Flight dysrhythmia , more commonly known as jet lag, comprises a constellation of symptoms consisting of daytime fatigue, impaired alertness, nighttime insomnia, loss of appetite, depressed mood, poor psychomotor coordination, and reduced cognitive skills, among other (Table 8.2) [18]. These symptoms are caused by the temporary misalignment between the circadian clock and external time, which occurs because of rapid travel across time zones. The number of time zones crossed and the direction of travel influence the severity of jet lag symptoms. Eastward travel tends to cause difficulty in falling asleep whereas westward travel usually interferes with sleep maintenance.

In jet lag, the recovery time for restoring the normal rhythm profile (re-entrainment) can differ significantly from one physiological function to another. Although during the period of re-entrainment individual circadian rhythms generally move in a direction that corresponds with that of the environmental time shift, in some cases the circadian system moves in a direction that is opposite to that of the environmental change, giving rise to a phenomenon called “splitting.” Phase map “partitioning” is then more complex, involving a partial re-entrainment by some phase maps in a direction that is opposite to that of other phase maps [13].

Jet lag affects the health status of frequent air travelers. The disruptive effect of jet lag has been documented in experimental animals at the molecular level of clock genes in the SCN and in the clock genes present in peripheral tissues [19]. Eastbound travel causes a phase advance in all the body’s circadian rhythms, whereas westward flight has the opposite effect, i.e., it produces a phase delay. Consequently, travelers tend to synchronize their bodily rhythms at a speed of 1.5 h a day after westward and 1 h a day after eastward flight, irrespective of whether they travel during the day or at night. This difference in adjustment time is usually attributed to the greater ability of the internal body clock to adapt to a longer rather than to a shorter day (τ longer than 24 h, Chap. 2).

Jet-lag disorder falls under the category of circadian rhythm sleep disorders. The symptomatology of jet-lag disorder includes both physiological and psychological disturbances (Table 8.2). Several studies suggest that chronic or repeated jet-lag exposure can lead to cognitive decline and temporal lobe atrophy in humans if there is a short recovery time between flights. Model jet-lag disorder is also associated with tumor progression in rodents and elevated mortality rate in aged mice [13].

Jet-lag disorder symptoms show considerable inter- and intra-individual variability. Age is one important factor. In simulated jet-lag disorder, middle-aged male subjects had more symptoms than younger men. Moreover, those over 60 years are reported to have greater difficulty in adapting to jet-lag disorder [20]. Another important variable is the individual’s “chronotype” (Chap. 2). Individuals who are “morning chronotypes” generally have less difficulty in phase-advancing their body rhythms (i.e., adjusting after a flight from west to east) than “evening chronotypes,” and vice versa in the case of a phase delay. Generally, those who had “rigid” sleep habits had more severe symptoms after a transmeridian flight [21].

Several studies have examined the effects of simulated and real jet lag on physiological and psychological variables in different populations including aircrew members, and have confirmed that these frequent flyers suffer marked sleep–wake problems because of jet lag. For example, in a 2-year collaborative field study of Spanish pilots flying the routes from Madrid, Spain, to Mexico City, Mexico (−7 time zones) or from Madrid to Tokyo, Japan (+8 time zones) we used telemetry to record pilots’ activity, temperature, and heart rate [22, 23]. Subjective time estimation and other psychological variables such as anxiety, tiredness, and performance were recorded. Urinary 6-sulphatoxymelatonin and cortisol excretion (determined in 6-h intervals) were also measured. Activity/rest and heart rate rhythms, linked to a “weak” or exogenous oscillator, became rapidly synchronized, whereas temperature or 6-sulphatoxymelatonin excretion rhythms, which are closely regulated by the biological clock (Chap. 5) showed a more rigid response after the phase shift of the light/dark cycle [22]. In both young (<50 years old) and old (>50 years old) pilots arriving in Mexico or Tokyo, the activity/rest rhythm rapidly adjusted to the new schedule, whereas the acrophase of the temperature rhythm tended to fluctuate near the original temporal zone. This desynchronization was evident until the return flight (day 5) and persisted after arrival in Madrid [22]. The sequelae of desynchronization were less tolerable in older than younger pilots. Skin temperature rhythm did not become entrained neither on reaching Tokyo nor after the return flight to Madrid in the group of older pilots [22]. The changes in urinary 6-sulphatoxymelatonin and cortisol excretion were consistent with these conclusions.

