Why Sleep Is Important for Health: A Psychoneuroimmunology Perspective

“Inflammatory responses are thought to be linked to 15–20% of all deaths from cancer worldwide (Mantovani et al. 2008), in part due to cancer-related activation of NF-κB and multiple inflammatory cytokines (such as IL-1β, IL-6, and TNF-α) (Karin 2006).”

“Partial-night sleep deprivation induces an increase in TLR-4-stimulated production of IL-6 and TNF, which is especially prominent in women who show sustained elevations ADRB2 TLR4 Circulation SNS nerve fibers Cardiovascular disease Major depressive disorder Cancer NF-κB Expression of proinflammatory immune response ge…”

“One example is the Insomnia Severity Index, which assesses sleep quality, fatigue, psychological symptoms, and quality of life, with a high sensitivity and specificity for the detection of insomnia cases (Morin et al. 2011).”

“…about 25% of the population of the United States report insomnia complaints (LeBlanc et al. 2009), and nearly 10% fulfill diagnostic criteria for chronic insomnia (Morin et al. 2006b; Ohayon 1996, 2002), which is persistent for as long as three years in nearly 50% of patients (Morin et al. 2009).”

“Transcription factor binding motifs that were overrepresented in the sleep-deprivation condition included the promoters of genes involved in regulation by cyclic adenosine monophosphate/protein kinase A (cAMP/PKA)-induced transcription factors of the cAMP response element–binding protein/activating transcription facto…”

“…the role of insomnia in the onset of depression (for a review, see Riemann 2010), with meta-analytic findings showing that sleep disturbance yields a twofold increased risk of depression (Baglioni et al. 2011) or is one of the first clinical signs of a depressive disorder (Dryman & Eaton 1991).”

“The purpose of the present review is to provide an integrated understanding of how sleep health (Buysse 2014) affects one salient biological mechanism, the immune system, with implications for infectious and inflammatory disease risk.”

“As such, actigraphy provides reasonably accurate sleep continuity indices as compared to polysomnography (Ancoli-Israel et al. 2003).”

“Ford & Kamerow (1989) were among the first to note such a relationship in a longitudinal epidemiologic study, and to date more than 40 studies have been published that have tested the role of insomnia in the onset of depression (for a review, see Riemann 2010), with meta-analytic findings showing…”

“Such a conserved transcriptional response to adversity, of which sleep disturbance is one type, has been extensively discussed in prior reviews (Irwin & Cole 2011, Slavich & Irwin 2014).”

“Finally, antagonism of endogenous inflammation shows promise in reducing depressive symptoms and possibly in the remission of depression in groups of depressed patients with high levels of inflammation (Raison et al. 2013, Tyring et al. 2006).”

“…with compelling evidence that disturbances of sleep including insomnia complaints and extremes of sleep duration adversely influence risk of infectious and inflammatory disease and contribute to allcause mortality (Dew et al. 2003, Kripke et al. 2002, Mallon et al. 2002, Vgontzas et al. 2013).”

“During NREM or SWS, sympathetic activity is decreased; during REM sleep, SNS outflow is higher, similar to daytime levels (Somers et al. 1993).”

“…about 25% of the population of the United States report insomnia complaints (LeBlanc et al. 2009), and nearly 10% fulfill diagnostic criteria for chronic insomnia (Morin et al. 2006b; Ohayon 1996, 2002), which is persistent for as long as three years in nearly 50% of patients (Morin et al. 2009).”

“Certain aspects of sleep disturbance, as well as sex differences, differentially impact inflammation, with evidence that poor sleep efficiency may be salient in the association with higher levels of CRP (Okun & Coussons-Read 2007) and IL-6 (Friedman et al. 2005), especially in women with poor social relationships.”

“…about 25% of the population of the United States report insomnia complaints (LeBlanc et al. 2009), and nearly 10% fulfill diagnostic criteria for chronic insomnia (Morin et al. 2006b; Ohayon 1996, 2002), which is persistent for as long as three years in nearly 50% of patients (Morin et al. 2009).”

“Short sleep duration alone appears to have a robust effect on cardiovascular disease risk, similar to the effects of short sleep duration on inflammation (Ayas et al. 2003, Hoevenaar-Blom et al. www.annualreviews.org • Sleep, Immunity, and Health 159 A nn u.”

“…cytokines during the rest period have been observed, often during the early SWS-dominated portion of sleep, in humans as well as in animals, on the mRNA and protein levels in different tissues including the brain, adipose tissue, and lymph nodes (for a review, see Besedovsky et al. 2012).”

“Finally, antagonism of endogenous inflammation shows promise in reducing depressive symptoms and possibly in the remission of depression in groups of depressed patients with high levels of inflammation (Raison et al. 2013, Tyring et al. 2006).”

“…periods of sleep restriction (i.e., seven nights) induce increases in plasma concentrations of IL-6 in men and women, increases of TNF in men only (Vgontzas et al. 2004a), and increases in inflammatory transcripts of IL-1β, IL-6, and IL-17 (van Leeuwen et al. 2009), with evidence that such…”

“In contrast to HPA activation, the SNS “steers” immune responses between antiviral and proinflammatory immune responses (Irwin & Cole 2011).”

