Circadian rhythms balance waking states with the need and urge to sleep. They dictate different sleep patterns for different organisms. Humans are diurnal; evolution shaped us to be primarily active during the day and to sleep at night. Bright light, darkness and the hormones, melatonin and cortisol, are among the most studied and predictable factors involved in regulating circadian rhythm in humans (Figure 1). In settings that more closely resemble the environment of evolutionary adaptation, cortisol production initially spikes when humans come into contact with morning sunlight and subsides during the day. Melatonin is actively metabolized during daylight hours and synthesized with decreased exposure to light, causing feelings of drowsiness. While circadian rhythm governs the timing of sleep, the initiation and termination of sleep and the specific phases of sleep control the regulatory processes that maintain homeostasis in the brain and body [1, 2].

[enlarge]

Figure 1. A representation of sleep regulation. Note how light changes in the environment dictate the cycle of sleepiness and alertness in part due to the activity of the hormones cortisol and melatonin.

Early in the study of sleep, researchers identified and classified phases of sleep as deep, light and a phase known for characteristic rapid eye movement called REM sleep. Investigations on this hypothesis showed that the reduction in energy was nominal during light and deep “non-REM” sleep (NREM) and that REM sleep was distinguished by cortex wide synchronous waves of neuronal activation. This intense neuronal activity suggested strongly that sleep was not a state of conserving energy, especially since sleep quality declines as we age, presumably when energy is at a premium [3].

Advances in sleep research reveal that deep and REM sleep in particular are vital for maintaining synaptic homeostasis and increasingly focuses on the impact of disruptions in glymphatic function associated with ageing and disease. The brain, comprising 2% of the entire weight of the body, consumes 25% of the resting caloric requirement for the whole body [4]. This monumental expenditure of energy, the free radicals and metabolic waste produced, and the damage to molecule, micro and macro structures in the brain caused by all this activity require extensive cleanup and repair. The glymphatic system is the cleanup and delivery for the required suites of maintenance genes and materials. These genes are transcribed reliably at certain time points, including as soon as sleep initiates, immediately before and after waking, with changes in light levels, or during specific phases of sleep - light sleep, deep sleep or REM sleep. Healthy brains cycle through REM and NREM sleep on 90 minute intervals that decrease in length as we age. Increased susceptibility to signals to wake and biological interruptions that often increase in likelihood with age like snoring and nocturia result in shorter phases of REM and nREM sleep and frequent waking (Figure 2). For example, this aberrant architecture of sleep can also indicate disease states like those that either cause or are caused by aggregates in the brain [5].

[enlarge]

Figure 2. Graphical representation of sleep patters. A. More ordered sleep. B. Representation of less ordered sleep with prolonged sleep latency, a wake up event, reduced deep sleep phases and overall shorter duration.

The decline in quantity and quality of deep sleep associated with ageing is also a hallmark of degenerative diseases of the brain. The relationship between decline in sleep quality and worsening disease states are discordant with respect to overall health. Sleep is conspicuously intertwined with every other element of human health and activity. For example, cardiovascular health correlates directly with optimal glymphatic function; low quality and insufficient sleep coincide with excess heart age (the difference between chronological age and heart age) and cardiovascular risk profile. This relationship between sleep quality and overall health speaks to the inextricable relationships between body systems [6].

Ageing brains become more sensitive to sleep interruptions, increasingly sensitive to signals to wake and have longer sleep latency (the time it takes to fall asleep). These disruptions are just one factor contributing to more disordered and shorter duration of sleep as we age. Even in the absence of clinical dementia, decreased glymphatic efficiency and efficacy potentially have a profound impact on neurological decline [7, 8].

Sleep studies typically involve monitoring sleeping participants in the controlled environment of the laboratory. These studies observe humans via electrocardiogram (ECG) to monitor heart rate and electroencephalogram (EEG) to record electrical activity in the brain. Many of these studies also monitor blood oxygen levels and breathing as well as eye and limb movement [9].