Systematic and incorrectly planned work schedules of airline pilots produce a chronic disruptive condition, a higher incidence of stress-related emotional changes, and a diminished life expectancy. The optimal work strategy for this population is a compromise between two extreme possibilities: a long rest period at stopovers until full re-entrainment is achieved, or a short stop accompanied with relative isolation, maintaining the original “home” local habits to prevent re-entrainment. With the first strategy, aircrew would be systematically exposed to a re-entrainment process, with a permanent disruption to the circadian system, whereas the second approach, although less disturbing to the body clock, would probably not allow pilots to have the necessary rest and alertness for the return flight [24].

Sleep deprivation produces an allostatic overload that can have deleterious consequences [25]. Restriction of sleep to 4 h per night is associated with increases in BP pressure, decreases in parasympathetic tone, increases in evening cortisol and insulin levels, and increases in appetite through the elevation of ghrelin, a pro-appetitive hormone, and decreases in the levels of leptin, which has anorexic activity (Chap. 5). Proinflammatory cytokine levels are also increased, along with decreases in performance in tests of psychomotor vigilance after a modest sleep restriction to 6 h per night. Allostatic overload in animal models causes atrophy of neurons in the hippocampus and prefrontal cortex, the brain regions involved in memory, selective attention, and executive function. It also causes hypertrophy of neurons in the amygdala, the brain region involved in fear and anxiety, and aggression (Chap. 6). Thus, the ability to learn and remember and to make decisions may be compromised and may be accompanied by increased levels of anxiety and aggression.

Both long-term and short-term exposure to transmeridian flights have an impact on cognitive functioning. For example, in a group of individuals who were on a transmeridian flight and who underwent functional magnetic resonance imaging study, participants from the jet-lag group presented decreased activation in the bilateral medial prefrontal and the anterior cingulate cortex [26]. The results are suggestive of a negative impact of jet lag on important cognitive functions such as emotional regulation and decision-making during the first few days after individuals arrive at their destination.

A wide range of work schedules is referred as “shift work.” They include occasional on-call overnight duty, rotating schedules, and steady, permanent night work (Fig. 8.5) [6]. Owing to the overlap of these categories, it is difficult to generalize about shift work disorder. Over 10% of night workers and of rotating workers met the minimal criteria for shift work disorder.

Several studies have now confirmed that there is a relationship between cardiovascular disease and shift work (Fig. 8.6). Shift workers are at a 40% higher risk of developing ischemic heart disease. The association between shift work and metabolic syndrome, a major risk factor for cardiovascular disease, also occurs. Alternating shift work has been reported to be a significant independent risk factor for high BP, an effect that was more pronounced than that of age or body mass index [6].

In 2007, the International Agency for Research on Cancer classified shift work as a probable human carcinogen (2A). Women who work on rotating night shifts are reported to be at a moderately increased risk of breast cancer after extended periods of working night shifts [27], as are female cabin crew [28]. Because melatonin has oncostatic effects, including effects on estrogen and fat metabolism, it may play a role in both breast and endometrial cancer. Light exposure at night reduces melatonin levels, but the role of melatonin in both of these cancers remains to be defined.

