Later sleep timing and social jetlag are related to increased inflammation in a population with a high proportion of OSA: findings from the Cleveland Family Study.

STUDY OBJECTIVES: To examine the association between sleep midpoint and inflammation in a population with a large proportion of individuals diagnosed with obstructive sleep apnea syndrome (OSAS), a group that is already prone to increased inflammation. METHODS: Subjects from the Cleveland Family Study underwent overnight polysomnography and completed surveys on sleep habits. Morning and evening blood samples were collected and assayed for proinflammatory biomarkers interleukin (IL)-1, IL-6, and tumor necrosis factor α (TNF-α). Linear regression models were used, adjusting for potential confounders and sleep duration. RESULTS: The study population included 587 adults (52.3% with OSAS). Mean ± standard deviation weekday sleep midpoint was 3.52 ± 2.09 (3:31 am) and weekend sleep midpoint was 4.46 ± 1.69 (4:28 am). The Mean difference between weekday and weekend sleep midpoint (social jetlag) was 0.94 ± 2.08 hours. After adjusting for OSA severity, greater social jetlag was associated with higher levels of the inflammatory cytokine IL-1 (beta: 0.435 pg/mL, 95% confidence interval [CI]: 0.091 to 0.779). Additionally, later timing of sleep during both the weekdays and the weekends was associated with increased levels of IL-6 (weekday beta: 0.182 pg/mL; 95% CI: 0.013 to 0.350; and weekend beta: 0.188 pg/mL; 95% CI: 0.004 to 0.373). No trends were observed with TNF-α and any sleep exposure. CONCLUSIONS: Later sleep timing was associated with elevated levels of IL-6 while increased social jetlag was associated with elevated levels of IL-1. Our results indicate that later sleep schedules and increased social jetlag may lead to higher inflammation, even after controlling for OSA severity. CITATION: Girtman KL, Baylin A, O'Brien LM, Jansen EC. Later sleep timing and social jetlag are related to increased inflammation in a population with a high proportion of OSA: findings from the Cleveland Family Study. J Clin Sleep Med. 2022;18(9):2179-2187.

Adverse Effect of Circadian Rhythm Disorder on Reparative Angiogenesis in Hind Limb Ischemia.

Background Circadian rhythm disorders, often seen in modern lifestyles, are a major social health concern. The aim of this study was to examine whether circadian rhythm disorders would influence angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia. Methods and Results A jet-lag model was established in C57BL/6J mice using a light-controlled isolation box. Control mice were kept at a light/dark 12:12 (12-hour light and 12-hour dark) condition. Concentrations of plasma vascular endothelial growth factor and circulating endothelial progenitor cells in control mice formed a circadian rhythm, which was diminished in the jet-lag model (P<0.05). The jet-lag condition deteriorated tissue capillary formation (P<0.001) and tissue blood perfusion recovery (P<0.01) in hind limb ischemia, which was associated with downregulation of vascular endothelial growth factor expression in local ischemic tissue and in the plasma. Although the expression of clock genes (ie, Clock, Bmal1, and Cry) in local tissues was upregulated after ischemic injury, the expression levels of cryptochrome (Cry) 1 and Cry2 were inhibited by the jet-lag condition. Next, Cry1 and Cry2 double-knockout mice were examined for blood perfusion recoveries and a reparative angiogenesis. Cry1 and Cry2 double-knockout mice revealed suppressed capillary density (P<0.001) and suppressed tissue blood perfusion recovery (P<0.05) in the hind limb ischemia model. Moreover, knockdown of CRY1/2 in human umbilical vein endothelial cells was accompanied by increased expression of WEE1 and decreased expression of HOXC5. This was associated with decreased proliferative capacity, migration ability, and tube formation ability of human umbilical vein endothelial cells, respectively, leading to impairment of angiogenesis. Conclusions Our data suggest that circadian rhythm disorder deteriorates reparative ischemia-induced angiogenesis and that maintenance of circadian rhythm plays an important role in angiogenesis.

Changes in the Biorhythms of Biochemical Parameters in Animals with Modeled Acute Desynchronosis.

