Christopher M. Depner

Circadian misalignment, as experienced during shiftwork, impairs glucose metabolism and body weight regulation, yet the underlying biochemical mechanisms remain incompletely understood. Characterizing how circadian misalignment alters circulating metabolites provides a promising avenue to help identify these mechanisms. Although data from metabolomics studies have identified circulating metabolites with daily rhythms, it is not comprehensively known which rhythms shift during circadian misalignment and whether such shifts relate to metabolic impairment. We conducted 24-hour (h) metabolomic profiling every 4 h in 14 healthy adults (8 women) aged 26.4 ± 1.2 years (mean ± SD), undergoing a 6-day simulated night-shiftwork protocol. 24-h modeling analyses identified metabolite rhythms influenced by circadian versus behavioral cycles (sleep, food intake) and quantified internal circadian misalignment using acrophase shifts. Metabolic outcomes included glucose homeostasis (test meals) and energy expenditure (EE; whole-room calorimetry). Night-shiftwork produced widespread alterations in metabolite rhythms, with significant internal misalignment in multiple metabolites across pathways including pyrimidine metabolism, bile acid–microbiome signaling, and lipid metabolism. During misalignment, glucose and insulin area under the curve increased ( p < 0.05) and EE decreased ( p < 0.05). Internal misalignment of uridine and glycoursodeoxycholic acid was associated ( p < 0.05) with impaired glucose tolerance, while their circulating concentrations were associated with decreased EE. Misalignment of uridine and glycoursodeoxycholic acid suggests dysregulated pyrimidine and bile acid–microbiome pathways as potential mechanisms linking circadian misalignment to cardiometabolic disease risk.

Study Objectives: We examined the impact of a sleep extension intervention on multiple dimensions of sleep in adults with habitual short sleep duration. Methods: Thirty healthy participants (14 women; aged 23.1 ± 4.5 years; BMI 22.3 ± 2.2 kg/m2 [mean ± SD]) with <6.5 h sleep/night completed a 2-week baseline assessment followed by a 4-week sleep extension intervention (2 h/night increased time in bed). Wrist actigraphy, at-home electroencephalography (EEG; DREEM headband), Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and daily quality/satisfaction and alertness Likert-scales quantified sleep. Results: Baseline total sleep time (TST) was 5.5 ± 0.7 h. During sleep extension, actigraphy time in bed and TST increased (p < .001) by 60.8 ± 46.7 and 46.6 ± 41.1 minutes, respectively, sleep onset shifted earlier (p < .001) by 51.9 ± 64.5 minutes, with regularity similar to baseline. EEG showed increases (all p < .05) in TST (61.8 ± 75.6 minutes), Stage N1 (5.09 ± 6.51 minutes), Stage N2 (39.54 ± 41.78 minutes), rapid eye movement sleep (13.58 ± 28.86 minutes), and wakefulness after sleep onset (4.86 ± 8.03 minutes), with a nonsignificant decrease (p = .07) in sleep efficiency (−1.38 ± 4.15%). Subjective alertness, ISI, PSQI, and ESS each improved (all p < .05) during sleep extension. Conclusion: Our findings help establish efficacy of sleep extension as an experimental intervention the sleep field can leverage across diverse contexts to study potential health benefits of increasing free-living TST. During sleep extension, the largest effects were observed for improved TST and ESS. Alternatively, some sleep dimensions including sleep regularity remained unchanged, highlighting a potential need for developing multi-component interventions that can improve more dimensions of sleep as both short and irregular sleep are linked with adverse health outcomes. Clinical Trials: Biomarkers of Increased Free Living Sleep Time. URL: https://clinicaltrials.gov/study/NCT04214184. ClinicalTRIALS.gov ID: NCT04214184. Statement of Significance We provide a comprehensive evaluation of the effects of a free-living sleep extension intervention on multiple dimensions of sleep health in adults with habitual short sleep duration. Using multiple objective and subjective outcomes, we show that extending time in bed for 4 weeks increases total sleep time and selectively increases N1, N2, and rapid eye movement sleep, while sleep regularity and N3 sleep remain unchanged. Sleep extension also improves subjective sleepiness and sleep quality. These findings help establish sleep extension as an experimental intervention for increasing free-living sleep duration and improving specific dimensions of sleep health. Importantly, the lack of improvement in some dimensions highlights the need for multi-component interventions to address sleep health and related disease risk more fully.

