Dietary Restriction Impacts Peripheral Circadian Clock Output Important for Longevity in Drosophila.

Circadian clocks may mediate lifespan extension by caloric or dietary restriction (DR). We find that the core clock transcription factor Clock is crucial for a robust longevity and fecundity response to DR in Drosophila. To identify clock-controlled mediators, we performed RNA-sequencing from abdominal fat bodies across the 24 h day after just 5 days under control or DR diets. In contrast to more chronic DR regimens, we did not detect significant changes in the rhythmic expression of core clock genes. Yet we discovered that DR induced de novo rhythmicity or increased expression of rhythmic clock output genes. Network analysis revealed that DR increased network connectivity in one module comprised of genes encoding proteasome subunits. Adult, fat body specific RNAi knockdown demonstrated that proteasome subunits contribute to DR-mediated lifespan extension. Thus, clock control of output links DR-mediated changes in rhythmic transcription to lifespan extension.

Light at night in older age is associated with obesity, diabetes, and hypertension.

Light at night (LAN) has been associated with negative health consequences and metabolic risk factors. Little is known about the prevalence of LAN in older adults in the United States and its association with CVD risk factors. We tested the hypothesis that LAN in older age is associated with higher prevalence of individual CVD risk factors. Five hundred and fifty-two community-dwelling adults aged 63-84 years underwent an examination of CVD risk factor profiles and 7-day actigraphy recording for activity and light measures. Associations between actigraphy-measured LAN, defined as no light vs. light within the 5-hour nadir (L5), and CVD risk factors, including obesity, diabetes, hypertension, and hypercholesterolemia, were examined, after adjusting for age, sex, race, season of recording, and sleep variables. LAN exposure was associated with a higher prevalence of obesity (multivariable-adjusted odds ratio [OR] 1.82 [95% CI 1.26-2.65]), diabetes (OR 2.00 [1.19-3.43]), and hypertension (OR 1.74 [1.21-2.52]) but not with hypercholesterolemia. LAN was also associated with (1) later timing of lowest light exposure (L5-light) and lowest activity (L5-activity), (2) lower inter-daily stability and amplitude of light exposure and activity, and (3) higher wake after sleep onset. Habitual LAN in older age is associated with concurrent obesity, diabetes, and hypertension. Further research is needed to understand long-term effects of LAN on cardiometabolic risks.

Rest-activity rhythm disturbance in liver cirrhosis and association with cognitive impairment.

Cognitive impairment and disturbed sleep-wake rhythms are disabling complications of liver cirrhosis, yet there is limited understanding of how they are related. We tested the hypothesis that alterations of sleep, rest-activity, and light exposure patterns are associated with worse cognition in cirrhosis. A total of 54 ambulatory adult patients with cirrhosis and 41 age-/gender-matched healthy controls wore wrist actigraphy for rest-activity and light measurements and completed Patient-Reported Outcomes Measurement Information System sleep instruments for self-reported sleep quality. We used standard nonparametric descriptors to characterize rest-activity and light patterns, and wake after sleep onset and sleep efficiency to assess objective sleep quality. The NIH Toolbox cognition battery was used for objective cognitive evaluation using T-scores from a demographically adjusted population reference. Spearman's correlation and multivariable models were used to explore associations between measures of cognition, sleep, rest-activity, and light. Cognition was significantly impaired in cirrhosis patients. Sleep quality was worse in cirrhosis patients by subjective and objective measures compared with controls. Cirrhosis patients exhibited fragmented and dampened rest-activity rhythms, lower daytime and higher nighttime light exposure compared with controls. Worse working memory and processing speed was associated with lower daytime activity level, higher rest-activity fragmentation, lower day-to-day stability, and greater nocturnal light exposure. No association was found between cognition and sleep quality. Rest-activity fragmentation and abnormal light exposure patterns are common in patients with liver disease and are associated with the severity of cognitive impairment. Further research is needed to investigate the effects of timed bright light and exercise intervention on cognitive function in patients with liver disease.

Autonomic dysregulation and sleep homeostasis in insomnia.

STUDY OBJECTIVES: Insomnia is common in older adults, and is associated with poor health, including cognitive impairment and cardio-metabolic disease. Although the mechanisms linking insomnia with these comorbidities remain unclear, age-related changes in sleep and autonomic nervous system (ANS) regulation might represent a shared mechanistic pathway. In this study, we assessed the relationship between ANS activity with indices of objective and subjective sleep quality in older adults with insomnia. METHODS: Forty-three adults with chronic insomnia and 16 age-matched healthy sleeper controls were studied. Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), objective sleep quality by electroencephalogram spectral components derived from polysomnography, and ANS activity by measuring 24-h plasma cortisol and norepinephrine (NE). RESULTS: Sleep cycle analysis displayed lower slow oscillatory (SO: 0.5-1.25 Hz) activity in the first cycle in insomnia compared to controls. In insomnia, 24-h cortisol levels were higher and 24-h NE levels were lower than controls. In controls, but not in insomnia, there was a significant interaction between NE level during wake and SO activity levels across the sleep cycles, such that in controls but not in insomnia, NE level during wake was positively associated with the amount of SO activity in the first cycle. In insomnia, lower 24-h NE level and SO activity in the first sleep cycle were associated with poorer subjective sleep quality. CONCLUSION: Dysregulation of autonomic activity may be an underlying mechanism that links objective and subjective measures of sleep quality in older adults with insomnia, and potentially contribute to adverse health outcomes.

