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Sleep Research and Treatment Center (A.N.V., E.O.B., A.V.-B., A.K.), Department of Psychiatry, and Health Evaluation Sciences (H.-M.L.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033; Pediatric and Reproductive Endocrinology Branch (M.Z., G.P.C.), National Institutes of Health, Bethesda, Maryland 20892; Department of Psychiatry and Biobehavioral Sciences (P.P.), University of California, Los Angeles, California 90095
Address all correspondence and requests for reprints to: Alexandros N. Vgontzas, M.D., Department of Psychiatry H073, Penn State University College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033. E-mail: axv3{at}psu.edu.
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Abstract |
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secretion is increased by sleep loss or restriction. IL-6 secretion progressively increases with age, yet its association with decreased quality and quantity of sleep in old adults is unknown. This study examined the alteration of 24-h secretory pattern of IL-6, TNF, and cortisol in 15 young and 13 old normal sleepers who were recorded in the sleep laboratory for four consecutive nights. Serial 24-h plasma measures of IL-6, TNF, and cortisol were obtained during the fourth day, and daytime sleepiness was assessed with the multiple sleep latency test. Old adults, compared with young subjects, slept poorly at night (wake time and percentage stage 1 sleep were increased, whereas their percentage slow wave sleep and percentage sleep time were decreased, P < 0.05). Accordingly, their daytime sleep latency was longer than in young adults (P < 0.05). The mean 24-h IL-6 and cortisol levels were significantly higher in old than young adults (P < 0.05). In both groups, IL-6 and cortisol plasma concentrations were positively associated with total wake time, with a stronger association of IL-6 and cortisol with total wake time in the older individuals (P < 0.05); their combined effect was additive. IL-6 had a negative association with rapid eye movement (REM) sleep only in the young (P < 0.05), but cortisol was associated negatively with REM sleep both in the young and old, with a stronger effect in the young. We conclude that in healthy adults, age-related alterations in nocturnal wake time and daytime sleepiness are associated with elevations of both plasma IL-6 and cortisol concentrations, but REM sleep decline with age is primarily associated with cortisol increases. |
Introduction |
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IL-6 and TNF are somnogenic and fatigue-inducing proinflammatory cytokines (12, 13, 14, 15), but the hypothalamic-pituitary-adrenal (HPA) axis stimulates arousal and suppresses sleepiness (16, 17). The daytime secretion of IL-6 is negatively influenced by the quantity and quality of the previous night’s sleep, and lack of sleep or poor sleep leads to daytime IL-6 hypersecretion, and sleepiness and fatigue (14). Both IL-6 and TNF stimulate the activity of the HPA axis, but their secretion is suppressed by glucocorticoids (18). Old age is associated with increased IL-6 secretion (19) and higher evening cortisol concentrations (20). The association of the former with age-related sleep changes is unknown, but the latter has been associated with lower amount of REM sleep independently of age (6). The goal of the present study was to examine in healthy young and old adults whether deterioration in nighttime sleep quality and quantity is associated with alterations of IL-6, TNF, and cortisol levels. Another objective was to examine the association of the interaction of these hormones with age-related daytime sleep/alertness changes.
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Subjects and Methods |
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Fifteen young (12 men and 3 women) and 13 old (9 men and 4 women) normal sleepers matched for weight [mean ± SD 24.0 ± 4.0 vs. 71 ± 3.7 yr; body mass index (BMI), 26.5 ± 3.8 vs. 26.3 ± 2.6, respectively] participated in the study. The subjects were recruited from the community through a newspaper advertisement and from the medical and technical staff and students of the Milton S. Hershey Medical Center.
A complete medical history was recorded, and a complete physical examination was performed, including mental status assessment and a battery of clinical tests (including complete cell blood count, urinalysis, thyroid indices, and electrocardiogram). All potential research subjects were interviewed and required to complete a comprehensive questionnaire and a Multiple Minnesota Personality Inventory (MMPI)-II. The questionnaire provided a detailed history of sleep habits, sleep complaints, general health, medication use, tobacco use, and consumption of caffeinated beverages.
