Sleep associated endocrine and immune changes in the elderly

Advances in Cell Aging and Gerontology

Sleep associated endocrine and immune changes in the elderly Boris Perrasa,b and Jan Borna,* a

Institute of Neuroendocrinology, University of Lu¨beck, Germany Department of Internal Medicine I, University of Lu¨beck, Germany *Correspondence address: J. Born, University of Lu¨beck, Institute of Neuroendocrinology, Haus 23a Ratzeburger Allee 160, 23538 Lu¨beck, Germany. Tel: þ49-4515003641; fax: þ49-4515003640. E-mail address: [email protected] b

Contents 1. Introduction 2. Regulation of sleep-related endocrine systems in young humans 2.1. The HPA and somatotropic system 2.2. Vasopressin (VP) 2.3. Prolactin, melatonin, and other hormones 3. Regulation of sleep-related immune function in young humans 3.1. Undisturbed sleep 3.2. Deprivation of sleep 3.3. Cytokine effects on sleep 4. Sleep and endocrine regulation in the aged 4.1. Sleep-endocrine regulation of the HPA and the somatotropic system 4.2. Vasopressin in the elderly 4.3. Effects of hormone administration on sleep in the aged 5. Immune function during sleep in the aged 5.1. Immune system function in the aged 5.2. Sleep-associated immune function in the aged 5.3. Endocrine mediation of sleep-immune changes in the aged 6. Summary and conclusion

1. Introduction Wakefulness and sleep show remarkable differences in electrical brain activity, which are paralleled by characteristic changes in the pattern of endocrine secretion and immune activity. These fluctuations in hormonal and immune activity, however, reflect not only an interaction with mechanisms regulating sleep and Advances in Cell Aging and Gerontology, vol. 17, 113–154 ß Published by Elsevier B.V. DOI: 10.1016/S1566-3124(05)17005-9

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wakefulness, but also influences from various other factors modulating sleep– endocrine and sleep–immune interactions. Most important in this respect are circadian oscillators playing a supra-ordinate role in sleep–wake regulation. In addition, environmental (e.g., light exposure) and behavioral conditions (e.g., stress), and factors such as gender and age are to be considered in this context as potent modulators. During the wake phase, neuroendocrine and neuroimmune mechanisms assist the body in coping with stressful environmental and internal events. However during sleep, stressors and stress responses are absent, and activity in the neuroendocrine and immune systems becomes subjected to a spontaneous and basal mode of ‘‘self-regulation’’ whose mechanisms are not yet fully understood. In the course of aging, prominent sleep-related changes of endocrine secretion and immune function occur and contribute to the morbidity and mortality in the elderly. Here we review the interaction of neuro-endocrine as well as neuro-endocrine– immune regulation with sleep, first in young and then in aged humans. The focus will be on the hypothalamo-pituitary-adrenal (HPA) system, the somatotropic system, and the vasopressinergic system. Apart from ‘‘efferent’’ influences of the sleeping brain on the release of hormones into the blood stream, the ‘‘afferent’’ effects of circulating hormones and cytokines of the immune system on the sleeping brain will also be discussed. 2. Regulation of sleep-related endocrine systems in young humans 2.1. The HPA and somatotropic system Together with the sympathetic nervous system, the body’s response to stressful events during wakefulness is mediated through the secretory activity of both the HPA axis and the somatotropic axis. Stress stimulates corticotropin-releasing hormone (CRH), which is secreted from the hypothalamus with highest concentrations of the hormone found in the nucleus paraventricularis. This CRH induces release of adrenocorticotropic hormone (ACTH) from the anterior pituitary into the circulating blood, which subsequently induces the release of cortisol from the adrenals. Stimulation of the HPA axis by physical, metabolic, and mental stressors is in many cases paralleled by the secretion of growth hormone-releasing hormone (GHRH) mainly from the basomedial hypothalamus, i.e., the arcuate nucleus. This GHRH is the secretagogue of growth hormone (GH), which is released from the anterior pituitary to regulate metabolic requirements at a cellular level, mainly via stimulating the hepatic release of insulin-like growth factor I (IGF-I). With the ending of the stress stimulus, the secretion of CRH and GHRH and all subsequent hormones is terminated by negative feedback regulation. Since sleep is generally regarded as a state devoid of stress, and in the light of the predominance of stress-related activity in the wake phase, activity of the HPA and somatotropic system during sleep can be expected to be low. However, examination of the temporal patterns of ACTH/cortisol and GH secretion during sleep reveals a complex and surprising relation between sleep, sleep stages, and hormonal activity.

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Figure 1 illustrates the typical time course of HPA and somatotropic secretory activity during nocturnal sleep in a healthy young man: the cyclic appearance of nonREM sleep or slow wave sleep (SWS) and REM sleep over the night changes in that the first half of the night is characterized by a predominance of SWS while the latter part of the night is dominated by REM sleep. In parallel, the changing hormonal secretion shows very low ACTH and cortisol plasma concentrations and concurrent bursts of plasma GH levels during the SWS-rich early part of sleep. In contrast, in the second, late part of nocturnal sleep, the secretory activity of W REM

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Fig. 1. Time course of HPA and somatotropic secretory activity during nocturnal sleep in a healthy young man. The upper panel shows the sleep profile characterized by a predominance of slow wave sleep (SWS) during the early part of sleep, and a predominance of REM sleep during the late part. The middle panel indicates associated plasma ACTH (dashed line) and cortisol (solid) levels indicating activity of the HPA system. The lower panel shows the associated plasma growth hormone (GH) profile.

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the HPA system is distinctly increasing, while activity of the somatotropic system is minimal. 2.1.1. The HPA-system Plasma levels of ACTH and cortisol are subject to a circadian rhythm (Weitzman et al., 1971; Gallagher et al., 1973). This rhythm can be observed independent of sleep and wakefulness. However, sleep plays an important synergistic role in this regulation of HPA activity during the 24-h cycle. During normal nocturnal sleep, both ACTH and cortisol concentrations reach a 24-h minimum (nadir) during the early SWS-rich part of sleep and increase during the late part when REM-sleep is predominant (Kupfer et al., 1983). Several studies have elucidated the relation between sleep and release of ACTH and cortisol by manipulating sleep. For example, Spa¨th-Schwalbe et al. (1993) stimulated ACTH and cortisol secretion by intravenous bolus injection of CRH during different periods of sleep and wakefulness. In one condition CRH was injected during early sleep while the subject was in a period of SWS. In another condition CRH was injected at the same time of the night with the subject kept awake this time. Compared to the wake state, the ACTH/cortisol secretory response to CRH was distinctly suppressed during early SWS. No such suppression was found during late sleep when REM sleep prevails. These and related observations indicate that early sleep and in particular, SWS inhibits pituitary–adrenal activity. The contribution of late sleep to the regulation of the HPA-axis is illustrated in another experiment indicating that in comparison with wakefulness during the REM sleep-rich late part of the night, the HPA system is disinhibited, so that plasma concentrations of ACTH and cortisol are relatively increased during this period of sleep (Spa¨th-Schwalbe et al., 1991). Also, shortly after awakening in the morning ACTH/cortisol concentrations decrease again which has led to the hypothesis that the increase in HPA activity during late sleep ‘‘prepares’’ the organism for the stress anticipated in the upcoming wake phase (Born et al., 1999; Pruessner et al., 2003). Additionally, differential effects of sleep stages and the ultradian structure of sleep on the HPA system have been revealed. Especially during the late part of nocturnal sleep the cyclic nature of sleep with the alternate appearance of nonREM and REMsleep is closely linked to respectively, global increases and decreases in secretory activity of the anterior pituitary (Follenius et al., 1988). In conditions of free running circadian rhythms and also when the sleep phase is experimentally shifted (by up to 12 h), it becomes evident that the suppressing influence of SWS on secretion of ACTH/cortisol is most prominent during a limited period around the habitual bedtime, indicating an entrainment of this sleep-related inhibition of pituitary– adrenal activity to the circadian oscillation (Weitzman et al., 1971; Pietrowsky et al., 1994; Weibel et al., 1995). Thus, when SWS is shifted by more than about 3 h into the late part of the night or is advanced by the same time into the evening, the suppressive influence of SWS on pituitary adrenal function vanishes. However, if occurring in phase with the circadian rhythm this inhibitory effect of early SWS is quite effective and cannot be overridden even by stimulation of the HPA system with a combined application of CRH and vasopressin (Bierwolf et al., 1997).

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In sum, HPA activity is subject to a circadian influence, with nadir values during the early night and peak activity during the early morning hours. Nocturnal sleep enhances this temporal pattern. Early sleep and, particularly, SWS suppresses HPA secretory activity whereas late sleep has an overall activating influence on HPA-system which, however, is not mediated by REM sleep. 2.1.2. The somatotropic system GH levels show a pattern reciprocal to that of HPA activity, reaching a maximum during early SWS which coincides with nadir plasma concentrations of cortisol (Takahashi et al., 1968). Minimum levels are observed during late sleep. Contrary to the HPA system, secretory activity of the somatotropic system displays no clear circadian rhythm and also shows remarkable differences between males and females. Whereas in men 70% of the total amount of GH secreted in a 24-h period is released during the first half of night-time sleep, in women, secretory patterns appear to be more variable, with GH pulses more frequently occurring also spontaneously during daytime before sleep and during the late half of the night (Quabbe et al., 1966; Antonijevic et al., 1999). The reason for this sexual dimorphism is not known at present. Nevertheless, as shown for men, the secretory activity of the GHRH–GH system is linked closely to the onset of sleep (Born et al., 1988). In this study, delayed sleep onset (by 3 h) resulted in a parallel delay of the nocturnal rise in GH plasma concentrations. To investigate the dependence of GH secretion on SWS, in a further condition the men were selectively deprived of SWS during the early part of the night by gently arousing them at the occurrence of first signs of SWS without awakening them. The absence of SWS did not influence the nocturnal peak in plasma GH concentration which remained time-locked to sleep onset and did not significantly decrease in amplitude. Another study expanded these observations to daytime sleep, examining two groups of subjects who, after they had stayed awake the previous night, were allowed to sleep for 8 h either after 11.00 am or 3.00 pm. (Pietrowsky et al., 1994). Regardless of the time of sleep, the rise in GH secretion was always closely linked to sleep onset showing a maximum within about 1 h after sleep onset. Corroborative evidence for the strong dependence of GH release on sleep stems from studies employing the constant routine protocol. In periods of this protocol where sleep is absent, GH secretion is largely reduced and a distinct GH peak near habitual bedtime is no longer observed (Czeisler et al., 1999). The striking temporal coincidence of the rise of GH concentrations and the first periods of SWS led to further investigations indicating that the amount of GH released is proportional to the amount of SWS (Van Cauter et al., 2000a). Also, GHRH exerts a promoting influence on SWS which is, however, independent of its effect on GH release. A commonly accepted view is that GHRH – although originating from different hypothalamic structures – is initiating both GH secretion as well as SWS during the early part of sleep (Ehlers et al., 1986; Obal et al., 1992; Spa¨th-Schwalbe et al., 1995; Zhang et al., 1996; Toppila et al., 1997). However, GH secretion as well as SWS do not solely depend on GHRH, and are each under the control of separate factors. Thus, GH secretion is inhibited by somatostatin (Mu¨ller et al., 1999) and strongly stimulated by ghrelin