This article describes models for the study of acute desynchronosis: jetlag syndrome and acute desynchronosis under physical stress for possible pharmacological correction of these disorders. The cosinor analysis allowed assessing significance of changes in biological rhythms in 2 biological models: the jetlag-type diurnal rhythm shift model and the model with changed light mode. The revealed changes in the rhythms of biochemical parameters in the blood serum of animals with acute desynchronosis indicate significant changes in the intensity of carbohydrate-lipid metabolism, which affected the processes of cell bioenergetics. These changes are most pronounced in the group of animals that were kept under conditions of constant darkness, which can serve as a marker of the initial stage of pathological desynchronosis. The jetlag-type model can be used to evaluate the effectiveness of the pharmacological correction of physiological desynchronosis. The model with modified light regimen can be used for evaluation of the effectiveness of pharmacological correction of pathological desynchronosis.

The erythrocyte membrane stability is associated with sleep time and social jetlag in shift workers.

The osmotic stability of the erythrocyte membrane (OSEM) has been associated with changes in lipid profile, blood glucose and blood pressure. Changes in these parameters are very frequent in shift workers, possibly because of the lack of synchronization of biological rhythms, which results in the social jetlag. However, the existence of association between OSEM and circadian misalignment has not been investigated in this population. Therefore, this study investigated whether shift work, sleep time and social jetlag (SJL) are associated with biochemical and hematological variables. A population consisting of 79 men working at night (n = 37) or during the day (n = 42), aged between 21 and 65 years and with a mean BMI of 27.56 ± 4.0 kg/m2, was investigated cross-sectionally in relation to sleep time, SJL, anthropometric (height, weight and waist circumference) and blood variables, with emphasis on the OSEM. SJL was calculated by the absolute difference between the midpoint of sleep on work and rest days. The Generalized Linear Model (GzLM) was used to investigate the existence of associations between SJL and average sleep time in relation to the analyzed variables. Workers without SJL presented lower baseline lysis values of erythrocytes in isotonic medium in relation to workers with SJL. In addition, workers who slept on average less than 6 hours had higher OSEM, and higher total and LDL-cholesterol in relation to those who slept more than 6 hours, regardless of the shift. It is possible that the association of sleep deprivation and SJL with erythrocyte membrane stability is mediated through changes in the lipid profile.

Association of Self-Reported Sleep and Circadian Measures With Glycemia in Adults With Prediabetes or Recently Diagnosed Untreated Type 2 Diabetes.

OBJECTIVE: Sleep disturbances and circadian misalignment (social jet lag, late chronotype, or shift work) have been associated with worse glycemic control in type 2 diabetes (T2D). Whether these findings apply to adults with prediabetes is yet unexplored. We hypothesized that self-reported short sleep, poor sleep quality, and/or circadian misalignment are associated with higher glycemia, BMI, and blood pressure (BP) in adults with prediabetes or recently diagnosed, untreated T2D. RESEARCH DESIGN AND METHODS: Our cohort included 962 overweight/obese adults ages 20-65 years with prediabetes or recently diagnosed, untreated T2D who completed a 2-h oral glucose tolerance test and validated sleep questionnaires. Independent associations of sleep and circadian variables with glycemia, BMI, and BP were evaluated with regression models. RESULTS: The multiethnic cohort was 55% men, with mean ± SD age 52.2 ± 9.5 years and BMI 34.7 ± 5.5 kg/m2. Mean sleep duration was 6.6 ± 1.3 h. Poor sleep quality was reported by 54% and high risk for obstructive sleep apnea by 64%. HbA1c was significantly higher in those reporting <5 or >8 h sleep per night. Sleep duration >8 h was also associated with higher fasting glucose and <6 h with higher BMI. Shift work was also associated with higher BMI. Social jet lag and delayed chronotype were associated with higher BP. CONCLUSIONS: In our cohort, self-reported short and long sleep were both associated with adverse measures of glycemia, and short sleep and shift work were associated with higher BMI. Further research using objective measures of sleep is needed to better delineate the relationship between sleep and glycemia in adults with prediabetes or T2D.

