Transcriptional Signatures of Sleep Duration Discordance in Monozygotic Twins.

Introduction: Habitual short sleep duration is associated with adverse metabolic, cardiovascular, and inflammatory effects. Co-twin study methodologies account for familial (eg, genetics and shared environmental) confounding, allowing assessment of subtle environmental effects, such as the effect of habitual short sleep duration on gene expression. Therefore, we investigated gene expression in monozygotic twins discordant for actigraphically phenotyped habitual sleep duration. Methods: Eleven healthy monozygotic twin pairs (82% female; mean age 42.7 years; SD = 18.1), selected based on subjective sleep duration discordance, were objectively phenotyped for habitual sleep duration with 2 weeks of wrist actigraphy. Peripheral blood leukocyte (PBL) RNA from fasting blood samples was obtained on the final day of actigraphic measurement and hybridized to Illumina humanHT-12 microarrays. Differential gene expression was determined between paired samples and mapped to functional categories using Gene Ontology. Finally, a more comprehensive gene set enrichment analysis was performed based on the entire PBL transcriptome. Results: The mean 24-hour sleep duration of the total sample was 439.2 minutes (SD = 46.8 minutes; range 325.4-521.6 minutes). Mean within-pair sleep duration difference per 24 hours was 64.4 minutes (SD = 21.2; range 45.9-114.6 minutes). The twin cohort displayed distinctive pathway enrichment based on sleep duration differences. Habitual short sleep was associated with up-regulation of genes involved in transcription, ribosome, translation, and oxidative phosphorylation. Unexpectedly, genes down-regulated in short sleep twins were highly enriched in immuno-inflammatory pathways such as interleukin signaling and leukocyte activation, as well as developmental programs, coagulation cascade, and cell adhesion. Conclusions: Objectively assessed habitual sleep duration in monozygotic twin pairs appears to be associated with distinct patterns of differential gene expression and pathway enrichment. By accounting for familial confounding and measuring real life sleep duration, our study shows the transcriptomic effects of habitual short sleep on dysregulated immune response and provides a potential link between sleep deprivation and adverse metabolic, cardiovascular, and inflammatory outcomes.

Sleep, ghrelin, leptin and changes in body weight during a 1-year moderate-intensity physical activity intervention.

OBJECTIVE: To investigate cross-sectional and longitudinal relationships among exercise, sleep, ghrelin and leptin. METHODS: We randomly assigned 173 post-menopausal sedentary overweight (body mass index >or=24.0 kg/m(2) and >33% body fat) women aged 50-75 years living in western Washington State to either a facility- and home-based moderate-intensity physical activity intervention or a stretching control group. Fasting plasma ghrelin, leptin, measured height, weight and self-reported sleep were assessed at baseline and 12 months. RESULTS: There were no consistent cross-sectional patterns between self-reported sleep measures and ghrelin or leptin at baseline. The weight loss differences between exercisers and stretchers were greater for those who slept less at follow-up than at baseline compared to those whose sleep duration did not change (-3.2 kg, 95% confidence interval (CI) -5.8, -0.5). Improvements in sleep quality were associated with significantly greater differences between exercisers and stretchers for ghrelin increases (improved vs same sleep quality: +115 pg/ml, 95% CI +25, +206) and leptin decreases (improved vs worsened sleep quality: -5.7 ng/ml, 95% CI -9.5, -1.5). CONCLUSION: There was only limited evidence that changes in sleep duration or quality modified exercise-induced changes in weight, ghrelin or leptin. Moreover, the observed differences were not in the directions hypothesized. Future longitudinal studies including population-based samples using objective measures of sleep and long follow-up may help to clarify these relationships.

Sleep disturbances in patients with Alzheimer's disease: epidemiology, pathophysiology and treatment.