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(Kojima et al., 1999), a gut hormone recently discovered as an endogenous ligand of the growth hormone secretagogue receptor. An interaction between sleep and secretion of somatostatin and ghrelin has been suggested, although this remains to be further clarified in humans (Steiger et al., 1992; Weikel et al., 2003; Dzaja et al., 2004). In sum, somatotropic activity is linked to sleep onset showing a maximum during the first epochs of SWS. It is not clearly influenced by circadian mechanisms. The GHRH activity is probably a stimulus for both SWS and GH release coinciding during the early part of nocturnal sleep. 2.2. Vasopressin (VP) Vasopressin is produced in the nucleus supraopticus and nucleus paraventricularis of the hypothalamus. Both nuclei project to the posterior pituitary, i.e., the neurohypophysis, where VP is stored till release. Another source of VP is the nucleus suprachiasmaticus of the hypothalamus which is the structure representing the brain’s major circadian oscillator (Klein et al., 1991; Moore et al., 2002). VP plays an important role in the regulation of fluid homeostasis and blood pressure. It is released from the posterior pituitary following osmotic stimuli and after the stimulation of volume receptors in the systemic circulation. Also, VP is known to act in addition as a potent stimulus of pituitary–adrenal activity. Naturally, it acts synergistically with CRH to regulate the response to various stressors (Spa¨th-Schwalbe et al., 1987; Sugimoto et al., 1994). During sleep, VP plasma concentrations are elevated with peak concentrations during the early part of the night (Forsling, 1993). This temporal pattern seems to be linked to the nocturnal rise of melatonin (Forsling, 2000). An association of VP secretion specifically to sleep stages has not been thoroughly examined although in one study such relationship was not found (Rubin et al., 1978). Based on the high proportion of VP reactive neurons in the nucleus suprachiasmaticus (Moore et al., 2002), a role of VP in circadian regulation has been proposed. This view has been corroborated by findings of a marked 24-h cycle in the VP-producing activity of neurons in human nucleus suprachiasmaticus (Hofman and Swaab, 1994; Hofman, 2003). In combination with the lack of evidence for a sleep stage associated modulation of VP release, the presence of large numbers of VP-expressing neurons in the nucleus suprachiasmaticus suggest that potential interactions of VP with sleep arise from its role in the circadian regulation of the sleep–wake cycle. 2.3. Prolactin, melatonin, and other hormones For the secretion of various other hormones, rhythms have been identified that appear to be linked to sleep, sleep stages, as well as to circadian oscillations. For example, the secretion of prolactin is enhanced during sleep and appears to be secreted in particular during the early periods of SWS (Haus et al., 1980; Follenius et al., 1988; Spiegel et al., 1995). During REM sleep, prolactin secretion is inhibited. Plasma concentrations of thyroid stimulating hormone display a circadian

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variation with a peak in the evening before nocturnal sleep exerting an inhibitory influence on the release of this hormone (Brabant et al., 1990; Goichot et al., 1992; Allan and Czeisler, 1994). A hormone that has attracted much interest in sleep research is melatonin, a product of the pineal gland. Diurnal melatonin plasma concentrations are low and secretion of the hormone can be totally inhibited by light. With the onset of darkness, melatonin levels rise sharply to reach a peak in the middle of the night, thus representing an excellent indicator of the circadian clock. Sleep per se does not substantially change melatonin secretion. However, melatonin has been consistently found to facilitate sleep, thus reflecting the drive of circadian rhythm on sleep propensity. Probably this effect is mediated by an influence on sleep inducing thermoregulatory mechanisms (Cajochen et al., 2003). Further hormones for which nonREM-REM sleep and sleep-dependent rhythms of secretion have been described, are luteinizing hormone (Fehm et al., 1991), oxytocin (Forsling, 2000), renin (Brandenberger et al., 1998), and aldosterone (Charloux et al., 1999; see Czeisler and Klerman, 1999; Steiger, 2003; Touitou and Haus, 2000 for reviews). Also, there are hormones, such as atrial natriuretic peptide, the secretion of which does not follow a clear nycthemeral pattern (Follenius et al., 1992). 3. Regulation of sleep-related immune function in young humans Many of the endocrine signals discussed above exert distinct influences on immune functions. Accordingly, the sleep specific regulation of endocrine activity goes along with a specific regulation of immune functions during sleep. The characteristics of immune regulation specific to sleep have been the object of a growing number of studies in humans (Moldofsky, 1995; Born, 1998; Sothern and Roitmann-Johnson, 2001; Irwin, 2002; Marshall and Born, 2002). Most of these studies examined variations in immune functions during undisturbed sleep or after deprivation of sleep. To describe various aspects of the acute innate and adaptive immune function in these human studies white blood cell differential counts, cytokine activity, proliferative capabilities of lymphocyte, and antibody responses were measured. The principal effector cells of innate immunity are mononuclear phagocytic cells (monocytes, macrophages), polymorphonuclear neutrophils, dendritic cells and natural killer (NK) cells. Some of the cells of innate immunity, notably macrophages, after infection secrete cytokines that produce inflammation. These so called proinflammatory cytokines include interleukin-1 (IL-1 ), tumor necrose factor- (TNF-) and IL-6. Development of an adaptive immune response relies on an interplay of T and B lymphocytes mainly with antigen presenting macrophages and dendritic cells. The adaptive immune response leads eventually to the differentiation of antigen specific effector and memory T and B cells, the latter producing antigen specific antibodies. The T cell derived cytokine IL-2 plays a key role in the formation of an adaptive immune response mainly by stimulating proliferation and differentiation of T cells. Overall, the presently available data in humans point to an enhancing effect of sleep specifically on aspects of adaptive immunity, while acute innate immune functions appear to be less affected

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or even diminished by regular sleep. Some evidence supports the notion that sleep may play a facilitating role in establishing a primary adaptive immune response to an antigen.

3.1. Undisturbed sleep Undisturbed nocturnal sleep, embedded in a regular sleep–wake schedule, is associated with most prominent variations in the numbers of circulating white blood cells. Numbers of granulocytes, monocytes as well as the major lymphocyte subsets, including T-helper cells (CD4þ), cytotoxic T cells (CD8þ), activated T cells (HLA-DRþ) and B cells (CD19 þ), all appear to reach a maximum in the evening hours and to decline most of the night-time in sleep to reach a minimum in the morning hours (Ritchie et al., 1983; Miyawaki et al., 1984; Haus, 1992; Palm et al., 1996; Born et al., 1997b; Haus and Smolensky, 1999). In contrast, NK cell counts as well as the cytotoxic activity of these cells reach a minimum during the first part of nocturnal sleep, and thereafter increase till the afternoon hours. While this pattern points to a differential regulation of cell counts within the different leukocyte subsets, their physiological meaning remains obscure. A decrease in subset counts could reflect increased migration of respective cells into extravascular and lymphoid tissues, but could likewise be due to a margination of the cells sticking to the walls of blood vessels or to an accumulation in the spleen. Nocturnal sleep appears to be also accompanied by specific changes in cytokine activity although overall results are less consistent. This may in part be due to the fact that, with the exception of IL-6, most cytokines of interest do not have a hormone-like function. Thus, under normal non-pathological conditions the endogenous levels of these cytokines in blood are close to the lower detection limit of most assays. With this background, rather than determining cytokine levels in serum some more recent studies measured the production of cytokines after stimulating respective blood cells in vitro with mitogens, and with this approach appeared to reveal more consistent changes in sleep-dependent cytokine activity. Lipopolysaccharides (LPS) were used in most of these studies as mitogen stimulant for cytokines released from monocytes and macrophages (IL-1 , TNF-), whereas phytohemagglutinin and concavalin A were used for stimulating release of T cell cytokines, like IL-2 and interferon- (IFN- ). Several reports suggested that the production of IL-1 and TNF- during undisturbed nocturnal sleep is most of the time decreasing (Zabel et al., 1990, 1993; Hohagen et al., 1993; Petrovsky and Harrison, 1998; Petrovsky et al., 1998). However, these findings were based on absolute cytokine production determined for the sampled blood. When the production of IL-1 and TNF- was put into relationship with the respective numbers of monocytes, the main cellular source of this cytokine in the blood samples, the sleep-related temporal dynamics in cytokine activity disappeared (Born et al., 1997b). This suggests that the sleep-related variations in IL-1 and TNF- do not primarily reflect changes in cytokine