“Partial-night sleep deprivation induces an increase in TLR-4-stimulated production of IL-6 and TNF, which is especially prominent in women who show sustained elevations ADRB2 TLR4 Circulation SNS nerve fibers Cardiovascular disease Major depressive disorder Cancer NF-κB Expression of proinflammatory immune response ge…”

“In addition, sleep complaints—possibly through effects on inflammation—contribute to cardiovascular disease risk (Mullington et al. 2009).”

“…insomnia with short sleep duration are more likely to show increases in urinary catecholamines and levels of their metabolites than are insomniacs without objective sleep disturbance, similar to the greater activation of inflammatory biomarkers in this more severe phenotype (Vgontzas et al. 2013).”

“…who reported insomnia lasting more than one year and who also had short sleep duration (≤5 h) had a fivefold greater risk of having hypertension (Vgontzas et al. 2009), with prospective findings showing that this combination led to a fourfold increased risk of incident hypertension…”

“In addition, inflammation appears to be a prognostic factor predicting breast cancer recurrence (Cole 2009, Pierce et al. 2009).”

“Additionally, sleep disturbance appears to be a critical pathway by which psychological stress and major depression lead to a reduction in NK activity (Cover & Irwin 1994, Irwin & Miller 2007). www.annualreviews.org • Sleep, Immunity, and Health 155 A nn u.”

“To further complicate these observations, the effects of sleep duration might depend on the proinflammatory cytokine; Patel et al. (2009) found that each additional hour of sleep duration resulted in an increase in CRP and an increase in IL-6, whereas a shorter sleep duration was associated with an…”

“Partial-night sleep deprivation, when repeated for several nights (i.e., 10 nights), induces robust increases in C-reactive protein (CRP) (Meier-Ewert et al. 2004) and IL-6 (Haack et al. 2007).”

“However, when sleep restriction or sleep fragmentation is limited to only one or two nights (Abedelmalek et al. 2013, Schmid et al. 2011, Stamatakis & Punjabi 2010), or when sleep restriction occurs in the midst of intervening daytime naps (Faraut et al. 2011, Shearer et al. 2001), circulating…”

“Both partial- and totalnight sleep deprivation reduce T cell production of IL-2, and this effect is independent of the total number of circulating T cells (Born et al. 1997; Irwin et al. 1996, 1999).”

“Likewise, Pressman et al. (2005) found that loneliness and poor sleep efficiency were associated with poorer antibody response to influenza vaccine.”

“In experimental studies in which healthy adults are inoculated with a rhinovirus that produces symptoms of the common cold, poor sleep efficiency was associated with increased susceptibility to the common cold and greater symptom reporting (Cohen et al. 2009).”

“Third, experimental activation of inflammation induces increases of depressive symptoms along with activation of brain sites that regulate positive and negative affect (Eisenberger et al. 2009, 2010a,b).”

“Nocturnal sleep also enhances the production of IL-12 by precursor dendritic cells as well as by monocytes (Lange et al. 2006b, 2010); IL-12 is a key cytokine for the induction of Th1-type adaptive immune responses.”

“…with compelling evidence that disturbances of sleep including insomnia complaints and extremes of sleep duration adversely influence risk of infectious and inflammatory disease and contribute to allcause mortality (Dew et al. 2003, Kripke et al. 2002, Mallon et al. 2002, Vgontzas et al. 2013).”

“Second, markers of inflammation are elevated in depressed compared to nondepressed individuals, with prospective findings showing that increases of CRP and IL-6 predict the occurrence of depression (Gimeno et al. 2009).”

“Partial-night sleep deprivation induces an increase in TLR-4-stimulated production of IL-6 and TNF, which is especially prominent in women who show sustained elevations ADRB2 TLR4 Circulation SNS nerve fibers Cardiovascular disease Major depressive disorder Cancer NF-κB Expression of proinflammatory immune response ge…”

“Finally, depression is well known to be a potent risk factor for cardiovascular disease ( Joynt et al. 2003), with recent findings indicating that sleep disturbance has a critical role in mediating the association between depressive symptoms and hypertension incidence (Gangwisch et al. 2010) as…”

“Yet, early night sleep deprivation delays the nocturnal increase of IL-6 (Redwine et al. 2000), and total night sleep deprivation diminishes the increase in IL-6 by about half (Vgontzas et al. 1999).”

“Although beyond the scope of this review, circadian rhythm disturbances (i.e., shift work) and co-occurring sleep disturbance are implicated in cancer risk (for a review, see Haus & Smolensky 2013).”

“…about 25% of the population of the United States report insomnia complaints (LeBlanc et al. 2009), and nearly 10% fulfill diagnostic criteria for chronic insomnia (Morin et al. 2006b; Ohayon 1996, 2002), which is persistent for as long as three years in nearly 50% of patients (Morin et al. 2009).”

“F or p er so na l u se o nl y. PS66CH06-Irwin ARI 11 November 2014 14:35 2011, Mallon et al. 2002).”

