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Circadian Rhythm Alterations with Aging
Abstract
Sleep disturbances, specifically early morning awakenings, insomnia, and increased daytime napping, show higher prevalence with advanced age. Age-related circadian changes are seen at all levels, from molecular and cellular within the SCN to physiologic, hormonal, and behavioral output of the circadian clock. Modifications in circadian rhythms alone do not fully explain common age-related difficulties, such as advanced sleep phase or the decrease in the amplitude of the sleep-wake activity cycle. It is likely that changes in both circadian and sleep homeostatic processes, or the interaction between the two, are responsible for the impaired sleep of older adults. Although age-related changes have been reported in healthy "usual" older adults, evidence suggests that, in addition to age, health status, medications, social structure, and physical environment are perhaps even more important contributors to the high prevalence of circadian-related sleep disturbances. As Ohayon and coworkers [19] noted...the aging process per se is not responsible for the increase of insomnia often reported in older people. Instead, inactivity, dissatisfaction with social life, and the presence of organic diseases and mental disorders were the best predictors of insomnia, age being insignificant. Healthy older people (i.e., without organic or mental pathologies) have a prevalence of insomnia symptoms similar to that observed in younger people. Increasing evidence suggests that alterations in the circadian system, which are evident later in life, may begin to appear during the middle years and that this is the time to begin to take measures to prevent or delay their onset. Advances in understanding of the circadian system and its interactions with sleep have resulted in some promising treatment options. Interventions that target the circadian system, such as selective application of bright light, structuring daily activities, increased exercise, and in some studies administration of melatonin, have been shown to improve circadian rhythm-based sleep disorders.
... Changes in sleep quality and polysomnographic (PSG) architecture as well as in the homeostatic and circadian control of sleep propensity accompany healthy aging (for reviews, see [4,5,[8][9][10][11][12]. Studies using PSG (e.g., [13,14]), actigraphy (e.g., [15]) and subjective measures of sleep (e.g., [14]) reveal changes in sleep quality with aging that include decreased total sleep time (TST), increased wake time after sleep onset (WASO), and decreased sleep efficiency (for review, see ref. [8]). ...
... The frequency of diurnal naps increases markedly with aging and this increase continues from "young-old" into "old-old" age [22]. Changes in social patterns may also decrease natural light exposure [23] and reduce exposure to other naturally occurring time cues (zeitgebers) [12]. Circadian disruption may be further exacerbated by the normative circadian phase advance that accompanies healthy aging [12]. ...
... Changes in social patterns may also decrease natural light exposure [23] and reduce exposure to other naturally occurring time cues (zeitgebers) [12]. Circadian disruption may be further exacerbated by the normative circadian phase advance that accompanies healthy aging [12]. ...
Aging is accompanied by changes in sleep quality that include decreases in total sleep time and sleep efficiency as well as increases in wake time after sleep onset and early-morning awakenings. These changes produce an overall decline in sleep quality that can be further exacerbated by behavioral factors such as increased daytime napping and diminished exposure to circadian time cues as well as by a wide variety of medical and neuropsychiatric conditions. Prominent changes in sleep architecture with normal aging include decreases in slow wave sleep time and its accompanying spectral power as well as decreases in rapid eye movement (REM) density in REM sleep and stage 2 sleep spindles and K-complexes in non-REM sleep. Intrinsic circadian rhythms of sleep and wake propensity are damped in amplitude and advanced (shifted to earlier times) in older relative to younger adults. Paradoxically, vigilant attention is less degraded by experimental sleep loss in older vs. younger adults due, possibly, to lesser accumulation of sleep pressure with prolonged waking. Nonetheless, sleep-dependent memory consolidation, a cognitive process taking place during sleep itself, is strongly impacted by normal aging. Specifically, sleep-dependent consolidation of procedural memory, such as learning a specific motor sequence, is diminished with aging, whereas sleep continues to facilitate consolidation of declarative memory (e.g., verbal memory) in older adults. Despite buffering of vigilance against sleep loss and preservation of some forms of sleep-dependent memory consolidation with healthy aging, the concurrent degradation of sleep due to medical and neuropsychiatric issues in many elders may greatly reduce benefits to cognition provided by sleep in younger adults. A prominent example of such is the mutually exacerbating conditions of anxiety and insomnia. Thus, treatment of anxiety and/or insomnia may help to restore other cognitive benefits of good sleep in the elderly.
Clinical features Restless legs syndrome The most characteristic features of the restless legs syndrome (RLS) are uncomfortable sensations in one or more - usually lower - limbs, associated with an urge to move the affected limbs. Those sensations vary widely in severity from merely annoying to significantly unpleasant. It is occasionally difficult for the individual to express the discomfort that is caused by these sensations. Whereas some individuals with RLS describe them as uncomfortable and inside the leg, others speak of pain, pulling, burning, tearing or creepy-crawly sensations, “like ants crawling” or an electric current. All sensations are accompanied by an irresistible urge to move, described as “focal akathisia.” Symptoms typically begin or worsen during periods of rest or inactivity, such as lying or sitting, e.g., when watching television or trying to fall asleep in bed. Whenever the person is forced to sit still, whether this is at the cinema, in the theatre, or on a long-distance flight, discomfort increases. In moderately and severely affected individuals this may lead them to avoid those precipitating situations, and it significantly influences their quality of life. Symptoms of RLS demonstrate a circadian pattern, with a maximum of severity in the evening and at night. Disturbance of sleep onset and frequent awakenings at night with difficulty returning to sleep are therefore clinical features of moderate to severe RLS. Many individuals with RLS may initially complain about sleep disturbances or increased daytime sleepiness and report specific RLS symptoms when directly asked. © Cambridge University Press 2008 and Cambridge University Press, 2009.
Aging and its impact on sleep While physiological sleep needs and patterns change throughout life, sleep disorders are not part of the normal aging process. As more is learned about the relationship of sleep to quality of life and conditions such as memory impairment and cardiovascular problems, it is the responsibility of healthcare providers to address sleep and its disturbances in the care of older individuals. The description of “older” is arbitrary, but it is clear that as persons age, the sleep problems they experience are different from those experienced by the younger adult population. One widely accepted paradigm defines older people to be 65 years or over. Estimates project that by 2050, 85 million Americans will be over 65. Many European countries project that at least 10% of their population will be aged 80 years or over by 2050. The analysis of age-related changes in sleep requires the accumulation of data on a healthy population over 65 years of age. However, increased age raises the risk of cardiovascular, metabolic, cognitive, psychiatric, musculoskeletal, renal, hepatic, and hematological conditions. Therefore, it might be difficult to study a group of “healthy” individuals over 65 years of age, as it is largely the advances in medical knowledge, and the diagnostic and treatment techniques of medical conditions, that allow these individuals to grow old. The subjective experience and the physiology of sleep, as well as its electrophysiological correlates, change with age. © Cambridge University Press 2008 and Cambridge University Press, 2009.