Both young and old controls were in good physical health, not using any medication that could affect either sleep or hormone levels, not doing shift work, and having the battery of clinical tests negative for abnormal findings. None of the women were using hormonal contraceptives or hormonal replacement therapy. Both groups had no sleep complaints, and they were screened in the sleep laboratory for sleep apnea, nocturnal myoclonus, or other primary sleep disorders. The study was approved by the Institutional Review Board, and each subject signed a written informed consent.
Sleep laboratory recordings
Nighttime testing. Subjects were recorded in the sleep laboratory for four consecutive nights. The first night allowed for adaptation to the new sleeping environment and was not included in the analysis. Sleep laboratory recording was carried out in a sound-attenuated, light- and temperature-controlled room that has a comfortable bedroom-like atmosphere. During this evaluation, each subject was monitored continuously for 8 h. The sleep schedule in the sleep laboratory was similar to the subjects’ normal sleep schedule, which was between 2200–2300 to 0600–0700 h. The average start time of sleep recording for young and old subjects was 2233 ± 6 vs. 2236 ± 5 min, respectively. Electroencephalographic, electrooculographic, and electromyographic recordings were obtained in accordance with standard methods (21). The sleep recordings were amplified using standard clinical polygraphs (model 78d and e; Grass Instrument Co., Quincy, MA). The sleep records were scored independently of any knowledge of the experimental condition, according to standardized criteria (21).
Sleep parameters, assessed from the sleep recordings, included sleep induction, or sleep latency (SL); sleep maintenance wake time after sleep onset (WTASO); total wake time (TWT), which is the sum of SL and WTASO; total sleep time (ST) and percentage ST (which is total ST, as percentage of time in bed); percentage of the various sleep stages (REM, 1, 2, combined 3 and 4 for SWS, which is calculated as the minutes in each stage as the percentage of total ST); and REM latency, which is the interval from sleep onset to the first REM period. Sleep onset was defined as the latency from lights out to the first occurrence of any stage sleep for a duration of 1 min or longer. If, however, the initial stage of sleep was stage 1, then it had to be followed without any interfering wake, by at least 1 min, of any other stage.
Throughout the study, subjects completed a postsleep questionnaire upon awakening in the morning and estimated time to fall asleep, number of nightly awakenings, total ST, early final awakening, soundness and quality of sleep, and morning sleepiness. Each morning and evening, tension and anxiety were also assessed on a 10-cm analog scale that ranged from extremely calm to extremely agitated conditions. Throughout the study, subjects were instructed not to nap, alter their level of physical activity, or use any medication.
Daytime testing. During the fourth day, the subjects’ level of sleepiness and alertness was evaluated using Multiple Sleep Latency Test. The measurement of SL during brief daytime naps is used to detect sleepiness and considered the gold standard for daytime sleepiness (22). Typically, the test consists of 20-min opportunities to sleep at 2-h intervals beginning at 0900 h. In our study, we allowed five brief naps at 0900, 1200, 1500, 1700, and 1900 h. Onset of sleep was established by the presence of any sleep stage for a duration of 1 min or longer. However, if the initial stage of sleep is stage 1, it must be followed, without any intervening wakefulness, by 60 sec of stages 2, 3, 4, or REM. If the subject fell asleep in less than 20 min, he/she was allowed to sleep for only one additional minute to verify the establishment of sleep onset. We chose not to define sleep onset only in the presence of stage 1 because its recognition during the recording can be unreliable and may result in premature ending of the test without obtaining true sleep. For analyses purposes, sleep onset was defined in two ways: 1) presence of any sleep stage for 1 min or longer, and (2) presence of at least 60 sec of stages 2, 3, 4, or REM. Also, before each nap opportunity, subjective levels of sleepiness were assessed using a visual analog scale that ranged from 0 (not sleepy at all) to 10 (extremely sleepy) and a 7-point question, "How sleepy are you now?"
