Research shows that sleep disorders are becoming increasingly common. Not only do 69 percent of primary care patients report that they suffer from insomnia, but 70 percent of older adults say they have trouble sleeping. Patients typically complain of nonrestorative sleep, difficulty resuming or maintaining sleep, and difficulty initiating sleep.
The quality and rhythm of sleep are deeply intertwined with immune function and our ability to modulate inflammatory cytokines. The homeostatic role of sleep in the regulation of innate immunity and inflammation biology impacts duration of sleep, and sleep quality.
SLEEP ARCHITECTURE
Understanding the relationship between sleep and immune function first requires an understanding of sleep macro-structure and the sleep-wake cycle.
Sleep has four sequential stages:
- Stage 1 is non-REM sleep (NREM), which is a transitional stage between wakefulness and deep sleep.
- Stage 2 is a deeper sleep state in which sleepers are unaware of their surroundings but can be easily aroused.
- Stage 3 is the first stage of slow-wave sleep (SWS), which has both fast and slow brainwaves.
- Stage 4 is the second stage of SWS, and consists of mostly slow brainwaves. This stage includes the rapid eye movement (REM) sleep during which dreaming occurs.
Stages 3 and 4 are considered to be times of deep sleep, characterized by energy conservation and renewal, and repair and restoration. Quality slow-wave sleep is associated with robust and well-modulated immune function.
NREM-REM sleep occurs in five to six cycles per night of about 90 minutes per cycle. The amount of time spent in each phase shifts, with NREM sleep more prevalent in early stages and REM sleep more prevalent in later cycles, towards morning. These cycles are part of the larger sleep-wake cycle.
SLEEP-WAKE CYCLE
The sleep-wake cycle is part of our 24-hour circadian rhythm, which also influences body temperature, hormonal secretions, and metabolism. Our biological clock is synchronized to cycles of dark and light by the “central pacemaker”—the suprachiasmatic nucleus (SCN) located in the hypothalamus.
The neurons of the SCN are entrained by environmental light signals coming from the retina. As the amount of light stimulating the retina decreases, the SCN stimulates the pineal gland to produce melatonin. Increased melatonin secretion is a dark signal to the brain, and is associated with increased sleepiness.
Studies show that night-shift workers and airline staff who have disrupted 24-hour biological cycles also have disruptions in normal melatonin secretion.
The T, B, and natural killer cells of the immune system also have 24-hour circadian rhythms influenced by clock genes, which in turn influence transcription. The circadian rhythm of the immune system is regulated by both the central nervous system and the SCN in the brain, and by peripheral influences impacting clock gene expression.
INFLAMMATORY CYTOKINES, SLEEP, AND WAKEFULNESS
Products of the immune system such as cytokines regulate and influence sleep and wakefulness. Inflammatory cytokines maintain homeostatic regulation of the sleep-wake cycle.
Cytokines are messengers of the immune system. These messenger molecules are produced throughout the body by macrophages and lymphocytes, and can be pro-inflammatory or anti-inflammatory. Many cells throughout the body and the brain have surface receptors for cytokines.
Natural circadian cycling of these cytokines is linked to feelings of sleepiness. In particular, cytokines IL-1, IL-2, IL-6, and TNFa have been studied in relationship to sleep. IL-1 has been found to be prevalent during early stages of NREM sleep.
Elevations of these cytokines are also linked to the subjective feeling of fatigue and lethargy. And “sickness behavior,” which includes feelings of sleepiness, lethargy, anorexia, and apathy, is linked to elevated levels of inflammatory cytokines.
Dysregulation of sleep may trigger activation of pro-inflammatory gene expression and an increased risk of inflammation-related disorders and autoimmune syndromes. Targeting inflammation can improve sleep macro-structure, and treating sleep complaints can reverse inflammation and lead to “healthy sleep.”
Sleep deprivation and progressive sleep loss lead to increased secretion of cytokines IL-1 IL-6, TNFa, and IL-2, along with elevated C-reactive protein (CRP) levels. In addition, immune antibody response to vaccinations is blunted in sleep-deprived patients. Patients who report less than seven hours of sleep per night have a threefold increased risk of acquiring a cold compared with patients who report eight or more hours of sleep per night. Furthermore, sleeping at night favors immune defense.
Sleep disturbances also worsen chronic autoimmune inflammatory conditions due to increases in the production of pro-inflammatory cytokines.
