A pinboard by

I'm a cell biologist with a lot of air miles.


Jet lag is the downside of travel, but is it unhealthy and can it be prevented?

Travelling far? Travelling across time zones fast leads to jet lag, a disruption in the body’s circadian rhythm. Jet lag can have a range of negative effects, but steps can be taken to reduce them.

What’s the evidence? Studies in mice have shown that disruption of circadian rhythm through aberrant light-dark cycles leads to increased stress, depressive-like behaviour, reduced immune response and higher inflammation, even when other circadian measures – such as the amount of sleep or core body temperature – remained unchanged.

In people, a study of major-league baseball players found that jet lag following eastward travel (but not westward travel) had a negative effect on athletic performance. Studies on long-haul cabin crew have shown that jet lag affects sleep quality and melatonin levels. One such study showed that simply the belief in jet lag increased its effects, suggesting that jet lag may be in part a psycho-social phenomenon, not simply a biological one.

Why does it happen? Scientists believe that the brain has not evolved to process rapid light-dark changes, such as those taking place in jet lag or in night shift workers. The master pacemaker of the brain, the hypothalamic suprachiasmatic nucleus (SCN), has two parts that respond to environmental light cues or stored circadian rhythmicity, producing predictable waves of gene expression that define one circadian period. Researchers suggest that the misalignment of these two components leads to jet lag, which in turn can cause hormonal and neural signals to be inappropriately timed.

Preventing jet lag Luckily, steps can be taken before travel to reduce jet lag. Adjusting to your destination’s time zone can be achieved by modifying your sleeping schedule by an hour per day a few days prior to travel, changing light exposure by spending more or less time in natural and artificial light, and supplementing with medication such as melatonin to gradually modify your body’s circadian rhythm.


Associations between period 3 gene polymorphisms and sleep- /chronotype-related variables in patients with late-life insomnia.

Abstract: A variable number tandem repeat polymorphism (VNTR) in the period 3 (PER3) gene has been associated with heritable sleep and circadian variables, including self-rated chronotypes, polysomnographic (PSG) variables, insomnia and circadian sleep-wake disorders. This report describes novel molecular and clinical analyses of PER3 VNTR polymorphisms to better define their functional consequences. As the PER3 VNTR is located in the exonic (protein coding) region of PER3, we initially investigated whether both alleles (variants) are transcribed into messenger RNA in human fibroblasts. The VNTR showed bi-allelic gene expression. We next investigated genetic associations in relation to clinical variables in 274 older adult Caucasian individuals. Independent variables included genotypes for the PER3 VNTR as well as a representative set of single nucleotide polymorphisms (SNPs) that tag common variants at the PER3 locus (linkage disequilibrium (LD) between genetic variants < 0.5). In order to comprehensively evaluate variables analyzed individually in prior analyses, dependent measures included PSG total sleep time and sleep latency, self-rated chronotype, estimated with the Composite Scale (CS), and lifestyle regularity, estimated using the social rhythm metric (SRM). Initially, genetic polymorphisms were individually analyzed in relation to each outcome variable using analysis of variance (ANOVA). Nominally significant associations were further tested using regression analyses that incorporated individual ANOVA-associated DNA variants as potential predictors and each of the selected sleep/circadian variables as outcomes. The covariates included age, gender, body mass index and an index of medical co-morbidity. Significant genetic associations with the VNTR were not detected with the sleep or circadian variables. Nominally significant associations were detected between SNP rs1012477 and CS scores (p = 0.003) and between rs10462021 and SRM (p = 0.047); rs11579477 and average delta power (p = 0.043) (analyses uncorrected for multiple comparisons). In conclusion, alleles of the VNTR are expressed at the transcript level and may have a functional effect in cells expressing the PER3 gene. PER3 polymorphisms had a modest impact on selected sleep/circadian variables in our sample, suggesting that PER3 is associated with sleep and circadian function beyond VNTR polymorphisms. Further replicate analyses in larger, independent samples are recommended.

Pub.: 10 Mar '17, Pinned: 27 Jun '17

Chronotypes in the US - Influence of age and sex.

Abstract: An individual's chronotype reflects how the circadian system embeds itself into the 24-h day with rhythms in physiology, cognition and behavior occurring accordingly earlier or later. In view of an increasing number of people working at unusual times and linked health and safety risks, the wide range in human chronotypes may provide opportunities to allow people to work (and sleep) at times that are in synch with their circadian physiology. We aimed at estimating the distribution of chronotypes in the US population by age and sex. Twelve years (2003-2014) of pooled diary data from the American Time Use Survey were used to calculate chronotype based on mid-point of sleep on weekends (MSFWe, n = 53,689). We observed a near-normal distribution overall and within each age group. The distribution's mean value is systematically different with age, shifting later during adolescence, showing a peak in 'lateness' at ~19 years, and shifting earlier thereafter. Men are typically later chronotypes than women before 40, but earlier types after 40. The greatest differences are observed between 15 and 25 for both sexes, equaling more than 50% of the total chronotype difference across all age groups. The variability in chronotype decreases with age, but is generally higher in males than females. This is the first study to estimate the distribution and prevalence of individual chronotypes in the US population based on a large-scale, nationally representative sample. Our finding that adolescents are on average the latest chronotypes supports delaying school start times to benefit their sleep and circadian alignment. The generally wide range in chronotypes may provide opportunities for tailored work schedules by matching external and internal time, potentially decreasing long- and short-term health and safety risks.