Blood-drawing technique
Twenty-four-hour blood sampling was performed serially, every 30 min, on the fourth day. An indwelling catheter was inserted in the antecubital vein about 30 min before the first blood draw. The catheter was kept patent with small amounts of heparin. During the sleep-recording period, blood was collected outside the subjects’ room, through a perforation in the wall, via extended tubing, to decrease sleep disturbance from the blood drawing. During the daytime, the subjects were ambulatory, and they were allowed to watch television, play computer and table games, go to the bathroom, and engage in other similar activities. Also, they were instructed not to change their diet, and their three daily meals were at about 0700, 1200, and 1800 h.
Hormone assays
Blood collected from the indwelling catheter was transferred to an EDTA-containing tube and refrigerated until centrifugation (within 3 h). The supernatant was frozen at -20 C, for the hormones, until assay. Cortisol levels were measured by specific immunoassay techniques as previously described (16). The lower limit of detection for cortisol was 19.31 nmol/liter, and the intra- and interassay coefficients were, respectively, 4.6% and 6.0%.
Plasma TNF and IL-6 were measured by ELISA (R&D Systems, Minneapolis, MN). The intra- and interassay coefficients of variation ranged from 5.6–6.1% and 7.5–10.4%, respectively, for TNF and from 3.2–8.5% and 3.5–8.7% for IL-6. The lower detection limits for TNF and IL-6 were 0.18 and 0.094 pg/ml, respectively.
Statistical analyses
Descriptive statistics (percentages, means, and SD) were used to characterize the sample except when comparisons were made between young and old, in which case variability estimates were expressed as SE. Baseline sleep and MMPI-II profiles were compared between young and old controls, using t tests. Twenty-four-hour serial plasma cortisol, IL-6, and TNF levels were analyzed using multivariate ANOVA, assuming the covariance type was of a heterogeneous first-order autoregressive structure. In addition, the circadian rhythmicity of cortisol, IL-6, and TNF secretion was assessed with cosinor-multiple-components rhythmometry (23), by fitting a curve to each individual profile and the entire population profile. This method allowed fitting a model with several cosine functions to the data. The data were analyzed after they were transformed to percentage of the mean, which is the preferred approach, when the focus of the analysis is on the pattern of change across the 24-h period rather than on the absolute values (24). Furthermore, because the IL-6 values were higher at the end of the blood sampling, compared with the values at the beginning of the blood drawing at about the same time, IL-6 data were detrended. For each individual, a linear regression line was fit for the 24-h IL-6 data. The detrended IL-6 residuals were then used for the cosinor analysis to test whether rhythmicity existed. The IL-6 slopes were then compared between the young and old groups using the t test. Moreover, the IL-6 slopes were regressed on age, TWT, and their interaction to test whether the IL-6 slopes were associated with age and quality of sleep. For each age group, the changes in IL-6 with the changes in cortisol were examined using the cross-correlation analysis with cortisol being the lagging series. Correlations for every 30-min lag period were estimated and tested for statistical significance.
Association between sleep variables (TWT and REM sleep) (dependent variables) and IL-6 and cortisol plasma levels (independent variables) was assessed using multiple linear regressions. In this analysis, we chose the lowest value of cortisol in 24 h (nadir) as an index of HPA axis activity because aging affects more the evening nadir and less the 24-h mean cortisol level or the morning maximum values (6, 20). To detect the minimum cortisol value for each individual, we fitted the 24-h cortisol data using the cubic smoothing spline curve. Then we interpolated the nadir cortisol value and the time at which it occurred. The cubic smoothing spline function is a smoothly joined piecewise polynomial function of 3 and is widely used for interpolation (25). For IL-6, we computed the average value between the 1800 and 2000 h time window. The 1800 and 2000 h window was chosen because: 1) during this window the daytime IL-6 plasma levels were the highest (see Fig. 2
); 2) our preliminary cross-correlation analysis between IL-6 and cortisol showed that the lag time for cortisol to respond to the change of IL-6 was approximately 3–4 h for the old group and 5–6 h for the young group (because the time at which the nadir cortisol value occurred was around midnight, it seemed reasonable to select the 1800- to 2000 h interval for IL-6); and 3) the IL-6 concentration between 1800 and 2000 h correlated strongly with 24-h IL-6 secretion (r = 0.7, P < 0.001).
