degrees C/min) until it reached a minimum. Sleep and slow wave activity (SWA), an index of sleep intensity, were associated with declining temperature. Cross-correlation analysis revealed that the rhythm of T(br) preceded that of SWA by 2-10 min. We also investigated the thermoregulatory and sleep-wake responses of SCNx rats and controls to mild ambient cooling (18 degrees C) and warming (30 degrees C) over 24-h periods. SCNx rats and controls responded similarly to changes in ambient temperature. Cooling decreased REM sleep and increased wake. Warming increased T(br), blunted the amplitude of ultradian T(br) rhythms, and increased the number of transitions into NREM sleep. SCNx rats and controls had similar percentages of NREM sleep, REM sleep, and wake, as well as the same average T(b) within each 24-h period. Our results suggest that, in rats, the SCN modulates the timing but not the amount of sleep or the homeostatic control of sleep-wake states or T(b) during deviations in ambient temperature.     

Expression of Clock Genes in Human Peripheral Blood Mononuclear Cells throughout the Sleep/Wake and Circadian Cycles

The rhythmic expression of circadian clock genes in the neurons of the suprachiasmatic nucleus (SCN) underlies the manifestation of endogenous circadian rhythmicity in behavior and physiology. Recent evidence demonstrating rhythmic clock gene expression in non‐SCN tissues suggests that functional clocks exist outside the central circadian pacemaker of the brain. In this investigation, the nature of an oscillator in peripheral blood mononuclear cells (PBMCs) is evaluated by assessing clock gene expression throughout both a typical sleep/wake cycle (LD) and during a constant routine (CR). Six healthy men and women aged (mean±SEM) 23.7±1.6 yrs participated in this five‐day investigation in temporal isolation. Core body temperature and plasma melatonin concentration were measured as markers of the central circadian pacemaker. The expression of HPER1, HPER2, and HBMAL1 was quantified in PBMCs sampled throughout an uninterrupted 72 h period. The core body temperature minimum and the midpoint of melatonin concentration measured during the CR occurred 2:17±0:20 and 3:24 ±0:09 h before habitual awakening, respectively, and were well aligned to the sleep/wake cycle. HPER1 and HPER2 expression in PBMCs demonstrated significant circadian rhythmicity that peaked early after wake‐time and was comparable under LD and CR conditions. HBMAL1 expression was more variable, and peaked in the middle of the wake period under LD conditions and during the habitual sleep period under CR conditions. For the first time, bi‐hourly sampling over three consecutive days is used to compare clock gene expression in a human peripheral oscillator under different sleep/wake conditions.     

Effects of obstructive sleep apnea on endogenous circadian rhythms assessed during relaxed wakefulness; an exploratory analysis

ABSTRACT

Obstructive sleep apnea (OSA) is associated with hypertension, cardiovascular disease, and a change in the 24 h pattern of adverse cardiovascular events and mortality. Adverse cardiovascular events occur more frequently in the middle of the night in people with OSA, earlier than the morning prevalence of these events in the general population. It is unknown if these changes are associated with a change in the underlying circadian rhythms, independent of behaviors such as sleep, physical activity, and meal intake. In this exploratory analysis, we studied the endogenous circadian rhythms of blood pressure, heart rate, melatonin and cortisol in 11 participants (48 ± 4 years; seven with OSA) throughout a 5 day study that was originally designed to examine circadian characteristics of obstructive apnea events. After a baseline night, participants completed 10 recurring 5 h 20 min behavioral cycles divided evenly into standardized sleep and wake periods. Blood pressure and heart rate were recorded in a relaxed semirecumbent posture 15 minutes after each scheduled wake time. Salivary melatonin and cortisol concentrations were measured at 1–1.5 h intervals during wakefulness. Mixed-model cosinor analyses were performed to determine the rhythmicity of all variables with respect to external time and separately to circadian phases (aligned to the dim light melatonin onset, DLMO). The circadian rhythm of blood pressure peaked much later in OSA compared to control participants (group × circadian phase, p < .05); there was also a trend toward a slightly delayed cortisol rhythm in the OSA group. Rhythms of heart rate and melatonin did not differ between the groups. In this exploratory analysis, OSA appears to be associated with a phase change (relative to DLMO) in the endogenous circadian rhythm of blood pressure during relaxed wakefulness, independent of common daily behaviors.     

Melatonin rhythm observed throughout a three-cycle bright-light stimulus designed to reset the human circadian pacemaker.