Preventive effect of L-carnitine on the disorder of lipid metabolism and circadian clock of mice subjected to chronic jet-lag.

Circadian clock plays an essential role in orchestrating daily physiology, and its disruption can evoke metabolic diseases such as obesity. L-Carnitine can reduce blood lipid levels, and ameliorate fatty liver through regulating lipid metabolism. However, whether L-Carnitine administration may affect the disturbance of lipid metabolism and circadian rhythm of mice induced by prolonged circadian disruption is still unknown. Herein, we investigated the effects of L-Carnitine on conditions of circadian clock and lipid metabolism through a chronic jet-lag mice model which was developed by reversing 12 h light/12 h dark cycle every 4 days for a continuous 12 weeks. Results showed that L-Carnitine administration significantly decreased levels of serum glutamic-oxaloacetic transaminase (GOT) and triglycerides (TG), which were remarkably elevated by chronic jet-lag. More importantly, quantitative real-time polymerase chain reaction (qRT-PCR) analysis indicated that L-Carnitine supplementation would effectively counteract the negative alterations in gene expression which related to lipid metabolism (Srebp1, Acaca, Fasn, and Scd1), metabolic regulator (mTOR) and circadian rhythm (Bmal1, Per1, Cry1 and Dec1) in the liver of mice subjected to the chronic jet-lag. As a conclusion, L-Carnitine was partly effective in preventing the disruption of circadian clock and lipid metabolic disorders induced by the chronic jet-lag.

Effects of chronic jet lag on the central and peripheral circadian clocks in CBA/N mice.

The disruption of the circadian clock by frequent shifts in the light-dark cycle, such as shift-work or frequent jet lag, increases the risk of many diseases, including cancer. Experimental disruption of the circadian clock also increases tumor development in mice, although most studies used the strains that are genetically impaired in melatonin synthesis and secretion. Here, we examined the effects of experimental chronic jet lag with 8 h advances of the light-dark cycle every 2 days for 10 days on the central and peripheral clocks of CBA/N mice, the strain with normal profiles of melatonin synthesis and secretion. Mice were exposed to constant darkness after the 10 days of chronic jet lag. In the suprachiasmatic nucleus (SCN), chronic jet lag shifted the temporal expression of most clock genes examined without causing total disturbance of circadian oscillations. In the liver, the temporal patterns of Per1, Bmal1, and Dbp expression were phase-shifted, and Per2 expression was significantly upregulated by chronic jet lag. Further, the expression of cell cycle-related genes, c-Myc and p53 in the liver was significantly activated by the chronic jet lag schedule with a significant positive correlation between Per2 and p53 expression. We determined the plasma concentrations of melatonin and corticosterone as candidate hormonal messengers of chronic jet lag, but their overall levels were not affected by chronic jet lag. Moreover, the expression of the MT1 melatonin and glucocorticoid receptors in the liver was suppressed by chronic jet lag. These data suggest that in CBA/N mice, frequent advances of light-dark cycles modify the phases of central clock in the SCN and disturb the peripheral clock in the liver and apoptotic functions, which may be associated with the suppression of hormone receptors.

Effects of ramelteon on insomnia symptoms induced by rapid, eastward travel.

OBJECTIVE: Ramelteon, an MT(1)/MT(2) melatonin receptor agonist, was evaluated for its ability to reduce sleep-onset difficulties associated with eastward jet travel. METHODS: Healthy adults (n=110) with a history of jet lag sleep disturbances were flown eastward across five time zones from Hawaii to the east coast of the US. Ramelteon 1, 4, or 8 mg or placebo was administered 5 min before bedtime (local time) for four nights. Sleep parameters were measured using polysomnography (PSG) on Nights 2, 3, and 4. Next-day residual effects were assessed using psychomotor and memory function tests. RESULTS: Compared to placebo, there was a significant decrease in mean latency to persistent sleep (LPS) on Nights 2-4 with ramelteon 1mg (-10.64 min, P=0.030). No consistent significant differences were observed with ramelteon vs. placebo on measures of next-day residual effects except on Day 4 where participants in all ramelteon groups performed significantly worse on the immediate memory recall test compared with placebo (P < or = 0.05). The incidence of adverse events was similar for ramelteon and placebo. CONCLUSION: After a 5-h phase advance due to eastward jet travel, ramelteon 1mg taken before bedtime for four nights reduced mean LPS relative to placebo in healthy adults.