Older adults represent an ever-growing proportion of the population of the industrialised nations, with a corresponding increase in the numbers of patients with dementing disorders. A common complaint in both normal aging and the dementias is that of significant sleep disturbance. The major causes of sleep disruption in aging and dementia include: (i) physiological changes that arise as part of normal, 'nonpathological' aging; (ii) sleep problems due to one of many physical or mental health conditions and their treatments; (iii) primary sleep disorders; (iv) poor 'sleep hygiene', that is, sleep-related practices and habits; and (v) some combination of these factors. Disrupted sleep in patients with dementia is a significant cause of stress for caregivers and frequently leads to institutionalisation of patients. It should be a target of clinical management when the goal is sustained home care, and when it is associated with disturbances of mood or behaviour. While the neuropathology of dementia can directly disrupt sleep, sleep disturbances in patients with dementia often have multiple causes that require systematic evaluation. Thorough assessment of associated psychopathology, day-time behaviour, medical disorders, medications, pain and environmental conditions is needed for optimal management. Differential diagnosis of a sleep problem in dementia is the basis of rational pharmacotherapy. However, patients with dementia are likely to be more sensitive than elderly persons without dementia to adverse cognitive and motor effects of drugs prescribed for sleep. Clinicians need to: (i) evaluate sleep outcomes when treating medical, psychiatric and behavioural disorders in older adults; (ii) be alert to emerging behavioural and environmental approaches to treatment; (iii) combine nonpharmacological strategies with drug therapies, when required, for added value; and (iv) avoid use of multiple psychotropic medications unless they prove essential to the adequate management of sleep disturbances.

Dawn simulation and bright light in the treatment of SAD: a controlled study.

BACKGROUND: Some small controlled studies have found that dawn simulation is effective in treating seasonal affective disorder (SAD). With a larger sample size and a longer duration of treatment, we compared dawn simulation with bright light therapy and a placebo condition in patients with SAD. METHOD: Medication-free patients with SAD were randomly assigned to one of three conditions: bright light therapy (10,000 lux for 30 min, from 6:00 AM to 6:30 AM), dawn simulation (1.5 hour dawn signal from 4:30 AM to 6:00 AM peaking at 250 lux), and a placebo condition, a dim red light (1.5 hour dawn signal from 4:30 am to 6:00 AM peaking at 0.5 lux.) Over the subsequent 6 weeks, the subjects were blindly rated by a psychiatrist using the Structured Interview Guide for the Hamilton Depression Rating-Seasonal Affective Disorder Version (SIGH-SAD). We modeled the profiles of the remissions (SIGH-SAD < or = 8) and response (> or =50% decrease in SIGH-SAD) to treatment over time using Cox proportional hazards models. RESULTS: The sample consisted of 95 subjects who were randomized to the three conditions: bright light (n = 33), dawn simulation (n = 31) and placebo (n = 31). Dawn simulation was associated with greater remission (p <.05) and response (p <.001) rates compared to the placebo. Bright light did not differ significantly from the placebo. Dawn simulation was associated with greater remission (p <.01) and response (p <.001) rates compared to the bright light therapy. The mean daily hours of sunshine during the week before each visit were associated with a significant increase in likelihood of both remission (p <.001) and response (p <.001). CONCLUSIONS: Dawn simulation was associated with greater remission and response rates compared to the placebo and compared to bright light therapy. The hours of sunshine during the week before each assessment were associated with a positive clinical response.

Estrogen replacement therapy moderates the sleep disruption associated with nocturnal blood sampling.

STUDY OBJECTIVES: To determine whether chronic oral estrogen replacement therapy (ERT) (1) improves the sleep of older, non-symptomatic postmenopausal women; and (2) reduces the sleep disruption associated with a stressor (frequent remote nocturnal blood-sampling through an intravenous catheter). DESIGN: Descriptive, cross-sectional, secondary analysis of a larger study. SETTING: The General Clinical Research Center at the University of Washington Medical Center. PARTICIPANTS: Women aged 57-80 (mean age = 70) at least 5 years past menopause were recruited from the community. Hot flashes and significant sleep difficulties were exclusion criteria. The ERT group (n=37) consisted of women on chronic oral ERT for > or = 2 years. The NERT group (n=56) consisted of women not using estrogen (NERT) for > or = 2 years. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Following an adaptation night, polysomnographic measures were collected for 2 consecutive nights. A blood sample was collected every 20 minutes for the last 24 hours (including Night 2), through an intravenous catheter. The only group difference in sleep on the baseline (non-catheter) night was that NERT women had a shorter sleep latency. Sleep on the catheter night was characterized by increased wakefulness, longer sleep latency, and decreased REM sleep for both groups relative to the baseline. However, the impact of nocturnal blood sampling was much greater for NERT than for ERT women: they experienced significantly greater percent changes in more sleep-wake variables, particularly slow-wave sleep (SWS). CONCLUSIONS: In this cross-sectional study, the use of chronic oral ERT was associated with little effect on the sleep of older postmenopausal women not experiencing hot flashes, except in the presence of a challenge to sleep. ERT ameliorated the disruptive effect of nocturnal blood sampling on both objectively assessed and subjectively assessed sleep.