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production per se, but rather a decrease in the number of circulating cells producing these cytokines. In contrast with IL-1 and TNF-, concentrations of IL-6 in blood are much higher, and this cytokine also acts as an important stimulus of pituitary– adrenal secretory activity (Spa¨th-Schwalbe et al., 1996, 1998). However, reports vary largely regarding a possible association of variations in IL-6 concentrations with sleep. While some studies failed to find any systematic changes in IL-6 concentrations across the 24-h cycle (Born et al., 1997b; Lissoni et al., 1998), findings from others suggest significant maxima at different times of the day (Gudewill et al., 1992; Zabel et al., 1993; Bauer et al., 1994; Sothern et al., 1995; Vgontzas et al., 1999; Redwine et al., 2000). This divergence reflects in part a methodological problem. The IL-6 measurements obtained by frequent blood sampling using an indwelling venous catheter over extended time periods have been shown to produce spurious results, most likely due to local proinflammatory activity resulting from mechanical irritation of venous walls by the catheter (Haack et al., 2002). Distinct increases during nocturnal sleep have been observed for the production of the T cell derived cytokine IL-2 (Born et al., 1997b; Lissoni et al., 1998). The T-cellular production of IFN- seemed likewise to be enhanced during nighttime sleep (Hohagen et al., 1993; Petrovsky et al., 1994, 1998; Petrovsky and Harrison, 1998). The increase in production of these T cell cytokines in these studies started already before the sleep period and are independent of changes in the number of circulating T cells. Petrovsky and Harrison (1997) examined 24-h variations in the ratio of IFN- to IL-10 production as an indicator of the balance between T helper 1/T helper 2 (Th1/Th2) cytokine activity, considered an essential determinant for the selection of the effector mechanisms of immune defense. The Th1 cells releasing mainly IFN- , aside from other cytokines including IL-2, become activated in response to intracellular viral and bacterial challenges and support various cellular (type 1) responses, including macrophage activation and antigen presentation. In contrast, the cytokines characteristic of Th2 immunity, such as IL-4, IL-5, and IL-10, tend to drive humoral (type 2) defense via stimulating mast cells, eosinophils, and B cells against extracellular pathogens. Predominance of type 2 cytokines, as observed for example in aged humans, has been associated with an inferior response to vaccination (Ginaldi et al., 1999a). The work of Petrovsky and Harrison (1997, 1998) suggests that nocturnal sleep favors a shift towards Th1 (predominance of IFN- ) mediated immune defense, peaking around 03:00 h. 3.2. Deprivation of sleep While changes in immune functions observed in conditions of undisturbed night-time sleep have apparent clinical relevance, their origin is ambiguous, since they can reflect an influence of a circadian oscillator rather than of sleep. To dissociate influences of sleep from those of circadian rhythm, typically effects of nocturnal sleep deprivation are compared with those of undisturbed nocturnal sleep.

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Sleep deprivation, especially if extended for more than one night represents a stressful experience that via activation of the major stress hormonal systems can per se influence immune functions. However, in humans, when staying awake for a single night voluntarily such side effects appear to be limited. In fact, assessment in humans indicates that plasma levels of cortisol and catecholamines during deprivation of nocturnal sleep on a single night, although significantly enhanced in comparison with sleep, do not reach the levels seen during daytime wakefulness or stress (e.g., Dodt et al., 1994a; Lange et al., 2003). Overall data from studies employing total or partial deprivation of sleep in a single night confirm that sleep per se enhances signs of adaptive immunity. For some parameters, the effect of sleep appears to add synergistically to a circadian influence. Thus, compared with a night awake or partial sleep deprivation, regular nocturnal sleep was consistently found to induce reductions in the number of granulocytes, monocytes, and the major lymphocyte subsets, but to increase NK cell counts (McClintick et al., 1994; Irwin et al., 1996; Born et al., 1997b). In parallel, production of T cell derived IL-2 has been demonstrated to be enhanced during regular sleep as compared to nocturnal wake conditions (Uthgenannt et al., 1995; Irwin et al., 1996). Also, nocturnal sleep was shown to induce a shift in the Th1/Th2 cytokine balance towards increased Th1 activity, as indicated by an increased ratio of IFN- /IL-4 producing T helper cells. However, the Th1 shift was only of moderate size and replaced by Th2 dominance during late sleep (Dimitrov et al., 2004a). Moreover, recent studies provided the first evidence for a facilitating effect of sleep on a primary adaptive immune response to vaccination (Spiegel et al., 2002; Lange et al., 2003). In the latter study healthy young humans either regularly slept or stayed awake on the night following primary vaccination with inactivated hepatitis A virus (at 9.00 am). Hepatitis A virus antibody titers measured 28 days after vaccination, a time when antibody titers have reached a plateau, were nearly two-fold higher in the subjects who had regular sleep following vaccination, than in the subjects who stayed awake on this first night. Proinflammatory cytokines of acute innate immunity, like IL-1 and TNF- showed sleep associated decreases in comparisons with conditions of sleep deprivation in some studies, although this again could reflect mainly a sleep-related decrease in the number of monocytes as a main source for these cytokines (Uthgenannt et al., 1995; Born et al., 1997b). In combination, results speak for an enhancing effect of sleep on processes of adaptive immunity establishing antigen-specific defense, whereas acute innate responses are less influenced by sleep or even superior during times of continued waking than during sleep. Indeed, periods of sleep deprivation extended over 3–4 days have been found to be associated not only with distinctly increased counts of neutrophils and monocytes as well as NK cell activity but also with increased plasma IL-6 concentration (Dinges et al., 1994; Shearer et al., 2001). Lymphocyte counts decreased under such conditions. Together this picture speaks for a stress-like effect of extended periods of sleep deprivation, enhancing in particular signs of non-specific phagocyte-related immunity (Boyum et al., 1996).

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3.3. Cytokine effects on sleep Observations of increased tiredness that can accompany acute infection have stimulated the hypothesis that some cytokines – especially those involved in acute innate immunity – act as signals to the brain to promote sleep. In animals, this view was elaborated by the group of Krueger (Krueger et al., 1999, 2003) who showed that proinflammatory cytokines such as IL-1 and TNF- stimulate two major cascades of reactions that promote SWS via activation of GHRH and via activation of nuclear factor-B (NF-B) followed by induction of prostaglandin 2 or IL-2, respectively. In humans, sleep promoting effects of proinflammatory cytokines are overall less well established. The group of Pollma¨cher (Pollma¨cher et al., 1993, 1995; Korth et al., 1996; Mullington et al., 2000) administered healthy humans Salmonella abortus endotoxin inducing acute increases in plasma concentrations of TNF-, IL-6, GH, ACTH, and cortisol. After doses of 0.8 and 0.4 ng/kg body weight of endotoxin, there was a significant increase in time spent in sleep stage 2, whereas SWS remained unaffected. However, when an even lower dose of 0.2 ng/ kg body weight of endotoxin was administered which unlike the higher doses did not induce fever or cortisol release, time spent in SWS was acutely enhanced. On the other hand, endotoxin at higher doses decreased time in REM sleep. This effect is probably due to the increased release of cortisol known to acutely suppress REM sleep (Born et al., 1989). Two studies investigated changes in sleep in healthy humans after subcutaneous administration of low doses of IL-6 and interferon- (IFN-) representing key mediators of acute innate immunity to bacterial and viral infection, respectively (Spa¨th-Schwalbe et al., 1998, 2000). Both cytokines acutely suppressed SWS, which dominates the early part of nocturnal sleep. Following IL-6, the acute suppression was followed by enhanced rebound of SWS during the latter part of the night, suggesting that via secondary mechanisms IL-6 might have delayed the enhancing effects on SWS. Interestingly, the suppression of SWS following both cytokines was associated with substantially increased feelings of tiredness measured before sleep, a pattern observed similarly in many depressed patients who complain of fatigue but simultaneously show reduced SWS (Born and Spa¨th-Schwalbe, 1999). Indirect evidence that proinflammatory cytokines such as IL-1 and TNF- exert enhancing influences on SWS derives from a study by Schuld et al. (1999) on the effects of granulocyte-colony stimulating factor (G-CSF). The G-CSF administered subcutaneously before sleep reduced SWS within the first 2 h of the sleep period. The decrease occurred in parallel to steep increases in the plasma levels of IL-1 receptor antagonist (IL-1ra) and soluble TNF- receptors (p55, p75) known to antagonize effects of IL-1 and TNF-, respectively. Moreover, an increase in TNF- during the late night after G-CSF was paralleled by an increase in SWS. The T cell cytokine IL-2 proved ineffective in modulating sleep after administration of low doses in humans (Lange et al., 2002). Overall these data from human studies suggest that proinflammatory cytokines of acute innate immunity at concentrations inducing fever acutely suppress SWS and enhance feelings of tiredness. However, very slight increases in plasma

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concentration of these cytokines – as they may occur as part of non-pathological fluctuations or follow acute innate responses – could support the expression of sleep and SWS.