High-density EEG is often used to analyze oscillatory neural activity during sleep. With regard to brain areas contributing to sleep regulation, regions related to learning were found to be associated with activity during subsequent sleep. Sleep oscillatory activity in these areas diminished with ageing. In particular, sleep delta and theta activities decreased with age in the left-weighted motor cortical network, while sigma activity was negatively affected in the left primary motor cortex [10].

Genetic studies in rodents and drosophila have revealed the conserved genetics of circadian rhythm. Transcription of cryptochrome (CRY) and period (PER) are chiefly activated by BMAL1 and CLOCK or the paralogue NPAS2. Free CRY and PER form a heterodimer that self-suppress CRY and PER transcription. CRY genes are conserved in plants and throughout many parts of the animal kingdom. These flavoproteins behave as blue/UV-A receptors, though this activity has not been conclusively verified in mammals. The suite of genes controlled by BMAL1, CLOCK, CRY and PER is stimulated by signals originating from the suprachiasmatic nucleus (SCN) in the hypothalamus. The ability of the SCN to coordinate the feedback loops of independent oscillators throughout the body is at the heart of homeostasis in alternating circadian states. The relationship between SCN and serum response factor (SRF) in sleep deprivation studies showed how long term disturbances from external sources can affect gene-expression and phenotype with plieotropic effects [11].

Transcriptome analysis and review of environmental factors has played heavily into our understanding of better known sleep disorders like apnea, hypersomnia, insomnia and enuresis as well as inherited diseases like fatal familial insomnia (FFI) and and familial advanced sleep phase syndrome (FASPS).

Clinical depression often co-occurs with disordered sleep. While the nature of sleep disorders associated with depression varies, they are often the reason why most patients seek medical intervention. Hypersomnia or insomnia are present in the vast majority of clinically depressed patients before treatment and pharmaceutical interventions also affect sleep patterns. Studies on the genetics of depression related sleep disorders have yet to yield clear results. Large scale studies have only suggested gene candidates for further study [12, 13].

Enuresis was originally thought to be a psychiatric disorder, often considered to be the result of psychological trauma. Subsequent research has shown that enuresis is linked to a suite of factors with a clear somatic origin. Chief among them are deficiency of the antidiuretic hormone, vasopressin; this is usually accompanied by increased activity of the muscle of the bladder wall, the detrusor, and an increased sensitivity to signals to wake, in this case, the arousal threshold for breathing and other internal signals. The genetic basis for this phenotype has not yet been identified, but research suggests that enuresis may be linked to other disorders like ADHD and deficits in arousal [14].

[enlarge]

Figure 3. Relationships between sleep and body systems with suggestions for intervention. A. A nutrition plan should include adequate micronutrients to support neural tissue maintenance and repair and monitor macronutrients and limit foods that promote inflammation and oxidative stress to support cardiovascular health. B. A sensible exercise plan can improve cardiovascular health and improve overall sleep quality. C. Apps that limit blue light from electronic devices after dusk or restricting use of backlit screens in the hours before bed reduces their influence on circadian rhythm. D. Supplementing with melatonin before bed reinforces circadian signals to sleep. E. Cognitive behavioral therapy can improve sleep latency, control aberrant cortisol synthesis and improve other factors involved in overall sleep and cognitive health.

Apnea is another common sleep disorder with heritable factors for predisposition and contributing phenotypes. The structure of the sinuses and other parts of the skull and soft tissues of the face and airways and obesity contribute to obstructive sleep apnea, but there is no definitive serum biomarker. Studies investigating the roles of biomarkers related to inflammation, oxidative stress, metabolism and proteins associated with various neuropathologies have revealed candidates for apnea itself as well as markers in common with neurodegenerative disease. Polymorphisms in tumor necrosis factor ɑ (TNF-ɑ), subtype EP3 prostaglandin E2 receptor (PTGER3) and lysophosphatidic acid receptor 1 (LPAR1). While TNF-ɑ is well known as a cytokine responsible for modulating inflammatory response, TNF-ɑ and LPAR1 are both markers for cancers. PTGER3 sensitizes pathways associated with the peripheral and spinal nociceptive neurons. The precise roles of these genes in sleep apnea has yet to be elucidated; in time we will know if their roles are up- or downstream of apnea. The involvement of amyloid-β, tau proteins, and pro-inflammatory cytokines are shared in common with dementia, suggesting a progression that must be addressed in holistic models of disease [15, 16].