Associations between jet lag and cortisol diurnal rhythms after domestic travel.

OBJECTIVE: Millions of adults in the United States travel abruptly across time zones each year. Nevertheless, the impact of traveling over relatively short distances (across 3 or fewer time zones) on diurnal patterning of typical physiological response patterns has yet to be studied in a large, epidemiological sample. DESIGN: The current research focuses on 764 middle-aged men comparing variations in diurnal cortisol regulation based on number of time zones traveled eastward or westward the day before. MAIN OUTCOME MEASURE: Participants provided samples of salivary cortisol at waking, 30-min postwaking, 10 a.m., 3 p.m., and bedtime. RESULTS: Eastward travel was associated with a steeper salivary cortisol awakening response (p < .01) and lower peak (PEAK) levels of salivary cortisol the next morning (p < .05). Westward travel was associated with lower peak levels of cortisol the next morning (p < .05). Effect sizes for these differences ranged from Cohen's d = .29 to .47. Differences were not present for 2 days in their home environment. CONCLUSIONS: The results provide evidence that traveling across time zones is associated with diurnal cortisol regulation and should be studied further to understand the subsequent impacts on health and well-being in large national samples.

Measurement of internal body time by blood metabolomics.

Detection of internal body time (BT) via a few-time-point assay has been a longstanding challenge in medicine, because BT information can be exploited to maximize potency and minimize toxicity during drug administration and thus will enable highly optimized medication. To address this challenge, we previously developed the concept, "molecular-timetable method," which was originally inspired by Linné's flower clock. In Linné's flower clock, one can estimate the time of the day by watching the opening and closing pattern of various flowers. Similarly, in the molecular-timetable method, one can measure the BT of the day by profiling the up and down patterns of substances in the molecular timetable. To make this method clinically feasible, we now performed blood metabolome analysis and here report the successful quantification of hundreds of clock-controlled metabolites in mouse plasma. Based on circadian blood metabolomics, we can detect individual BT under various conditions, demonstrating its robustness against genetic background, sex, age, and feeding differences. The power of this method is also demonstrated by the sensitive and accurate detection of circadian rhythm disorder in jet-lagged mice. These results suggest the potential for metabolomics-based detection of BT ("metabolite-timetable method"), which will lead to the realization of chronotherapy and personalized medicine.

Temporal variations of coagulation factor VII activity in mice are influenced by lighting regime.

It was recently reported that the circadian clock machinery controls plasma levels of factor (F) VII, the serine protease triggering blood coagulation. Here, by exploiting the mouse model, this study showed that variations of photoperiod (i.e., winter or summer conditions or simulated chronic jetlag conditions) have a strong impact on plasma FVII activity levels. Under conditions mimicking summer or winter photoperiods, FVII activity showed a clear 24 h rhythmicity. Interestingly, mean daily FVII activity levels were significantly reduced in mice exposed to summer photoperiods. Behavioral activity rhythms under both photoperiods were synchronized to LD cycles, and the amount of activity per 24 h was comparable. The authors also investigated the influence of chronic jetlag (CJL) on the FVII activity rhythms, which can be easily mimicked in mice through continuous abrupt shifts in the lighting schedule. The exposure of mice to simulated CJL of either consecutive westward or consecutive westward and eastward flights for 15 days did not abolish the behavioral activity rhythms but was associated with a period significantly different from 24 h. Intriguingly, both types of CJL exerted a strong influence on FVII activity rhythms, which were virtually suppressed. Moreover, the mean daily FVII activity was significantly lower in the CJL than in the winter photoperiod condition. Taken together, these findings in mice provide novel insights into the modulation of FVII activity levels, which might have implications for human pathophysiology.

Advancing circadian rhythms before eastward flight: a strategy to prevent or reduce jet lag.