Sleep disorders such as insomnia, sleep-disorder breathing (i.e., snoring, obstructive sleep apnea, and obesity hypoventilation syndrome), shift-work disorder, sleep deprivation, and restless legs syndrome can have a significant impact on a patient’s health-related quality-of-life, workplace productivity, and daily functioning. Sleep is considered vital for preserving daytime cognitive function and physiological well-being. Sleep disorders are commonly associated with other major medical problems such as chronic pain, cardiovascular disease, mental illness, dementias, gastrointestinal disorders, and diabetes mellitus. The resultant economic burden at both the individual and societal levels is significant. Thus, in order to properly care for patients presenting with sleep-related morbidity, and to reduce the ensuing economic burden, accurate screening efforts and efficacious/cost-effective treatments need to be developed and employed.
Sleep–activity patterns were objectively recorded over a 24-hr period in 19 elderly nursing home residents. On average, both sleep and wake times were observed during every hour of the 24 recorded hours; however, the sleep pattern of the residents was fragmented so that they rarely experienced even a single hour of consolidated time spent sleeping. It is hypothesized that several independent factors, including compensation for lost sleep, increased total time in bed, weakening of social constraints, and deterioration of the circadian sleep–wake rhythm, are interacting to produce this increase in sleep fragmentation.
Circadian rhythm disturbances are frequently present in Alzheimer disease (AD). In the present study, we investigated the expression of vasopressin (AVP) mRNA in the human suprachiasmatic nucleus (SCN). The in situ hybridization procedure on formalin-fixed paraffin-embedded material was improved to such a degree that we could, for the first time, visualize AVP mRNA expressing neurons in the human SCN and carry out quantitative measurements. The total amount of AVP mRNA expressed as masked silver grains in the SCN was 3 times lower in AD patients (n = 14; 2,135 +/- 597 microm2) than in age- and time-of-death-matched controls (n = 11; 6,667 +/- 1466 microm2) (p = 0.003). No significant difference was found in the amount of AVP mRNA between AD patients with depression (n = 7) and without depression (n = 7) (2,985 +/-1103 microm2 and 1,285 +/- 298 microm2, respectively; p = 0.38). In addition, the human SCN AVP mRNA expressing neurons showed a marked day-night difference in controls under 80 years of age. The amount of AVP mRNA was more than 3 times higher during the daytime (9,028 +/- 1709 microm2, n = 7) than at night (2,536 +/- 740 microm2, n = 4; p = 0.02), whereas no clear diurnal rhythm of AVP mRNA in the SCN was observed in AD patients. There was no relationship between the amount of AVP mRNA in the SCN and age at onset of dementia, duration of AD and the neuropathological changes in the cerebral cortex. These findings suggest that the neurobiological basis of the circadian rhythm disturbances that are responsible for behavioral rhythm disorders is located in the SCN. It also explains the beneficial effects of light therapy on nightly restlessness in AD patients.
Age has not been sufficiently explored as a variable that can influence circadian periodicity. The present experiments (1) re-evaluated changes in hamster circadian period with age while controlling for access to wheels; (2) studied whether the limits of entrainment differ between young and old animals; and (3) examined whether age influences the probability of rhythm splitting under prolonged constant light conditions. The circadian wheel-running period shortened with age, generally regardless of prior wheel access. Access to wheels was associated with increased weight gain, and animals with prolonged access to wheels died younger than animals without wheel access. These two measures may have been related to the housing conditions associated with wheel access. Although equal proportions of young and old hamsters entrained equally to all T-cycles used, loss of entrainment to long T-cycles was more rapid for old than for young animals. About 60% of young animals showed rhythm splitting, compared to 7% of old animals. The data are consistent with the observation that the circadian rhythm period of the male hamster shortens with age.
A series of findings over the past decade has begun to identify the brain circuitry and neurotransmitters that regulate our daily cycles of sleep and wakefulness. The latter depends on a network of cell groups that activate the thalamus and the cerebral cortex. A key switch in the hypothalamus shuts off this arousal system during sleep. Other hypothalamic neurons stabilize the switch, and their absence results in inappropriate switching of behavioural states, such as occurs in narcolepsy. These findings explain how various drugs affect sleep and wakefulness, and provide the basis for a wide range of environmental influences to shape wake-sleep cycles into the optimal pattern for survival.
Regulation of circadian period in humans was thought to differ from that of other species, with the period of the activity
rhythm reported to range from 13 to 65 hours (median 25.2 hours) and the period of the body temperature rhythm reported to
average 25 hours in adulthood, and to shorten with age. However, those observations were based on studies of humans exposed
to light levels sufficient to confound circadian period estimation. Precise estimation of the periods of the endogenous circadian
rhythms of melatonin, core body temperature, and cortisol in healthy young and older individuals living in carefully controlled
lighting conditions has now revealed that the intrinsic period of the human circadian pacemaker averages 24.18 hours in both
age groups, with a tight distribution consistent with other species. These findings have important implications for understanding
the pathophysiology of disrupted sleep in older people.
We examined the possibility that alterations in the timing of cyclic luteinizing hormone (LH) release during the middle age transition to infertility reflect differences in the circadian pattern of neural function in pacemaker areas of the hypothalamus, particularly the suprachiasmatic nucleus. We measured local cerebral glucose utilization (LCGU) because this parameter is an index of local brain function. We assessed LCGU in several brain areas of young and middle-aged ovariectomized estradiol-treated rats since LH surges are altered when rats are middle-aged. This alteration is correlated with changes in the diurnal pattern of neurotransmitter turnover in several hypothalamic areas that regulate cyclic LH release. The data demonstrate a circadian rhythm in glucose utilization in the dorsal and ventral suprachiasmatic nucleus. In young rats, LCGU increases within 1 hr of lights-on, increases further just prior to the initiation of the LH surge, and decreases within 1 hr of lights-off. In contrast, middle-aged rats show a more gradual increase in LCGU after lights-on, with no further increase prior to the LH surge, and a premature decrease during the afternoon and evening. The data suggest that changes in the circadian pattern of LCGU may be related to the alteration in timing and amplitude of estradiol-induced LH surges in middle-aged rats. Changes in the integrity of the biological clock or in the ability of the biological clock to entrain other neurochemical events may underlie the onset of altered cyclic reproductive function and the transition to irregular estrous cyclicity.