4. Sleep and endocrine regulation in the aged 4.1. Sleep-endocrine regulation of the HPA and the somatotropic system Disturbed sleep is a common complaint in the elderly. Assessment in the sleep laboratory reveals that the elderly at night, typically display increased time in bed, a fragmentation of sleep by frequent arousals, and increased time spent awake and in stage 1 sleep after sleep onset. Also, a reduction in total sleep time, SWS and – in advanced age – in REM sleep is observed (Prinz et al., 1990). Furthermore, SWS in the elderly is characterized by a reduced EEG power (Ehlers and Kupfer, 1989). However, subjective complaints of sleep loss do not necessarily predict sleep laboratory results, although correlations between subjective and polysomnographic indicators of sleep quality appear to be higher in aged than in young subjects (Carskadon et al., 1976; Roehrs et al., 1983; Mendelson et al., 1986). Aging is also associated with distinct alterations of the neuroendocrine pattern of sleep, which appear to be even more pronounced than those of central nervous sleep architecture (Kern et al., 1996; Deuschle et al., 1997; Van Cauter et al., 2000b; Steiger, 2003). The most prominent feature of these alterations pertains to the regulation of the HPA and the somatotropic systems (Fig. 2). In parallel with the well-known and distinct decrease in SWS with increasing age, a gradual and highly significant increase in cortisol secretion in the course of aging can be observed which is particularly consistent around the time of nadir concentrations during early sleep. This basal hypercortisolism indicates a weakening of inhibitory control over HPA activity during early sleep. Concomitantly, the GH peak amplitude during early sleep distinctly declines with age (Kern et al., 1996). These hallmarks of the age-related decrease in endocrine function are of considerable clinical relevance since they contribute essentially to the morbidity in elderly people. Disorders common in the aged which are associated with a more or less pronounced hypercortisolism are obesity, the metabolic syndrome, depression, and memory loss (Seeman and Robbins, 1994; Lupien et al., 1999; Sapolsky, 1999; McEwen, 2000). Additionally, characteristic changes in the circadian timing system develop in the course of aging. The most obvious of these circadian changes are a phase advance of the sleep–wake cycle and an attenuation of the amplitude of circadian rhythms. The disturbances are linked to obvious functional changes in brain structures like the nucleus suprachiasmaticus representing the circadian clock. For example, the number and circadian oscillation of VP-reactive neurons in this nucleus have been found to deteriorate with aging which results in a dampening of the circadian rhythm and probably also of circannual rhythms (Hofman et al., 1994; Swaab, 1995). Also, factors arising from age-related behavioral changes in environmental adaptation, such as a decreased exposure to light and social clues, as well as general physical and

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10 5 0 15 25 35 45 55 65 75 85 95 age (years) SWS (min) 35 30 r = −0.56 25 p< 0.01 20 15 10 5 0 15 25 35 45 55 65 75 85 95 age (years)

140 120 100 80 60 40 r = 0.79 p< 0.001 20 0 15 25 35 45 55 65 75 85 95 age (years) REM (min) 35 r = −0.55 30 p< 0.01 25 20 15 10 5 0 15 25 35 45 55 65 75 85 95 age (years)

Fig. 2. Age-related impairment in the sleep associated regulation of HPA and somatotropic secretory activity. The GH peak amplitude during early sleep distinctly declines with increasing age (top left). Concomitantly, cortisol nadir values steadily increase during early sleep with increasing age, indicating a disinhibiting influence of age on basal HPA secretory activity during early sleep (top right). SWS and REM sleep (bottom panels) show the well-known and distinct decrease in SWS and REM sleep with increasing age. (From Kern et al., 1996).

mental impairments can adversely affect the circadian timing system thereby aggravating the circadian maladaptation in the aged. The mechanisms accounting for the age-related sleep-endocrine changes are presently unclear. A promising approach to this issue probably relies on a detailed analysis of the mechanisms mediating the inhibition of HPA activity in conjunction with the increase in somatotropic activity during early sleep. In addition, contributions of impaired circadian control are to be considered. It has been proposed, that in combination the phase advance and reduced amplitude of circadian rhythms in aged lead to a desynchronization of major endogenous circadian rhythms, so that rhythms like those of cortisol, melatonin, and temperature are not properly coupled to the sleep–wake cycle. This desynchronization may indeed account for some of the sleep disturbances in the aged (Czeisler et al., 1992; Touitou and Haus, 2000; Pandi-Perumal et al., 2002). 4.1.1. Hippocampal control of HPA activity Hormonal secretory activity of the HPA axis is controlled via supra-ordinate brain structures. Most important in this context is the hippocampus, a structure of the limbic system, that is believed to regulate the HPA system to achieve homeostatic

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balance and adaptation to stress. Hippocampal influence affects both circadian rhythm and stress regulation of pituitary–adrenal activity. But the hippocampus is also the target of feedback signals from the periphery within the HPA system and mediates inhibition of the system by negative feedback (Jacobson and Sapolsky, 1991). Thus, the hippocampus is responsible for timely and adequate termination of the stress response during wakefulness, while during sleep, it mediates tonic inhibition of pituitary–adrenal activity (De Kloet et al., 1998). To understand disturbances of HPA activity in the aged, the dysregulation of feedback signals in the course of aging is of interest, especially of those signals regulating the basal activity of this system during sleep. At a cellular basis glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) participate in the regulation of feedback. The GR are widely distributed in the brain, whereas MR are expressed at a high density selectively in the hippocampus and some associated regions. These receptors play a most important role in the tonic control of HPA activity during sleep, but to a lesser degree are also involved in the regulation of the HPA system during wakefulness (Deuschle et al., 1998; Young et al., 1998). Binding affinity of cortisol to MR is higher than to GR. Accordingly, the relative occupation of the receptors by cortisol depends critically on the plasma concentrations of the steroid. The balance between MR and GR activation in turn determines the effect of the hippocampus on the HPA system (De Kloet et al., 1998). In humans, at the time of the cortisol nadir during early sleep there is little occupation of the classical GR in the brain while MR in the hippocampus remain occupied by more than 80%. With the rise in cortisol during late sleep, in addition, GR become increasingly occupied. Blocking of MR by (pre-) treating healthy humans with canrenoate almost completely abolishes sleep-dependent suppression of pituitary–adrenal activity during the early night and also reduces SWS substantially, a pattern resembling that of early sleep in the aged (Born et al., 1997a). Moreover, experiments showed that increased activation of MR after administration of lower doses of cortisol increased the time in SWS (Born et al., 1991; Friess et al., 1994, 2004). On the other hand, a reduction in SWS is observed following administration of GR agonists like dexamethasone or when cortisol concentrations are very high. Also, activation of GR by dexamethasone decreases REM sleep in the late part of the night. A similar REM sleep reduction can be induced by cortisol administration adding to the high endogenous cortisol levels during late nocturnal sleep (Born et al., 1991). Thus hypercortisolism in conjunction with reduced limbic MR expression could be a mechanism relevant for the age-associated decreases in both SWS and REM sleep. 4.1.2. Disturbance of hippocampal function during aging A commonly held view is that protective and adaptive effects of HPA hormones turn out to be damaging if their action prevails inadequately long. Hyperactivity of the HPA-system has been detected in a number of clinically relevant conditions – not only in patients with obesity, diabetes, and the metabolic syndrome exhibiting a predominant increase of abdominal fat, but also in patients with insomnia

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(Bjorntorp, 2001; Vgontzas et al., 2001; Rosmond, 2003) . In the case of aging, it has been hypothesized that repetitive stressful events during lifetime result in an elevation of steroid plasma concentrations due to an increasing impairment of feedback inhibition. Compelling evidence has been provided that elevated steroid levels affect brain function adversely with the hippocampus being the structure in the brain most susceptible to these effects (McEwen, 1999; Sousa et al., 2000). Following repeated stress, reduced excitability of hippocampal neurons, suppression of neurogenesis in the dentate gyrus and atrophy of the dendrites of the CA 3 region of the hippocampus have been reported (Pavlides et al., 1995; Gould et al., 1997; De Kloet et al., 1998; McEwen, 1999). As a consequence, the loss of MR leads in the hippocampus to a weakening of the tonic basal inhibition of the HPA axis (Sapolsky et al., 1986). Additionally, overactivity of the HPA system negatively interferes with other neuronal functions in the hippocampus. Hippocampal atrophy in the elderly is associated with mild cognitive impairment (Golomb et al., 1994; Convit et al., 1995). Furthermore, enhanced cortisol plasma concentrations seem to be correlated with impaired memory in parallel with reduced hippocampal volume in the elderly humans (Lupien et al., 1998). Apart from aging, hippocampal nerve atrophy has also been found in dementia, depressive illness, and Cushings disease (De Leon et al., 1993; Sheline et al., 1996; Starkman et al., 1999). Overall, the age-related dysfunction of the hippocampus primarily via loss of MR expressing neurons gives rise to the overactivity of the pituitary–adrenal system seen most consistently during the basal nadir activity of early sleep. The release of tonic inhibition manifests in an augmented hypothalamic release and action of CRH at the pituitary level. The CRH itself has a disturbing effect on sleep. In humans, the intravenous administration of four repetitive boluses of 50 mg of CRH during the early part of nocturnal sleep significantly reduced the amount of SWS and REM sleep (Holsboer et al., 1988). Furthermore, there is evidence suggesting a role of CRH in the development of depression which is also often associated with age-like disturbances of sleep, i.e., a reduction in sleep continuity and amounts of SWS (Benca et al., 1992). In light of the similarity of the sleep disturbances in the elderly and depressed patients to those resulting from administration of CRH, it has been proposed that an increased release of CRH is the principal neuroendocrine factor mediating the changes in sleep architecture in aging (Steiger, 2002). 4.1.3. Corticotropin release-inhibiting factor Effective inhibition of HPA secretory activity during early nocturnal sleep is essential for normal neuroendocrine sleep regulation and implies an active mechanism of control by limbic-hippocampal structures (Bierwolf et al., 1997; Born and Fehm, 1998). This inhibition can be established via MR mediated neural inhibition of the CRH releasing cells, but also by stimulating the hypothalamic release of a corticotropin release inhibiting factor (CRIF), that could serve to counteract the stimulating influence of CRH on pituitary release of ACTH (Engler et al., 1999). Up to now, a substance that selectively acts as CRIF has not been identified. However, there are some candidates which inhibit HPA secretory activity in humans and might exert this action naturally during early nocturnal sleep (Engler