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Results |
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Old, compared with young, adults slept poorly (WTASO and percentage stage 1 sleep were increased whereas percentage SWS and percentage ST were decreased, all P < 0.05) (Table 1). In old adults the amount of REM sleep was decreased by about 9 min (NS).
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). Daytime SL was also significantly shorter in young, compared with old, adults at 0900, 1200, and 1500 h (P < 0.05). Maximum sleep propensity was observed at about 1500 h for both groups. However, this rhythm of sleepiness/alertness was significant only in the young group as indicated by the differences of sleep latencies between 0900 and 1500 h (-2.9 ± 2.0 min, NS in the old; -3.7 ± 1.9 min, P < 0.05 in the young) and between 1500 and 1700 h (1.2 ± 1.82 min NS in the old; 4.7 ± 1.7 min, P < 0.01 in the young). Subjective data also indicated that old subjects were less sleepy than young subjects (NS). None of the subjects in either group had MMPI-II clinical scales elevated in the pathologic range (T score 
65).
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, and cortisol
The mean 24-h IL-6 and cortisol concentrations were significantly higher in old than in young adults (respectively, 4.6 ± 0.4 vs. 3.0 ± 0.3 pg/ml; 246.66 ± 7.81 vs. 220.25 ± 8.86 nmol/liter, both P < 0.05) (Fig. 1
). IL-6 secretion was circadian in both groups and uniformly increased both during the daytime and nighttime; the cortisol secretion was higher during the evening and nighttime (sleep) periods in the old adults (Fig. 2). The overall amount of TNF was not different between the two groups (Fig. 2).
A significant positive cross-correlation between IL-6 and cortisol was observed in both groups with IL-6 leading cortisol. Specifically, in the old group, the cross-correlation reached statistical significance at lag time 3.5 h (r = 0.15, P = 0.03), and in the young group, the cross-correlation reached statistical significance at lag time 5.5 h (r = 0.14, P = 0.03).
Circadian analysis
Both young and elderly subjects demonstrated a biphasic circadian pattern of IL-6 secretion with two nadirs at about 0900–1000 and 2100 h and two zeniths at about 1700 and 0300 h (Fig. 3). Cosinor analyses, both for the individual and population IL-6 data, indicated a significant circadian rhythm with a multiple component curve including periods of 12 and 24 h (P < 0.01; Fig. 3). However, in the elderly, compared with the young, the circadian secretory pattern was flattened (P < 0.01; ANOVA). Furthermore, cosinor analysis of the detrended data showed again the biphasic circadian pattern of IL-6 secretion, which was significant in the young (P < 0.01) and borderline significant in the old (P < 0.1). Similar to the analysis of the raw data, both groups showed two peaks and two nadirs at about the same times. However, in the elderly the amplitude of the nighttime peak was about equal to the daytime peak, whereas in the young the nighttime peak was the major peak and daytime was secondary. Furthermore, we tested the effect of age and sleep quality (TWT) and their interaction on the slope of the regression using multiple regression, and no significant effect was detected for either of the variables and their interaction. TNF secretion showed a circadian pattern with a nadir before sleep onset and a peak just before sleep offset; such a circadian pattern was not found in the elderly group (Fig. 3). Cortisol secretion was circadian in both groups, with higher evening and night levels in the older individuals (Fig. 3).
