Some authors reported several major effects of sleep deprivation (SDES) arising in rats after TSD or paradoxical sleep deprivation (PSD) through the disk-over-water (DOW) method [3]. These effects listed in Table 1 were subsequently confirmed by other groups [4,5] (Table 1).

Altogether, these studies demonstrated that TSD and PSD inevitably lead to a sleep-related syndrome with harmful effects on psychophysical health. In particular, sleep-deprived rats tend to show specific characteristics of progressive energy burn, typical skin lesions, thermoregulatory unbalance, leading to death, features never described in stressed rats [3,4].

The past four decades have witnessed a major paradigm shift in the study of the effect of sleep disturbances on the host immune response to invading pathogens [4]. Early studies about alteration of immune functions in TSD and PSD rats, assessing the amount of splenocytes, mitogen-induced lymphocyte proliferation test, and in vitro and in vivo plaque formation in response to various antigens, did not report significant differences from control group, suggesting that sleep deprivation does not lead to immune suppression [6]. By contrast, Everson isolated opportunistic and facultative anaerobe microbes in the blood of 5/6 near-terminal TSD rats, but none in controls, indicating, for the first time, an association between TSD and impaired immune response [7]. Everson’s results were subsequently confirmed [8,9] even though in vivo studies have produced conflicting results [10] (Table 2).

Data supporting that the gut is one of the primary sites of immune system dysregulation came from experiments on TSD rats orally treated with a mix of broad-spectrum antibiotics, where no bacteria could be found in the gut, blood, liver, kidneys and mesenteric nodes. The fact that these antibiotic-treated TSD rats continued experiencing a body temperature decline, a profound catabolic state manifested by high food intake and weight loss, and died “on schedule” in the absence of systemic bacterial infection supports the notion that an impaired immune response, caused by TSD, may play a decisive role in rat death [8]. However, taking together published data on this matter, we do not have a clear picture of how specific the effects of TSD may be in these animals. Indeed, sleep is so physiological in mammals that effects of its deprivation could be quite similar since produced by similar pathways [3,4]. Moreover, Sun Q et al. showed the effects of sleep deprivation on different signaling pathways, in particular, reduced expression of insulin receptor substrate (IRS)/phosphoinositide 3-kinase (PI3K)/AKT and the mammalian target of rapamycin (mTOR) as well as FoxO1 signaling pathways. Another important axis, the one regulated by the long isoform of the leptin receptor (LepRb)-mediated JAK2/STAT3 resulted attenuated by sleep deprivation. Young rats sleep deprived also experienced an alteration of the genes involved in the transcriptional feedback loop regulated by CLOCK and BMAL1 proteins. All these events confirm that alteration of sleep length causes dysregulation of several pathways in the hypothalamus with consequences in the regulation of hunger and energy consumption [15].