HPA AXIS, SLEEP, AND IMMUNITY
A reciprocal relationship exists between sleep-cycle sleep duration and the hypothalamic pituitary axis (HPA).
The circadian pacemaker, the SCN, impacts the hormonal secretions of the HPA via inhibition. The HPA is associated with response to stress. The hormones it secretes include corticotropin releasing hormone (CRH), corticotropin, and cortisol—all of which inhibit sleep and promote wakefulness.
In normal physiology, these hormones are lowest during sleep and highest during wakefulness. But disruptions of the normal sleep-wake cycle and sleep duration (interrupted sleep) are linked to abnormal cortisol cycling. And patients experiencing increased levels of stress have higher circulating levels of hormones associated with the HPA.
Cortisol secretion has a wave-form pattern over 24 hours. Cortisol is at its lowest level at about midnight, and then starts to rise in the early morning and early waking hours, peaking at 9 a.m. and gradually declining throughout the day. Low levels of cortisol during the evening and night are associated with relaxation and sleep.
During times of stress, cortisol releasing hormone is elevated, increasing sleep EEG frequency (brain activity), decreasing short-wave sleep, increasing light sleep, and promoting frequent waking. Sleepiness is associated with low HPA activation and low cortisol, while sleeplessness is associated with HPA activation. This can become a vicious cycle when anxiety about sleep increases cortisol secretion, further disrupting and fragmenting normal sleep.
Reducing cortisol levels and supporting the HPA axis can be an effective approach to promoting and sustaining healthy sleep.
BEHAVIORAL INTERVENTIONS
In alignment with creating long-term solutions for our patients, our goal is not just to sedate them so they can enter into sleep, but rather to address root causes of their sleep disruption. Our goal is long-term, durable, healthy sleep.
Cultivating healthy sleep behaviors and stress resilience, as well as addressing dysregulation of the HPA and the upregulation of cortisol due to stress, comprises a comprehensive approach to sleep disturbances related to stress. Of course, there are multiple sources of “stress” and sleep dysregulation. The following sleep-hygiene and sleep-habit interventions focus on addressing stress-related disrupted cycles of cortisol secretion and upregulation of inflammatory cytokines.
Be consistent with bedtime and wake time
- Stick to a sleep schedule, which encourages normal 24-hour cycling of melatonin, neurotransmitters, hormones, and cytokines.
- Avoid naps during the day so you can sleep at night and stay attuned to natural cycles of dark and night.
Engage in behavioral rituals that signal your brain you are preparing for sleep
- Dim the lights.
- Turn off all electronics.
- Take a hot bath or gently stretch (get into your body and out of your mind).
- Change into sleep clothing.
- Brush your teeth and wash your face.
- Read an inspirational passage.
- Meditate, visualize, or pray.
- Put on soothing, relaxing music.
- Give yourself the auto-suggestion that you will enjoy deep, restful, restorative sleep; fall asleep easily; and wake refreshed.
Make your bedroom conducive to and supportive of sleep
- Darken the room by using window coverings and removing all light-emitting electronics.
- Lower the temperature to make the room as cool as possible.
- Do not work, eat, check email, watch TV or movies, talk on the phone, or deal with conflict or business in bed. Focus on sleeping.
- Minimize all noise and distractions. Use earplugs, soothing sounds, or white-noise recordings if there are outside intrusions of noise.
Disconnect electronically
- Avoid blue light–emitting screens at night. Blue is the light of morning. When blue light hits the eye, the brain perceives morning and ceases the normal production of melatonin.
- Turn off your WIFI.
- Do not sleep with your phone or other electronic devices near your head. If you must have your phone nearby, put it into airplane mode.
Adopt a sleep-hygiene lifestyle
- Eat an organic, whole-food, plant-focused, anti-inflammatory diet.
- Do not eat for at least four hours before bedtime.
- Avoid alcohol, cigarettes, caffeine, chocolate, and heavy meals in the evening.
- Exercise regularly during the daytime.
- Keep a sleep diary.
DIETARY CONSIDERATIONS
A variety of dietary ingredients have been shown to support healthy sleep. Four of the most-researched ingredients, and their mechanisms of action, are listed below.
Melatonin. This neurohormone produced by the pineal gland signals the brain in the presence of darkness, and helps reset the 24-hour circadian rhythm. Studies show melatonin may support normal sleep induction, sleep duration, and sleep quality.
Melatonin acts as an immune modulator by down-regulating inflammatory prostaglandins and leukotrienes and inhibiting inflammasome formation. Melatonin as an antioxidant helps quench oxidative stress.
