27 Feb Circadian clocks: drivers of health and disease
Our body is driven by biological clocks that influence multiple aspects of our health. We call these circadian clocks.
- Our body functions through a complex network of circadian clocks, which regulate the function of multiple organs through the so-called circadian rhythms.
- Circadian clocks have a genetic basis, as they are controlled by a series of genes that activate and deactivate throughout the day.
- Factors like our sleep/wake patterns and the nutrients we consume influence the optimal function of our circadian rhythms.
- Alterations of our circadian rhythms can lead to the development of multiple diseases.
- Keeping our circadian rhythms in check requires significant changes to our lifestyle.
Under optimal conditions, our body functions under the direction of a complex network of circadian clocks, which regulates our metabolism in synchrony with the light/darkness patterns that occur throughout the day. In other words, our circadian clocks help coordinate the occurrence of important metabolic events with daily changes in the environment. For example, by activating or deactivating genes depending on whether we are awake or asleep, or whether it is midday or midnight.
In the human body, circadian clocks are found in nearly every tissue and organ, regulating specific metabolic functions. All these clocks are coordinated by a master clock found in the brain, in the region called the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN receives information about the outside world, such as light signals from the eyes. With this information, the SCN circadian clock generates the circadian rhythms that regulate a variety of biological processes, including body temperature, neuroendocrine function, autonomic function, memory and psychomotor performance during our wake and sleep phases1. For example, at night, when it is dark outside, our SCN sends a signal to the pineal gland to produce the hormone melatonin. Melatonin induces night state physiological functions that promote sleep, such as decreased body temperature and respiration rate. In contrast, light inhibits the production of melatonin, promoting wakefulness.
Given the regulatory role of the circadian clock system in many physiological functions, the disruption of this circadian system can negatively impact human health. Disruption of circadian rhythms has been linked to various chronic health conditions, including sleep disorders, metabolic impairments, poor stress management and major depression 2-5. Likewise, some conditions, such as neurological disorders, can contribute to the disruption of circadian rhythms and sleep cycles.
Genetic regulation of our circadian clockwork
The body’s circadian clocks are controlled by two core or master “clock genes”, called CLOCK and BMAL1. Together, these master genes control the expression of other clock genes, such as “per” and “cry”, which in turn affect the function of thousands of other genes involved in different body functions. The per and cry genes also encode two special types of proteins, called PERIOD and CRYPTOCHROME, which have a repressor role: their job is to halt the function of the CLOCK and BMAL1 complex. This whole process occurs at specific times of the day. For instance, during the daytime, the CLOCK/BMAL1 complex is formed. Then, during the afternoon the per and cry genes become active and towards the end of the day, as the product of these two genes (PERIOD and CRYPTOCHROME) becomes more abundant, they inhibit the function of the master clock genes.
This is how the circadian clock works at the levels of genes in the body. The ultimate goal is to express the genes your body needs to function only during the times of increase activity (when you are awake) and to shut it down when you are off to bed.
Stress and the circadian clock
When exposed to stress, the body activates various biological processes, collectively known as the stress response system, aimed at protecting and restoring homeostasis. This system involves the activation of the autonomous nervous system (ANS) and the hypothalamus-pituitary-adrenal (HPA) axis6.
When the HPA axis is working to achieve and maintain homeostasis as part of a stress response, it relies on the circadian clock to optimise the secretion of hormones in different tissues at different times of the day. The HPA axis also uses the circadian clock to regulate the so-called ultradian rhythms, which help optimise the release of glucocorticoids in specific tissues at specific timeframes. This allows for the rapid reactivity needed in a stress response.
Good sleep keeps our clocks in check
Sleep is considered the most important regulator of the body’s circadian rhythms. Hence, why it is so important to keep a firm sleep schedule. Alterations to our optimal sleep cycle have been associated with multiple conditions, including brain-related disorders and heart disease.
Patients with psychiatric disorders and neurodegenerative disease often suffer from abnormal circadian rhythms and sleep patterns7. Conditions like Parkinson disease (PD), Alzheimer’s disease (AD), schizophrenia, bipolar disorder, anxiety, Huntington’s disease and multiple sclerosis have been associated with disturbances of sleep and circadian rhythms.
- Parkinson disease – About 80-90% of patients with PD suffer from a sleep disorder, including difficulties to fall asleep, motor activity during sleep, post-sleep behaviour or daytime somnolence. PD patients also experience a disruption in the patterns of melatonin release7-9.
- Alzheimer’s disease – patients with AD suffer from fragmented night sleep, due to alterations to their sleep and circadian rhythms. These disturbances result from damage caused by AD pathology to different parts of the brain related to control of sleep and vigilance10.
- Anxiety-related disorders – multiple conditions, including anxiety, panic, obsessive-compulsive disorder, post-traumatic stress disorder and depression are associated with disrupted circadian and sleep patterns11.
Multiple studies have linked the circadian clock to optimal heath function, particularly involving changes in blood pressure or response to drugs like aspirin12-13. Various conditions are included in this category, such as unhealthy blood pressure, accelerated heart aging and increased resting heart rate14.
These include various conditions, like insomnia, restless leg syndrome, narcolepsy and other pathologies of sleep11. Alterations of the circadian clocks can affect sleep through their effect on the release of sleep-related hormones.