Pub.: 22 Jun '17, Pinned: 27 Jun '17

Social jet-lag potentiates obesity and metabolic syndrome when combined with cafeteria diet in rats.

Abstract: Modern lifestyle promotes shifted sleep onset and shifted wake up time between weekdays and weekends, producing a condition termed "social-jet lag." Disrupted sleep promotes increased appetite for carbohydrate and fat-rich food, which in long term leads to overweight, obesity and metabolic syndrome. In order to mimic the human situation we produced an experimental model of social-jet lag (Sj-l). With this model, we explored the link between shifted sleep time with consumption of a cafeteria diet (CafD) and the development of obesity and metabolic syndrome.The first experiment was designed to create and confirm the model of Sj-l. Rats (n=8-10/group) were exposed to a shifted sleep time protocol achieved by placing the rats in slow rotating wheels from Monday to Friday during the first 4h of the light period, while on weekends they were left undisturbed. The second experiment (n=8-12/group) explored the combined effect of Sj-l with the opportunity to ingest CafD. All protocols lasted 12weeks. We evaluated the development of overweight and indicators of metabolic syndrome. The statistical significance for all variables was set at P<0.05.Sj-l alone did not affect body weight gain but induced significant changes in cholesterol in metabolic variables representing a risk factor for metabolic syndrome. Daily restricted access to CafD in the day or night induced glucose intolerance and only CafD during the day led to overweight. Sj-l combined with CafD induced overconsumption of the diet, potentiated body weight gain (16%) and promoted 5 of the criteria for metabolic syndrome including high insulin and dislipidemia.Present data provide an experimental model of social-jet lag that combined with overconsumption of CafD, and maximized the development of obesity and metabolic syndrome. Importantly, access to CafD during the night did not lead to overweight nor metabolic syndrome.

Pub.: 24 Jun '17, Pinned: 27 Jun '17

Meal Timing Regulates the Human Circadian System.

Abstract: Circadian rhythms, metabolism, and nutrition are intimately linked [1, 2], although effects of meal timing on the human circadian system are poorly understood. We investigated the effect of a 5-hr delay in meals on markers of the human master clock and multiple peripheral circadian rhythms. Ten healthy young men undertook a 13-day laboratory protocol. Three meals (breakfast, lunch, dinner) were given at 5-hr intervals, beginning either 0.5 (early) or 5.5 (late) hr after wake. Participants were acclimated to early meals and then switched to late meals for 6 days. After each meal schedule, participants' circadian rhythms were measured in a 37-hr constant routine that removes sleep and environmental rhythms while replacing meals with hourly isocaloric snacks. Meal timing did not alter actigraphic sleep parameters before circadian rhythm measurement. In constant routines, meal timing did not affect rhythms of subjective hunger and sleepiness, master clock markers (plasma melatonin and cortisol), plasma triglycerides, or clock gene expression in whole blood. Following late meals, however, plasma glucose rhythms were delayed by 5.69 ± 1.29 hr (p < 0.001), and average glucose concentration decreased by 0.27 ± 0.05 mM (p < 0.001). In adipose tissue, PER2 mRNA rhythms were delayed by 0.97 ± 0.29 hr (p < 0.01), indicating that human molecular clocks may be regulated by feeding time and could underpin plasma glucose changes. Timed meals therefore play a role in synchronizing peripheral circadian rhythms in humans and may have particular relevance for patients with circadian rhythm disorders, shift workers, and transmeridian travelers.

Pub.: 06 Jun '17, Pinned: 28 Jun '17

Chronotype modulates sleep duration, sleep quality, and social jet lag in shift-workers.

Abstract: This study explores chronotype-dependent tolerance to the demands of working morning, evening, and night shifts in terms of social jet lag, sleep duration, and sleep disturbance. A total of 238 shift-workers were chronotyped with the Munich ChronoType Questionnaire for shift-workers (MCTQ(Shift)), which collects information about shift-dependent sleep duration and sleep timing. Additionally, 94 shift-workers also completed those items of the Sleep Questionnaire from the Standard Shift-Work Index (SSI) that assess sleep disturbances. Although all participants worked morning, evening, and night shifts, subsamples differed in rotation direction and speed. Sleep duration, social jet lag, and sleep disturbance were all significantly modulated by the interaction of chronotype and shift (mixed-model ANOVAs). Earlier chronotypes showed shortened sleep duration during night shifts, high social jet lag, as well as higher levels of sleep disturbance. A similar pattern was observed for later chronotypes during early shifts. Age itself only influenced sleep duration and quality per se, without showing interactions with shifts. We found that workers slept longer in fast, rotating shift schedules. Since chronotype changes with age, investigations on sleep behavior and circadian misalignment in shift-workers have to consider chronotype to fully understand interindividual and intraindividual variability, especially in view of the current demographic changes. Given the impact of sleep on health, our results stress the importance of chronotype both in understanding the effects of shift-work on sleep and in devising solutions to reduce shift-work-related health problems.