Magnesium. This mineral is essential to hundreds of pathways in the cells and is important for healthy cardiovascular function and neurologic function.
Magnesium is required for the relaxation of skeletal muscle, and may help to relax the mind and body, making it easier to fall asleep. Magnesium helps to regulate the production of melatonin, promoting a normal sleep-wake cycle. It also supports normal levels of gamma aminobutyric acid (GABA), a calming neurotransmitter. Regular use of magnesium over time may improve overall sleep quality.
Lavender oil (Lavandula angustifolia). This plant in the Labiatiae family is rich in aromatic terpenes. Simply smelling lavender oil or taking a lavender bath helps support relaxation and ease. Some people use lavender aromatherapy for a sense of calm and restful sleep. Lavender oil acts as a modulator of immune inflammatory response. It may be taken as a capsule to support sleep quality and sleep duration.
Valerian root (Valeriana officinalis). This herb is native to Asia and Europe. It has traditionally been used for sleep support for hundreds of years—with records dating back as far as ancient Greece. Valerian root is commonly used to support ease of falling asleep, sleep quality, and a calm mood.
The following dietary ingredients support healthy sleep by supporting HPA axis regulation and stress resilience.
Ashwagandha (Withania somnifera). This rejuvenating tonic and adaptogenic herb is used in the traditional Ayurvedic system. It’s a GABA mimetic supporting relaxation and calm mood. Ashwagandha has been shown to support normal corticosteroid levels in stressed rats, thus supporting stress resilience. Withaferin-A also supports normal inflammation control.
Honokiol. This polyphenolic neolignan derived from Chinese magnolia bark (Cortex Magnolia officinalis spp.) has been widely used in Traditional Chinese Medicine.
Honokiol is a GABA mimetic supporting relaxation, calm mood, and restful sleep. It has been shown to shorten sleep latency and increase NREM sleep. Honokiol can also support normal modulation of stress response and normal inflammation response.
L-theanine (γ-glutamylethylamide). This amino acid is found primarily in green tea plants. A single cup of green tea may contain 25 mg of l-theanine. L-theanine inhibits glutamate uptake by neurons, and increases GABA in the brain. L-theanine also increases brain glycine levels—which supports relaxation—and enhances normal inflammatory signaling.
Phosphatidylserine (PS). This primary phospholipid component of brain neurons impacts sleep by enhancing the regulation of the HPA axis and cortisol during stress. PS can blunt the rise in cortisol in response to stress and support recovery and stress resilience, allowing for restful and uninterrupted sleep.
MIND-BODY INTERVENTIONS
The following interventions have been shown to support sleep regulation, sleep quality, and healthy sleep.
Acupuncture. This treatment has been shown to improve sleep quality and modulate stress in multiple studies. Acupuncture is an effective adjunctive therapy to support the resolution of sleep dysregulation. It also has demonstrated effects on modulation of cortisol-secretion immune response and expression of inflammatory cytokines.
Typically, a series of eight to 12 weekly acupuncture treatments is required to produce a durable change in sleep patterns.
Tai chi. This mindful-movement meditation significantly improves sleep quality in both healthy adults and patients with chronic health conditions.
Tai chi may be considered as an alternative behavioral therapy in the treatment of insomnia, and compares favorably to mindfulness-based stress reduction and cognitive behavioral therapy in producing a durable response and healthy sleep.
Mindfulness meditation and mindfulness-based stress reduction. Increased practice of these interventions is associated with improved sleep and a decrease in cognitive processes that interfere with sleep.
Mindfulness meditation demonstrates improvements in sleep disturbance and sleep quality, along with a reduction in stress, mood disturbance, and fatigue. Mindfulness meditation also promotes normal morning wakefulness.
Nalini Chilkov, LAc, OMD, is the founder of the American Institute of Integrative Oncology Research and Education (aiiore.com) and IntegrativeCancerAnswers.com. She’s the author of the best-seller 32 Ways to Outsmart Cancer, and is recognized as an authority and pioneer in the fields of integrative cancer care, cancer prevention, and immune enhancement. She has also lectured at UCLA and UC Irvine Schools of Medicine, and is a frequent expert resource to the media. Dr. Chilkov’s OutSmart Cancer system utilizes her more than 35 years of experience with thousands of patients, as well as her passion for training front-line clinicians worldwide to become skilled and confident in serving the health needs of patients whose lives have been touched by cancer. Her private practice is located in Santa Monica, California.