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A significant positive association was detected between IL-6, cortisol, and their interaction with TWT in the old group (all P < 0.05), but in the young group, only the association between IL-6 and wake time was significant (P < 0.05) (Fig. 4). The association of both IL-6 and cortisol was stronger in the old than the young. Specifically, in the old, an increase of IL-6 plasma levels by 1 pg/ml was associated with an increase of TWT by 21.1 min, and an increase of cortisol levels by 1 µg/dl was associated with an increase of TWT by 22.8 min, whereas their additive effect was 39 min. In the young, an increase of IL-6 by 1 pg/ml was associated with an increase of TWT by 9.9 min (P < 0.05), and an increase of cortisol by 1 µg/dl was associated with an increase of TWT by 10.0 min (NS), whereas their synergistic effect was 17.0 min (again NS). Within the same age group, age residual (see Subjects and Methods) did not have additional contribution to the total wake time.
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). The effect of cortisol on REM sleep was stronger in the young than the old. Specifically, in the young, an increase of IL-6 by 1 pg/ml was associated with a decrease of REM sleep by 17.2 min and an increase of cortisol by 1 µg/dl with a decrease of REM sleep by 33 min, whereas their additive effect was associated with a 46-min decrease of REM sleep. In the old group, a change of IL-6 levels did not have an effect on REM sleep, whereas an increase of cortisol plasma levels by 1 µg/dl was associated with a 13-min decrease of REM sleep. Within the same age group, age had an independent negative association with REM sleep (P < 0.01).
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Discussion |
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The association of IL-6 and cortisol with wake time were stronger in the old than in the young adults. This finding is consistent with our previous report that middle-aged men show increased vulnerability of sleep to stress hormones, compared with the young (30). It is possible that old adults are more vulnerable to sleep disturbances during periods of stress. We suggest that changes in sleep physiology associated with aging, including elevations of sleep-disturbing hormones and increased sensitivity of the sleep-controlling target organ to the actions of these hormones, play a significant role in the marked increase of insomnia prevalence with aging. We should note that in our study, the elevations of IL-6 and cortisol were not associated with chronic emotional stress or disorder because both clinical evaluation and the results on the MMPI-II test ruled out these conditions.
The decline of REM sleep associated with aging, in our study, was more related with the elevation of cortisol than that of IL-6. Previous studies demonstrated an association between lower amounts of REM sleep and higher evening cortisol concentrations independently of age (6). Our study demonstrated that the decline of REM sleep with aging may only partially be attributed to increased cortisol concentrations, and other factors affected by aging and not assessed in this study may play a role in REM decrease. Exogenously administered CRH or corticosteroids have been associated with a reduction in the amount of REM sleep, and we have suggested that this reduction is mediated through a negative feedback regulation loop between the REM sleep cycle and the HPA axis (27). We previously demonstrated that this effect was stronger in young than middle-aged men (30). We now postulate that the reduced effect of cortisol on REM with age may be secondary to an impairment of the negative feedback loop between HPA axis and REM sleep.
Our study showed that, contrary to the common belief that sleepiness is increased among old adults, sleep propensity was decreased with age. Our findings using objective sleep testing are similar to previous reports that compared young and old adults and used the same methodology as ours (10, 11). Furthermore, these results are consistent with recent findings that the prevalence of excessive daytime sleepiness is decreased in old, compared with young, adults in a large general random sample (31). Although these well-replicated findings may sound paradoxical, they agree with the tenets of sleep physiology and can be easily explained if we differentiate between sleepiness and fatigue. Another hypothesis, not mutually exclusive, is that the age difference in daytime SL may reflect increased sleep propensity in the young subjects because of chronic sleep debt.