“These findings have substantial public health implications because about 25% of the population of the United States report insomnia complaints (LeBlanc et al. 2009), and nearly 10% fulfill diagnostic criteria for chronic insomnia (Morin et al. 2006b; Ohayon 1996, 2002), which is persistent for as…”

“…concentrations of IL-6 in men and women, increases of TNF in men only (Vgontzas et al. 2004a), and increases in inflammatory transcripts of IL-1β, IL-6, and IL-17 (van Leeuwen et al. 2009), with evidence that such increases persist even after a night of recovery sleep (van Leeuwen et al. 2009).”

“Counts of NK cells and NK activity are at a minimum during the early part of the night and reach a maximum in the late morning hours (Kronfol et al. 1997); this nocturnal increase is attenuated in persons who evidence sleep disturbance (Irwin et al. 1996, Redwine et al. 2003).”

“Additionally, sleep loss induces an increase in transcription of IL-6 and TNF (Irwin et al. 2006b) due an activation of NF-κB, the key transcription control pathway in the inflammatory signaling cascade (Irwin et al. 2008b).”

“Increases of TNF emerge as early as after one or two nights (Chennaoui et al. 2011), although elevations in IL-6 do not appear to occur until after four nights (Shearer et al. 2001).”

“…lasting more than one year and who also had short sleep duration (≤5 h) had a fivefold greater risk of having hypertension (Vgontzas et al. 2009), with prospective findings showing that this combination led to a fourfold increased risk of incident hypertension (Fernandez-Mendoza et al. 2012).”

“Following a night of partial sleep loss, immunologic response to an influenza A vaccination was reported to be reduced by over 50% as compared to the response in those who maintained a regular sleep schedule (Spiegel et al. 2002).”

“Third, experimental activation of inflammation induces increases of depressive symptoms along with activation of brain sites that regulate positive and negative affect (Eisenberger et al. 2009, 2010a,b).”

“…workers, slightly to moderately increased risk for breast, prostate, colon, and endometrial epithelial malignancies plus non-Hodgkin’s lymphoma is found (Conlon et al. 2007; Kubo et al. 2006, 2011; Parent et al. 2012), although other studies have reported no association (Schwartzbaum et al. 2007).”

“…about 25% of the population of the United States report insomnia complaints (LeBlanc et al. 2009), and nearly 10% fulfill diagnostic criteria for chronic insomnia (Morin et al. 2006b; Ohayon 1996, 2002), which is persistent for as long as three years in nearly 50% of patients (Morin et al. 2009).”

“…questionnaire that evaluates seven clinically derived domains of sleep difficulties (i.e., quality, latency, duration, habitual efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction), is used to identify clinically significant sleep impairment (Cole et al. 2006).”

“…duration of sleep was also associated with prevalent hypertension (Wang et al. 2012) as well as a greater risk of other cardiovascular disease (Kronholm et al. 2011, Wang et al. 2012), with a U-shaped risk profile in both men and women (Cappuccio et al. 2011, Ikehara et al. 2009, Wang et al. 2012).”

“Yet, early night sleep deprivation delays the nocturnal increase of IL-6 (Redwine et al. 2000), and total night sleep deprivation diminishes the increase in IL-6 by about half (Vgontzas et al. 1999).”

“For example, a recent meta-analysis of 11 prospective studies (Meng et al. 2013) found that short sleep duration, as well as complaints of sleep maintenance and early-morning awakening, but not difficulty falling asleep, predicted an increased risk of hypertension; another systematic review…”

“However, when sleep loss is extended beyond a single night of sleep deprivation, numbers of circulating granulocytes and monocytes increase (Dinges et al. 1994, Irwin et al. 1996).”

“For example, Lange et al. (2003) found that EEG slow-wave activity on the night after vaccination against hepatitis A correlated with the percentage of antigen-specific Th cells measured one year after vaccination, with evidence that increased release of growth hormone and prolactin but decreased…”

“…liver, and prostate (Ko et al. 2012), especially in men (Baune et al. 2011), with other data showing that inflammation is linked to breast cancer incidence (Touvier et al. 2013) and interacts with other factors (e.g., smoking) to increase lung cancer risk (Shiels et al. 2013, Siemes et al. 2006).”

“…less than seven hours per night entailed increased risk of cardiovascular mortality (Heslop et al. 2002), with a linear relationship between sleep duration and prospective risk of cardiovascular disease (Chien et al. 2010) that indicates an optimal sleep duration between seven and eight hours.”

“…between self-reported and objective (i.e., polysomnographic) sleep duration and markers of inflammation (Larkin et al. 2005, Lee et al. 2009, Marsland et al. 2008, Ramey et al. 2012, Rief et al. 2010, Taheri et al. 2007), even when measures of sleep quality and sleep efficiency were…”

“…periods of sleep restriction (i.e., seven nights) induce increases in plasma concentrations of IL-6 in men and women, increases of TNF in men only (Vgontzas et al. 2004a), and increases in inflammatory transcripts of IL-1β, IL-6, and IL-17 (van Leeuwen et al. 2009), with evidence that such…”

“…events (Sabanayagam et al. 2011), although even sleeping less than seven hours per night entailed increased risk of cardiovascular mortality (Heslop et al. 2002), with a linear relationship between sleep duration and prospective risk of cardiovascular disease (Chien et al. 2010) that…”

“Activation of vascular endothelial markers (i.e., E-selectin, sICAM-1), which typically follows increases in inflammation, also occurs after a single night of sleep loss (Frey et al. 2007, Sauvet et al. 2010).”

