One minute you’re counting sheep. The next minute you’re riding a unicorn alongside David Attenborough. So, what happened? No, this isn’t another blog about psychedelics. It’s about something better. Sleep.
Sleep is a naturally recurring state of altered consciousness that is highly conserved across animal evolution. From 20 hours of sleep like the Koala, to 2 hours of sleep for the giraffe, all animals (apart from a rare few) need some form of rest or sleep.
But why can some of us sleep on trains, while others lie awake every night tossing and turning?
In this blog, we delve into the role sleeping plays in human health and how our genetics can underpin how much beauty sleep we actually get.
The sleep phenomenon
What is sleep?
Sleep to many of us is a time to relax and dream about winning the lottery (or if you are unlucky, losing your front teeth). We have all had weird dreams at night and then woken up the following morning to immediately Google it and find out the meaning.
But what does it actually mean to sleep?
Well, sleep remains one of the big mysteries in biology. It is a state that seemingly freezes all productive activity and puts us in danger of being caught out by predators (like the clown under my bed).
So, why would all animals put themselves at such risk? Sleep, in fact, serves an important purpose that has survived millions of years of evolution. Despite humans spending a considerable portion of their lives in this state (>24 years for most of us), we still know very little about its numerous functions.
Sleep is a normal, reversible, recurrent state of reduced responsiveness to external stimuli. It is accompanied by complex and predictable changes in physiology. These changes involve fluctuations in hormone levels, relaxation of muscles as well as coordinated and spontaneous brain activity. Sleep is a dynamic state that influences all physiology, rather than a single organ or isolated system.
The clock doesn’t stop
Sleep occurs in repeating periods (Figure 1), during which the body alternates between two distinct modes – REM sleep and non-REM sleep. Rapid eye movement (REM) sleep is characterised by random rapid movement of the eyes, a faster pulse and breathing rate, increased bodily movement and more vivid dreaming. In comparison, during non-REM (NREM) sleep there is synchronisation of the electroencephalogram (EEG) with little or no eye movement. NREM is divided into three stages: N1, N2 and N3. The whole period normally proceeds in the order: N1 → N2 → N3 → N2 → REM.
Sleeping is controlled by the circadian clock and sleep-wake homeostasis. These two processes work in tandem to promote a good night’s sleep.
Sleep is dependent on hormonal signals from the circadian clock. The circadian clock is a complex neurochemical system which uses signals from an organism’s environment to recreate day and night internally. The normal body clock oscillates with an endogenous period of exactly 24 hours. The suprachiasmatic nucleus (SCN), located in the hypothalamus, is considered the most important regulator of this process.
The circadian clock exerts constant influence on the body. For example, the SCN has a direct neural connection to the pineal gland which releases the hormone melatonin at night. The internal circadian clock is heavily influenced by changes in light. Exposure to small amounts of light at night can suppress melatonin secretion and increase body temperature and wakefulness. Unfortunately, humans are often desynchronised from their internal circadian clock due to work, travel and universal indoor lighting. Misalignment of the circadian rhythm can result in sleep deficiency, hormonal imbalance, inflammation, impaired metabolism and dysregulated cell cycles. This has been found to result in a range of medical conditions, including obesity, metabolic syndrome, compromised immune function, increased cancer risk and mood disorders.
The other process that affects sleep is sleep homeostasis, more commonly known as sleep pressure. We have all been there, trying to stay awake at night, whether it be to watch a film or catch a flight, and the only option is to down some coffee or literally pin your eyes open.
The longer an organism is awake, the more it feels the need to sleep. The balance between sleeping and waking is regulated by homeostasis. The process is driven by the depletion of glycogen and accumulation of adenosine in the forebrain. Adenosine levels in the brain increase during prolonged periods of wakefulness and decrease again during sleep-recovery. Interestingly, coffee and caffeine temporarily block the effects of adenosine, enabling prolonged sleep latency. Sleep deprivation can result in slow brain waves in the frontal cortex, shortened attention span, impaired memory, increased anxiety and – everyone’s favourite – a foul mood. Research using neurophysiological and functional imaging studies has shown that frontal regions of the brain are particularly responsive to homeostatic sleep pressure.
While the humans are away the brain comes out to play
When we sleep, the body rests but the brain remains active. During this time, the brain performs several different functions.
One of the main functions of sleep is restoration. Unlike the rest of the body, the brain requires sleep for restoration. While awake, brain metabolism generates end products, like reactive oxygen species (ROS), which can be damaging to brain cells. During sleep, the rate of metabolism and ROS production are reduced which allows for restorative processes to occur. Researchers more recently have also shown that toxins are flushed out of the brain during sleep. The brain has a ‘waste management system’ called the glymphatic system (Figure 2) that uses a system of channels to promote efficient elimination of proteins and metabolites from the CNS. The glymphatic system functions mainly during sleep and is largely disengaged during wakefulness.