Studies on type 1 narcolepsy (NT1) have pinpointed mutations in the human leukocyte antigen (HLA) which is characterized by cataplexy, but not type 2 narcolepsy (NT2) which shares all other major symptoms, most notably exaggerated sleepiness during the day, in common with NT1. Augmented levels of hypothalamic hypocretin (orexin) and cerebrospinal fluid are common to narcolepsy, cataplexy, hypersomnia and traumatic brain injury. Reduced orexin synthesis typically results from the destruction of cells that produce the hormone. Orexin plays an important role in regulating sleep by promoting arousal and also by integrating metabolic, circadian and sleep deficit signals. Orexin deficiency is implicated in a number of sleep disorders and cataplexy. Moreover, orexin activates neural synchronization in hypothalamic cultures. Administration of orexin in the lateral hypothalamus intensified wakefulness in rats, implying orexin regulated wakefulness by stimulating neural synchrony in the hypothalamus [17]. A mechanism describing sleep disturbances during ageing has recently been reported by Li et al [18]. The authors have found that aged hyperexcitable hypocretin/orexin (Hcrt/OX) Hcrt neurons had hyperexcitability with decreased expression of KCNQ2 gene and disbalanced M-current, mediated by KCNQ2/3 channels. Furthermore, the KCNQ-selective activator flupirtine affected Hcrt neurons and restored sleep architecture in aged mice.

These data along with the suite of alleles associated with NT1 at the HLA class II beta chain paralog HLA-DQB1 suggest that this is a multifactor disease that involves both environmental and heritable factors. HLA-DQB1 is also associated with Celiac disease and the prion neurodegenerative disease, Creutzfelt-Jacob’s. Other genes with amino acid changes associated with inherited and idiopathic NT1 involve purinoceptor 11 (P2RY11) and DNA methyltransferase 1 (DNMT1) for patients suffering from the heritable autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). There are large scale changes to methylation in patients suffering from NT1 alone and in ADCA-DN patients [19-21].

While many of these cognitive and physiological disorders are difficult to disentangle from the associated sleep disorders, others have a distinct progression of disease. FFI is characterized by a mutation at codon 178 in the prion protein gene and the wild-type acidic, charged moiety of aspartate to a neutral, polar amino acid asparagine results in aggregation of these prion proteins and a disease phenotype characterised by progressive sleep loss, psychosis and eventually death. This clear association between a sleep disorder and protein aggregates that cannot be cleared through normal glymphatic pathways demonstrates the importance of glymphatic function and the role of aggregate “junk” in brain dysfunction [21-23].

The glymphatic system itself has been studied extensively in mice as well as humans, primarily using tools like functional MRI (fMRI) and contrast enhanced MRI (ceMRI) along with tracers of varied molecular weight. Tracers like Texas Red Dextran (TRd) and fluorescein isothiocyanate-dextran (FITCd) revealed the sizes of molecules delivered and swept away by the active glymphatic system and the pathways they take [24].

Bioactive compounds like ouabain, acetazolamide and amiloride show the importance of transmembrane gradients in the flow of cerebrospinal fluid (CSF) in glymphatic function. Not surprisingly, aquaporins 1 and 4 (AQP1 and AQP4 respectively) also play a critical role in the flow and synthesis of CSF and the transport of fluids throughout the brain and genetic studies of these transport molecules in rodents have revealed routes for cascading aberrations in cardiovascular function and the role of inflammation in cognitive decline [25-27].

Disordered Sleep and Safeguarding Sleep: Research has shown that light is incredibly important for circadian rhythms. Bright light stimulates wakeful states and impedes our ability to fall asleep quickly. This is because bright light, particularly blue wavelengths, suppresses synthesis of the hormone melatonin. Sleeping during the day lacks the restorative properties of night time sleep in part due to light conditions [28].