“…with insomnia disorder, increases in daytime circulating levels of CRP (Razeghi et al. 2012) and IL-6 are found (Vgontzas et al. 2002), with elevated levels of IL-6, for example, extending into the mid-afternoon and early evening (Vgontzas et al. 2002) and even into the night (Burgos et al. 2006).”

“Extreme sleep habits, i.e., short and long sleep duration, have been linked to adverse health outcomes (Youngstedt & Kripke 2004), with similar effects on inflammation.”

“In addition, this association appears to be specific to those with a history of depression (Cho et al. 2008), although persistent insomnia was found to predict risk for depressive symptoms over six years even in those without a depression history ( Jaussent et al. 2011).”

“During nocturnal sleep, but not during a period of nocturnal wakefulness, T cell production of IL-2 (Lissoni et al. 1998), as well as IFN-γ (Petrovsky et al. 1998), is enhanced.”

“Third, experimental activation of inflammation induces increases of depressive symptoms along with activation of brain sites that regulate positive and negative affect (Eisenberger et al. 2009, 2010a,b).”

“The American Academy of Sleep Medicine does not recommend polysomnography for the routine assessment of insomnia, although it is helpful in the evaluation of other sleep disorders such as sleep apnea (Littner et al. 2003).”

“…well as complaints of sleep maintenance and early-morning awakening, but not difficulty falling asleep, predicted an increased risk of hypertension; another systematic review (Palagini et al. 2013) as well as a largescale epidemiologic study (n = 4,794) (Suka et al. 2003) had similar conclusions.”

“In addition, this association appears to be specific to those with a history of depression (Cho et al. 2008), although persistent insomnia was found to predict risk for depressive symptoms over six years even in those without a depression history ( Jaussent et al. 2011).”

“Activation of vascular endothelial markers (i.e., E-selectin, sICAM-1), which typically follows increases in inflammation, also occurs after a single night of sleep loss (Frey et al. 2007, Sauvet et al. 2010).”

“…into Cancer and Nutrition (EPIC)-Potsdam study (n = 23,620), those who reported a sleep duration of <6 h had a significantly increased risk of cancer as compared with those who reported 7 h of sleep, similar to the increased risk of stroke and overall chronic diseases (von Ruesten et al. 2012).”

“This adrenergic signaling cascade suppresses transcription of antiviral type I IFN genes (Cole et al. 1998) and upregulates transcription of the proinflammatory immune response genes IL1B, TNF, and IL6, leading to increases in systemic inflammatory activity (Cole et al. 2010).”

“Additionally, sleep loss induces an increase in transcription of IL-6 and TNF (Irwin et al. 2006b) due an activation of NF-κB, the key transcription control pathway in the inflammatory signaling cascade (Irwin et al. 2008b).”

“…prolonged sleep deprivation induced an activation of innate immunity, although measures of circulating levels of cytokines relied on bioassays that lacked specificity and it was not known what cytokine contributed to reported increases in IL-1like and IL-2-like activity (Moldofsky et al. 1989).”

“…by sleep loss is NK activity, although changes in NK activity parallel the suppressive effects of sleep loss on adaptive immunity, with robust reductions in NK activity (Irwin et al. 1994, Irwin et al. 1996) and in the ability of NK cells to become activated by IL-2 activation (Irwin et al. 1996).”

“…vulnerable to the effects of sleep loss on cellular inflammation (as noted above) (Irwin et al. 2008b, 2010), it is interesting to note that Suarez (2008) found that overall poor sleep quality was associated with increases in inflammatory biomarkers, but only for women, similar to the…”

“…well as complaints of sleep maintenance and early-morning awakening, but not difficulty falling asleep, predicted an increased risk of hypertension; another systematic review (Palagini et al. 2013) as well as a largescale epidemiologic study (n = 4,794) (Suka et al. 2003) had similar conclusions.”

“…sleep duration and markers of inflammation (Larkin et al. 2005, Lee et al. 2009, Marsland et al. 2008, Ramey et al. 2012, Rief et al. 2010, Taheri et al. 2007), even when measures of sleep quality and sleep efficiency were correlated with inflammation in the same population (Friedman 2005).”

“…studies have found no relationship between self-reported and objective (i.e., polysomnographic) sleep duration and markers of inflammation (Larkin et al. 2005, Lee et al. 2009, Marsland et al. 2008, Ramey et al. 2012, Rief et al. 2010, Taheri et al. 2007), even when measures of sleep…”

“Indeed, both meta-analyses noted above (Cappuccio et al. 2011, Wang et al. 2012) found that long duration of sleep was also associated with prevalent hypertension (Wang et al. 2012) as well as a greater risk of other cardiovascular disease (Kronholm et al. 2011, Wang et al. 2012), with a U-shaped…”

“…workers, slightly to moderately increased risk for breast, prostate, colon, and endometrial epithelial malignancies plus non-Hodgkin’s lymphoma is found (Conlon et al. 2007; Kubo et al. 2006, 2011; Parent et al. 2012), although other studies have reported no association (Schwartzbaum et al. 2007).”

