Human circadian health

Humans live with diverse daily schedules, lifestyles, and food preferences; these choices may affect health and wellbeing. Circadian regulation of the endocrine system, autonomic nervous system, and nutrient metabolism contributes to metabolic and physiological homeostasis. Indeed, because the circadian rhythms are influenced by external cues including food intake, light exposure, and social pressures, there is a complicated feedback between circadian physiology and behavior. Experimental animal models and epidemiological data indicate that chronic circadian rhythm disruption increases the risk of metabolic diseases (Panda, Science, 354:1008–1015). When chronic circadian disruption adversely affects sleep patterns, it provokes cognitive and mood changes (Wright et al, Front Mol Neurosci, 5:50). Shift-workers, adolescents, and other people who have disrupted sleep patterns are at risk of both short term cognitive and long term health problems. During puberty, the adolescent circadian system naturally delays the onset of sleep to a later time through lengthening of the circadian period. This natural change in sleep preference is in contrast to typical high school schedules which require attendance between 7 and 8AM. Since 2014, the American Academy of Pediatrics (AAP) recommends delaying school start times until 8:30AM for adolescents. Both shift workers and adolescents often suffer from social jetlag: a change in sleep schedule from one day to another, due to social factors like work shift change or weekday-weekend behavior differences.

In work with Horacio de La Iglesia (University of Washington) I am analyzing sleep, movement, and light exposure data from high school students before and after their school start time was delayed by an hour. The Seattle School District decided to delay the start time for secondary schools from 7:50 to 8:45AM. This change was implemented for the 2016–2017 academic year and allowed us to conduct a pre-/post-study in which we measured sleep-wake cycles using wrist activity devices (Philips Actiwatch Spectrum Plus) during the spring of 2016 (pre) and the spring of 2017 (post). The study populations included sophomores of two public high schools in Seattle. In each year, at the same time of the year, an independent sample of students taking the same science class was studied in each school. The was an increase in the daily median sleep duration of 34 min post as compared to pre, associated with a 4.5% increase in the median grades of the students and an improvement in attendance. Importantly, social jet lag (difference in sleep schedule between schooldays and non-school days) was reduced in the post period. The onset of light bright enough to inhibit of melatonin release (and therefore affect circadian timing) was significantly later in the post period, but the offset of light that bright was the same for both years. However, while it is possible that the light exposure changes could induce further circadian changes, the sleep data did not show that. The difference in sleep duration reported above came from a change in sleep onset, not offset. In total, the results of this paper support the 2014 AAP guidelines for delayed school start times. Further work on this topic is currently underway. We are seeking to understand if the positive changes observed in 2017 continue, and also to find out if there are seasonal differences in sleep and light exposure that correlate with academic performance or mood.

• GP Dunster, L de la Iglesia, M Ben-Hamo, C Nave, JG Fleischer, S Panda, HO de la Iglesia (2018). Sleepmore in Seattle: Later school start times are associated with more sleep and better performance in high school students. Science Advances, 4 (12), eaau6200.

In work with Satchindananda Panda (Salk Institute) I am analyzing data from metabolic blood biomarkers, continuous blood glucose monitors, movement, sleep, and light exposure data from adult study participants to understand the role of Time Restricted Eating (TRE) in controlling metabolic disease. TRE is an emerging dietary intervention that aims to maintain a consistent daily cycle of feeding and fasting to support robust circadian rhythms (Panda, Science, 354:1008–1015). TRE emphasizes a limited and consistent daily eating duration that does not need to involve caloric restriction. TRE reduces body weight, improves glucose and insulin profiles, and reduces insulin resistance in mouse models, even in the presence of a high-fat diet. TRE in humans is less well studied, but has shown promise in controlling weight and metabolic blood markers in a half dozen small controlled studies of both healthy and overweight individuals. One open question is whether the particular time window matters in TRE, or if the benefits are to be seen regardless of if the window of eating starts earlier in the day or later in the day. In our study 15 patients at risk for for Type 2 Diabetes were randomized to either an early (8am start) or late (12pm start) TRE protocol that allowed a 9 hour eating window. The study used a cross-over design; after 1 week in a TRE protocol participants had a two week washout period and then switched to the other TRE protocol for one week. Patients were assessed in both continuous blood glucose readings and via blood panels at certain test points. We observed that while only the early TRE protocol lowered mean fasting glucose, both early and late TRE protocols improved glycemic responses to a test meal.

• AT Hutchison, P Regmi, ENC Manoogian, JG Fleischer, GA Wittert, S Panda, LK Heilbronn. (2019) Time-restricted feeding improves glucose tolerance in men at risk of type 2 diabetes: a randomized crossover trial. Obesity, 27:724–732.

Another question is if TRE may help as an add-on treatment for patients with metabolic disease who are already receiving standard of care. In our study 19 participants with metabolic syndrome, the majority of whom were on a statin and/or antihypertensive therapy, underwent 10 hour duration TRE for 12 weeks in a single arm, paired-sample trial. We found that TRE improved cardiometabolic health for these patients after the 12 week treatment as compared to their baselines. Patients were assessed with actiwatches, continuous blood glucose monitors and blood panels during baseline and post-intervention, as well as answering questionnaires about sleep, cognition, and mood. Patients also logged all of their caloric intake using a smart phone app, enabling us to track both study adherence and to estimate caloric intake. TRE reduced body weight and improved body composition post intervention. Post intervention showed significant positive changes in biomarkers that are risk factors for cardiovascular disease such as LDL cholesterol and blood pressure. Furthermore 16 of 19 patients showed more sleep duration post intervention, and there was a significant increase in reported morning restfulness.

• MJ Wilkinson, ENC Manoogian, A Zadourian, H Loa, S Fakourib, A Shoghib, JG Fleischer, S Navlakha, S Panda, PR Taub. (2019) Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome. Cell Metabolism, 31:1–13.

My contributions to the research reported in this section are in exploratory data analysis, software development, and statistical model building. For all of these papers I have built novel visualization methods and shared the software to do so.

• X Wang, ENC Manoogian, JG Fleischer, and S Panda (2019) Novel Methods to Visualize Circadian Data. Poster at Fall Workshop on Biological Timing, Center for Circadian Biology, University of California San Diego.