The circadian system maintains optimal biological functions at the appropriate time of day, and the disruption of this organization can contribute to the pathogenesis of cardiometabolic disorders. The timing of eating is a prominent external time cue that influences the circadian system. “Chrononutrition” is an emerging dimension of nutrition and active area of research that examines how timing‐related aspects of eating and nutrition impact circadian rhythms, biological processes, and disease pathogenesis. There is evidence to support chrononutrition as a form of chronotherapy, such that optimizing the timing of eating may serve as an actionable strategy to improve cardiometabolic health. This report summarizes key information from the National Heart, Lung, and Blood Institute's virtual workshop entitled “Chrononutrition: Elucidating the Role of Circadian Biology and Meal Timing in Cardiometabolic Health,” which convened on May 2 to 3, 2023, to review current literature and identify critical knowledge gaps and research opportunities. The speakers presented evidence highlighting the impact on cardiometabolic health of earlier and shorter eating windows and more consistent day‐to‐day eating patterns. The multidimensionality of chrononutrition was a common theme, as it encompasses multiple facets of eating along with the timing of other behaviors including sleep and physical activity. Advancing the emerging field of chrononutrition will require: (1) standardization of terminology and metrics; (2) scalable and precise tools for real‐world settings; (3) consideration of individual differences that may act as effect modifiers; and (4) deeper understanding of social, behavioral, and cultural influences. Ultimately, there is great potential for circadian‐based dietary interventions to improve cardiometabolic health.

The circadian system regulates 24‐h time‐of‐day patterns of cardiovascular physiology, with circadian misalignment resulting in adverse cardiovascular risk. Although many proteins in the coagulation‐fibrinolysis axis show 24‐h time‐of‐day patterns, it is not understood if these temporal patterns are regulated by circadian or behavioral (e.g., sleep and food intake) cycles, or how circadian misalignment influences these patterns. Thus, we utilized a night shiftwork protocol to analyze circadian versus behavioral cycle regulation of 238 plasma proteins linked to cardiovascular physiology. Six healthy men aged 26.2 ± 5.6 years (mean ± SD) completed the protocol involving two baseline days with 8‐h nighttime sleep opportunities (circadian alignment), a transition to shiftwork day, followed by 2 days of simulated night shiftwork with 8‐h daytime sleep opportunities (circadian misalignment). Plasma was collected for proteomics every 4 h across 24 h during baseline and during daytime sleep and the second night shift. Cosinor analyses identified proteins with circadian or behavioral cycle‐regulated 24‐h time‐of‐day patterns. Five proteins were circadian regulated (plasminogen activator inhibitor‐1, angiopoietin‐2, insulin‐like growth factor binding protein‐4, follistatin‐related protein‐3, and endoplasmic reticulum resident protein‐29). No cardiovascular‐related proteins showed regulation by behavioral cycles. Within the coagulation pathway, circadian misalignment decreased tissue factor pathway inhibitor, increased tissue factor, and induced a 24‐h time‐of‐day pattern in coagulation factor VII (all FDR < 0.10). Such changes in protein abundance are consistent with changes observed in hypercoagulable states. Our analyses identify circadian regulation of proteins involved in cardiovascular physiology and indicate that acute circadian misalignment could promote a hypercoagulable state, possibly contributing to elevated cardiovascular disease risk among shift workers.

Short sleep duration is associated with heightened cardiometabolic disease risk and has reached epidemic proportions among children, adolescents and adults. Potential mechanisms underlying this association are complex and multifaceted, including disturbances in circadian timing, food intake and appetitive hormones, brain regions linked to control of hedonic eating, physical activity, an altered microbiome and impaired insulin sensitivity. Sleep extension, or increasing total sleep duration, is an emerging and ecologically relevant intervention with significant potential to advance our understanding of the mechanisms underlying the association between short sleep duration and the risk of cardiometabolic disease. If effective, sleep extension interventions have potential to improve cardiometabolic health across the lifespan. Existing data show that sleep extension is feasible and might have potential cardiometabolic health benefits, although there are limitations that the field must overcome. Notably, most existing studies are short term (2–8 weeks), use different sleep extension strategies, analyse a wide array of cardiometabolic health outcomes in different populations and, frequently, lack adequate statistical power, thus limiting robust scientific conclusions. Overcoming these limitations will require fully powered, randomized studies conducted in people with habitual short sleep duration and existing cardiometabolic risk factors. Additionally, randomized controlled trials comparing different sleep extension strategies are essential to determine the most effective interventions. Ongoing and future research should focus on elucidating the potential cardiometabolic health benefits of sleep extension. Such studies have high potential to generate crucial knowledge with potential to improve health and quality of life for those struggling with short sleep duration. image