Misalignment between the circadian pacemaker and the timing of sleep, wake, and work occurs in shift workers, and shift work disorder, with insomnia, reduced sleep, and excessive sleepiness, is common. All these impair cognitive function, alertness, and mood, and increase the risk of accidents. For years, the public, media, and regulatory authorities have blamed the effects of excessive speed and alcohol as the main causes of road accidents. However, it is important to note that the lack of sleep produces the same effects on the ability to drive a vehicle as drinking alcohol. In psychometric studies, to be awake for 17–18 h disturbs the ability to drive a vehicle in a similar manner to the effect of an alcohol concentration in the blood of 0.05 g/dL [29]; moreover, both situations may add up to decreased attention. Between 20 and 25% of road accidents are caused by fatigue and sleepiness of drivers, being more frequent between 0200 and 0800 h. This trend is particularly evident on motorways and monotonous routes.

In several studies on this subject, high number of drivers refer to often being drowsy at the wheel. Clearly, there are more sleepy drivers than drunk ones on roads. For example, in representative samples of public transportation drivers in the Metropolitan Area of Buenos Aires and long-distance drivers covering various geographical corridors of the country, we conducted surveys on health and working conditions and applied objective measures of physiological variables, including evaluation of the sleep/wake rhythm using actigraphy, circadian rhythmicity by the peripheral rhythm of body temperature, alertness by determining psychomotor response to a stimulus, autonomic activity by heart rate variability, and endocrine response to stress by measuring cortisol in the saliva [30, 31].

In short-distance drivers, a high prevalence of work-related stress, overweight, obesity, physical inactivity, and hypertension was observed. The quantity and quality of sleep on weekdays was poor, with partial recovery at the weekend, a high frequency of daytime sleepiness, and high risk of apnea. The neurohormonal weekday pattern was consistent with stress and a significant drop in psychomotor performance was observed during working hours, especially the morning shift [30, 31].

In long-distance drivers, a high prevalence of cardiovascular risk factor s, such as overweight, physical inactivity, and smoking, was also found. Sleep patterns of poor quality, with little sleep at home, while traveling, and at the destination, and a decrease in amplitude circadian rhythms, were observed. The pattern was consistent with high cortisol levels, with little recovery in the days out of work, and a decrease in alertness at the end of the return trips [30, 31].

In addition to the known effects on sleep, eating patterns, and alterations in social life, gastrointestinal disorders are very common in shift workers. The association between rotational work shifts and gastrointestinal disorders has several causes. Irregular ingestion habits of workers affect the synchronization of numerous circadian rhythms, in particular, those related to digestive functions and metabolism [32]. Gastrointestinal disorders may be due to ingestion of food at the “wrong” times, which induces anomalous patterns of motility and digestive secretions. In addition, the absence of hot food, which occurs frequently during the night (with a predominance of snacks), a high carbohydrate intake, caffeine and alcohol, and high consumption of tobacco have all been proposed as causes of gastrointestinal disorders in shift workers.

This term defines the changes in amplitude and phase of circadian rhythms that are found in acute or chronic illness, even in mild situations such as common flu (“poor wakefulness, poor sleep”) [14–17]. The clock itself, the information pathways from synchronizing agents to the clock or the efferent pathways of the clock can be affected alone or conjointly (Fig. 8.4). The deterioration of circadian rhythms with age is an example of a change with many components, which implies a decrease in the effectiveness of many aspects of the circadian system, from a reduced influence of the synchronizers, to a deterioration of the clock itself, to a decrease in the ability to obey the clock output signal [33].

The observation that the circadian system is not functioning normally does not necessarily imply that it is the primary cause of the alteration. Rather, the primary defect may have originated elsewhere, and its effects on the circadian system be one of the many changes it causes. In this case, and although treating the circadian system could improve the individual’s nocturnal sleep and diurnal activity, we would not be addressing the real cause of the problem. A combined (specific and chronobiological) treatment is needed for full recovery (Figs. 8.7 and 8.8) [14–17].

In the present world, food has become abundant and simultaneously, the need for physical effort has been greatly reduced. From an evolutionary perspective, this is another “environmental mutation,” that, together which the advent of artificial lighting, has greatly contributed to the loss of the experience of a differentiated day and night. Chronodisruption, with a disturbed balance among the three different configurations of organ and system regulation in a 24-h cycle, is a direct consequence of this (Fig. 8.2).