The effects of aging and housing in an enriched environment were assessed in young adult (4-7 months) and old (27-31 months) male Brown Norway rats by conducting 24-h sleep-wake recordings. Comparison of recordings made in rats of different ages, housed in a standard laboratory environment, revealed a reduction of the time spent in slow wave and desynchronized sleep during the light period in the old rats. Furthermore in the old rats, sleep was more fragmented and the amplitude of the circadian sleep-wake rhythm was reduced. In both age groups, housing in an enriched environment resulted in an increase of the time spent in slow wave and desynchronized sleep during the light period. Old "enriched" rats showed an additional alleviation of the senescence-related shortening of sleep cycles and desynchronized sleep epochs. The reduction of the circadian sleep-wake amplitude observed in old age was, however, not affected by the differential housing period. It is concluded that the similarity of the changes in sleep pattern in young and old rats after increased environmental complexity may reflect a preserved capacity of the senescent nervous system to adapt to environmental changes.
Aging is associated with a loss of cyclic gonadotropin release in female animals. This deficit may reflect dampened circadian rhythmicity of neuroendocrine events and/or altered function in hypothalamic nuclei important to regulation of cyclic female reproduction. The purpose of this study was to determine if diurnal periodicity and glucose metabolism in the hypothalamus are altered with age and whether such changes could help to explain the age-related deficits in gonadotropin release. Young (3-4-month-old) and old (18-21-month-old) rats were ovariectomized and subjected to the 2-deoxy-D-1-14C-glucose technique to measure rates of cerebral glucose utilization (GU), an index of neural function (Sokoloff et al., 1977) in various brain areas and in the pineal gland. We measured GU during the light (1400 hours) and the dark (2200 hours) in 17 anatomical regions including the following hypothalamic areas: medial preoptic nucleus, suprachiasmatic preoptic nucleus, suprachiasmatic nucleus, paraventricular nucleus, arcuate nucleus, and median eminence. Serum concentrations of luteinizing hormone (LH) and prolactin were measured in the same rats to determine the effect of age on both of these hormones. Diurnal periodicity of GU was observed in the suprachiasmatic nucleus and the pineal gland in young and old rats. Although there was no age difference in GU of the pineal gland, GU was reduced during the light and dark in the suprachiasmatic nucleus and all other hypothalamic areas examined except the suprachiasmatic preoptic nucleus and the median eminence. Ovariectomy induced an attenuated increase in concentrations of LH in old, compared to young rats.(ABSTRACT TRUNCATED AT 250 WORDS)
The biological rhythms of rectal temperature were documented in young (circadian variations) and elderly (circadian and seasonal variations) human subjects either in apparent good health or suffering from senile dementia of Alzheimer type (SDAT). All the subjects were synchronized. Data obtained showed a decrease of the body core temperature rhythm amplitude in the healthy elderly for each documented season but not in patients with SDAT. Seasonal variations in these rhythms were observed in these elderly groups of persons.
Human subjects during extended isolation from environmental time cues show complex variations in timing and duration of sleep with a progressive pattern, which eventually results in rest-activity and body temperature rhythms having different average periods. We present a model where temperature and rest-activity are each governed by an oscillator of the van der Pol type, denoted x and y, respectively. The oscillators affect one another through "velocity" type coupling, the effect of x on y being about four times greater than y on x. Periodic zeitgeber, z, is modeled as forcing only on y. We find that the entire pattern sequence can be realistically reproduced by causing only the intrinsic period of the y oscillator to increase while that of x remains stable. Desynchronization between x and y is the result of the intrinsic periods of the two oscillators becoming so disparate that the coupling is no longer able to enforce synchrony. Prior to desynchronization both human subjects and our model exhibit "phase trapping" wherein the relative phase of x and y is slowly modulated although the average x and y periods match. The model phase relations between temperature and both the timing and duration of sleep are, throughout, in good agreement with entrained and free-running human data. Most importantly, the model shows that the dramatic change in the length of the rest-activity cycle when desynchronization occurs is actually due to a relatively small variation in the governing variable, y.
Background: Morningness-eveningness refers to interindividual differences in preferred timing of behavior (ie, bed and wake times). Older people have earlier wake times and rate themselves as more morning-like than young adults. It has been reported that the phase of circadian rhythms is earlier in morning-types than in evening types, and that older people have earlier phases than young adults. These changes in phase have been considered to be the chronobiological basis of differences in preferred bed and wake times and age-related changes therein. Whether such differences in phase are associated with changes in the phase relationship between endogenous circadian rhythms and the sleep-wake cycle has not been investigated previously. Methods: We investigated the association between circadian phase, the phase relationship between the sleep-wake cycle and circadian rhythms, and morningness-eveningness, and their interaction with aging. In this circadian rhythm study, 68 young and 40 older subjects participated. Results: Among the young subjects, the phase of the melatonin and core temperature rhythms occurred earlier in morning than in evening types and the interval between circadian phase and usual wake time was longer in morning types. Thus, while evening types woke at a later clock hour than morning types, morning types actually woke at a later circadian phase. Comparing young and older morning types we found that older morning types had an earlier circadian phase and a shorter phase-wake time interval. The shorter phase-wake-time interval in older "morning types" is opposite to the change associated with morningness in young people, and is more similar to young evening types. Conclusions: These findings demonstrate an association between circadian phase, the relationship between the sleep-wake cycle and circadian phase, and morningness-eveningness in young adults. Furthermore, they demonstrate that age-related changes in phase angle cannot be attributed fully to an age-related shift toward morningness, These findings have important implications for understanding individual preferences in sleep-wake timing and age-related changes in the timing of sleep.