The ways in which disordered sleep contributes to neurodegeneration is confounded by disease states’ negative influence on sleep. Often, decline in health of one system erodes the integrity of other body systems and contributes to worsening disease states. Research focused on night shift workers, the largest and most diverse group of sleep disordered individuals, is hallmarked by this phenomenon. From studies focused on the third shift workforce, we have learned that inverting evolved circadian rhythms correlates with weight gain, increased reports of stress, and measurable decrease in cognitive abilities. Notably, night shift workers are predisposed to neurodegenerative diseases and only this specifically is attributed to daytime sleep [29]. Daytime sleep has reduced quality and quantity relative to sleep that conforms with Circadian cycles [2, 30].

Many factors contribute to disordered sleep and understanding the origin of any disruption is at the heart of the most dramatic improvements in sleep quality.

Sleep hygiene is a combination of daily routine and environmental factors oriented toward promoting healthy sleep patterns. Observing good sleep hygiene can improve the quality of wakeful states by promoting synaptic homeostasis. Because sufficient high quality sleep contributes positively to so many aspects of life ranging from improved mood and cognition, performance for accuracy and speed in tasks and recovery from physical exertion, research offers many insights to improving sleep through environmental maintenance in everything from what we wear to bed to the temperature and incline of our mattresses. Ideally anyone seeking to improve the quality of their sleep would first have a conversation with their physician about whatever medications they might be taking. Many prescription medications have well studied effects on sleep and simple acts like timing when medications are taken or changing ones that might negatively impact sleep for other options can improve sleep [31, 32].

A consistent exercise routine synergizes strongly with a healthy sleep schedule. Promoting cardiovascular health facilitates glymphatic function which improves the restorative qualities of sleep. Many studies have shown that adopting a sensible exercise routine reliably improves sleep itself, especially in middle-aged and elderly adults [8, 33]. The converse relationship is also true; sleep deprivation negatively impacts athletes’ performance and enhances the sensation and even causes pain, in turn, leading to a decline in sleep quality [34]. The synergy between sleep and exercise is robust particularly as we age, but important for all stages of life as a way to preserve cardiovascular health. The risks for chronic health issues for the sleep disordered are magnified when those individuals also forgo exercise. Overall, regular exercise is among the most important changes one can make to improve health and quality of sleep and to slow or delay the cognitive decline associated with ageing [35, 36].

The effects of local temperature reveal that more is at stake than just personal comfort. The data suggest that increased heat and humidity can increase sensitivity to signals to wake. This means that regulating temperature and humidity either within the entire home or locally, just in the sleeping quarters or the bed itself can improve sleep quality [37, 38].

A number of neurotransmitters, botanical products, and other bioactive compounds have been investigated as supplements to enhance sleep or for their ability to perturb healthy sleep cycles. These include but are not limited to gamma-aminobutyric acid, serotonin, orexin, melanin-concentrating hormone, histamine, galanin, melatonin, noradrenaline, and tryptophan. Botanical extracts focused largely on lavender, chamomile, and valerian root, but included a broad variety of compounds. Valerian root, passionflower, kava kava and lavender were the most studied. Many studies on chamomile. valerian root, passionflower, kava kava and lavender have mixed results. This suggests that their efficacy may be highly individualized and that trial and error along with sensitivity for confirmation bias should guide their use. Alternatively, stimulants and depressants are also an important area of research for understanding sleep, the ubiquitous caffeine and alcohol are chief among them [34, 39].

Caffeine, a widely available stimulant, is a reliable disruptor of sleep patterns even when taken as long as six hours before bedtime. Caffeine is particularly disruptive for daytime sleep habits of night shift workers as they age, causing increased sensitivity to circadian signals to wake and by stimulating the synthesis of cortisol. In studies, the beneficial properties of caffeine follow an inverted J-shaped relationship with generally desirable health outcomes like improved alertness, reduced incidence of gout, and neurological diseases like Parkinson’s and glioma as low doses are more beneficial than high doses or abstention [40-44].