Sleep is also key for the nervous system. A lack of sleep can affect our memory, performance and ability to think. People who are severely sleep deprived can experience neurological problems such as hallucinations and mood swings. Sleep allows for our nerve cells to repair. One study identified that sleep increased chromosome dynamics in zebrafish neurons which are key to reduce the number of double-strand breaks. This indicates a role for sleep in neuronal nuclear maintenance.
Sleep has also been shown to be important in the formation of long-term memory and general consolidation of learning and experience. The benefits of sleep, however, appear to depend on the phase of sleep and the type of memory. For example, REM sleep is linked with the consolidation of nondeclarative memories (a task that can be done without consciously thinking). Whereas non-REM sleep is associated with the consolidation of declarative memories, things that need to be consciously remembered, such as learning dates.
Research also suggests that sleep plays a key role in the immune system, which is critical to overall health. Interestingly, sleep and the immune system have a bidirectional relationship. For example, during infection immunological mediators, such as interleukins and cytokines, are released which have subsequent effects on the nervous system and modulate behaviours such as sleep. In addition, sleep can strengthen immune memory, reduce inflammation and save energy to allow the immune system to perform critical tasks. Studies have also shown that sleep improves the effects of vaccines, highlighting sleep’s benefits for adaptive immunity.
Another ‘function’ of sleep is dreaming. The exact function of dreaming is still elusive. Many theories have been postulated, including Sigmund Freud’s hypothesis that dreams are the symbolic expression of frustrated desires that have been relegated to the unconscious mind. Although frequently bizarre and seemingly irrational, dreams often incorporate concepts, situations, people and objects from everyday life that would not normally go together.
Aside from its surreal qualities, sleep (more specifically, REM sleep) can de-escalate people’s emotional reactivity as this type of sleep is the only time where the brain is devoid of the anxiety-triggering molecule, noradrenaline. Dreaming has also been shown to enhance creativity and problem-solving, as REM sleep involves the fusing and blending of memories together in abstract ways. During this state, the brain will be exposed to waves of acquired knowledge that then has to be extracted, creating a mindset that can help us solve problems.
I can’t get no beauty sleep
Around 70 million individuals in the United States chronically suffer from sleep disorders, which hinder their health and longevity. Below are just some of the common sleep disorders:
- Insomnia: The inability to fall or remain asleep. It can be caused by jet lag, stress and anxiety, hormones or digestive problems. Insomnia is extremely common. Up to 50 percent of American adults experience it at some point in their lives.
- Fatal familial insomnia (FFI): A prion disease of the brain caused by a mutation to the gene encoding protein PrPC. There is no known cure and it involves progressively worsening insomnia until the symptoms get so bad that the individual dies.
- Sleep apnoea: Characterised by pauses in breathing during sleep, which causes the body to take in less oxygen. There are two types – obstructive (airway is obstructed or too narrow) and central (problem in the connection between the brain and the muscles)
- Parasomnias: A class of sleep disorders that cause abnormal movements and behaviours during sleep. These include, sleepwalking, sleep talking, sleep paralysis, nightmares, bedwetting and teeth grinding.
- Restless leg syndrome: An overwhelming need to move the legs which is sometimes accompanied by a tingling sensation in the legs.
- Narcolepsy: Characterised by ‘sleep attacks’ that occur while awake, which means you suddenly feel extremely tired and fall asleep without warning.
- Circadian rhythm sleep disorders: A group of sleep disorders that all share the common feature of a disruption in the timing of sleep. They are caused by desynchronisation between internal rhythms and the light-darkness cycle.
Low quality or short sleep duration has been linked to a range of conditions, including cardiovascular disease, obesity, mental health disorders and neurodegenerative diseases. While these conditions tend to result in sleep problems, there is a growing body of evidence to suggest that they can also act as a cause. Such evidence includes:
- Cardiovascular disease (CVD): Some evidence has shown that short sleep duration (<7 hours) is associated with increased risk of coronary heart disease (CHD) mortality. Beyond isolated characteristics, researchers have also explored the relationship between clinical sleep disorders and CVD risk. For example, moderate-to-severe sleep apnoea has been shown to predict increased CVD risk. Extended sleep duration (> 9 hours) is also correlated with CHD and stroke.
- Obesity: Data has indicated that short sleep duration is associated with increased odds of obesity among both children and adults. Experimental data has also shown that sleep deprivation alters hormones that regulate appetite, including increased ghrelin (hunger hormone) and decreased leptin (regulates fullness)
- Mental health disorders: Around 65-90% of adults with major depressive disorder (MDD) report sleep problems and 90% of children with depression report disturbed sleep. One of the strongest pieces of evidence showing the causal role of sleep in the development of mental health problems comes from studies of sleep problems and depression. For example, a meta-analysis showed that insomnia symptoms significantly predicted the subsequent development of MDD.