“In the transition from wakefulness to sleep, there is a shift from sympathetic to parasympathetic outflow, which is dependent on the stage of sleep as well as sleep depth (Boudreau et al. 2013).”

“During nocturnal sleep, but not during a period of nocturnal wakefulness, T cell production of IL-2 (Lissoni et al. 1998), as well as IFN-γ (Petrovsky et al. 1998), is enhanced.”

“This adrenergic signaling cascade suppresses transcription of antiviral type I IFN genes (Cole et al. 1998) and upregulates transcription of the proinflammatory immune response genes IL1B, TNF, and IL6, leading to increases in systemic inflammatory activity (Cole et al. 2010).”

“…have demonstrated a relationship between insomnia complaints and objective measures of hypertension (Vozoris 2013), and some have found only modest or no associations when insomnia complaints are reported in the absence of short sleep duration (Phillips et al. 2009, Phillips & Mannino 2007).”

“…workers, slightly to moderately increased risk for breast, prostate, colon, and endometrial epithelial malignancies plus non-Hodgkin’s lymphoma is found (Conlon et al. 2007; Kubo et al. 2006, 2011; Parent et al. 2012), although other studies have reported no association (Schwartzbaum et al. 2007).”

“…liver, and prostate (Ko et al. 2012), especially in men (Baune et al. 2011), with other data showing that inflammation is linked to breast cancer incidence (Touvier et al. 2013) and interacts with other factors (e.g., smoking) to increase lung cancer risk (Shiels et al. 2013, Siemes et al. 2006).”

“Indeed, when sleep disturbance is defined by questionnaire threshold scores (i.e., PSQI > 5), high levels of CRP have been found among poor sleepers in clinical (Chiu et al. 2009), adult (Okun et al. 2009), and older adult (Christian et al. 2011) populations.”

“In addition, a night of wakefulness is associated with a shift in the Th1 to Th2 cytokine balance toward increased Th2 cytokine activity, especially in the morning hours (Dimitrov et al. 2004, Lange et al. 2006a).”

“Prather et al. (2012) found that shorter sleep duration (i.e., less than six hours per night as confirmed by actigraphy) was strongly linked to a decreased likelihood of protection from a hepatitis B vaccination in 125 midlife adults.”

“For example, in the Whitehall II epidemiologic study (n = 4,677) (Miller et al. 2009), women, but not men, who slept less than eight hours tended to have higher levels of IL-6 as well as higher levels of CRP.”

“Importantly, in healthy adults, an intervening nap appears to be protective, as increases of IL-6 following four nights of sleep restriction are reversed by a two-hour nap (Vgontzas et al. 2007).”

“Furthermore, the effects of sleep loss were persistent for up to one year; these effects included a reduced frequency of antigen-specific Th cells as well as reduced levels of antigen Ag-specific immunoglobulin G1 (Lange et al. 2011).”

“…measured by blood pressure, heart rate variability, and impedance cardiography) are found in patients with insomnia (Bonnet & Arand 1997, De Zambotti et al. 2011, Lanfranchi et al. 2009, Riemann 2010, Vgontzas et al. 2013) and following sleep deprivation (Irwin et al. 1999, Irwin & Ziegler 2005).”

“…with insomnia disorder, increases in daytime circulating levels of CRP (Razeghi et al. 2012) and IL-6 are found (Vgontzas et al. 2002), with elevated levels of IL-6, for example, extending into the mid-afternoon and early evening (Vgontzas et al. 2002) and even into the night (Burgos et al. 2006).”

“Extremes of sleep duration are related to infectious disease risk, with epidemiologic evidence that both reduced (e.g., <5 h) and prolonged (e.g., >9 h) habitual sleep duration are correlated with an increased risk of pneumonia (Patel et al. 2012).”

“Cellular production of IL-6 and TNF is thought to be due in part to aberrant increases of TLR activity, which in turn have been linked to inflammatory diseases such as rheumatoid arthritis (Andreakos et al. 2004) and heart failure (Satoh et al. 2005).”

“Naturalistic sleep disturbance, in contrast to experimental sleep loss, is associated with alterations in the relative distribution of immune cells; marked decreases in the numbers of CD3+, CD4+, and CD8+ T cells have been reported in patients with chronic insomnia (Savard et al. 2003).”

“…sleep duration and markers of inflammation (Larkin et al. 2005, Lee et al. 2009, Marsland et al. 2008, Ramey et al. 2012, Rief et al. 2010, Taheri et al. 2007), even when measures of sleep quality and sleep efficiency were correlated with inflammation in the same population (Friedman…”

“…long duration of sleep was also associated with prevalent hypertension (Wang et al. 2012) as well as a greater risk of other cardiovascular disease (Kronholm et al. 2011, Wang et al. 2012), with a U-shaped risk profile in both men and women (Cappuccio et al. 2011, Ikehara et al. 2009, Wang et al.…”

“Increases of TNF emerge as early as after one or two nights (Chennaoui et al. 2011), although elevations in IL-6 do not appear to occur until after four nights (Shearer et al. 2001).”