Alcohol, a fairly ubiquitous depressant, consistently impacts the quality and quantity of sleep in different ways depending on the amount and regularity or consumption. Generally, low doses of alcohol have been shown to have positive or no effect on health depending on the study and frequency of use and high doses are broadly damaging, especially when used chronically. In mice, however, low doses of alcohol improved glymphatic function by acting as a vasodilator. Humans rarely titrate their alcohol intake to mimic laboratory conditions, so clinical studies typically observe alcohol abuse rather than use. Aberrant sleep patterns induced by alcohol use is a risk factor for alcohol abuse, according to studies. Prevailing wisdom based on the literature is that alcohol and sleep are not a good match for optimal health, but it remains to be seen if this bears out for low levels of alcohol like those found in some alcohol-infused desserts or non-alcoholic beers and wines [45, 46].

Melatonin falls into the lower risk range of treatments for sleep disordered individuals. While prescription drugs like doxepin, suvorexant, and zolpidem are established treatments for insomnia, melatonin remains safe and proven as an over-the-counter sleep aid. Small doses administered before bed time can promote healthy sleep architecture by combatting the influence of blue light and reduce sensitivity to external and internal signals to wake [47, 48]. Duffy et al treated healthy aged participants with low and high doses of melatonin and found that 0.3 mg melatonin moderately improved sleep efficiency overall, while 5 mg melatonin significantly enhanced sleep efficiency by affecting Stage 2 non-rapid eye movement sleep and decreasing awakenings [49].

As cannabis decriminalization and legalization become increasingly widespread, these bioactive compounds are studied more intensively for their impact on sleep. Similar to alcohol studies, chronic use and abuse negatively or (at best) variably impact sleep and intermittent use has potential to dramatically improve sleep. Most of these negative effects are attributed to delta-9 tetrahydrocannabinol (THC) and the positive effects are attributed to cannabidiol (CBD). THC does decrease sleep latency with occasional use, but stymies sleep quality long term in some studies. This means that whole cannabis might be better suited as a treatment for periodic disruptions in sleep, like disruptions to sleep caused by hormone fluctuations during the menstrual cycle or jet lag as opposed to a regular approach to improving sleep like melatonin and exercise. Much of the available data does examine the efficacy of cannabis and cannabis compounds in the context of other illnesses, but these are relevant to cultivating good sleep in a holistic context. The capacity of cannabis to reduce anxiety through regular use, for example, may synergize with cognitive behavioral therapy for improving sleep without some of the pharmaceutical interventions that are known to disrupt sleep. Of course, cannabidiol is only one compound in cannabis and hemp; there are many compounds in cannabis, like cannabinol, dronabinol and nabilone, that require more research and are promising as compounds for enhancing sleep [32, 50-52].

The interplay of nutrition and circadian rhythms is called “chrononutrition”. This area of research investigates what to eat and sometimes when to eat to optimize sleep quality along with interrelated aspects of overall health. Key nutrients for healthy sleep patterns include but are not limited to tryptophan, a precursor for melatonin and serotonin, is particularly important for individuals who suffer adverse effects when consuming melatonin itself as a sleep aid. B vitamins, B6 - pyridoxine and B3 - niacin, are also important for the synthesis of melatonin and serotonin. Magnesium plays several roles in optimized sleep architecture chiefly by improving melatonin secretion and by binding GABA (γ-aminobutyric acid) and promoting its synthesis; both activities promote the onset of sleep. Eating food close to bedtime and potential effects on sleep patterns and glymphatic function raises questions about whether to abstain or to select bedtime snacks carefully. Many studies suggest that consuming large quantities of food between dinner and bedtime leads to adverse health outcomes and that these effects are amplified in night shift workers. Other studies have suggested positive health outcomes for small snacks (~150 kilocalories) can improve various elements of metabolism, including higher insulin levels the following morning, improved muscle protein synthesis and decreased body weight over time. Very few studies have addressed the direct impacts of late night eating on sleep quality beyond a notable shift in markers of circadian rhythms, delayed synthesis of melatonin, caused by eating immediately before bed and skipping breakfast, individually or together [53-58].