Obesity has a profound impact on health, such as T2DM and hypercholesterolemia, mainly through its influence on secretion and insulin sensitivity. The metabolic syndrome comprises a group of metabolic abnormalities (hyperinsulinemia, insulin resistance, hypertension, obesity, hyperlipoproteinemia, hypertriglyceridemia) that increase the risk of cardiovascular disease and T2DM. The metabolic syndrome is also associated with an increased risk of nonalcoholic fatty liver disease and renal dysfunction. Similarly, there is evidence for the correlation of metabolic syndrome with dementia (“type 3 diabetes mellitus”) and with cancers, mainly of the breast, pancreas, and bladder [47].

There is impressive information indicating that the obesity is associated with low-grade inflammation of the white adipose tissue, which can subsequently lead to insulin resistance, impaired glucose tolerance, T2DM, and type 3 diabetes [48, 49]. Adipocytes actively secrete proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 and trigger a vicious circle that leads to additional weight gain, largely as fat (Fig. 8.12). Increased circulating levels of C-reactive protein and other inflammatory biomarkers also support the occurrence of inflammation in obesity.

The altered production of proinflammatory cytokines modulate adipocyte size and number through paracrine mechanisms that exert an important role in the regulation of fat mass (Fig. 8.12). The amounts of proinflammatory molecules derived from adipose tissue in obese patients diminishes after weight loss [50]. Therefore, the fat cells are both a source and a target for TNF-α, IL-1β, and IL-6 (Fig. 8.12).

A number of factors play an unequivocal role in increasing the risk of developing T2DM [51]. These factors include dysfunction of pancreatic β cells, abnormal adipogenesis and absence of adequate insulin responsiveness in the liver, genetic susceptibility, physical inactivity, excessive food consumption and/or high calorie food intake, and a sedentary life-style.

In addition to these predisposing factors, there is now an increasing amount of evidence that disruption of circadian timing mechanisms is a major contributor to the development of T2DM [49]. Various types of circadian disturbances have been correlated with T2DM, including disruption of the timing of bodily functions that are normally synchronized, improper timing of food intake, dampened clock gene expression and polymorphisms, sleep loss/disturbance and impairments of the melatonin signaling pathway [52].

In a study on 593 patients with a recent diagnosis of T2DM, sleep debt resulted in long-term metabolic disruption, which may promote the progression of the disease [53]. Sleep quality rather than sleep duration played an important role in insulin resistance in these newly diagnosed T2DM patients [54]. The increased obesity rate recorded in 100,000 women of the Breakthrough Generations Study, associated with increased levels of light at night exposure, supports this assumption [55].

Glucose metabolism is among the numerous physiological functions that are governed by the circadian apparatus [56]. It is known that the distribution of glucose to all parts of the body is organized by the molecular clock present in liver. Circadian regulatory mechanisms utilize both neural and humoral communication to exert close control over insulin, leptin, and plasma glucose levels (Chap. 2).

Direct evidence for the association between circadian clock disruptions and T2DM has been provided by studies in mice in which linkages between clock gene mutations and diabetes states were examined [57]. Per2 mutant mice show several abnormal profiles, including the absence of rhythmicity in plasma glucocorticoid levels, obesity, and low levels of neuropeptides involved in appetite regulation. Clock gene mutations promote delays in pancreatic gene expression, which in turn affects the regulation of the growth, development, and survival of insulin cells and thus of the glucose signaling pathway [58]. Clock-mutant mice showed a lack of rhythmicity in the action of insulin, a state that was reversible once the clock protein had been reintroduced [59].

Additional confirmatory evidence for circadian control over metabolic activity was provided by a study of mice in which the Bmal1 gene was specifically knocked in the pancreas. This produced an animal model that replicated T2DM in that blood glucose levels were found to be elevated throughout the 24-h cycle [58].