Studies examining levels of illumination in adult populations have demonstrated that the level and amount of light exposure are lower in the elderly compared with younger adults, particularly in institutionalized patients with dementia. Although insufficient light exposure has been implied as a cause of sleep fragmentation, evidence for such a relationship is scant. Sixty-six institutionalized elderly had their activity and light exposure monitored for a 3-day period. Mean and median light levels, minutes spent over 1000 and over 2000 lux, percent sleep and wake, and number of naps were computed for daytime intervals, defined as 07.00–18.59. Percentages of sleep and wake, number of awakenings and mean duration of wake periods were computed for night-time intervals, defined as 22.00–05.59. Mesor, amplitude and acrophase of activity and of light were determined by cosinor analysis. A mixed linear model was used to assess the effects of daytime Actillume measures on subsequent night-time measures, and vice versa. Spearman correlations were computed, and multiple regression analyses were carried out with light variables and dementia level as predictors and sleep–wake and activity measures as dependent variables. The median light level was 54 lux and a median of only 10.5 min were spent over 1000 lux. Higher light levels predicted fewer night-time awakenings, and severe dementia predicted more daytime sleep and lower mean activity. Increased bright light exposure predicted later activity acrophase. There was an association between the acrophases of light and of activity, with maximum illumination preceding peak activity. These results suggest that daytime light exposure has an impact on both night-time sleep consolidation and timing of peak activity level.
Objective.
—To determine the effects of moderate-intensity exercise training on self-rated (subjective) sleep quality among healthy, sedentary older adults reporting moderate sleep complaints.Design.
—Randomized controlled trial of 16 weeks' duration.Setting.
—General community.Participants.
—Volunteer sample of 29 women and 14 men (of 67 eligible subjects) aged 50 to 76 years who were sedentary, free of cardiovascular disease, and reported moderate sleep complaints. No participant was withdrawn for adverse effects.Intervention.
—Randomized to 16 weeks of community-based, moderate-intensity exercise training or to a wait-listed control condition. Exercise consisted primarily of four 30- to 40-minute endurance training sessions (low-impact aerobics; brisk walking) prescribed per week at 60% to 75% of heart rate reserve based on peak treadmill exercise heart rate.Main Outcome Measure.
—Pittsburgh Sleep Quality Index (PSQI).Results.
—Compared with controls (C), subjects in the exercise training condition (E) showed significant improvement in the PSQI global sleep score at 16 weeks (baseline and posttest values in mean [SD] for C=8.93 [3.1] and 8.8 [2.6]; baseline and posttest values for E=8.7 [3.0] and 5.4 [2.8]; mean posttest difference between conditions=3.4; P<.001; 95% confidence interval, 1.9-5.4), as well as in the sleep parameters of rated sleep quality, sleep-onset latency (baseline and posttest values for C=26.1 [20.0] and 23.8 [15.3]; for E=28.4 [20.2] and 14.6 [13.0]; net improvement=11.5 minutes), and sleep duration baseline and posttest scores for C=5.8 [1.1] and 6.0 [1.0]; for E=6.0 [1.1] and 6.8 [1.2]; net improvement=42 minutes) assessed via PSQI and sleep diaries (P=.05).Conclusions.
—Older adults with moderate sleep complaints can improve selfrated sleep quality by initiating a regular moderate-intensity exercise program.
Both subjective and electroencephalographic arousal diminish as a function of the duration of prior wakefulness. Data reported
here suggest that the major criteria for a neural sleep factor mediating the somnogenic effects of prolonged wakefulness are
satisfied by adenosine, a neuromodulator whose extracellular concentration increases with brain metabolism and which, in vitro,
inhibits basal forebrain cholinergic neurons. In vivo microdialysis measurements in freely behaving cats showed that adenosine
extracellular concentrations in the basal forebrain cholinergic region increased during spontaneous wakefulness as contrasted
with slow wave sleep; exhibited progressive increases during sustained, prolonged wakefulness; and declined slowly during
recovery sleep. Furthermore, the sleep-wakefulness profile occurring after prolonged wakefulness was mimicked by increased
extracellular adenosine induced by microdialysis perfusion of an adenosine transport inhibitor in the cholinergic basal forebrain
but not by perfusion in a control noncholinergic region.
Social engagement, which is defined as the maintenance of many social connections and a high level of participation in social activities, has been thought to prevent cognitive decline in elderly persons. Associations between a socially engaged lifestyle and higher scores on memory and intelligence tests have been observed among community-dwelling older persons (1–5). Short-term interventions to foster social and intellectual engagement have enhanced cognition among nursing home residents (6) and patients with dementia (7). In animal studies (8), mature rodents exposed to complex social and inanimate environments showed better maze-learning ability than those in sparser surroundings. Social engagement challenges persons to communicate effectively and participate in complex interpersonal exchanges. Besides providing a dynamic environment that requires the mobilization of cognitive faculties, social engagement may also indicate a commitment to community and family and engender a health-promoting sense of purpose and fulfillment. Another putative benefit of social engagement is greater availability of emotional support from relatives and friends. Lack of such support can predict adverse health outcomes (9), but its influence on cognitive decline has not been examined.
This chapter focuses on the number of examples of circadian, circaseptan, circatrigintan and circannual rhythms in the human life cycle. Subsequently, it looks at life span changes in the functional anatomy of the human suprachiasmatic nucleus (SCN), being the neural substrate of the biological clock. Special attention is paid to the possible role of the SCN in reproduction and sexual behavior. Biological rhythms play a prominent role in the human life cycle. The endogenous rhythms are entrained by the environment and have an astronomical counterpart that is obvious for daily, monthly, and yearly rhythms and may possibly also be present in weekly rhythms. Circadian rhythms are present in, for example, testosterone levels, spontaneous birth, strokes, and death from cardiovascular causes. The human SCN shows strong circadian and circannual fluctuations in the number of neurons expressing vasopressin. The vasopressin and vasoactive intestinal polypeptide (VIP) cell population of the SCN develop late—that is, for a major part postnatally. Sex differences are present in the shape of the vasopressin subnucleus of the SCN and in the VIP cell number. The sex differences in the SCN, the doubling of the number of vasopressin neurons in the SCN of homosexual men, and a variety of animal experimental observations indicate that the SCN is involved in sexual behavior and reproduction.
OBJECTIVES: To determine the role of activity status and social life satisfaction on the report of insomnia symptoms and sleeping habits.
DESIGN: Cross-sectional telephone survey using the Sleep-EVAL knowledge base system.
SETTING: Representative samples of three general populations (United Kingdom, Germany, and Italy).