Pub.: 23 Apr '13, Pinned: 27 Jun '17

Melatonin restores hippocampal neural precursor proliferation and prevents cognitive deficits induced by jet lag simulation in adult mice.

Abstract: Frequent flyers and shift workers undergo circadian dysrhythmia with adverse impact on body and mind. The circadian rhythm disorder "jet lag" disturbs hippocampal neurogenesis and spatial cognition, which represent morphological and functional adult brain plasticity. This raises the question if pro-neurogenic stimuli might prevent those consequences. However, suitable measures to mitigate jet lag induced adverse effects on brain plasticity have been neglected so far. Here, we used adult C57Bl6 mice to investigate the pro-neurogenic stimuli melatonin (8mg/kg i.p.) as well as environmental enrichment as potential measures. We applied photoperiod alterations to simulate "jet lag" by shortening the dark period every third day by six hours for three weeks. We found that "jet lag" simulation reduced hippocampal neural precursor cell proliferation by 24% and impaired spatial memory performance in the water maze indicated by a prolonged swim path to the target (~23%). While melatonin prevented both the cellular (~1%) as well as the cognitive deficits (~5%), environmental enrichment only preserved precursor cell proliferation (~12%). Our results indicate that lifestyle interventions are insufficient to completely compensate jet lag induced consequences. Instead melatonin is required to prevent cognitive impairment caused by the same environmental factors to which frequent flyers and shift workers are typically exposed to. This article is protected by copyright. All rights reserved.

Pub.: 09 Feb '17, Pinned: 18 May '17

Environmental disruption of the circadian clock leads to altered sleep and immune responses in mouse.

Abstract: In mammals, one of the most salient outputs of the circadian (daily) clock is the timing of the sleep-wake cycle. Modern industrialized society has led to a fundamental breakdown in the relationship between our endogenous timekeeping systems and the solar day, disrupting normal circadian rhythms. We have argued that disrupted circadian rhythms could lead to changes in allostatic load, and the capacity of organisms to respond to other environmental challenges. In this set of studies, we apply a model of circadian disruption characterized in our lab in which mice are housed in a 20h long day, with 10h of light and 10h of darkness. We explored the effects of this environmental disruption on sleep patterns, to establish if this model results in marked sleep deprivation. Given the interaction between circadian, sleep, and immune systems, we further probed if our model of circadian disruption also alters the innate immune response to peripheral bacterial endotoxin challenge. Our results demonstrate that this model of circadian disruption does not lead to marked sleep deprivation, but instead affects the timing and quality of sleep. We also show that while circadian disruption does not lead to basal changes in the immune markers we explored, the immune response is affected, both in the brain and the periphery. Together, our findings further strengthen the important role of the circadian timing system in sleep regulation and immune responses, and provide evidence that disrupting the circadian clock increases vulnerability to further environmental stressors, including immunological challenges.

Pub.: 30 Dec '14, Pinned: 18 May '17

Circadian clock manipulation for cancer prevention and control and the relief of cancer symptoms.

Abstract: Life has evolved on this planet with regular daily spans of direct solar energy availability alternating with nocturnal spans of dark. Virtually every earth-borne life form has factored this circadian pattern into its biology to ensure the temporal coordination with its resonating environment, a task essential for its individual survival and that of its species. The first whole genome inspections of mutations in human colon and breast cancer have observed specific retained clock gene mutations. Single nucleotide polymorphisms within the genes of clock, clock-controlled, and melatonin pathways have been found to confer excess cancer risk or protection from cancer. Experimental studies have shown that specific core clock genes (Per2 and Per1) are tumor suppressors because their genetic absence doubles tumor numbers, and decreasing their expression in cancer cells doubles cancer growth rate, whereas their overexpression decreases cancer growth rate and diminishes tumor numbers. Experimental interference with circadian clock function increases cancer growth rate, and clinical circadian disruption is associated with higher cancer incidence, faster cancer progression, and shorter cancer patient survival. Patients with advanced lung cancer suffering greater circadian activity/sleep cycle disruption suffer greater interference with function, greater anxiety and depression, poorer nighttime sleep, greater daytime fatigue, and poorer quality of life than comparable patients who maintain good circadian integration. We must now determine whether strategies known to help synchronize the circadian clocks of normal individuals can do so in advanced cancer patients and whether doing so allows cancer patients to feel better and/or live longer. Several academic laboratories and at least 2 large pharmaceutical firms are screening for small molecules targeting the circadian clock to stabilize its phase and enhance its amplitude and thereby consolidate and coordinate circadian organization, which in turn is likely to help prevent and control human cancer. These drugs and strategies can, in turn, be used to make cancer patients with advanced disease feel and function more normally.

Pub.: 21 Nov '09, Pinned: 18 May '17