In diabetes-prone, genetically engineered rats that were maintained in continuous light and jet-lag-like conditions, circadian disruption ensues [60]. Similar findings were obtained in a study of humans subjected to a forced desynchronization protocol for a period of 28 h. The treatment produced circadian misalignment in all subjects, with 30% of individuals exhibiting a disturbed glucose metabolism that resembled diabetes [61]. Also, all subjects showed a decreased concentration of leptin, a reversal of cortisol rhythm, and high amounts of glucose (postprandial) even in the presence of increased insulin. Additionally, the increased levels of cortisol late in the day, i.e., during the end of wakefulness, were a potentiating factor for insulin resistance and hyperglycemia [59]. These findings suggest that the misalignment of clock functions accelerates the development of T2DM (Fig. 8.13).

Light exposure at night, even at low levels, has been reported to alter food timing and body mass accumulation, thus suggesting that artificial lighting is an important contributing factor to the increased prevalence of metabolic disorders [56]. As discussed in Chap. 5, circadian rhythms could be entrained by manipulating the timing of food administration, and that this could be accomplished without the participation of the SCN (Fig. 5.​33). Taken together, the data indicate that the administration of food at inappropriate times may disrupt the metabolic profile, thus creating a desynchronized physiological state that is causally linked to the development of T2DM (Fig. 8.13).

The possible association between clock gene polymorphisms and T2DM has been explored in humans. In one study a polymorphic allele was identified in Cry2 that correlated with T2DM [62]. Two Bmal1 variants have been found to be associated with diabetes and hypertension in a British population [63]. In a study to examine the existence of Per3 variants in patients with T2DM we reported that, compared with the group without diabetes, the frequency of the occurrence of the five repeat alleles of Per3 among affected patients was greater, and that of the four repeat alleles was less [64]. Circadian clock variants have also been found to correlate with body mass index [65], and with weight loss, sleep duration, and total plasma cholesterol in obese Caucasian individuals [66]. Clock and Cry1 polymorphisms are involved in individual susceptibility to abdominal obesity in a Chinese Han population [67]. Single nucleotide polymorphisms in Bmal2 gene have been associated with a high risk of developing T2DM in obese patients [68]. Cross-sectional studies have reported associations between the clock gene polymorphisms and the prevalence of obesity, plasma glucose levels, hypertension, and T2DM. The association of the Clock polymorphism and stroke in T2DM was reported, indicating that core clock genes significantly contribute to increased cardiovascular risk in T2DM [69].

A high-fat diet that contributes to insulin resistance, impaired glucose metabolism, and obesity, can feedback to influence the biological clock. Rats on a 35% fat diet exhibited a disrupted 24-h rhythmicity of Per1, Per2, Cry1, and Cry2 expression, the Per2 expression profile being almost inverted by the high-fat diet (Fig. 8.14) [70]. These results indicate that the inherent transcription, translation, and post-translational modifications that give the clock its own natural rhythmicity are disrupted in obese rats. The current evidence thus suggests that these processes might have a reciprocal relationship, as an abnormal functioning of metabolism promotes altered expression of the clock genes, whereas impaired clock functioning can disrupt metabolic activity. Indeed, in T2DM patients, clock gene expression was directly associated with fasting glucose levels and with insulin mRNA and protein concentration [71].

In a recent survey, samples of subcutaneous adipose tissue from 50 overweight subjects were collected before and after an 8-week administration of a hypocaloric diet. The expression of core clock genes, Per2 and NR1D1, increased after the weight loss, and their levels correlated with the expression of several genes involved in fat metabolism [72]. Another study demonstrated that a weight loss intervention based on an energy-controlled Mediterranean diet influences the methylation levels of three clock genes, Bmal1, Clock, and NR1D1, being an association between the methylation levels and the diet-induced serum lipid profile [73]. Thus, an abnormal functioning of metabolism promotes the low expression of clock genes, whereas impaired clock functioning can disrupt metabolic activity. Figure 8.15 summarizes the factors and their output that may be responsible for T2DM. The findings thus underscore the importance of circadian regulation for normal metabolic functioning, and further, that clock gene expression appears to be disturbed in T2DM (Fig. 8.16).