PARTICIPANTS: 13,057 subjects age 15 and older: 4,972 in the United Kingdom, 4,115 in Germany, and 3,970 in Italy. These subjects were representative of 160 million inhabitants.
MEASUREMENTS: Clinical questionnaire on insomnia and investigation of associated pathologies (psychiatric and neurological disorders).
RESULTS: Insomnia symptoms were reported by more than one-third of the population age 65 and older. Multivariate models showed that age was not a predictive factor of insomnia symptoms when controlling for activity status and social life satisfaction. The level of activity and social interactions had no influence on napping, but age was found to have a significant positive effect on napping.
CONCLUSIONS: These results indicate that the aging process per se is not responsible for the increase of insomnia often reported in older people. Instead, inactivity, dissatisfaction with social life, and the presence of organic diseases and mental disorders were the best predictors of insomnia, age being insignificant. Healthy older people (i.e., without organic or mental pathologies) have a prevalence of insomnia symptoms similar to that observed in younger people. Moreover, being active and satisfied with social life are protective factors against insomnia at any age.
Aging alters circadian components such as the free-running period, the day-to-night activity ratio and photic entrainment in behavioral rhythms, and 2-deoxyglucose uptakes and neuronal firing in the suprachiasmatic nucleus (SCN). A core clock mechanism in the mouse SCN appears to involve a transcriptional feedback loop in which Period (Per) and Cryptochrome (Cry) genes play a role in negative feedback. The circadian rhythm systems include photic entrainment, clock oscillation, and outputs of clock information such as melatonin production. In this experiment, we examined clock gene expression to determine whether circadian input, oscillation, and output are disrupted with aging. Circadian expression profiles of rPer1, rPer2, or rCry1 mRNA were very similar in the SCN, the paraventricular nucleus of the hypothalamus (PVN), and the pineal body of young and aged (22–26 months) rats. On the other hand, the photic stimulation-induced rapid expression of Per1 and Per2 in the SCN was reduced with aging. The present results suggest that the molecular mechanism of clock oscillation in the SCN, PVN, and pineal body is preserved against aging, whereas the impairment of Per1 induction in the SCN after light stimulation may result in impaired behavioral photic entrainment in aged rats. J Neurosci. Res. 66:1133–1139, 2001. © 2001 Wiley-Liss, Inc.
• The circadian timing system has been implicated in age-related changes in sleep structure, timing and consolidation in humans. • We investigated the circadian regulation of sleep in 13 older men and women and 11 young men by forced desynchrony of polysomnographically recorded sleep episodes (total, 482; 9 h 20 min each) and the circadian rhythms of plasma melatonin and core body temperature. • Stage 4 sleep was reduced in older people. Overall levels of rapid eye movement (REM) sleep were not significantly affected by age. The latencies to REM sleep were shorter in older people when sleep coincided with the melatonin rhythm. REM sleep was increased in the first quarter of the sleep episode and the increase of REM sleep in the course of sleep was diminished in older people. • Sleep propensity co-varied with the circadian rhythms of body temperature and plasma melatonin in both age groups. Sleep latencies were longest just before the onset of melatonin secretion and short sleep latencies were observed close to the temperature nadir. In older people sleep latencies were longer close to the crest of the melatonin rhythm. • In older people sleep duration was reduced at all circadian phases and sleep consolidation deteriorated more rapidly during the course of sleep, especially when the second half of the sleep episode occurred after the crest of the melatonin rhythm. • The data demonstrate age-related decrements in sleep consolidation and increased susceptibility to circadian phase misalignment in older people. These changes, and the associated internal phase advance of the propensity to awaken from sleep, appear to be related to the interaction between a reduction in the homeostatic drive for sleep and a reduced strength of the circadian signal promoting sleep in the early morning.
While living under constant conditions and complete isolation from environmental time cues for about 4 weeks, 9 male subjects exercised on a bicycle ergometer seven times per 'day' during two weeks and refrained from physical activities during the other 2 weeks. The freerunning circadian rhythms of wakefulness and sleep and of rectal temperature showed, on the average, no difference between the two sections with regard to the autonomous period and the tendency towards internal desynchronization. Even in the one experiment in which the two rhythms became internally desynchronized, the periods of the rhythms remained unchanged during the time the subject worked on the bicycle. Only in one out of the nine subjects, the autonomous period was considerably longer under the influence of work than without it. The hypothesis is advanced that the period of an autonomous rhythm becomes normally independent of physical workload by way of a compensation mechanism.
Many elderly people complain of disturbed sleep patterns but there is not evidence that the need to sleep decreases with age; it seems rather that the timing and consolidation of sleep change. We tried to find out whether there is a concurrent change in the output of the circadian pacemaker with age. The phase and amplitude of the pacemaker's output were assessed by continuous measurement of the core body temperature during 40 h of sustained wakefulness under constant behavioural and environmental conditions. 27 young men (18-31 years) were compared with 21 older people (65-85 years; 11 men, 10 women); all were healthy and without sleep complaints. The mean amplitude of the endogenous circadian temperature oscillation (ECA) was 40% greater in young men than in the older group. Older men had a lower mean temperature ECA than older women. The minimum of the endogenous phase of the circadian temperature oscillation (ECP) occurred 1 h 52 min earlier in the older than in the young group. Customary bedtimes and waketimes were also earlier in the older group, as was their daily alertness peak. There was a close correlation between habitual waketime and temperature ECP in young men, which may lose precision with age, especially among women. These findings provide evidence for systematic age-related changes in the output of the human circadian pacemaker. We suggest that these changes may underlie the common complaints of sleep disturbance among elderly people. These changes could reflect the observed age-related deterioration of the hypothalamic nuclei that drive mammalian circadian rhythms.
Two different stimuli (i.e., benzodiazepines and dark pulses) inducing phase shifts in the circadian clock of young hamsters through changes in the level of activity do not induce phase shifts in old hamsters, despite the fact that these stimuli induce a similar acute change in locomotor activity in young and old animals. In contrast, old hamsters remain sensitive to the phase-shifting effects of stimuli clearly not associated with any change in locomotor activity (i.e., protein synthesis inhibitors or light). Thus the circadian system of old animals becomes selectively unresponsive to synchronizing signals mediated by the activity-rest state of the animals. Previous age-related changes in circadian rhythmicity that have been observed in mammals, including humans, may be related to a weakened coupling between the activity-rest cycle and the circadian clock.