- Neurodegenerative diseases: Sleep is related to neurodegenerative disorders in several ways including: patients with such disorders frequently have sleep problems, sleep problems may be risk factors for the development of these disorders and finally, sleep may relate to the pathophysiology of these disorders. For example, disrupted sleep can result in reduced glymphatic clearance of neurotoxic Aβ and tau proteins, which are important in Alzheimer’s disease pathology.
The genetics of sleep
With advances in the identification of the molecules regulating sleep and the realisation of the prevalence of sleep disorders, it has become clear that sleep is genetically controlled. Although there is a plethora of environmental factors, such as light exposure and noise, that can impact the duration and intensity of sleep, genetic regulation is clearly a critical component. This has been demonstrated by the heritability of sleep traits, the identification of genetic polymorphisms that affect these traits, and the existence of familial sleep disorders.
Influences on sleep duration and quality
Genetic model systems, such as flies and mice, have been important to study sleep and identify relevant molecules. For example, a study led by scientists at the National Heart, Lung, and Blood Institute (NHLBI) used fruit fly populations to model natural variation in human sleep patterns. The team were able to identify 126 differences in 80 genes that were associated with the duration of sleep. These genes played roles in several key developmental and signalling pathways, including EGFR, MAPK and Wnt.
In addition, in one of the largest genome-wide association studies (GWAS) of sleep to date, researchers used data from the UK Biobank to identify genes related to sleep duration. The findings revealed 76 novel loci associated with sleep duration. The study also found that short-duration variants were associated with traits such as smoking and insomnia, whereas long-duration variants were linked with schizophrenia, coronary artery disease and type II diabetes.
Another study, published in Neuron, identified a mutation in ADRB1 that lead to natural short sleep trait in humans. This gene encodes the beta-1 adrenergic receptor, a receptor for adenosine.
Other genes that can explain variation in sleep duration include ABCC9, DEC2, DRD2, ADA and FABP7.
Influences on the circadian clock
Alterations in the circadian clock can lead to abnormal sleeping patterns. The genetic basis for this process was first reported by Jones et al (1999), who observed three ‘morning larks’ with familial advanced sleep phase (FASP) disorder that had been inherited in an autosomal dominant manner. These individuals were later found to carry a mutation in the core clock protein PERIOD2 (PER2). Other core clock genes that have been linked to FASP include CRY2, CRY1 and CKIδ.
Although genetic variants have been identified that appear to participate in regulating the timing of sleep, the underlying mechanisms require more in-depth investigation. Large GWAS studies over the past few years on chronotype (morning/evening person) have identified variants in several loci near the FBXL13, RGS16, and AK5 genes. RGS16 is involved in signalling in the SCN, FBXL13 is associated with a lengthened circadian period in mice, and AK5 had not previously been known to be involved in the circadian system.
Studies have also indicated that variants in the PER3 (PERIOD3) gene can alter both the sleep phase and circadian clock processes.
Eat, sleep, research, repeat
Sleep health is an often underrecognised public health opportunity which can have significant implications for a range of critical health outcomes. Chronic sleep deprivation contributes to increased risk for many diseases, from cancer and autoimmune disease to psychiatric and neurodegenerative diseases. There are also higher rates of sleep deprivation among ethnic minorities, which further exacerbates existing health disparities. Therefore, addressing sleep health can not only help improve overall health, but it will also be an important step toward achieving health equity.
Public health communication and interventions, such as sleep health education awareness campaigns and workplace policies, will be key to improving sleep health at the population level. In addition, continued research into vulnerable populations will be important to help reduce disparities in health.
A part of these efforts will involve further research into sleep at the genetic and molecular levels, particularly within noncoding regulatory elements, which will be important to gain further insights into the mechanistic aspects of sleep. This will be crucial to understanding sleep regulation and function, and the consequences of when this is disrupted. It will also be key to identify individuals who are at increased risk of desynchronised sleep, which will allow for more targeted strategies and interventions be put in place. Who knows, maybe mandatory power naps will be a thing of the future!
References
- Walker M. Why Your Brain Needs to Dream. Greater Good Magazine. 2017. Access: https://greatergood.berkeley.edu/article/item/why_your_brain_needs_to_dream
- Suni E and Truong K. How Sleep Affects Immunity. Sleep Foundation. 2020. Access: https://www.sleepfoundation.org/physical-health/how-sleep-affects-immunity
- Hale L, Troxel W, Buysse DJ. Sleep health: An opportunity for public health to address health equity. Annual review of public health. 2020 Apr 1;41:81-99.
- Sehgal A, Mignot E. Genetics of sleep and sleep disorders. Cell. 2011 Jul 22;146(2):194-207.
- Maxime J, O’Hara BF, Franken P. Recent advances in understanding the genetics of sleep. F1000Research. 2020;9.