“…study of an older adult Taiwanese population, only longer sleep (greater than eight hours) was associated with increases in markers of inflammation (Dowd et al. 2011), although this study only tested the prospective role of inflammation on sleep as opposed to sleep duration on inflammation.”

“Miller et al. (2004) found an association between fewer hours of sleep, as indexed by ambulatory monitoring, and lower antibody response to the influenza vaccine, which accounted in part for the association between daily measures of psychological stress and the reduced response to the influenza…”

“One study found that extremes of sleep duration are more robustly associated with cardiovascular morbidity and mortality in women but not in men (Kronholm et al. 2011), whereas other data suggest that only long sleep duration is associated with cardiovascular disease risk (Suzuki et al. 2009).”

“…the role of insomnia in the onset of depression (for a review, see Riemann 2010), with meta-analytic findings showing that sleep disturbance yields a twofold increased risk of depression (Baglioni et al. 2011) or is one of the first clinical signs of a depressive disorder (Dryman & Eaton 1991).”

“Finally, nocturnal sleep favors a shift toward Th1 (predominance of IFN-γ), with a peak around 03:00 h (Petrovsky & Harrison 1997) or even at 06:30 h (Redwine et al. 2003), along with a reduction in production of the anti-inflammatory cytokine IL-10 by monocytes (Lange et al. 2006b).”

“…( Joynt et al. 2003), with recent findings indicating that sleep disturbance has a critical role in mediating the association between depressive symptoms and hypertension incidence (Gangwisch et al. 2010) as well as allcause and cardiovascular disease mortality (Azevedo Da Silva et al. 2014).”

“…workers, slightly to moderately increased risk for breast, prostate, colon, and endometrial epithelial malignancies plus non-Hodgkin’s lymphoma is found (Conlon et al. 2007; Kubo et al. 2006, 2011; Parent et al. 2012), although other studies have reported no association (Schwartzbaum et al. 2007).”

“…is limited to only one or two nights (Abedelmalek et al. 2013, Schmid et al. 2011, Stamatakis & Punjabi 2010), or when sleep restriction occurs in the midst of intervening daytime naps (Faraut et al. 2011, Shearer et al. 2001), circulating levels of inflammatory markers do not appear to change.”

“…research is needed to test explicitly whether antagonism of β-adrenergic signaling abrogates the effects of sleep disturbance on adaptive immunity, similar to the effects of β-adrenergic antagonism of stress-induced reduction of adaptive immune responses (Irwin & Cole 2011, Murray et al. 1992).”

“Additionally, it is important to note that sleep disturbance also occurs in the context of an acute infectious challenge (Toth 1995) as well as during chronic infections such as HIV (Reid & Dwyer 2005), although the impact of insomnia on infectious outcomes such as HIV is not known.”

“Nocturnal sleep also enhances the production of IL-12 by precursor dendritic cells as well as by monocytes (Lange et al. 2006b, 2010); IL-12 is a key cytokine for the induction of Th1-type adaptive immune responses.”

“In addition, inflammation appears to be a prognostic factor predicting breast cancer recurrence (Cole 2009, Pierce et al. 2009).”

“Cellular production of IL-6 and TNF is thought to be due in part to aberrant increases of TLR activity, which in turn have been linked to inflammatory diseases such as rheumatoid arthritis (Andreakos et al. 2004) and heart failure (Satoh et al. 2005).”

“However, when sleep restriction or sleep fragmentation is limited to only one or two nights (Abedelmalek et al. 2013, Schmid et al. 2011, Stamatakis & Punjabi 2010), or when sleep restriction occurs in the midst of intervening daytime naps (Faraut et al. 2011, Shearer et al. 2001), circulating…”

“…risk of colorectal cancer in the 11.3-year follow-up of the Women’s Health Initiative observational study (n = 75,828 postmenopausal women) ( Jiao et al. 2013), although one other large-scale prospective report found that only long sleep duration (>9 h) was associated with the risk of…”

“However, when sleep restriction or sleep fragmentation is limited to only one or two nights (Abedelmalek et al. 2013, Schmid et al. 2011, Stamatakis & Punjabi 2010), or when sleep restriction occurs in the midst of intervening daytime naps (Faraut et al. 2011, Shearer et al. 2001), circulating…”

“…(as measured by blood pressure, heart rate variability, and impedance cardiography) are found in patients with insomnia (Bonnet & Arand 1997, De Zambotti et al. 2011, Lanfranchi et al. 2009, Riemann 2010, Vgontzas et al. 2013) and following sleep deprivation (Irwin et al. 1999, Irwin & Ziegler…”

“Indeed, when sleep disturbance is defined by questionnaire threshold scores (i.e., PSQI > 5), high levels of CRP have been found among poor sleepers in clinical (Chiu et al. 2009), adult (Okun et al. 2009), and older adult (Christian et al. 2011) populations.”