The phase angle of entrainment of the circadian rhythm of the locomotor activity rhythm to a light-dark (LD) cycle was examined in young (2-5 mo old) and middle-aged (13-16 mo old) hamsters. An age-related phase advance in the onset of locomotor activity relative to lights off was seen during stable entrainment to a 14:10-h LD cycle. In addition, the effects of age on the rate of reentrainment of the circadian rhythm of locomotor activity were examined by subjecting young and middle-aged hamsters to either an 8-h advance or delay shift of the LD cycle. Middle-aged hamsters resynchronized more rapidly after a phase advance of the LD cycle than did young hamsters, whereas young hamsters were able to phase delay more rapidly than middle-aged hamsters. The age-related phase advance of activity onset under entrained conditions, and the alteration of responses in middle-aged hamsters reentraining to a phase-shifted LD cycle, may be due to the shortening of the free-running period of the circadian rhythm of locomotor activity with advancing age that has previously been observed in this species.
Insomnia is common in the elderly population. Difficulty in initiating and maintaining sleep affects nearly half of all patients over the age of 65, representing an increased prevalence in older versus younger patients. Nocturnal sleep time is decreased, frequent awakenings occur, and daytime napping is common. Age-related changes in sleep physiology correlate with the subjective complaints of disturbed sleep. Multiple etiologies for insomnia in the elderly have been described. Management strategies must include attention to both nonpharmacologic and pharmacologic aspects of care, especially with respect to the altered pharmacokinetics and pharmacodynamics associated with advanced age. Reassessing therapy is essential to promote the end goal of improvement of the elderly patient's quality of life.
Nine healthy old (80+ years) men were compared with nine healthy young (20-30 years) men in a protocol that required 36 hours of continuous wakeful bedrest. Body temperature rhythm measurement confirmed that the old had as robust an endogenous circadian (approximately 24 hours) rhythm generation mechanism as the young. However, in measures of affect, activation, visual search speed, verbal reasoning speed, manual dexterity, and vigilance hit rate, the old showed a linear decline over the 36 hours of the vigil, with little of the superimposed 24-hour rhythmicity that was apparent in the young. Thus, separate from the endogenous rhythm generation processes, there appeared to be some attenuation with advanced age, which led to the relative absence of rhythmic expression in these mood and performance variables. Such attenuation might contribute to some of the sleep and performance problems reported by elderly adults.
Quality of sleep influences the level of daytime functioning, including stress levels, psychosomatic complaints, general health, and overall well-being. As people age, they complain more about disturbed sleep, insomnia, increased time in bed, and sleep fragmentation. These complaints can be related to circadian rhythm desynchronization, hypnotic or other medication use, chronic bedrest, napping, dementia, or to sleep apnea, a disorder of respiratory cessation which is quite prevalent in the elderly. We review here the results of 12 years of research on sleep in the elderly. In studies of three populations of elderly, it was found that between 24% and 42% had five or more apneas per hour of sleep and 4%-14% had 20 or more apneas per hour of sleep. Since apnea is related to dementia and even to mortality, this high prevalence of apnea is of extreme importance.
Body core temperature was measured in healthy elderly men and women under entrained conditions. Female subjects showed a larger amplitude and a higher peak temperature than male subjects. In addition, acrophase was advanced for females by an average of 49 minutes. Variability in acrophase was greater for males than females. This pattern of gender differences varies considerably from the pattern others have observed in young subjects, suggesting that aging may affect the circadian timing system of males and females differently.
To delineate the physiological effects of aging on basal levels and temporal patterns of neuroendocrine secretions, the 24-h profiles of cortisol, thyroid-stimulating hormone (TSH), melatonin, prolactin, and growth hormone (GH) levels were simultaneously obtained at frequent intervals in eight healthy, active elderly men, age 67-84 yr and in eight young male adults, age 20-27 yr. The study was preceded by an extended period of habituation to laboratory conditions, and sleep was polygraphically recorded. Mean cortisol levels in the elderly were normal, but the amplitude of the circadian rhythm was reduced. Circulating levels of daytime and nighttime levels of both TSH and GH were greatly diminished in old age. In contrast, prolactin and melatonin concentrations were decreased during the nighttime only. The circadian rises of cortisol, TSH, and melatonin occurred 1-1.5 h earlier in elderly subjects, and the distribution of rapid-eye-movement stages during sleep was similarly advanced, suggesting that circadian timekeeping is modified during normal senescence. Despite perturbations of sleep, sleep-related release of GH and prolactin occurred in all elderly men. Age-related decreases in hormonal levels were associated with a decrease in the amplitude, but not the frequency, of secretory pulses. These findings demonstrate that the normal process of aging involves alterations in the central mechanisms controlling the temporal organization of endocrine release in addition to a reduction of secretory outputs.
Human sleep electroencephalograms, recorded in four experiments, were subjected to spectral analysis. Waking prior to sleep varied from 12 to 36 h and sleep was initiated at different circadian phases. Power density of delta and theta frequencies in rapid-eye-movement (REM) sleep and non-REM (NREM) sleep increased monotonically as a function of prior waking. The increase of power density in the theta frequencies contrasts with the reported decrease of theta activity as detected by period-amplitude analysis. Slow wave activity (power density, 0.25-4.0 Hz) in NREM sleep during the first 3 h of sleep did not deviate significantly from the homeostatic process S of the two-process model of sleep regulation. In contrast, visually scored slow wave sleep, stages 3 and 4, deviated from this prediction at some circadian phases. It is concluded that, in accordance with the two-process model of sleep regulation, slow wave activity in NREM sleep depends on prior waking and is not significantly influenced by circadian phase.