Exposure to light and darkness can rapidly induce phase shifts of the human circadian pacemaker. A type 0 phase response curve (PRC) to light that has been reported for humans was based on circadian phase data collected from constant routines performed before and after a three-cycle light stimulus, but resetting data observed throughout the entire resetting protocol have not been previously reported. Pineal melatonin secretion is governed by the hypothalamic circadian pacemaker via a well-defined neural pathway and is reportedly less subject to the masking effects of sleep and activity than body temperature. The authors reasoned that observation of the melatonin rhythm throughout the three-cycle light resetting trials could provide daily phase-resetting information, allowing a dynamic view of the resetting response of the circadian pacemaker to light. Subjects (n = 12) living in otherwise dim light (approximately 10-15 lux) were exposed to a noncritical stimulus of three cycles of bright light (approximately 9500 lux for 5 h per day) timed to phase advance or phase delay the human circadian pacemaker; control subjects (n = 11) were scheduled to the same protocols but exposed to three 5-h darkness cycles instead of light. Subjects underwent initial and final constant routine phase assessments; hourly melatonin samples and body temperature data were collected throughout the protocol. Average daily phase shifts of 1 to 3 h were observed in 11 of 12 subjects receiving the bright light, supporting predictions obtained using Kronauer's phase-amplitude model of the resetting response of the human circadian pacemaker. The melatonin rhythm in the 12th subject progressively attenuated in amplitude throughout the resetting trial, becoming undetectable for >32 hours preceding an abrupt reappearance of the rhythm at a shifted phase with a recovered amplitude. The data from control subjects who remained in dim lighting and darkness delayed on average -0.2 h per day, consistent with the daily delay expected due to the longer than 24-h intrinsic period of the human circadian pacemaker. Both temperature and melatonin rhythms shifted by equivalent amounts in both bright light-treated and control subjects (R = 0.968; p<0.0001; n = 23). Observation of the melatonin rhythm throughout a three-cycle resetting trial has provided a dynamic view of the daily phase-resetting response of the human circadian pacemaker. Taken together with the observation of strong type 0 resetting in humans in response to the same three-cycle stimulus applied at a critical phase, these data confirm the importance of considering both phase and amplitude when describing the resetting of the human circadian pacemaker by light.     

Internal rhythms in humans

Human physiology and behavior are characterized by a daily internal temporal dimension. This so-called circadian rhythmicity is present for almost all variables studied to date, persists in the absence of external cycles, and is synchronized to the external 24-h world by an internally generated circadian rhythm of light sensitivity. The light-sensitive circadian pacemaker, presumably also in humans located in the suprachiasmatic nucleus of the hypothalamus, drives the endogenous circadian component of rhythmicity for a number of variables including plasma melatonin, alertness, sleep propensity and sleep structure. Overt rhythmicity and the consolidation of vigilance states are generated by a fine-tuned interaction of this circadian process with other regulatory processes such as sleep homeostasis.     

Age-related reduction in the maximal capacity for sleep--implications for insomnia

Sleep changes markedly across the life span and complaints about insomnia are prevalent in older people [1]. Whether age-related alterations in sleep are due to modifications in social factors, circadian physiology, homeostatic drive, or the ability to sleep remains unresolved. We assessed habitual sleep duration at home and then quantified daytime sleep propensity, sleep duration, and sleep structure in an inpatient protocol that included extended sleep opportunities covering 2/3 of the circadian cycle (12 hr at night and 4 hr in the afternoon) for 3-7 days in 18 older and 35 younger healthy men and women. At baseline, older subjects had less daytime sleep propensity than did younger subjects. Total daily sleep duration, which was initially longer than habitual sleep duration, declined during the experiment to asymptotic values that were 1.5 hr shorter in older (7.4 +/- 0.4 SEM, hour) than in younger subjects (8.9 +/- 0.4). Rapid-eye-movement sleep and non-rapid-eye-movement sleep contributed about equally to this reduction. Thus, in the absence of social and circadian constraints, both daytime sleep propensity and the maximal capacity for sleep are reduced in older people. These data have important implications for understanding age-related insomnia.     

Expression profiles of PERIOD1, 2, and 3 in peripheral blood mononuclear cells from older subjects

AimsCircadian clocks regulate daily rhythms of behavior and physiology such as the sleep–wake cycle and hormonal secretion. Numerous characteristics of the behavioral and physiological processes change with age. In this study, we evaluated the circadian clockwork in older people by measuring daily profiles of PERIOD (PER) gene expression in peripheral blood mononuclear cells (PBMCs).Main methodsBlood samples were collected from 6 healthy older subjects (mean age 62 years) at 2-h intervals over a 24-h period under a semi-constant routine condition where masking effects are minimized. PBMCs were isolated from whole blood and temporal mRNA expression profiles of PER1, PER2, and PER3 were determined by RT-PCR. Phases of the PER rhythms, and times of sleep onset and offset were determined using data from those subjects who showed significant 24-h rhythms. The values for the parameters were compared between the older subjects and 8 young control subjects (mean age 21 years).Key findingsProminent daily rhythms of PER1, PER2, and PER3 mRNA levels, advanced sleep–wake timing and advanced phases of PER rhythms were observed in the older subjects compared to the young controls. There was no significant age-related phase difference in PER1 or PER2 rhythm with respect to sleep timing; however, PER3 expression pattern was altered in the older subjects.SignificanceThis preliminary study shows that human circadian clockwork in PBMCs remains intact at least until the presenile stage and suggests that the altered PER3 expression pattern may reflect decreased homeostatic sleep drive in older people.