“F or p er so na l u se o nl y. PS66CH06-Irwin ARI 11 November 2014 14:35 are also reported in persons who report sleep impairment (Erten et al. 2005, Friedman et al. 2005, Okun et al. 2007), although not all studies have confirmed these findings (van Mark et al. 2010).”

“Counts of NK cells and NK activity are at a minimum during the early part of the night and reach a maximum in the late morning hours (Kronfol et al. 1997); this nocturnal increase is attenuated in persons who evidence sleep disturbance (Irwin et al. 1996, Redwine et al. 2003).”

“However, recent findings from the National Health and Nutrition Examination Survey (NHANES) (n = 10,908) showed that complaints of nonrestorative sleep, as opposed to nocturnal insomnia symptoms, were associated with higher levels of CRP in both sexes (Zhang et al. 2013a).”

“%) increase in levels of soluble IL-6R (Dimitrov et al. 2006), which is most pronounced during the late part of the night, consistent with relative increases in REM sleep amounts and increases in IL-6 (Redwine et al. 2000).”

“Persistent insomnia is particularly potent in increasing the risk of depression, with a 14-fold greater risk of depression in the year following insomnia that had persisted for up to one year (Lee et al. 2013).”

“Even a modest amount of sleep can increase IL-2 production, as levels of IL-2 are similar during a night of uninterrupted sleep or partial sleep loss (Irwin et al. 1999).”

“…liver, and prostate (Ko et al. 2012), especially in men (Baune et al. 2011), with other data showing that inflammation is linked to breast cancer incidence (Touvier et al. 2013) and interacts with other factors (e.g., smoking) to increase lung cancer risk (Shiels et al. 2013, Siemes et al. 2006).”

“Finally, nocturnal sleep favors a shift toward Th1 (predominance of IFN-γ), with a peak around 03:00 h (Petrovsky & Harrison 1997) or even at 06:30 h (Redwine et al. 2003), along with a reduction in production of the anti-inflammatory cytokine IL-10 by monocytes (Lange et al. 2006b).”

“Indeed, when sleep disturbance is defined by questionnaire threshold scores (i.e., PSQI > 5), high levels of CRP have been found among poor sleepers in clinical (Chiu et al. 2009), adult (Okun et al. 2009), and older adult (Christian et al. 2011) populations.”

“…(AGES)-Reykjavik cohort (n = 2,102), men who had problems falling and staying asleep had a significantly increased risk of prostate cancer compared to men without such sleep problems (Sigurdardottir et al. 2013), with an even more robust association among those with advanced prostate cancer.”

“Additionally, sleep disturbance appears to be a critical pathway by which psychological stress and major depression lead to a reduction in NK activity (Cover & Irwin 1994, Irwin & Miller 2007). www.annualreviews.org • Sleep, Immunity, and Health 155 A nn u.”

“Yet, in a vulnerable population of individuals who report chronic sleep disturbance, a single night of sleep loss triggers an activation of inflammation with increases in IL-6 and TNF, which is not found in those who have no underlying sleep problems (Irwin et al. 2004).”

“…with increases in mortality and site-specific cancer mortality for lung, colorectal, liver, and prostate (Ko et al. 2012), especially in men (Baune et al. 2011), with other data showing that inflammation is linked to breast cancer incidence (Touvier et al. 2013) and interacts with other…”

“Additionally, it is important to note that sleep disturbance also occurs in the context of an acute infectious challenge (Toth 1995) as well as during chronic infections such as HIV (Reid & Dwyer 2005), although the impact of insomnia on infectious outcomes such as HIV is not known.”

“However, recent findings from the National Health and Nutrition Examination Survey (NHANES) (n = 10,908) showed that complaints of nonrestorative sleep, as opposed to nocturnal insomnia symptoms, were associated with higher levels of CRP in both sexes (Zhang et al. 2013a).”

“In the populationbased InCHIANTI study (n = 751), levels of TNF, but not IL-6 or CRP, were increased at extremes of both short and long sleep as compared to those who slept seven to eight hours (Stenholm et al. 2011).”

“…inflammation are prospectively associated with increases in mortality and site-specific cancer mortality for lung, colorectal, liver, and prostate (Ko et al. 2012), especially in men (Baune et al. 2011), with other data showing that inflammation is linked to breast cancer incidence (Touvier et…”

“…risk factors (Laugsand et al. 2012), whereas the Northern Finland 1966 Birth Cohort study (n = 4,011) showed insomnia was associated with higher levels of CRP in men, but not in women, and that these relationships were apparent only if insomnia at least moderate to severe (Liukkonen et al. 2007).”

“…have demonstrated a relationship between insomnia complaints and objective measures of hypertension (Vozoris 2013), and some have found only modest or no associations when insomnia complaints are reported in the absence of short sleep duration (Phillips et al. 2009, Phillips & Mannino 2007).”

“Whether it is possible to modify infectious disease risk profiles in persons with sleep problems is not known, although Irwin et al. (2013) recently reported that treatment of depressed older adults with a selective serotonin reuptake inhibitor normalizes attenuated vaccine responses to the zoster…”

“However, no prospective association between sleep complaints or sleep duration and risk of incident breast cancer was found in the Women’s Health Initiative (n = 110,011) (Vogtmann et al. 2013).”