In order to test predictions of the 2-process model of sleep regulation, the effects of slow wave sleep (SWS) deprivation by acoustic stimulation during the first part of the sleep period on EEG power density and sleep duration were investigated in 2 experiments. In the first experiment, 8 subjects were deprived of SWS during the first 5 h of a baseline nocturnal sleep period without awakening. Compared to the same interval of undisturbed sleep, power densities in the delta frequencies were attenuated. In the hour following SWS deprivation, power densities in the delta and theta frequencies were considerably enhanced in comparison with the same interval of undisturbed sleep. No change in sleep duration was observed. In the second experiment, 8 subjects were sleep deprived for 1 night and recovery sleep was initiated at 11 a.m. on 2 occasions. In 1 condition subjects were deprived of SWS during the first 3 h of recovery sleep. In the other condition recovery sleep was not experimentally disturbed. During undisturbed recovery sleep, power densities in the delta and theta frequencies were higher than during baseline sleep. During SWS deprivation, power densities in this frequency range were lower than during undisturbed recovery sleep. In the hour following SWS deprivation, power densities were enhanced relative to the same interval of undisturbed recovery sleep. Again, SWS deprivation did not cause an increase of sleep duration. The observed changes in EEG power density support the hypothesis that this EEG parameter reflects the homeostatic process S.(ABSTRACT TRUNCATED AT 250 WORDS)
Body core temperature and subjective sleep quality were measured in 22 healthy elderly men and women while they lived at home and continued their normal daily activities. The acrophase of body temperature was phase-advanced by an average of 1.25 h in the older women compared to the age-matched men. Habitual bedtimes did not differ between men and women, but usual wakeup time and average sleep duration did: women awakened earlier and slept for shorter durations. Women were also less satisfied with their sleep than were the men. For the group, the acrophase of body temperature was significantly positively correlated with habitual bedtime and wakeup time. These data support the notion that age-related changes in the circadian timing system are, in large part, gender-dependent. The findings are also consistent with the hypothesis that alterations in sleep timing and quality that typically accompany aging are closely tied to age-related changes in circadian physiology.
Sleep-activity patterns were objectively recorded over a 24-hr period in 19 elderly nursing home residents. On average, both sleep and wake times were observed during every hour of the 24 recorded hours; however, the sleep pattern of the residents was fragmented so that they rarely experienced even a single hour of consolidated time spent sleeping. It is hypothesized that several independent factors, including compensation for lost sleep, increased total time in bed, weakening of social constraints, and deterioration of the circadian sleep-wake rhythm, are interacting to produce this increase in sleep fragmentation.
Data for this report come from a nationally representative probability sample survey of noninstitutionalized adults, aged 18 to 79 years. The survey, conducted in 1979, found that insomnia afflicts 35% of all adults during the course of a year; about half of these persons experience the problem as serious. Those with serious insomnia tend to be women and older, and they are more likely than others to display high levels of psychic distress and somatic anxiety, symptoms resembling major depression, and multiple health problems. During the year prior to the survey, 2.6% of adults had used a medically prescribed hypnotic. Typically, use occurred on brief occasions, one or two days at a time, or for short durations of regular use lasting less than two weeks. The survey also found a small group of hypnotic users (11% of all users; 0.3% of all adults) who reported using the medication regularly for a year or longer. If we include anxiolytics and antidepressants, 4.3% of adults had used a medically prescribed psychotherapeutic drug that was prescribed for sleep; 3.1% had used an over-the-counter sleeping pill. The majority of serious insomniacs (85%) were untreated by either prescribed or over-the-counter medications.
Institutionalized elderly persons are said to have very disturbed sleep, yet few studies have collected empirical data on the sleep of these patients. We recorded sleep in 200 patients (131 females and 69 males; mean age = 81.9 years, SD = 8.6) in a skilled nursing facility. A modified Respitrace-Medilog portable recording system was used. In recordings averaging 15.4 hours, the patients were asleep for 7 hours, 58 minutes and awake for 7 hours, 28 minutes. To obtain that amount of sleep, the patients spent an extended time in bed during the day, for they averaged no more than 39.5 minutes of sleep per hour in any hour of the night, and 50% woke up at least 2 to 3 times per hour. In summary, although nursing home patients slept on average only one hour longer than independently living elderly, they had to spend substantially more time in bed to obtain the same amount of sleep.
The relationship of age to the circadian rhythms of melatonin and cortisol was investigated in 44 men and 27 women (age range 19-89 years). Subjects were physically and psychiatrically normal. Four hourly serial blood samples were drawn from 8:00 AM until 8:00 AM the next day, with additional samples at 10:00 PM and 2:00 AM. The indoor illumination was restricted to 300 lux during day and 50 lux during the night. Plasma melatonin and cortisol were estimated by radioimmunoassay. Results show that the means of melatonin and cortisol values decreased significantly with age when the subjects were divided into three age groups, i.e., 19-25 years, 42-65 years, and 66-89 years. They also showed a significant negative correlation with age. The acrophases of the two hormonal rhythms, however, showed different relationships to age. The acrophase of melatonin rhythm showed a positive correlation with age (r = 0.38, p less than 0.001), and cortisol showed a negative correlation with age (r = -0.56, p greater than 0.001). It is suggested that this may indicate a weakened responsiveness of the circadian system in the elderly to the day-night cycle and an altered relationship between the pacemakers driving melatonin and cortisol circadian rhythms. This may thus represent a biomarker for the intrinsic process of the aging of the brain.
Ten healthy middle-aged and elderly subjects (44-81 years old; 4 men and 6 women) were studied in time isolation experiments involving: (a) entrainment to the subject's habitual routine (EN condition) and (b) removal of all temporal constraints or "free-running" (FR condition) with the subjects able to choose their own bed and meal times. Subjective day lengths and circadian temperature cycle periods were longer under FR than under EN, but not by an equal amount. Perhaps as a consequence, although time-in-bed (TIB) fractions were greater under FR than under EN, actual sleep fractions were not, reflecting a decline in sleep efficiency. Neither was there an increase in slow-wave sleep (SWS) under FR compared with EN. Daytime subjective alertness did, however, increase upon release into FR, also showing a slightly earlier peak than that observed under the EN condition. The results point to the need to regard sleep and sleepiness as rhythmic, as well as homeostatic, processes.
Exposure to light was recorded from 10 healthy elderly adults and 13 age-matched subjects with senile dementia of the Alzheimer's type (SDAT). Data were recorded in the home, for an average of 5 days, while subjects continued their normal daily activities. Subjects were exposed to remarkably small intervals of illumination exceeding 2000 lux. Subjects with SDAT were exposed to bright light significantly less than healthy controls (0.5 vs. 1.0 hr). Whether or not they had SDAT, males were exposed to illumination exceeding 2000 lux significantly more than were females. Healthy elderly received about two-thirds the duration of bright light received by healthy younger subjects. These findings suggest an association between decreased exposure to bright light and the declines in sleep quality which typically accompany normal and pathological aging.