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et al., 1999; Jessop, 1999). Among them is atrial natriuretic peptide (ANP). Bierwolf et al. (1998) showed in humans, that nocturnal ACTH and cortisol responses to intravenous injections of a combination of CRH and VP were distinctly diminished when the subjects were simultaneously infused with a low dose of ANP over a period of 90 min, starting 15 min before CRH/VP injection. Plasma concentrations of ANP are known to increase with age (e.g., Kato et al., 2002). However, whether ANP or one of the related brain peptides functions as an inhibitor of HPA activity under natural conditions during early humans sleep is unknown. In contrast to ANP, GHRH is a substance whose inhibiting influence on pituitary–adrenal activity under natural conditions during early sleep is well documented. The somatotropic axis exhibits distinctly enhanced activity exactly at the time of the nadir of HPA activity. Repetitive intravenous injections of GHRH during early sleep reduced plasma cortisol concentrations during sleep (Steiger et al., 1992). This finding was confirmed using an intranasal route of GHRH administration known to enable a direct access of the peptide to the cerebrospinal fluid compartment (Perras et al., 1999a, Born et al., 2002). Notably, in contrast to the intravenous injection, intranasal GHRH simultaneously reduced secretion of GH during early sleep supporting the view that the peptide acted mainly at the hypothalamic level to induce inhibition of GHRH release. This hypothalamic action obviously overrides stimulating effects on pituitary GH release resulting from GHRH partly absorbed into the bloodstream. Together, the data indicate that GHRH suppresses HPA activity probably mainly at the hypothalamic level. The data lend themselves to suggest that decline in GHRH activity in the course of aging significantly contributes to the tonic overactivity of the HPA system during sleep in elderly. Another factor exerting inhibitory actions on HPA secretory activity during nocturnal sleep is melatonin the secretion of which depends on darkness (Leproult et al., 2001). Evidence for an inhibiting effect of melatonin on cortisol release during early sleep has been provided by a recent study in totally blind persons (Fischer et al., 2003). Aside from disturbed sleep patterns the blind in these experiments showed temporal patterns of ACTH and cortisol secretion which did not appear to be coupled to the sleep process. Specifically, they did not show minimum and maximum secretion of these hormones during early and late sleep, respectively, but the average concentration of these hormones did not at all differ between early and late halves of nocturnal sleep. The administration of melatonin before sleep normalized this pattern leading to distinctly suppressed levels of ACTH/cortisol during early sleep and increased levels during late sleep. The effects of melatonin were accompanied by a slight enhancement of SWS. The gradual decrease in nocturnal melatonin secretion occurring in the course of aging (e.g., Toutiou, 1995; Skene and Swaab, 2003) could thus well cause a desynchronisation between the sleep–wake rhythm and pituitary–adrenal activity during sleep in the aged, expressing in relatively enhanced cortisol levels during early sleep. Of note, since pineal melatonin secretion is triggered by darkness rather than sleep, the decrease in melatonin represents a contribution of a circadian impairment to the disturbed neuroendocrine pattern of sleep in the aged.

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There are several further candidate substances that may act as CRIF, such as preproTRH158–183 whose analog in the rat has been shown to inhibit stimulated cortisol release (Redei et al., 1995, 1998; McGivern et al., 1997), -endorphin and substance P (Jessop, 1999). However, the central nervous effects of these substances on HPA activity in humans are not clear, as well as their role during sleep (Lieb et al., 2002). Overall the available data suggest that the inhibition of HPA activity during early sleep involves multiple mechanisms acting not only at the pituitary but also at the hypothalamic (like GHRH, melatonin) level of this axis. Such signals mediate a supra-ordinate feedback control exerted by the hippocampus as well as a circadian control probably originating from the nucleus suprachiasmaticus. Inefficient inhibition of pituitary–adrenal activity during sleep in the aged could thus reflect a decline in production and release of substances acting as CRIFs at the hypothalamic and pituitary level in this system. Impaired release of these factors would add to the diminished hippocampal negative feedback sensitivity to cortisol in the aged, and thereby further weaken the tonic inhibitory control of ACTH/cortisol release. 4.1.4. The somatotropic system in the elderly For the somatotropic system an age associated deterioration in function is well known (Corpas et al., 1993, Rusell-Aulett et al., 1999). The amount of sleep associated release as well as stimulated release of GH is reduced. Consequently, insulin-like growth factor (IGF)-1 levels are also diminished. Several mechanisms may account for this impairment. The release of peptide in GHRH producing neurons is diminished in relation to age with a marked decrease of GH secretory pulses (De Gennaro Colonna et al., 1989). Also, the GH response to challenge of the somatotropic system by GH secretagogues is reduced (Shibasaki et al., 1984; Iovino et al., 1989; Deslauriers et al., 1991). Increased production of somatostatin probably adds to the age-related impairment of the GHRH-GH system (Cocchi et al., 1986). Whether ghrelin, a major stimulant of GH secretion, is also involved in the age associated decrease in GH release, is presently not clear. The somatotropic dysfunction in the aged is closely linked to the sleep disturbances. In particular, the amount of SWS declines in the course of aging, and is strongly correlated to the reduction of GH secretory activity (Prinz et al., 1995; Kern et al., 1996, Van Cauter et al., 2000a). Both reduced amounts of SWS and secreted GH reflect a decrease in GHRH secretory activity. This probably has several reasons, including decreased functioning of GHRH expressing neurons, increased release of somatostatin inhibiting GHRH release, and perhaps also a reduced sensitivity to GH secretagogues such as ghrelin. In the light of the unique constellation during the early SWS-rich part of sleep of stimulated somatotropic activity and a concomitantly inhibited HPA system it has been proposed, that the age-related disturbance of the neuroendocrine regulation is a consequence of an altered balance between the activity of the two systems. Higher nocturnal cortisol concentrations with lower GH levels in the aged as compared to young subjects thus indicates a shift in this balance in favor of the

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HPA system. The view of a balance between the two systems is supported by a body of evidence indicating opposite effects of these systems on sleep as well as mutually inhibiting effects between the systems (Ehlers et al., 1986; Ehlers and Kupfer, 1987; Steiger, 2002). Not only does GHRH promote SWS but also suppresses pituitary–adrenal activity during early sleep. In contrast, overactivity of CRH aside from stimulating ACTH/cortisol release results in sleep suppression. Also, increased HPA activity exerts some inhibitory influence on somatotropic activity. In humans repeated intravenous administration of CRH in parallel with reductions in SWS and REM sleep significantly reduced the amount of GH secreted during sleep (Holsboer et al., 1988). 4.2. Vasopressin in the elderly In the aged, findings on blood concentrations of VP during night-time and sleep are inconsistent. Compared to young subjects, elevated, reduced, and unchanged levels of VP have been observed depending on sex and the presence of the nocturnal polyuria syndrome (O’Neill and McLean, 1992; Johnson et al., 1994; Nadal et al., 1994; Asplund, 1995; Forsling et al., 1998). Also VP concentrations in the elderly are not related to serum osmolality as in young subjects, although a decreased ability of the kidneys to concentrate urine has been described (Johnson et al., 1994; Forsling et al., 1998). However, VP plasma levels do not necessarily reflect changes in VP related to the circadian alterations in the aged, since it does not stem from the nucleus suprachiasmaticus. In fact, aging differentially affects vasopressinergic transmission in the brain. While the VP content of the nucleus supraopticus and paraventricularis is constant or even increased in the aged, the number and volume of VP-producing cells in the nucleus suprachiasmaticus is reduced (Swaab, 1995). The selective loss of vasopressinergic neurons in a brain structure known as the circadian pacemaker of the body playing a key role in the regulation of the sleep–wake cycle led to the assumption, that disturbances of sleep and sleep–wake regulation can be explained by a dysfunction of vasopressinergic signaling in the nucleus suprachiasmaticus (Czeisler et al., 1992). 4.3. Effects of hormone administration on sleep in the aged In view of the pronounced changes in neuroendocrine activity developing in the course of aging, in a small but increasing number of studies, hormones have been administered in order to test them for possible ameliorating influences on sleep in elderly. Two different strategies have been adopted in these studies: In most cases the exogenous administration of a substance (like GHRH) aimed at compensating directly for a presumed age-related decline in endogenous activity of the respective hormone. However, hormones (like cortisol) were also administered in a few cases to enhance negative feedback effects in order to reduce a presumed age-related overactivity of a certain hypothalamic factor.

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4.3.1. Hormones of the HPA system The administration of cortisol at lower doses in young humans increased SWS, reduced REM sleep and in some studies increased also GH plasma concentrations (Born et al., 1989; Friess et al., 1994, 2004). A decrease in REM sleep is also seen following infusion of ACTH, presumably mediated via ACTH-induced cortisol release. Blocking MR by administration of canrenoate induced a decrease in SWS in combination with elevated plasma cortisol concentration, while activation of GR after administration of dexamethasone reduced REM sleep (Fehm et al., 1986; Born et al., 1991, 1997a). This pattern was taken to suggest that SWS can be enhanced by increasing activation of MR whereas predominant GR activation results mainly in reduced REM sleep. On this background the group of Steiger (Bohlhalter et al., 1997) conducted a remarkable experiment in aged humans, in which they assessed the influence of repeated intravenous injections of cortisol on the neuroendocrine architecture of sleep. Thus, the exogenous cortisol was added to already enhanced endogenous cortisol concentration in the aged. Cortisol injections started at 5.00 pm with a dose of 1 mg/kg body weight and were repeated hourly until 6 am the next morning, but with a reduced dose of 0.3 mg/kg body weight. In a parallel study in young subjects (Friess et al., 1994), it was shown that cortisol distinctly increased SWS, decreased REM sleep, and strongly increased the secretion of GH. Note these effects represent an immediate feedback influence of cortisol and are not expected with long-term administration of cortisol known to be associated with restlessness and insomnia (e.g., Krieger and Glick, 1974). The increase in SWS might reflect increased MR activity while the decrease in REM sleep could stem from enhanced GR activation in this experiment. However, experiments in dogs provided hints that aging is accompanied by a selective decrease in MR capacity while numbers of GR in the pituitary even increased with age (Reul et al., 1991; Rothuizen et al., 1993). Bohlhalter et al. (1997) took these data to argue that a mediation of the cortisolinduced increase in SWS in the aged is unlikely to be mediated via MR activation. They propose that the effects of cortisol on SWS and GH secretion rather originate from immediate effects on the somatotropic axis, enhancing sensitivity to GHRH (e.g., Seifert et al., 1985) and possibly reducing in parallel the inhibiting influence of somatostatin. A strengthened feedback suppression of hypothalamic CRH probably adds to the effects, given that in young humans CRH appears to disturb sleep (Holsboer et al., 1988; Chang and Opp, 2001). Together these data support the view of a disturbed balance between activation of the HPA and somatotropic system characterizing sleep in the aged, which acutely can be effectively shifted towards increased somatotropic activity by enhancing the cortisol feedback signal to the brain (Ehlers et al., 1986; Holsboer et al., 1988).