Circadian Gene Expression Rhythms During Critical Illness.

OBJECTIVES: Core clock genes regulate tissue-specific transcriptome oscillations that synchronize physiologic processes throughout the body, held in phase by the central circadian rhythm. The central circadian rhythm rapidly dampens with onset of critical illness, but the effect of critical illness on gene expression oscillations is unknown. The objective of this study was to characterize the rhythmicity and phase coherence of core clock genes and the broader transcriptome after onset of critical illness. DESIGN: Cross-sectional study. SETTING: ICUs and hospital clinical research unit. PATIENTS: Critically ill patients within the first day of presenting from the community and healthy volunteers. INTERVENTIONS: Usual care (critically ill patients) and modified constant routine (healthy volunteers). MEASUREMENTS AND MAIN RESULTS: We studied 15 critically ill patients, including 10 with sepsis and five with intracerebral hemorrhage, and 11 healthy controls. The central circadian rhythm and rest-activity rhythms were profiled by continuous wrist actigraphy, and serum melatonin sampled every 2 hours along with whole blood for RNA isolation over 24 hours. The gene expression transcriptome was obtained by RNA sequencing. Core clock genes were analyzed for rhythmicity by cosinor fit. Significant circadian rhythmicity was identified in five of six core clock genes in healthy controls, but none in critically ill patients. TimeSignature, a validated algorithm based on 41 genes, was applied to assess overall transcriptome phase coherence. Median absolute error of TimeSignature was higher in individual critically ill patients than healthy patients (4.90 vs 1.48 hr) and was correlated with encephalopathy severity by Glasgow Coma Scale in critically ill patients (rho, -0.54; p = 0.036). CONCLUSIONS: Gene expression rhythms rapidly become abnormal during critical illness. The association between disrupted transcriptome rhythms and encephalopathy suggests a path for future work to elucidate the underlying pathophysiology.

Strengthening sleep-autonomic interaction via acoustic enhancement of slow oscillations.

Slow-wave sleep (SWS) is important for overall health since it affects many physiological processes including cardio-metabolic function. Sleep and autonomic nervous system (ANS) activity are closely coupled at anatomical and physiological levels. Sleep-related changes in autonomic function are likely the main pathway through which SWS affects many systems within the body. There are characteristic changes in ANS activity across sleep stages. Notably, in non-rapid eye-movement sleep, the progression into SWS is characterized by increased parasympathetic activity, an important measure of cardiovascular health. Experimental manipulations that enhance slow-wave activity (SWA, 0.5-4 Hz) can improve sleep-mediated memory and immune function. However, effects of SWA enhancement on autonomic regulation have not been investigated. Here, we employed an adaptive algorithm to deliver 50 ms sounds phase-locked to slow-waves, with regular pauses in stimulation (~5 s ON/~5 s OFF), in healthy young adults. We sought to determine whether acoustic enhancement of SWA altered parasympathetic activity during SWS assessed with heart rate variability (HRV), and evening-to-morning changes in HRV, plasma cortisol, and blood pressure. Stimulation, compared with a sham condition, increased SWA during ON versus OFF intervals. This ON/OFF SWA enhancement was associated with a reduction in evening-to-morning change of cortisol levels and indices of sympathetic activity. Furthermore, the enhancement of SWA in ON intervals during sleep cycles 2-3 was accompanied by an increase in parasympathetic activity (high-frequency, HRV). Together these findings suggest that acoustic enhancement of SWA has a positive effect on autonomic function in sleep. Approaches to strengthen brain-heart interaction during sleep could have important implications for cardiovascular health.

Habitual light exposure relative to circadian timing in delayed sleep-wake phase disorder.

Study Objectives: To compare melatonin timing, a well-validated marker for endogenous circadian phase, and habitual light-exposure patterns in adults with delayed sleep-wake phase disorder (DSWPD) and intermediate chronotype controls. Methods: Twelve individuals with DSWPD (five females, mean age: 31.1) and 12 age-matched controls (six females, mean age: 33.6) underwent a minimum of 7 days of light and activity monitoring followed by an inpatient hospital stay, where blood was taken to assess melatonin timing (calculated as dim light melatonin onset-DLMO). Habitual light-exposure patterns were then compared with a human phase-response curve (PRC) to light. Results: Relative to clock time, individuals with DSWPD had a later light-exposure pattern compared with controls, but their light-exposure pattern was earlier relative to DLMO. According to the human PRC to light, individuals with DSWPD had less daily advancing light exposure compared with controls. The primary difference was seen in the late portion of the advancing window, in which individuals with DSWPD were exposed to fewer pulses of light of equivalent duration and intensity compared with controls. Conclusions: Diminished advancing light exposure may play a role in the development and perpetuation of delayed sleep-wake timing in individuals with DSWPD. Enhancing light exposure during the later portion of the advancing window represents an innovative and complementary strategy that has the potential to improve the effectiveness of bright light therapy in DSWPD.

Handicap principle implies emergence of dimorphic ornaments.

Species spanning the animal kingdom have evolved extravagant and costly ornaments to attract mating partners. Zahavi's handicap principle offers an elegant explanation for this: ornaments signal individual quality, and must be costly to ensure honest signalling, making mate selection more efficient. Here, we incorporate the assumptions of the handicap principle into a mathematical model and show that they are sufficient to explain the heretofore puzzling observation of bimodally distributed ornament sizes in a variety of species.