This section may be divided by subheadings. It should provide a concise and precise description of the experimental results, their interpretation, as well as the experimental conclusions that can be drawn. Many causes are responsible for loss or dysregulation of sleep and usually a multifactorial origin is recognized. Among the most common reported causes of sleep loss there are respiratory disorders like apnea, but also other neurological and psychiatric conditions such as insomnia, parasomnias, mood disturbances, restless leg syndrome, and psychosis. It has been shown that the sleep architecture may change with age; deep sleep (characterized by delta-waves) decreases while the proportion of lighter sleep increases; this may conduct to increased sleep dysregulation [16]. Sleep disorders are widely distributed, as reported by different studies. Sleep loss affects more than 50 million people in America [17]. Léger D et al. showed that in 20% of the young adults analyzed (range 25–45 years old), sleep was reduced by ninety minutes as compared to what is needed for wellbeing [18]. Other authors reported in the last thirty years a consistent decrease in the duration of sleep coming up to about 18 min for night [19,20]. The accelerated rhythms of our society, which keep us ever connected, for work or pleasure, using computers, mobile phones and other devices until late at night, will likely determine an increase of sleep disorders. The effects of sleep deprivation on health outcomes have also been heavily studied in humans. From these studies, it seems that the most frequently observed effect in both TSD rats and humans is increased hunger [11,12,13]. Moreover, a 72-h TSD in humans significantly increased urea excretion, as well as plasma urea nitrogen increased in TSD and PSD rats in TSD and PSD rats [21]. Increased appetite in PSD subjects was also reported by Dement and Sampson [22,23]. However, psychological effects of sleep loss are not as quickly evident in humans as in rats. If 13.6 h in rats vs. 8.0 h in humans are considered the mean sleep need, the effects of TSD should onset 1.7 time faster in rats than in humans [3]. Studies on PSD in humans did not show evident damaging symptoms but they were relatively short (range 1–16 nights) [24]. The first report on long-time PSD results was published by Wyatt et al., who chronically administered phenelzine, a monoamine oxidase inhibitor (MAOI), in seven narcoleptic subjects, inducing severe and prolonged PS loss. Based on periodic recordings, in two subjects, PS almost disappeared for more than a year, with only mild symptoms reported as side effects of the drug mainly increased weight for excessive eating [25]. It should, however, be pointed out that in the aforementioned studies, cataplexy occurred when there were present either short intervals of PS or PS like moments [3]. Further studies showed how PSD could affect cerebral activity. These effects included enhancement of evoked potentials, boosting of fantasy in subjects with poor imagination and relief of endogenous depression [26]. Sleep has also been involved in neuroplasticity and in the learning and memory processes. Many published data confirmed that sleep is implicated in the fixation of short-term memory. Subjects who were sleep-deprived during post-training nights showed virtually no performance improvement on the following days, whereas subjects allowed to sleep immediately after training displayed a significant performance enhancement [27].

Among risk factors for human healthiness, sleep deprivation is one of the most changeable.

The American Heart Association and the Centre for disease Control and Prevention (CDC) claim that a sleep period of seven hours/night is necessary for favouring well-being and decreased probability of diseases [28,29]. The effects of inadequate sleep are dangerous.

In fact, morbidity and mortality connected to cardiovascular diseases (CVD) are dangerously increased by sleep disorders [30,31]. Everyday rhythm is present in cardiac, smooth muscle, and endothelial cells, modulating heart rate, blood pressure, and endothelial activity, [32] all functions with daily variation. Endothelial dysfunction and platelet activation are the trigger of atherosclerosis processes, already present before clinical presentation of CVD [33,34,35]; and for this reason, a significant target for evaluating the initial effects of sleep deprivation on the cardiovascular system. Moreover, endothelial activity evaluated in coronary and peripheral arteries reveals following CVD episodes (i.e., myocardial infarction and stroke) and death [36,37]. This is particularly true in subjects with chronic respiratory diseases such as COPD during stability phases [38,39] and during exacerbations [40]. Sleep deprivation may favour the onset and progression of age-related endothelial dysfunction and through this process favour pathogenesis and development of CVD [41]. Consequently, understanding the involvement of sleep in maintaining endothelial function may be useful to reach a healthy vascular aging.

The impacts of different hormones levels have been found to have a pivotal role in sleep deprivation. In fact, a chronic deprivation of sleep seems to be associated with increased cortisol levels and conversely with decreased levels of testosterone. Testosterone is known to intensify the function of the main blocker of neurotransmissions (gamma-aminobutyric acid—GABA) and of serotonin, involved in the regulation stabilization of mood and depression. The reduced testosterone levels could be involved in the relationship between depression and anxiety. Furthermore, elevated serum cortisol levels are associated with depression, anxiety, hypertension, obesity, and type II diabetes. Chronic sleep deprivation is associated with high inflammatory mediators, which are elevated in both comorbid conditions and mental illnesses.

The subjective experience of sleep loss can be distressing and conduct to increased cortisol levels, which can increase blood sugar, blood pressure and cravings for carbohydrates causing weight gain and consequently either medical and psychiatric problems. For the aforementioned reasons sleep loss can have painful and detrimental effects depending on subjects and can worsen pre-existing conditions [42].