4.3.2. Hormones of the somatotropic system In order to compensate for the obvious decline in somatotropic activity in the course of aging, primarily treatments with GHRH have been considered. This is partly due to the fact that trials examining the effects of GH administration in

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healthy young subjects as well as in different groups of patients with GH deficiency failed to reveal consistently positive effects on sleep (Mendelsohn et al., 1980; Wu and Thorpy, 1988; Kern et al., 1993). Also, GHRH is preferred since the GH deficit during sleep in aged is considered to be caused by reduced hypothalamic GHRH activity. In fact, in a number of studies intravenous administration of GHRH in healthy controls not only increased GH release but also improved sleep, resulting in consistent though moderate increase in the time spent in SWS (Steiger et al., 1992; Kerkhofs et al., 1993; Marshall et al., 1996, 1999). However, also negative results were reported (Kupfer et al., 1991). Notably, the improving effects of GHRH on sleep appeared to depend critically on the way of administering the substance. Steiger et al. (1992) used the repetitive intravenous administration of four boli of 50 mg GHRH each (total dose 200 mg of GHRH) and observed significant increases in SWS and GH concentrations while plasma cortisol concentrations during sleep were decreased. Marshall et al. (1996, 1999) observed essentially the same changes when using the same repetitive mode of intravenous GHRH administration. However, no or only minor changes in sleep were obtained when comparable doses of GHRH were administered as continuous infusion or in repeated boli of smaller size. From these and related results Marshall et al. (1999) concluded that the shortterm induction of very high GHRH concentration in plasma is the factor critical for producing central nervous effects on sleep. The GHRH does not easily pass the BBB. Extreme peak concentrations as reached after a bolus of 50 mg GHRH may represent conditions in which a sufficient amount of the substance can enter the brain compartment. Based on the successful trials in young subjects, the group of Steiger conducted two trails in the aged with GHRH, relying on the same mode of administering repeated intravenous boli as used in the studies in young humans. Guldner et al. (1997) investigated thirteen healthy elderly with a mean age of 69 years, and found that GHRH acutely reduced the time awake and increased REM latency. Also GH secretion was enhanced, although not consistently. However, there was neither an effect on SWS nor on plasma cortisol concentrations. Murck et al. (1997) explored the effects of a long-term treatment with GHRH in two aged subjects. The two elderly were treated on a first night with four intravenous boli (50 mg each). Then, treatment was continued such that they received another GHRH bolus of 100 mg at 9.00 a.m. every second day for the 12 following days. However, subsequent testing in the sleep laboratory did not reveal substantial changes. Sleep period time and time in SWS in the two elderly were even reduced as compared with the baseline nights before treatment. Also, there was no effect of GHRH on GH release. From these overall less promising results the authors concluded that the process of aging leads to a reduced efficacy of GHRH which cannot be compensated by administering the substance. A possible explanation for this is an increased activity of or sensitivity to somatostatin in the aged. Consistent with this view, Frieboes et al. (1997) showed that in the elderly, administration of somatostatin further impaired sleep mainly by reducing total sleep time and REM sleep. This response contrasted with those in young humans who did not show notable changes in sleep structure following administration of somatostatin.

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Another reason for the reduced efficacy of GHRH in these studies could be, that even with the administration of repeated boli in the elderly the amount of substance reaching the brain is not sufficient for inducing notable effects on sleep. Based on this rationale Perras et al. (1999a) performed a study in the young and the elderly using an intranasal administration of GHRH. This route of administration has been proven in human studies to provide direct access of neuropeptides to the cerebrospinal fluid compartment (Born et al., 2002). After intranasal administration of GHRH in the elderly before the night in the sleep laboratory substantially improved several sleep-endocrine markers of aging (Perras et al., 1999a). The time in SWS and also in REM sleep was enhanced, with these changes concentrating in the late night. Remarkably, cortisol nadir concentrations in the aged after intranasal GHRH were on average even lower than those in the young men after placebo. Peak concentrations of cortisol were reached later in the night suggesting a phase delay of circadian rhythm. However, as noted earlier, nocturnal GH concentrations were significantly reduced after GHRH in both young and aged indicating that intranasal GHRH activates a short-loop negative feedback inhibition at the hypothalamic level of this system. Also, increases in SWS and REM sleep were comparable for the young and aged subjects, indicating that GHRH does not specifically compensate for the age related deficits in sleep, although the brain’s sensitivity to GHRH appeared to be preserved in the elderly. 4.3.3. Vasopressin Vasopressin was among the first neuropeptides whose effects on brain functions were studied in detail in animals. From these studies an important role of VP for memory and learning was inferred, although in humans the effects of vasopressin administration on these functions appeared to be generally less consistent (Nebes et al., 1984; Van Ree et al., 1985; De Wied et al., 1989; Dodt et al., 1994b; Born et al., 1998c). The trials in humans also included aged subjects with and without memory deficits. Despite the well-known presence of VP in the nucleus suprachiasmaticus as a circadian regulator of the sleep–wake cycle, surprisingly few studies in animals looked at the effects of VP on sleep (Urban et al., 1978; Danguir, 1983; Kruisbrink et al., 1987; Arnauld et al., 1989; Brown et al., 1989). The results were interpreted in terms of increased arousal induced by acute administration of VP. Arousing influences on sleep were observed also following acute administration of VP in humans. In young subjects, VP consistently increased time spent in stage 2 sleep and awake regardless of whether administered intranasally or intravenously (Timsit-Berthier et al., 1982; Born et al., 1992). Intravenous VP administration also reduced REM sleep. Subjective sleep quality was not found to be changed in one study following intranasal administration of an analog of VP (DGAVP, Snel et al., 1987). The failure to find consistently improving effects on brain functions in the elderly after single or short-term administration of VP led to the assumption that more encouraging benefits result perhaps from a more prolonged treatment with the peptide. Perras et al. (1996) tested this assumption first in a pilot study in two healthy elderly persons. The focus of this study was on brain indicators of cognitive

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functions (event-related brain potentials), but sleep was also tested. The two elderly persons were treated with VP twice daily (20 IU) for a period of three months. An intranasal route of VP administration was used to assure direct brain access of the peptide (Born et al., 2002). Surprisingly, results indicated most pronounced changes in sleep rather than on neurocognitive functions. The time spent in SWS was increased by about 100% with this enhancement emerging after six weeks of treatment. Interestingly, this long-term effect was opposite to the arousing effect of VP on sleep seen acutely after administration of a single dose of the peptide, pointing to a different mechanism activated with prolonged VP treatment. These results prompted more elaborate investigations of long-term intranasal treatment with VP in the elderly (Perras et al., 1999b, 2003). In the first of these studies, 26 healthy elderly (14 women and 12 men >70 years) were tested, who did not complain of poor sleep but, at the sleep laboratory, showed the typical fragmentation of sleep and predominance of light sleep. After three placebo nights, one group of subjects continued to take a placebo while the other group was treated with VP according to the same protocol as used in the foregoing pilot study (2
20 IU per day, Perras et al., 1996). The treatments were administered each day in the morning and in the evening, for three months. Revaluation of sleep at the end of the treatment epoch confirmed a pronounced increase in SWS in the VP group averaging 20 min. Moreover, compared to the controls the VP treated elderly slept longer (for  45 min) and displayed increased REM sleep (10 min, Fig. 3). No cardiovascular side effects or fluid retention were observed. The improvement in polysomnographical sleep was not correlated with an improvement of sleep quality ratings. However, this was probably a consequence of the fact that the elderly selected for this trial perceived a good sleep quality already before the study. Considering this remarkable improvement of sleep after prolonged VP treatment in the elderly, a further study (Perras et al., 2003) aimed to explore whether the beneficial effect is accompanied by changes in the neuroendocrine pattern of sleep in the aged. In particular, pituitary–adrenal activity was of interest since VP is known to be a potent co-stimulator of the pituitary release of ACTH following acute administration (Spa¨th-Schwalbe et al., 1987). The 26 healthy elderly (mean age 72.9 years) of this study, with only mild sleep complaints were treated with placebo or intranasal VP for a period of 10 weeks, according to the same study protocol and dosage of daily treatment as in the two previous studies with subchronic VP. However, this time polysomnographical recordings in the beginning and end of the treatment period were complemented by repeated blood sampling during the nights. Again, the prolonged intranasal treatment with VP led to a profound increase in SWS averaging 21.5 min. The VP-induced increase in SWS was persistent and was also observed on a night following the last treatment, i.e., 24 h after the last intake of VP, excluding any contributions of immediate effects of the peptide. Notably, rather than increasing pituitary–adrenal activity, VP significantly decreased the cortisol nadir during early sleep on average by 0.5 mg/dl. Changes in GH concentrations were not significant. Again, no side effects regarding fluid balance or cardiovascular activity were observed. Overall, these results indicate a promoting

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Fig. 3. Sleep profiles from two selected subjects (70 and 76 years old) before (left panel) and after (right panel) daily intranasal treatment with vasopressin during a period of 3 months. Note, sleep time, time in SWS and in REM sleep are distinctly increased in both subjects. Lights were turned off at 11.00 pm (23.00 h). W, awake time; S1, stage 1 sleep; S2, stage 2 sleep; S3, stage 3 sleep; S4, stage 4 sleep; S3+S4, SWS. (From Perras et al., 1999b).