“…workers, slightly to moderately increased risk for breast, prostate, colon, and endometrial epithelial malignancies plus non-Hodgkin’s lymphoma is found (Conlon et al. 2007; Kubo et al. 2006, 2011; Parent et al. 2012), although other studies have reported no association (Schwartzbaum et al. 2007).”

“F or p er so na l u se o nl y. PS66CH06-Irwin ARI 11 November 2014 14:35 are also reported in persons who report sleep impairment (Erten et al. 2005, Friedman et al. 2005, Okun et al. 2007), although not all studies have confirmed these findings (van Mark et al. 2010).”

“…measured by blood pressure, heart rate variability, and impedance cardiography) are found in patients with insomnia (Bonnet & Arand 1997, De Zambotti et al. 2011, Lanfranchi et al. 2009, Riemann 2010, Vgontzas et al. 2013) and following sleep deprivation (Irwin et al. 1999, Irwin & Ziegler 2005).”

“F or p er so na l u se o nl y. PS66CH06-Irwin ARI 11 November 2014 14:35 animals that were not sleep deprived (Brown et al. 1989), although three subsequent studies have failed to replicate these initial findings (Renegar et al. 1998a,b, 2000).”

“…are not known, although it is thought that the quiescent period of sleep serves to reallocate energy resources from functions related to wakefulness to processes that, for example, facilitate and promote immune responses to infectious challenge (Besedovsky et al. 2012, Motivala & Irwin 2007).”

“…of insomnia, it is important to note that certain single items predict daytime consequences, with the following hierarchical order: self-reported dissatisfaction, complaints of nonrestorative sleep, difficulty resuming or maintaining sleep, and difficulty initiating sleep (Ohayon et al. 2012).”

“…Health Study (n = 8,547) found no significant relationship between insomnia symptoms and CRP after adjustment for cardiovascular risk factors (Laugsand et al. 2012), whereas the Northern Finland 1966 Birth Cohort study (n = 4,011) showed insomnia was associated with higher levels of CRP in…”

“However, not all studies have demonstrated a relationship between insomnia complaints and objective measures of hypertension (Vozoris 2013), and some have found only modest or no associations when insomnia complaints are reported in the absence of short sleep duration (Phillips et al. 2009,…”

“F or p er so na l u se o nl y. PS66CH06-Irwin ARI 11 November 2014 14:35 are also reported in persons who report sleep impairment (Erten et al. 2005, Friedman et al. 2005, Okun et al. 2007), although not all studies have confirmed these findings (van Mark et al. 2010).”

“…( Joynt et al. 2003), with recent findings indicating that sleep disturbance has a critical role in mediating the association between depressive symptoms and hypertension incidence (Gangwisch et al. 2010) as well as allcause and cardiovascular disease mortality (Azevedo Da Silva et al. 2014).”

“…(i.e., polysomnographic) sleep duration and markers of inflammation (Larkin et al. 2005, Lee et al. 2009, Marsland et al. 2008, Ramey et al. 2012, Rief et al. 2010, Taheri et al. 2007), even when measures of sleep quality and sleep efficiency were correlated with inflammation in the same…”

“In addition, in a nationwide study in Taiwan (n = 98,198), clinically significant insomnia disorder was associated with an increased risk of acute coronary syndrome, and this relationship was especially robust in young adult men (Chung et al. 2013).”

“Nocturnal sleep also enhances the production of IL-12 by precursor dendritic cells as well as by monocytes (Lange et al. 2006b, 2010); IL-12 is a key cytokine for the induction of Th1-type adaptive immune responses.”

“Certain aspects of sleep disturbance, as well as sex differences, differentially impact inflammation, with evidence that poor sleep efficiency may be salient in the association with higher levels of CRP (Okun & Coussons-Read 2007) and IL-6 (Friedman et al. 2005), especially in women with poor social relationships.”

“Those sleeping less than five hours appear to show the greatest risk for cardiovascular events (Sabanayagam et al. 2011), although even sleeping less than seven hours per night entailed increased risk of cardiovascular mortality (Heslop et al. 2002), with a linear relationship between sleep…”

“…solely on women and found that postpartum sleep duration of less than five hours was prospectively associated with increases of IL-6 and CRP one to three years later (Taveras et al. 2011); shorter sleep duration was also associated with increases of CRP in adolescent girls (Larkin et al. 2005).”

“F or p er so na l u se o nl y. PS66CH06-Irwin ARI 11 November 2014 14:35 animals that were not sleep deprived (Brown et al. 1989), although three subsequent studies have failed to replicate these initial findings (Renegar et al. 1998a,b, 2000).”

“Whereas no study has systematically evaluated whether elevated levels of inflammation mediate the association between sleep disturbance and cardiovascular disease or other diseases that have an inflammatory component including cancer and depression, extensive data show that sleep disturbance, as well as extremes of sl…”

“To conclude, habitual short sleep duration and chronic sleep disturbances are related to a variety of diseases, including cardiovascular diseases, metabolic diseases, chronic pain conditions, some forms of cancer, and neuropsychiatric disease (255), all of which involve immune dysregulations.”