We have previously proposed that increased daytime secretion of somnogenic and fatigue-inducing cytokines, such as IL-6 and TNF, not associated with HPA axis activation, leads to sleepiness and deeper sleep, and a good example of this is sleep deprivation (14). On the other hand, cytokine hypersecretion associated with HPA axis activation, as occurs in chronic insomnia, leads to fatigue, but not sleepiness and poor sleep (12, 17, 27). The results of the present study are consistent with this model and suggest that in the elderly poor sleep, and daytime fatigue, manifested with decreased daytime sleep propensity and diminished performance (10, 11), are associated with IL-6 hypersecretion and HPA axis activation.
Such a model, which combines cytokine secretion and HPA axis function to explain sleepiness and increased sleep vs. fatigue and poor sleep, is supported by experiments on the effects of exogenous activation of the host defense system on sleep in humans. For example, exogenous administration of IL-6 in healthy humans in the evening was associated with both fatigue and a sleep-disturbing effect in the first half of the night, most likely caused by increased secretion of CRH, ACTH, and cortisol, during the early part of the night, induced by IL-6 (29). Also, in dose-response experiments using endotoxin, it was shown that subtle host defense activation not associated with HPA axis activation and increased body temperature enhanced the amount of non-REM sleep, whereas higher doses associated with increased cortisol secretion and increased body temperature resulted in reduced non-REM sleep and increased wakefulness (32).
The 24-h secretory pattern of IL-6 both in young and old healthy adults was bimodal consistent with our previous reports (12, 14). The amplitude of IL-6 and cortisol secretion was dampened in old compared with young adults, but the circadian rhythm of TNF was lost with age. Interestingly, in our study, old age was also associated with a loss of the circadian distribution of daytime sleep propensity. Indeed, increased sleepiness in midafternoon, compared with other times of the day, was significant only in the young. These similarities in terms of flattened circadian patterns between sleepiness and these three hormones support further the association of these hormones with sleep and sleepiness. Furthermore, it is possible that these alterations result from age-related changes in the output of the circadian pacemaker (33). Future studies should include measurements of a marker of circadian rhythm such as melatonin to assess the influence of circadian factors on the changes of IL-6, TNF, or cortisol associated with aging.
It has been previously suggested that increased HPA axis activity associated with aging is a result of the wear and tear of lifelong exposure to stress (6, 20). An alternative, not mutually exclusive, explanation is that the significant alteration of HPA axis activity associated with age is at least partially secondary to the hypersecretion of IL-6, whose peripheral levels are a good marker of increased morbidity and mortality (19). The source of IL-6 hypersecretion in the elderly is not known. However, we know that IL-6 peripheral levels correlate negatively with sex steroids levels, positively with the amount of adipose tissue, are decreased after a good night’s sleep and elevated in chronic pain/inflammatory syndromes (12, 17, 19, 27, 34, 35). Old age is associated with decreased sex steroid concentrations, increased proportional body fat, decreased quantity and quality of sleep, and frequent chronic pain/inflammatory conditions. Reducing the secretion of IL-6 in elderly, by administration of sex steroids, decreasing fat through diet and exercise, improving nighttime sleep, and controlling adequately chronic pain and inflammation with nonsteroidal antiinflammatory agents, may improve sleep, daytime alertness, and performance and decrease the risk of common ailments of old age, e.g. metabolic and cardiovascular problems, cognitive disorders, and osteoporosis (15, 36, 37).
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Acknowledgments |
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Footnotes |
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Abbreviations: BMI, Body mass index; HPA, hypothalamic-pituitary-adrenal; MMPI, Multiple Minnesota Personality Inventory; REM, rapid eye movement; SL, sleep latency; ST, sleep time; SWS, slow-wave sleep; TWT, total wake time; WTASO, sleep maintenance wake time after sleep onset.
Received July 29, 2002.
Accepted January 27, 2003.
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secretion from nighttime to daytime. Metabolism 51:887–892[CrossRef][Medline]
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) and old (
) individuals. Each data point represents the mean ± SE The darkened area indicates the sleep-recording period.
) and old (