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effect on sleep of prolonged intranasal treatment with VP in the aged, accompanied by a beneficial rather than impairing influence on sleep-associated HPA activity. The experiments show that the improving influence of VP on sleep requires a prolonged period of treatment. While the arousing influence of VP seen after short-term administration of the peptide probably reflects acute changes in neurotransmitter systems involved in arousal regulation, the effects of long-term VP administration obviously originate from slower processes, possibly inducing some kind of plastic changes in the respective neuronal networks. In rats, prolonged treatment with VP increased the capacity of MR in the hippocampus (Veldhuis et al., 1982). This change would be expected to strengthen the inhibiting influence of the hippocampus on basal HPA secretory and, thus, could well explain the reduction in cortisol nadir values during sleep in elderly developing after prolonged VP treatment. Given that blocking of MR substantially reduced SWS in young humans (Born et al., 1991), increased central nervous MR capacity after prolonged VP treatment could also explain the profound increase in SWS in the elderly of the VP group. Alternatively, prolonged VP administration may compensate for the age-related reduction of VP in the nucleus suprachiasmaticus (Swaab, 1995), thus improving VP-dependent output of the circadian pacemaker. This explanation would implicate changes towards enhanced activity during daytime, which remains to be examined. 5. Immune function during sleep in the aged While a considerable number of studies in animals and humans have provided convergent evidence for mutual and specific interactions between sleep and immune functions, surprisingly few studies have directly addressed this relationship in the aged organism, and of these studies, a minority have been conducted in humans. The paucity of studies regarding this issue is in contrast with its obvious clinical relevance. Aging is not only characterized by a specific impairment of sleep but also there is a general consensus that immune system function declines with age (Miller et al., 1996; Ginaldi et al., 1999 a,b,c; Franceschi et al., 2000; Linton and Dorshkind, 2004). Infections such as pneumonia and influenza are among the leading causes of death in persons aged 65 and older. The two principal questions to be answered in this context are: (i) Are the changes in immune system function in elderly persons in part a consequence of the altered sleep? (ii) To what extent does the age-related decline in immune function contribute to some of the disturbances characterizing the architecture of sleep in the elderly? Both questions cannot be answered on the basis of available data, although overall the data suggest that the disturbed sleep has at least an aggravating influence on the age-related decline in immune function. 5.1. Immune system function in the aged Aging is associated with multiple changes of immunity that have been collectively termed ‘‘immunosenescence’’. Its most prominent feature is a general decline in the

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number of T cells, mainly of naive T cells, which is commonly linked to a progressive involution of the thymus (Murasko and Goonewardene, 1990; Ginaldi et al., 1999a). The decline of naive cells is apparent for the CD4 þ T helper cell subset and associated with relatively increased numbers of CD4 þ cells with memory phenotype coexpressing CD45RO (Sansoni et al., 1993; Rea et al., 1996; Rink and Seyfarth, 1997; Ginaldi et al., 2000). For CD8 þ cytotoxic T cells the decline appears to be less dramatic. Also, T cell responsiveness is decreased in the elderly. Proliferation to stimulation with different mitogens is reduced as well as the diversity of the T cell receptor repertoire for different antigens (e.g., Pisciotta et al., 1967; Lehtonen et al., 1990; Posnett et al., 1994; Schwab et al., 1997). There has been a number of reports indicating that the production of T cell derived cytokines like IL-2 and IFN- is decreased in elderly humans (Gillis et al., 1981; Nagel et al., 1989), although with regard to IL-2 this was not confirmed in all studies especially in those using whole blood stimulation techniques (Sindermann et al., 1993; Ahluwalia et al., 2001). A further prominent feature of T cell related immunosenescence is a shift in the Th1/Th2 balance towards predominant production of Th2 cytokines including IL-4 and IL-10 (Cakman et al., 1996; Shearer, 1997). The B cell numbers and antibody production are likewise distinctly decreased in the elderly. This, in combination with the marked deficits mainly regarding the naive CD4 þ subset of the T cell compartment can explain the widely reported clinical observation of a decline in the response to vaccination also, for example to influenza vaccine and hepatitis B vaccine (Remarque, 1999; Looney et al., 2001). However, this decline has not been universally confirmed, highlighting the possibility of intervening variables including sleep that could act to modulate this relationship (Carson et al., 2000). The T cell related deficits contrast with signs of enhanced innate immunity with aging. While the number of monocytes/macrophages appear to remain stable with age the production of monocyte/macrophage-related proinflammatory cytokines such as IL-1 , TNF-, and IL-6 has been consistently found to be enhanced (e.g., Fagiolo et al., 1993; Rink et al., 1998). Also, the number of circulating NK cells is increased with age, although their proliferative responses and cytotoxic activity are decreased (Facchini et al., 1987; Solana and Mariani, 2000). The finding of an increased number of circulating activated T cells (Sansoni et al., 1993; Hulstaert et al., 1994) may likewise fit the picture of an enhanced state of innate immune activation that may be compensatory for the decline in T cell related immune function. 5.2. Sleep-associated immune function in the aged The characteristics of immunosenescence in some aspects bear distinct similarities with the changes observed in young subjects following deprivation of sleep. In both states, marked changes towards diminished T cell mediated immune functioning appear to be paralleled overall by selected signs of increased innate immune activation. Notably, both immunosenescence and sleep deprivation are associated with reduced production of the T cell cytokines IL-2 and IFN- , and a shift of the

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Th1/Th2 balance towards increased Th2 cytokine activity (Nagel et al., 1989; Born et al., 1997b; Shearer, 1997; Dimitrov et al., 2004a). Moreover, both states have been found to impair the formation of a primary adaptive immune response to vaccines (Remarque, 1999; Looney et al., 2001; Lange et al., 2003). Regarding innate immune functions, sleep deprivation like aging leads to increased numbers of circulating NK cells but, a diminished NK cell activity when considered on a per cell basis (Irwin et al., 1994; Solana and Mariani, 2000). Blood counts of activated T cells (HLA-DR) have likewise been found to be increased after sleep deprivation and in the aged (Sansoni et al., 1993; Born et al., 1997b). Also, the production of proinflammatory cytokines IL-1 , TNF- and IL-6 has been found to be enhanced in the aged as well as after sleep deprivation, although the effects of sleep deprivation were in general less pronounced and, if cytokines were assessed in mitogenstimulated whole blood samples, appeared to primarily reflect effects on circulating monocytes (Born et al., 1997b; Rink et al., 1998). Collectively these data suggest that the disturbances of sleep commonly present in aged persons induce a state of chronic sleep deficit that acts to suppress T cell mediated functioning and, in turn, upregulates certain aspects of innate immune functioning. However, there is currently no study providing a direct test of this hypothesis. Sakami et al. (2003) examined relationships between insomnia determined mainly as perception of insufficient sleep and T cell cytokine activity as well as NK cell activity in a larger sample of 254 men aged between 20 and 64 years. While age was inversely, but only moderately correlated with NK cell activity as well as with the IFN- to IL-4 ratio (r<0.19), the men suffering from insomnia had a significantly lower production of IFN- and, in fact, a shift towards prevailing Th2 cytokine activity. The NK cell activity was found to be independent of insomnia. On the background of the strong association between aging and disturbed sleep, this result provides first evidence that poor sleep, if present in an elderly person, probably contributes to a decline in specific T cell functioning by shifting the Th1/Th2 balance towards Th2. However, even though insomnia was examined in that study, the change in the Th1/Th2 balance may not be specific to the impairment of sleep but could likewise reflect the non-specific impact of a stressor. Stressors other than insomnia and chronic sleep deficit have also the capability to induce a dominance of Th2 cytokine activity, and such factors are difficult to dissociate from those of altered sleep, particularly so in the aged (Decker et al., 1996; Marshall and Agrarwal, 2000). There are also clear differences between the effects of sleep deprivation and aging mainly regarding blood cell counts. Most obvious are the opposite effects of both conditions on lymphocyte counts which increase during sleep deprivation (e.g., Dinges et al., 1994) but decrease with aging due to thymic involution. The increase in T and B cell counts in blood during sleep deprivation probably reflects a diminished emigration of these cells into extravascular and lymphoid tissues (Dickstein et al., 2000). Such differences underline that immunosenescence cannot be simply reduced to disturbances of sleep playing in this context the role of a modulating factor. Against this background, differences in immune regulation between old and young humans during sleep are expected to be a composite, on

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the one hand, of changes due to biological aging and, on the other hand, due to impairments of sleep. In one study in humans, white blood cell differential counts and cytokine production was compared between young and elderly subjects before and during regular nocturnal sleep (Born et al., 1995). All subjects were healthy and did not suffer from pathological sleep disturbances. The aged subjects (mean  SEM: 79.6  7.5 year) were recruited according to the strict criteria of the SENIEUR protocol. As expected, sleep in the elderly persons was worse than in the young persons, although total sleep time was roughly the same as in the young sleepers. Compared to the young subjects the elderly spent much more time awake (24.0 vs. 5.2%), and distinctly less time in SWS (7.7 vs. 20.0%) and REM sleep (10.0 vs. 19.9%). In parallel with this, the aged showed a general reduction in the number of circulating white blood cells. Monocyte counts were unchanged, while the circadian decrease in neutrophil counts in the late night appeared to be somewhat more pronounced in the aged. The T and B cell counts as well as the number of CD4 þ and CD8 þ were distinctly reduced at all times. The number of activated T cells were more than twofold enhanced in the aged throughout the recordings. Notably, only changes in NK cells appeared to depend on sleep. The NK cell numbers were comparable before sleep in both groups but, in young subjects decreased across nocturnal sleep, while in the aged, on an average, even a slight increase was observed. Contrary to expectations, there was no clear hint from this study at a decline in the production of IL-2 and IFN- by T cells in the aged. Although the production of these cytokines per T cell before sleep was on average lower in the aged than in the young, this difference was not significant, and this held true also during the time of sleep. However, T cells in the aged expressed a higher number of IL-2 receptors. In contrast with the T cell derived cytokines, the production of acute proinflammatory cytokines of innate immunity, IL-1 and TNF-, exhibited an increase in the aged which was most pronounced during sleep. This was partly due to the fact that average production of these cytokines tended to decrease across the sleep period only in the young subjects which confirmed previous studies (Hohagen et al., 1993, Zabel et al., 1993; Petrovsky et al., 1998). The sleep-associated enhancement in the production of IL-1 and TNF- in the aged remained significant also, when the production of the cytokines were determined per monocyte representing the major source of these cytokines in the stimulated whole blood samples. Together with the increase in NK cell numbers, the enhanced proinflammatory cytokine activity during sleep may indeed reflect acute consequences of the impaired sleep regulation in the aged. Another study in mice likewise failed to detect any sleep-related decline in signs of adaptive immune function with age (Renegar et al., 1998). This study aimed at dissociating effects of sleep deprivation on IgA and IgG levels in the upper and lower respiratory tract mucosa and in serum in young and senescent mice 72 h after a viral challenge test. The influenza immune mice were sleep deprived once or twice for up to 6 h on the day(s) before and after the viral challenge. While sleep deprivation remained without effect in the young mice, the old mice showed even increased