The possibility that a relationship might exist between melatonin and T2DM is supported by findings that insulin secretion is inversely proportional to plasma melatonin concentration. It is known that melatonin can alter insulin function and that, compared with normal healthy individuals, T2DM patients have lower circulating levels of melatonin. In vitro co-incubation of pancreatic cells with melatonin has been shown to inhibit the glucose-mediated release of insulin, additionally supporting the conclusion that melatonin activity plays a role in the function of insulin. Further, circadian disruption has been shown to alter melatonin secretion and to cause dysfunctions in pancreatic β cells. Genetic association studies that have shown that mutations in the melatonin receptor gene correlate with an increased susceptibility to T2DM [74].

It can be postulated that the alteration of phase, amplitude, and synthesis of melatonin could lead to impaired glucose metabolism in circadian disrupted individuals. Suppression of melatonin secretion by nocturnal light exposure could be a crucial factor for T2DM development [56]. In this respect, the successful management of T2DM may require an ideal drug that besides antagonizing the triggers of T2DM, also corrects the disturbed sleep–wake rhythm.

Melatonin, together with morning light, is an interesting chronotherapeutic option that can reset the phase and amplitude of circadian rhythms in T2DM patients. The combination of the specific and chronobiological treatment is needed for full recovery (Figs. 8.7 and 8.8). As has been shown in animal models of diabetes and obesity, melatonin also possesses cytoprotective properties that may prevent a number of unwanted effects in T2DM [75]. The efficacy of melatonin treatment for treating metabolic and cardiovascular comorbidities in T2DM has been reported (Fig. 8.17) [76–81]. However, melatonin treatment was reported to impair insulin release in humans who carry MTNR1B, the risk allele of the MT₂ receptor gene [82]. To what extent insulin resistance is ameliorated by melatonin in these patients remains to be defined. At an early stage of T2DM treatment, nonpharmacological approaches such as lifestyle modification, low-fat diet, and exercise are recommended [52].

The human species is very vulnerable to psychiatric diseases: 1% of the population suffers from schizophrenia, 4% from severe uni- or bipolar depression, and 15% of some form of reactive emotional illness in isolated episodes. There are epidemiological elements to suspect a genetic predisposition in the appearance of several of these diseases.

Emil Kraepelin, at the beginning of the twentieth century, was the first to develop a modern classification of mental illness, differentiating “precocious dementia” (schizophrenia) from the more benign and recurrent forms of illness (“manic disease”). Following Kraepelin, cognitive alterations (“disorders of thought” such as schizophrenia) and affective disorders (“emotional disorders” or “affective diseases” such as depression, manic depression, and anxiety) have been identified [83].

Emotional illnesses are characterized by an abnormality of emotional and expressive experiences that constitute affectivity. Normally, a person’s affectivity is in neutrality, with mild episodes of euphoria (called “happiness”) and mild episodes of sadness (called “unhappiness”). When one trespasses these limits, one enters emotional pathology. The pathological end of euphoria is called “mania ”; The pathological end of unhappiness is called “depression .” When individuals express both abnormal ends in a single episode or at different times throughout their life, they are diagnosed with bipolar disease type 1 or 2 (depending on the intensity of the manic phase).

Mania is defined by the presence of an abnormally expansive and irritable affectivity, coupled with several related symptoms. They include decreased need for sleep, excessive loquacity, changing thoughts, grandiosity, easy distraction, and increased activities with pleasurable objectives. This has important consequences: non-normal sexual behavior, risky economic ventures, etc. A maniac patient is often enthusiastic and positive, but tolerates little frustration. Because mania is not an unpleasant experience, patients rarely admit to being treated. However, relatives or close friends recognize this situation as dangerous for the patient. Ultimately, the persistence of the patient in the manic state may be accompanied by serious affective or economic breakdown for the patients and their families.