Treating age-related changes in somatotrophic hormones, sleep, and cognition.

Many of the body's systems that function to maintain optimal health and well-being decline with advancing age. Aerobic capacity, muscle mass, and strength all progressively decline. Significant sleep disturbances are associated with increases in morbidity and mortality. Cognition declines, impacting an older individual's ability to function independently. Interventions that could at least stabilize or possibly improve functional capacity, sleep quality, and cognitive function have the theoretical potential to prolong an older individual's ability to live independently, and interest in their possible utility is growing rapidly. One such intervention may be stimulation of the "somatotrophic" axis via growth hormone-releasing hormone (GHRH). Here we review the evidence for such somatotrophic interventions. We also report preliminary findings on the effects of chronic GHRH treatment on the somatotrophic hormones, body composition, functional status, sleep, and cognitive function of healthy older men and women from two major GHRH intervention studies, one recently completed and the other ongoing.

Effective treatment of sleep disturbances in older adults.

Sleep disturbance is a common and complex clinical problem, particularly in older adults. With advancing age, the normal sleep cycle begins to break down, resulting in a reduction in the deeper stages of sleep and an often-profound increase in the fragmentation of nighttime sleep by periods of intrusive wakefulness. Sleep disorders exacerbate these age-related changes, leading to reports of daytime fatigue, sleepiness, and impaired daily function. The resultant chronic sleep deprivation invariably leads to often-unsuccessful attempts by the patient to overcome the problem. Patients may stay in bed longer, take more naps during the day, or seek out agents that putatively restore normal sleep patterns. Paradoxically, these efforts often result in exacerbation of the sleep disturbance. This review delineates the common causes of disordered sleep in older persons. Further, it reviews effective diagnostic approaches and treatments for these conditions, including limitations of hypnotic medications and melatonin.

Effective treatments for age-related sleep disturbances.

Fundamental changes in sleep patterns are associated with normal aging, but disturbed sleep with resultant daytime sleepiness and fatigue is an extremely common occurrence among older persons and a frequent catalyst for physician visits. Sleep disorders result from multiple factors--including pharmacologic, physiologic, biologic, and behavioral--and can be mildly debilitating or life-threatening. Diagnosis includes consideration of the presence of physical or mental illness, drug and/or alcohol use or abuse, a primary sleep disorder such as sleep-disordered breathing or periodic limb movements during sleep, changes in circadian rhythms, or poor sleep hygiene. Despite a high rate of use, hypnotics are best suited for periodic rather than chronic sleep disorder symptoms and, in general, should be used only after adjustments in sleep hygiene prove unsuccessful as first-line therapy.

Growth hormone in postmenopausal women after long-term oral estrogen replacement therapy.

Studies of estrogen effects on growth hormone (GH) and its pulsatile release in postmenopausal women have typically utilized estrogen replacement therapy (ERT) of relatively short duration (days to weeks). The purpose of this study was to compare GH measures from healthy postmenopausal women who were on oral ERT for 3 years or more (n = 24; mean ERT duration = 16.1 years) with women not on ERT (NERT; n = 40). Blood samples were drawn remotely every 20 min for 24 h and then analyzed for mean 24-h GH, mean GH during sleep, and mean 24-h insulin-like growth factor-I (IGF-I). GH peak analyses were also performed. Mean 24-h GH and GH during sleep were significantly higher and IGF-I was significantly lower in ERT women compared with NERT women. In addition, use of long-term ERT was associated with more GH peaks relative to women not on ERT, but no change in GH peak amplitude or area. GH was not related to age in either group. GH was strongly and negatively correlated with measures of adiposity in NERT women but not in ERT women. In conclusion, long-term oral ERT is associated with increased circulating GH and decreased IGF-I levels, even after many years of treatment.

Successful behavioral treatment for reported sleep problems in elderly caregivers of dementia patients: a controlled study.

Although sleep problems are common among dementia caregivers, there has been no research thus far describing treatment of such problems using behavioral techniques. In this study, 36 elderly dementia caregivers with disturbed sleep were randomly assigned to either a brief behavioral intervention or a wait list control. The active treatment consisted of standard sleep hygiene, stimulus control, and sleep compression strategies as well as education about community resources, stress management, and techniques to reduce patient disruptive behaviors. Caregivers in active treatment showed significant improvements in sleep at post-treatment and 3-month follow up. No significant differences between groups were observed for caregiver mood, burden, or patient behavior problems, suggesting that sleep improvements were not an artifact of depression treatment. Treatment responders tended to be younger and more compliant with treatment recommendations than non-responders. Results suggest that behavioral techniques may well be a viable alternative to medication for sleep problems in aging caregivers.