Eating to maintain cardiovascular health can also improve the restorative properties of sleep by promoting glymphatic function. Many studies show that weight maintenance and diet can postpone the onset of diseases like Alzheimer’s. Researchers hypothesize that the combination of decreased inflammation, improved nutrition and healthier cardiovascular system all support a robust glymphatic system to keep the brain free of plaque forming proteins. Many diets have been studied for their neuroprotective potential and themes are consistent among them. The recommendations that have been shown to promote cardiovascular and brain health generally include diets rich in whole grains, colorful fruits and dark green vegetables as sources of soluble and insoluble fiber, phytochemicals and other antioxidants and abundant micronutrients. Certain oils rich in unsaturated fatty acids like those from nuts and olives also make frequent appearances in diet plans that are shown to promote cognitive health. Plans with neuroprotective potential also warn against high cholesterol foods and foods that can promote inflammation like cheeses, cured or smoked meats and red meat, in favor of fish, seafood and plant-based proteins. Also among foods to avoid are sweets and pastries, fried foods, highly processed foods and foods rich in synthetic preservatives, flavors and colorants [59-62].

Commercially available devices track many of the same metrics that are the focus of laboratory controlled sleep studies. These devices are available to monitor sleep at home on a regular basis; they can determine when we fall asleep and wake, and demarcate REM from light and deep NREM parts of our sleep cycle. Typically they are also programmed to offer insights on the quality of our sleep based on personal data like age and gender. Many also reliably monitor heart rate and breathing, all of which is useful information for ways we can improve our sleep. Understanding the quality of our sleep can be the first step to improving our experience in cases where there is no obvious disorder like working the night shift, night terrors or sleep walking. They might also help answer questions why some, but not all of us, did not sleep well for cyclic environmental factors that might not show up in a controlled study, like regular hormonal fluctuations in a woman’s cycle [63] or near and during the full moon when the sky is brighter at night [64] at a much lower cost and with fewer disruptions to daily life than in-lab sleep studies [65].

Some models are designed to be worn on the body and others are intended to clip onto pillows, sit on nearby surfaces or rest between mattresses and box springs for a less intrusive experience. Typically, they offer reliable data that might be shared with a physician, inform choices about sleep hygiene at home and satisfy personal curiosity [66-68]. These devices may also become increasingly important for older patients as telemedicine becomes more popular and when the cost of in-lab polysomnography is prohibitive [69]. These measurements can reveal mundane, but relevant sleep disturbances like intermittent or progressive snoring and apnea. They might also point to disturbances that in-lab sleep studies would certainly miss, like a pet jumping on the bed or noises linked to the home or surrounding environment. From visiting a physician to discuss treatment plans for apnea or to consider excluding companion animals from the bedroom, all of these tools and the metrics they make available can inform ways we can improve our sleep.

Quality sleep is a cornerstone of brain health and the best method for slowing and delaying the onset of cognitive decline and disease. While a sensible diet and exercise plan is probably the most potent way to improve sleep, we must remember that disordered sleep has many causes, is usually a symptom of another perturbance in homeostasis and has cascading impacts on other aspects of health.

Ageing-associated sleep disorders lead to endoplasmic reticulum (ER) stress. A mouse model of ageing was used to study if supplementing chaperone levels diminishes ER stress and improves sleep quality [70]. Treatment with the chemical chaperone 4-phenyl butyrate (PBA) optimized sleep and wake, and enhanced learning in aged mice. Also, overexpression of the chaperone protein in hippocampus improved cognitive abilities.

With regard to Alzheimer's disease (AD), Blackman et al have reported that Apolipoprotein E epsilon 4 (APOE-ε4) affects sleep by mechanisms not related to pathological processes specific for AD dementia [71]. After evaluating more than two hundred subjects, the researchers have found that APOE-ε4 homozygosity was associated with sleep disturbance. Furthermore, the effects of sleep on cognitive decline and depression have also been studied [72]. Mediation analysis has shown that sleep quality partly regulates the association between cognitive decline and depression. The association between telomere length (TL) and sleep quality and effects of ApoE-ε4 allele have been studied by Varinderpal et al [73]. The study has shown that sleep duration was associated with shorter TL. Also, according to the study, the presence of APOE-ε4 allele may influence sleep duration.

Another study has reported that impaired sleep patterns in ageing mice might be related to defective IGF-I signaling onto orexin neurons in the lateral hypothalamus [74]. In particular, both slow and fast electrocorticographic activation and excitation of orexin neurons by systemic IGF-I have been found to be decreased in old mice.