Approximately one in three adults in the United States sleeps less than the recommended 7 h per night. Decades of epidemiological data and data from experimental sleep restriction studies demonstrate short sleep duration is associated with adverse cardiometabolic risk, including risk of type 2 diabetes and cardiovascular disease. However, the precise mechanisms underlying this risk are not fully elucidated and there is a lack of sleep-based interventions designed to mitigate such risk. One strategy to overcome these limitations is to develop biomarkers that link habitual short sleep duration with adverse cardiometabolic risk. Such biomarkers could inform biochemical mechanisms, identify new targets for interventions, support precision medicine by identifying individuals most likely to benefit from sleep-based interventions, and ultimately lead to improved cardiometabolic health in people with habitual short sleep durations. Early progress demonstrates proof-of-principle that omics-based technologies are a viable approach to create biochemical signatures (biomarkers) of short sleep duration, primarily derived from acute studies of experimental sleep restriction. Yet, much work remains. Notably, studies that translate early findings from experimental sleep restriction to free-living adults with habitual short sleep duration have high potential to advance the field. Such studies also create an exciting opportunity for larger randomized controlled trials that simultaneously identify biomarkers of habitual short sleep duration and evaluate the efficacy of sleep-based interventions. Ultimately, early progress in developing molecular biomarkers of short sleep duration combined with the prior decades of progress in the sleep and metabolism fields provide the foundation for exciting progress in the biomarker development space.

Although weekend recovery sleep is common, the physiological responses to weekend recovery sleep are not fully elucidated. Identifying molecular biomarkers that represent adequate versus insufficient sleep could help advance our understanding of weekend recovery sleep. Here, we identified potential molecular biomarkers of insufficient sleep and defined the impact of weekend recovery sleep on these biomarkers using metabolomics in a randomized controlled trial. Healthy adults (n = 34) were randomized into three groups: control (CON: 9-h sleep opportunities); sleep restriction (SR: 5-h sleep opportunities); or weekend recovery (WR: simulated workweek of 5-h sleep opportunities followed by ad libitum weekend recovery sleep and then 2 days with 5-h sleep opportunities). Blood for metabolomics was collected on the simulated Monday immediately following the weekend. Nine machine learning models, including a machine learning ensemble, were built to classify samples from SR versus CON. Notably, SR showed decreased glycerophospholipids and sphingolipids versus CON. The machine learning ensemble showed the highest G-mean performance and classified 50% of the WR samples as insufficient sleep. Our findings show insufficient sleep and recovery sleep influence the plasma metabolome and suggest more than one weekend of recovery sleep may be necessary for the identified biomarkers to return to healthy adequate sleep levels.

Despite clear research findings showing that sleeping less than seven hours per night has an array of health consequences, over 1 in 3 American adults report sleeping less than seven hours per night. Many studies exploring the consequences of insufficient sleep are restricted to small sample sizes and are of relatively short duration due to a significant cost of gold-standard polysomnography in terms of participant burden, expense, time, and reliance on trained sleep technicians. Additionally, many studies of short sleep duration use a paradigm of experimental sleep restriction on otherwise healthy sleepers, which excludes people who chronically obtain short sleep duration over months to years. Here, we explore possible solutions to these issues by implementing a sleep extension protocol in 14 adults (average age 20.6±2.5y; +/- SD) with self-reported habitual sleep duration less than 6.5h/night. Participants completed 2 weeks of baseline monitoring (habitual short sleep duration) and then were instructed to increase time in bed to ≥8h/night for four weeks. Sleep was monitored using wrist-actigraphy and the Dreem 2 headband, a wireless dry electrode consumer electroencephalography (EEG) device. Compared to wrist-actigraphy, the Dreem 2 shows minimal systemic skew for nights with data quality over 75% (as assigned by the Dreem algorithm). However, Bland Altman analysis shows significant random error with limits of agreement approximately +/- 70 minutes between actigraphy and the Dreem. Exploration of sleep metrics from the Dreem 2 during baseline short sleep versus sleep extension revealed an increase in total sleep time; increase in all recorded sleep stages; and no significant changes in sleep onset latency, wakefulness after sleep onset, or sleep efficiency. Although several limitations of producing high quality data were identified, the Dreem 2 headband shows promise as a home environment sleep research device. With an improvement in data quality, the Dreem headband, or another wireless consumer sleep device, has the potential to help advance the sleep field in ways that were previously inaccessible with clinical PSG.