Factors of the insulin resistance syndrome in nondiabetic and diabetic elderly Japanese-American men.

Factor analysis has previously identified four independent factors that characterize the insulin resistance syndrome in women, interpreted as 1) weight/waist, 2) lipids, 3) insulin/glucose, and 4) systolic and diastolic blood pressure. Because it is not known whether similar factors emerge for men, or for diabetics, factor analysis was used to investigate the clustering of features characterizing the insulin resistance syndrome using data from 3,159 elderly (71-93 years) Japanese-American men participating in the fourth examination of the Honolulu Heart Program during 1991-1993. Consistent with previous results, factor analysis reduced eight risk factors (insulin, glucose, systolic blood pressure, diastolic blood pressure, triglycerides, high-density lipoprotein cholesterol, weight, and waist circumference) to four uncorrelated factors that explained 78.2% and 74.7% of the variance in nondiabetics (n = 2,760) and diabetics (n = 399), respectively. These factors were interpreted as 1) weight/waist, 2) blood pressure, 3) lipids, and 4) insulin/glucose. Modest differences in the associations between fasting insulin and factors 1, 3, and 4 were noted for diabetics. These consistently identified composite factors may represent markers for underlying pathophysiologic mechanisms of the insulin resistance syndrome and risk of non-insulin-dependent diabetes mellitus.

Memory-scanning task performance in Alzheimer's disease.

Individuals with mild Alzheimer's Disease (AD) and healthy normal control (NC) older adults performed a varied-set version of the Sternberg memory-scanning task with Set Sizes 1, 2, 3, and 4. The AD group (N = 23) had slower and more variable reaction times (RT) than the NC group (N = 38). RT differences between groups were bigger for NO than for YES responses. The linear relationship between RT and set size was not as strong for the AD group as for the NC group. However, in contrast to earlier studies with fewer subjects, participants with AD and healthy older individuals did not differ in the rate at which they scan items in the memory set.

Potential applications of GH secretagogs in the evaluation and treatment of the age-related decline in growth hormone secretion.

The two classes of GH secretagogs--GH-releasing hormone (GHRH) and the GH-releasing peptides and their analogs (GHRP's)--retain their ability to endogenous GH secretion in healthy and frail elderly subjects. They have very limited utility in assessment of the state of the GH/IGF-I axis except to confirm an intact pituitary, but they are attractive potential alternatives to GH as therapeutic agents. There is wide interest in the possibility that elevating GH and IGF-I might increase muscle mass, physical strength and performance, and possible sleep and cognition in aging. The GH secretagogs, like GH, can produce a sustained stimulation of this axis; in contrast to GH, they preserve feedback regulation at the pituitary level and stimulate a near-physiologic pulsatile pattern of GH release. GHRP's and their nonpeptide analogs are also active when given orally, a significant practical advantage. Short-term treatment studies have shown that GHRH and the GHRP's can enhance GH secretion and elevate IGF-I and IGFBP-3 levels; that GHRH may promote sleep; and that these agents are generally well tolerated. Longer-term studies assessing effects upon body composition and physical and psychological function are underway.

Circadian temperature and cortisol rhythms during a constant routine are phase-delayed in hypersomnic winter depression.

Circadian temperature, cortisol, and thyroid-stimulating hormone (TSH) rhythms during a constant routine were assessed in 6 female controls and 6 female patients with hypersomnic winter depression (seasonal affective disorder, SAD) before and after morning bright light treatment. After sleep was standardized for 6 days, the subjects were sleep-deprived and at bed rest for 27 hours while rectal temperature, cortisol, and TSH levels were assessed. The minimum of the fitted rectal temperature rhythm was phase-delayed in the SAD group compared to the controls 5:42 AM vs. 3:16 AM (p < .005); with bright light treatment, the minimum advanced from 5:42 AM to 3:36 AM (p = .06). The minimum of the cortisol rhythm was phase-delayed in the SAD group compared to the control group, 12:11 AM vs. 10:03 PM (P < .05); with bright light treatment, the minimum advanced from 12:11 AM to 10:38 PM (P = .06) [corrected]. The acrophase of the TSH rhythm was not significantly phase-delayed in SAD subjects compared to control, though the trend appeared to be toward a phase-delay (p = .07). After bright light therapy, the TSH acrophase was not significantly different in the SAD subjects; the trend was a phase-advance (p = .09). Overall, the data suggest that circadian rhythms are phase-delayed relative to sleep in SAD patients and that morning bright light phase-advances those rhythms.