Sleep-wakefulness rhythms were recorded for at least 5 consecutive days in young adult (n = 6; 5-8 months) and old (n = 4; 30-32 months) rats. During the continuous recordings the rats were maintained in isolated cabins under constant temperature and constant dim, red light. The period length and amplitude of the free-running circadian rhythms of wakefulness (W), slow wave sleep (SWS) and desynchronized sleep (DS) were estimated by means of a cosine curve fitting program. Age-related amplitude differences were absent under the constant recording conditions. The circadian period of the W- and DS-rhythms, however, was significantly shorter in the old rats. These results are consistent with the notion that circadian organization is changed in old age.
The core body temperatures of ten healthy young adult and eight healthy aged men were recorded continuously for 14-24 hours using rectal thermometers and analog tape recorders. Aged subjects had significantly higher temperatures at the nadir of the temperature curve compared to the young subjects. Cosinor analysis of the data revealed that, while all subjects' data significantly fit an idealized cosine function of 24 hours periodicity, the peak to trough amplitude of the rhythm was significantly lower in the aged group. No group differences in the 24-hour mean temperature, the mean temperature during the sleep period time, the mesor, or the acrophase were found. These data are in essential agreement with previously reported data but expand upon those findings and demonstrate that the age-related changes in amplitude of the temperature rhythm are not confined to subjects studied under isolated laboratory environments.
The suprachiasmatic nucleus (SCN) is considered to be the endogenous clock of the brain, essential for the ovulation cycle and the temporal organization of sleep-wake patterns, among other things. Immunocytochemical staining with anti-vasopressin as a marker permitted a morphometric study of this nucleus in the human brain, which revealed that the shape of the SCN is sexually dimorphic. The shape of the SCN was elongated in women and more spherical in men. In both sexes a decrease in SCN volume and cell number was observed in senescence (80-100 years). The latter change was especially pronounced in patients with senile dementia of the Alzheimer type (SDAT). This suggests the presence of a structural defect in the SCN which underlies the general disturbance of biological rhythms in senescence and SDAT.
Three groups of two subjects each were kept in underground chambers, first for 4 days in an artificial light-dark cycle, and
thereafter for 4 days in complete darkness. They lived on a rigorous time schedule. Physiological as well as psychological
functions were measured at 3-hour intervals. There were no differences in the results between the two sections of the experiment.
Social cues are sufficient to entrain human circadian rhythms, and absence of light has no immediate effect on the functions
measured.
Five long sleepers (LS) and 5 short sleepers (SS) were selected from 310 medical students. Nine regular sleepers (RS) were used as a control. The sleep was recorded during 3 reference nights, one recovery night after a 36 h sleep deprivation (R2), one morning sleep after a 24 h sleep deprivation (D1) and the night following D1(R1). According to previous data slow wave sleep (SWS) amounts were the same in the 3 groups while stage 2 and paradoxical sleep (PS) amounts increased with the sleep duration. The hourly distribution of intervening wakefulness and SWS were similar for all groups. When compared to RS or SS the hourly distribution in LS of PS was lower until the sixth hour. As a function of experimental conditions, sleep patterns of LS were the most affected. In R2 the sleep of LS more closely resembled that of RS or SS than in reference nights, while in R1 LS' sleep was the most disturbed. Morning sleep durations were very similar for all groups, but in LS intervening wakefulness was increased and PS was decreased when compared to RS and SS. Negative correlations (Spearman rank test) were found between the morning increase of body temperature after a sleep-deprived night and both TST and PS durations. In all recorded sleep periods, SWS amounts were positively correlated with prior wakefulness duration and the PS amount with TST.
A model for the timing of human sleep is presented. It is based on a sleep-regulating variable (S)--possibly, but not necessarily, associated with a neurochemical substance--which increases during wakefulness and decreases during sleep. Sleep onset is triggered when S approaches an upper threshold (H); awakening occurs when S reaches a lower threshold (L). The thresholds show a circadian rhythm controlled by a single circadian pacemaker. Time constants of the S process were derived from rates of change of electroencephalographic (EEG) power density during regular sleep and during recovery from sleep deprivation. The waveform of the circadian threshold fluctuations was derived from spontaneous wake-up times after partial sleep deprivation. The model allows computer simulations of the main phenomena of human sleep timing, such as 1) internal desynchronization in the absence of time cues, 2) sleep fragmentation during continuous bed rest, and 3) circadian phase dependence of sleep duration during isolation from time cues, recovery from sleep deprivation, and shift work. The model shows that the experimental data are consistent with the concept of a single circadian pacemaker in humans. It has implications for the understanding of sleep as a restorative process and its timing with respect to day and night.
Studies were carried out on a group of six young (ages 23-30) and six older (ages 53-70) normal men who lived under conditions of temporal, but not social isolation, from three to eight weeks. During entrained and non-entrained (free-running) conditions, comparative measurements were made of sleep-wake cycles, sleep stages and rectal temperature rhythms for these two age groups. Results demonstrated a reduction in the period and amplitude of the body temperature rhythms during free-running in the older group. Sleep efficiency, total sleep time, REM sleep latency, REM episode length, percent REM in the last 2 hours of sleep, the length and frequency of arousals during sleep, and the terminal wake latency were all age related and dependent on entrainment. The period of the sleep-wake cycle, terminal awakenings from REM and percent REM in the first 3 hours of sleep were not age related but were dependent on entrainment. Sleep stages as percents of total sleep time were found to be age related but independent of entrainment, while sleep latency, mid-REM to mid-REM cycle length and the ratio of sleep to total time were neither age related nor dependent on entrainment. In addition, individual chronobiological differences were prominent in the older group. Changes of period and of the phase relationship of sleep-wake and temperature rhythms occurred in several subjects during the non-entrained condition.
In a group of 6 male subjects sleep was displaced to seven different times of day (one displacement condition per week). The subjects were isolated from external time cues (daylight, clocks, noise) and sleep was allowed to terminate spontaneously. The results showed a pronounced time-of-day variation of total sleep time, stage 2, and rapid eye movement (REM) sleep. Maxima occurred after bedtimes at 1900 hr and 2300 hr, while the minima occurred after bedtimes at 0700 hr and 1100 hr. The latter also was the time of maximum propensity to wake up. Slow wave sleep showed a rapid decrease from high initial levels, irrespective of time of day. Ratings of sleepiness showed a highly significant circadian variation peaking between 0500 hr and 0700 hr. The lowest level of sleepiness coincided with the maximum tendency to wake up, and it was suggested that sleep termination may be closely related to the sleepiness/alertness rhythm.