STUDY OBJECTIVES: To develop a practical pre-eastward flight treatment to advance circadian rhythms as much as possible but not misalign them with sleep. DESIGN: One group had their sleep schedule advanced by 1 hour per day and another by 2 hours per day. SETTING: Baseline at home, treatment in lab. PARTICIPANTS: Young healthy adults (11 men, 15 women) between the ages of 22 and 36 years. INTERVENTIONS: Three days of a gradually advancing sleep schedule (1 or 2 hours per day) plus intermittent morning bright light (one-half hour approximately 5000 lux, one-half hour of <60 lux) for 3.5 hours. MEASUREMENTS AND RESULTS: The dim light melatonin onset was assessed before and after the 3-day treatment. Subjects completed daily sleep logs and symptom questionnaires and wore wrist activity monitors. The dim light melatonin onset advanced more in the 2-hours-per-day group than in the 1-hour-per-day group (median phase advances of 1.9 and 1.4 hours), but the difference between the means (1.8 and 1.5 hours) was not statistically significant. By the third treatment day, circadian rhythms were misaligned relative to the sleep schedule, and subjects had difficulty falling asleep in the 2-hours-per-day group, but this was not the case in the 1-hour-per-day group. Nevertheless, the 2-hours-per-day group did slightly better on the symptom questionnaires. In general, sleep disturbance and other side effects were small. CONCLUSIONS: A gradually advancing sleep schedule with intermittent morning bright light can be used to advance circadian rhythms before eastward flight and, thus, theoretically, prevent or reduce subsequent jet lag. Given the morning light treatment used here, advancing the sleep schedule 2 hours per day is not better than advancing it 1 hour per day because it was too fast for the advance in circadian rhythms. A diagram is provided to help the traveler plan a preflight schedule.

Immediate effects of an 8-h advance shift of the rest-activity cycle on 24-h profiles of cortisol.

To investigate the adaptation of plasma cortisol profiles to an abrupt phase advance of the rest-activity cycle, eight normal young subjects were submitted in a sleep laboratory to an 8-h advance shift of their sleep-wake and dark-light cycles. The shift was achieved by advancing bedtimes from 2300-0700 to 1500-2300. Blood samples were obtained at 20-min intervals for 68 consecutive hours. The shift resulted within 6-9 h in a 3- to 4-h advance of timings of the nadir of the cortisol profile and of the end of the quiescent period but had no immediate effect on the timing of cortisol acrophase. The quiescent period of cortisol secretion was shortened and fragmented. Thus a major advance shift achieved without enforcing sleep deprivation results in a rapid partial adaptation of the temporal profiles of cortisol but also in a marked disruption of the cortisol quiescent period. Sleep onset was consistently followed by a decrease in cortisol concentrations. Conversely, both sleep-wake and dark-light transitions were consistently associated with cortisol secretory pulses.

Re-entrainment of the circadian rhythms of plasma melatonin in an 11-h eastward bound flight.

We investigated the re-entrainment of melatonin rhythm in an 11-h eastward-bound flight. Eight male subjects participated in the present study. Blood sampling was carried out once before the flight and twice after the flight. During the daytime the subjects were exposed to natural zeitgeber outdoors on the day except the blood sampling. Seven of eight subjects showed antidromic re-entrainment, and the other subject showed orthodromic re-entrainment. The intensity of natural day light in New York amounted to 20 000 lx. As for the direction of the re-entrainment in New York the antidromic re-entrainment is naturally dominant.

Effect of 3 mg melatonin on jet lag syndrome in an 8-h eastward flight.

In order to assess the effect of melatonin on jet lag a field study was undertaken. The process of re-entrainment of circadian melatonin rhythm was investigated in six subjects. Except during 24-h blood sampling, the subjects were exposed to natural zeitgeber (time giver) outdoors and given 3 mg melatonin at 23:00 h. The subjects were exposed to bright sunlight from 3000 to 12000 lx. All of them showed orthodromic re-entrainment with taking melatonin, while two out of the six did not show orthodromic re-entrainment without taking melatonin. Melatonin accelerated the rate of the re-entrainment of the circadian melatonin rhythm. Melatonin was useful to jet travel from Tokyo to Los Angeles.