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serum levels of influenza specific IgG after viral challenge under one of the deprivation conditions. The finding may fit the predominance of Th2 cytokine activity supporting specific antibody secretion from B cells. However, it would be also consistent with an increased response in the old mice to the stress of sleep deprivation. Whether sleep does at all exert regulatory influences on a secondary response in the solidly immune organism is questionable. In humans, an enhancing effect of sleep has been found on antibody titers only in the context of a primary immunization (Spiegel et al., 2002; Lange et al., 2003). In any case, it would be premature to generalize these findings in rodents to the human being, in light of the fact that effects of age on immune reactions can widely differ among species. In another animal study in rats, LPS was administered to examine effects of the acute phase proinflammatory cytokines on sleep in young and middle-aged rats (Schiffelholz and Lancel, 2001). The LPS is a robust stimulus of the secretion of IL1 , TNF- and IL-6 from monocytes in rats and humans. Sleep in the young and middle-aged rats differed in this study mainly regarding REM sleep and pre-REM sleep (a type of nonREM sleep at the transition into REM sleep) which were both reduced in the middle aged rats. The intraperitoneal administration of LPS induced a comparable increase in body temperature in both groups. However, while the young rats showed increased amounts of SWS in response to LPS, in the middle-aged rats EEG power decreased in most frequency bands pointing to flattened sleep. This response in the middle-aged rats resembles that seen in adult humans following administration of higher pyrogenic doses of LPS (Pollma¨cher et al., 1995). This result well agrees with the notion that the sensitivity of innate immunity to LPS is enhanced with aging (e.g., Gabriel et al., 2002), and extends it to the acute phase sleep response to immune challenge. In sum these data indicate that the impaired sleep in aged is acutely associated with a state of increased responsiveness of some innate immune functions. In the case of acute infection increased amounts of circulating proinflammatory cytokines could contribute to a further flattening of central nervous sleep processes in the aged. Also, the reduced depth of sleep may support the predominance of Th2 cytokine activity in the elderly. However, although primary T cell cytokines like IL-2 and IFN- have been shown to be acutely enhanced by sleep and to be generally reduced with aging, so far no evidence has been provided that these cytokines are particularly suppressed during the sleep period in aged. Thus, the decline in lymphocyte generation and function representing one of the most prominent sign of immunosenescence, appears to go in parallel with an insensitivity to the acute consequences of poor sleep. 5.3. Endocrine mediation of sleep-immune changes in the aged Sleep in the aged is associated with distinct endocrine changes. Many of the hormones, the release of which is specifically regulated during sleep, exert specific immune-regulatory functions and, thus, could play an important role for the manifestation of age-related changes in the immune system function, i.e., for the acute changes emerging during the sleep period as well as for the persistent changes

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of immunosenescence. Research in this regard has focussed on GH and prolactin, cortisol, and melatonin. Also functions of other hormones like TSH showing a sleepassociated decrease in aged (Van Coevorden et al., 1991), and catecholamines, which are secreted at a reduced rate during sleep and at an increased rate in aged, and counteract proinflammatory cytokines and NK cell activity, might be relevant in this context but will not be considered here (Maess et al., 2000; Elenkov and Chrousos, 2002; Irwin et al., 2003). As noted before, the profound decrease in GH secretion is a landmark of sleep in the aged. There is now a body of evidence indicating that subchronic treatment with GH and also with IGF-1 can restore the architecture of the involuted thymus gland by reversing the loss of immature cortical thymocytes and preventing the decline in thymulin synthesis that occurs in old and GH-deficient animals and probably also in humans (Weigent and Blalock, 1995; Burgess et al., 1999). This implicates that the persisting decline in sleep-associated GH secretion is one factor playing a causative role for the age-dependent thymic involution explaining the enduring decrease in T cell numbers and generation in elderly. Reduced secretion of GH at the same time could also contribute to some of the changes in T cell function characterizing immunosenescence. The GH has been found to enhance mitogen-stimulated T cell differentiation, and to increase Th1 related cytokine activity but to reduce Th2 activity (Postel-Vinay et al., 1997; Mellado et al., 1998; Takagi et al., 1998; Dimitrov et al., 2004b). In children, repeated GH administration increased serum levels of IL-2 and IFN- as well as of proinflammatory cytokines (IL-1 and TNF-; Bozzola et al., 2003). A stimulating influence of GH on NK cell activity is less well established (Bidlingmaier et al., 1997). However, GH appears to stimulate macrophage activity also (Edwards et al., 1992). The decline in GH in the elderly probably acts in synchrony with a similar sleepassociated decline in the release of prolactin with aging (Van Coevorden et al., 1991). Like GH, prolactin is preferentially released during SWS and acts via receptors of the same cytokine/hemopoetin receptor superfamily, sharing binding affinity and a similar intracellular protein cascade during transduction (Matera et al., 2000; Yu-Lee, 2002). A supportive action on Th1 cytokine activity has been demonstrated also for melatonin (Garcia-Maurino et al., 1997; Lissoni et al., 1998; Kuhlwein and Irwin, 2001). The age-related decrease in the secretion of melatonin during nocturnal sleep could thus further add to the T cell related deficits characterizing immunosenescence. However, at the same time melatonin appears to stimulate proinflammatory cytokines such as TNF- and IL-6 (e.g., Sutherland et al., 2002). The corticosteroids are, of course, the best studied hormonal regulators of immune functions, which at the same time are subject to a sleep specific regulation, and the release of which during sleep increase with aging. Cortisol is known to strongly affect the distribution of white blood cells inducing a pronounced decrease in the numbers of circulating lymphocytes. Also, it inhibits production of proinflammatory cytokines as well as T cell cytokines (Fauci et al., 1976, Angeli et al., 1999). Petrovsky and Harrison (1997) showed that the shift in the Th1/Th2 balance towards increased Th1 cytokine activity during early nocturnal sleep can be

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effectively inhibited by prior administration of cortisol. However, the concentrations of corticosteroids examined in these experiments were in general rather high in comparison with the small size of the age-related increased plasma cortisol concentrations seen during sleep. This should caution against a premature generalization from these studies to the conditions in the elderly. It can also not be excluded that small increases in cortisol exert effects opposite to those of higher doses (Calandra et al., 1995). Though, it is more likely that slight increases in cortisol as seen during sleep in the aged in the long run act in the same way as the acute but much higher corticosteroid concentrations, typically used for experimental purposes. The increased activity of proinflammatory cytokines during sleep in the aged can conversely act to modulate the neuroendocrine architecture of sleep. Cytokines such as IL-1 , TNF- and IL-6 have strong influences on the pituitary, where they stimulate pituitary–adrenal activity and at the same time suppress GH release (e.g., Jones and Kennedy, 1993, Spa¨th-Schwalbe et al., 1996). These influences suggest that the enhanced state of innate immune responsiveness in the aged could contribute to the sleep impairment seen in the aged, at least with respect to its neuroendocrine features. This contrasts, however, with a concept derived from animal studies of a promoting effect of such proinflammatory cytokines on sleep which in part is mediated via induction of GHRH (e.g., Kru¨ger and Majde, 2003). Overall these obvious discrepancies call for further research directly addressing the conditions of sleep in aged humans. 6. Summary and conclusion Early sleep is characterized by a trias of neuroendocrine phenomena, comprised of a predominance of SWS, a maximum inhibition of HPA activity, and a strong activation of somatotropic activity. During aging, there are distinct changes of this trias. It decreases SWS, disinhibits pituitary–adrenal activity, and reduces somatotropic activity during this time. In addition, sleep in the aged is less deep, fragmented by frequent awakenings and influenced by a phase advance of circadian sleep–wake regulation. Immunological measures reflect an acute sleep-related enhancement of signs of innate immune activity in the aged, beyond a general decline in T cell related immune function, which is not restricted to the sleep period. The mechanisms of these changes are presently not clear. A key role is played by the hypothalamic structures balancing the activity between CRH and GHRH secreting neurons, which in aged enable a shift towards increased activity of CRH and the pituitary adrenal system. This shift in neuroendocrine balance during sleep is likely responsible for some of the enduring changes characterizing immunosenescence, in particular, the decline of T cell numbers and function. However, it cannot explain acute increases of signs of innate immune function in the aged. The balance between the activity of the HPA and the somatotropic system is under the control of several supra-ordinate structures. Two of these structures are

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the hippocampus and the nucleus suprachiasmaticus. Aging is associated with a deterioration of hippocampal functioning including a reduction of MR receptor expressing cells. The resulting decrease in inhibitory feedback regulation of the HPA system probably adds to the overactivity of the HPA system seen during sleep in the elderly. Aging is also associated with a decrease in vasopressin-expressing cells selectively in the nucleus suprachiasmaticus representing the brain’s major circadian clock. Such a decrease in combination with decreases in other circadian signals, such as pineal melatonin, might be responsible for the circadian disturbances of sleep manifesting a generally more shallow and phase advanced sleep. The neuroendocrine changes of sleep in the aged are pronounced and clinically relevant. With this background, an increasing number of trials have been started that are aimed at ameliorating sleep in the aged by the administration of hormones centrally involved in neuroendocrine sleep regulation. Promising approaches pertain to the administration of substances counteracting HPA overactivity during sleep and to the replacement of factors assumed to improve circadian functioning in the aged, such as vasopressin and melatonin.

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