Successful 6-month endurance training does not alter insulin-like growth factor-I in healthy older men and women.

BACKGROUND: Lean body mass, strength, and endurance decline with advancing age, changes paralleled by declines in anabolic hormones, including growth hormone (GH) and insulin-like growth factor-I (IGF-I). Acute exercise has been shown to stimulate the GH/IGF-I axis, and long-term exercise increases GH. This study examined the effect of endurance training on IGF-I in healthy older men and women. METHODS: Thirty-one healthy older men (66.9 +/- 1.0 yrs, mean +/- SEM) and 21 healthy older women (67.1 +/- 1.7 yrs) were randomized to either 3d/wk, 6-month endurance (ET3) or stretching/flexibility (SF3) protocols. Another group of 15 healthy older men (69.0 +/- 1.3 yrs) participated in a more intensive 5d/wk, 6-month endurance protocol (ET5). Before and after training, subjects were weight stabilized and participated in maximal exercise tolerance testing, body composition assessment, and fasting blood sampling. RESULTS: ET3 training resulted in a significant increase (14%) in maximal aerobic power (VO2max), significant decreases in body weight (BW), fat mass (FM), and waist/hip ratio (WHR), and a significant increase in fat-free mass (FFM). No significant VO2max or body composition changes were observed in the SF3 group. For the ET5 group, a significant increase (22%) in VO2max and significant decrease in BW, FM, and WHR were observed. No significant changes in IGF-I were observed for any of the three groups. Pre- versus post-training IGF-I values were very stable (r = .86, p < .001) across subjects. CONCLUSIONS: Within-subject basal levels of IGF-I in healthy seniors were extremely stable between pre- and post-training assessments. Two endurance training protocols of magnitudes sufficient to significantly increase aerobic capacity and decrease measures of body adiposity did not significantly increase basal levels of IGF-I in healthy older men and women.

Sleep, alcohol and alcohol abuse.

Use and abuse of alcohol is extremely common in many countries. Sometimes alcohol may be used to self-treat insomnia. However, alcohol consumption for any reason will affect an individual's sleep quality. The effects of alcohol use and abuse on sleep are complex and interactive. Anyone who consumes alcohol is likely to observe them, although the particular pattern and severity of the sleep impairment will differ with both the amount and duration of alcohol consumption. The fact that alcohol is a sedative and can induce rapid onset of sleep may contribute to its use, while the resultant disturbance of night-time sleep quality and of respiration may possibly result in post-consumptive daytime impairment. The persistent sleep disturbance that accompanies both acute and chronic alcohol abstinence syndromes may contribute to the continued craving and urge to resume drinking seen among chronic alcoholics. This review broadly examines the interaction of alcohol consumption and sleep disturbance. Beginning with a brief overview of normal sleep it examines the effects of modest acute alcohol consumption on sleep, sleepiness, night-time respiration and cognitive function; examines the sleep patterns of chronic alcoholics both while drinking and during acute and chronic alcohol withdrawal; reviews what is known of the relationship between alcohol use and night-time respiratory dysfunction; and concludes with some reflections on the implications of this information for drinking practices.

Effects of endurance training on the circadian rhythm of fibrinolysis in men and women.

This randomized study compared the fibrinolytic circadian rhythm of healthy older men and older women (average age 66 +/- 5), before and after 6 months of endurance training versus stretching controls. Compared with men, women at baseline had similar rhythms for tissue plasminogen activator (t-PA) activity and plasminogen activator inhibitor 1 (PAI-1) activity, but lower levels of total t-PA antigen. In men (N = 16), endurance training increased VO2max 15% (P < 0.001), while decreasing PAI-1 activity 37% (P = 0.034) and total t-PA antigen 18% (P = 0.0003) between midnight and 6 a.m., but did not affect t-PA activity. In women (N = 9), endurance training increased VO2max 18% (P = 0.003), and increased t-PA activity 20% (P = 0.027) and total t-PA antigen 55% (P = 0.007) between 10 p.m. and 4 a.m., but had no effect on PAI-1 activity. After endurance training there were no significant differences in the fibrinolytic circadian rhythm of men versus women. Six months of nonaerobic stretching had no effect on VO2max or fibrinolysis in men (N = 11) or women (N = 8). This study indicates that potentially favorable changes occur in fibrinolytic factors after endurance training in older men and older women.