Keeping your circadian clocks in check
The easiest way to maintain healthy circadian rhythms is to commit to a healthy sleep schedule and following regular and consistent eating habits.
Other approaches that can help improve our circadian and sleep cycles involve different therapies and the use of certain supplements. For example,
Anyone who experiences sleep restrictions due to odd work schedules, jet lag, or issues with daylight saving adjustments, can end up with disrupted HPA axis and metabolic functions. Here, simple but effective treatment is exposure to sunlight or short-wave light upon awakening. This is a natural way to help correct the circadian rhythms of the HPA axis15-16.
Disruption of circadian rhythms can result in reduced secretion of melatonin, which, in turn, causes sleep disorders. Supplementation of melatonin, ideally near bedtime, can help mimic the body’s natural pattern of light/dark melatonin secretion17.
There are various natural treatments for circadian disruptions that involve the use of plant-based supplements, such as Valerian root (Valeriana officianalis), Hops strobile (Humulus lupulus), Passionflower (Passiflora incarnata), Jujube seed (Ziziphus jujuba), Chamomile flowers (Matricaria recucita), Kava root (Piper methysticum), Rhodiola rosea and Lemon Balm (Melissa officinalis)18-20.
Treatment with other supplements can also help deal with problems associated with sleep and circadian rhythms alterations. Compounds like Phosphatidylserine, taurine, magnesium, selenium, zinc or L-tryptophan, L-theanine and 5HTP have shown different effectiveness in the treatment of sleep disorders21. For example:
- Zinc – this essential metal is needed for optimal body function, for example:
- It is absorbed and used by the intestine, liver and kidney
- It is involved in mood, sleep and cognitive functions, through its inhibitory role against a receptor called NMDA, found in nerve cells.
- Studies have shown that sleep duration is correlated with an optimal ratio of zinc to copper in your body22-24.
- L-theanine – this is a well-known amino acid that works as sleep modulator. It is also one of the most common amino acids found in tea and is considered a relaxing agent. Studies have reported anti-stress effects for this amino acid in humans, as well as improvement in sleep. In mice, one study showed L-theanine improved conditions like shortened life, span cerebral atrophy, learning impairment, behavioural depression, and others25-26.
- 5-HTP – this molecule is an intermediate metabolite of the amino acid L-tryptophan, needed for the synthesis of serotonin. In other words, it is a molecule required to produce serotonin. 5-HTP can easily move in and out of the brain and is known to increase the production of serotonin in the central nervous system. 5-HTP has also been shown to affect different stages of sleep, like Random Eye Movement (REM) or Slow Wave Sleep (SWS)27.
- Magnesium – this is one of the most abundant elements found in our body and cells. It is also very important, as it is involved in more than 300 biochemical reactions of the body. One key function of magnesium is its role as co-factor of various important enzymatic reactions involved in energy metabolism and neurotransmitter synthesis. Magnesium also has important effects on sleep regulation. A study on elderly subjects, for example, found that consumption of magnesium for eight weeks improved various symptoms associated with insomnia, such as sleep efficiency, sleep time and early morning awakening28-30.
- Zinc – this essential metal is needed for optimal body function, for example:
Treatment with any of these approaches has shown varying efficacy for conditions like insomnia and stress management. Consultation with a functional medical practitioner about their potential use is an important first step.
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- Albrecht U. Circadian clocks in mood-related behaviors. Annals of medicine. 2010 Jan 1;42(4):241-51.
- Barclay JL, Husse J, Bode B, Naujokat N, Meyer-Kovac J, Schmid SM, Lehnert H, Oster H. Circadian desynchrony promotes metabolic disruption in a mouse model of shiftwork. PloS one. 2012 May 21;7(5):e37150.
- Mukherjee S, Coque L, Cao JL, Kumar J, Chakravarty S, Asaithamby A, Graham A, Gordon E, Enwright III JF, DiLeone RJ, Birnbaum SG. Knockdown of Clock in the ventral tegmental area through RNA interference results in a mixed state of mania and depression-like behavior. Biological psychiatry. 2010 Sep 15;68(6):503-11.
- Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, Laposky A, Losee-Olson S, Easton A, Jensen DR, Eckel RH. Obesity and metabolic syndrome in circadian Clock mutant mice. Science. 2005 May 13;308(5724):1043-5.
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- Arnulf I, Leu S, Oudiette D. Abnormal sleep and sleepiness in Parkinson’s disease. Current opinion in neurology. 2008 Aug 1;21(4):472-7. Read it!
- Willis GL, Kelly AM, Kennedy GA. Compromised circadian function in Parkinson’s disease: enucleation augments disease severity in the unilateral model. Behavioural brain research. 2008 Nov 3;193(1):37-47. Read it!
- Wu H, Dunnett S, Ho YS, Chnag RC. The role of sleep deprivation and circadian rhythm disruption as risk factors of Alzheimer’s disease. Frontiers in neuroendocrinology. 2019 May 15:100764. Read it!
- Coles ME, Schubert JR, Nota JA. Sleep, circadian rhythms, and anxious traits. Current psychiatry reports. 2015 Sep 1;17(9):73. Read it!
- Montaigne D, Marechal X, Modine T, Coisne A, Mouton S, Fayad G, Ninni S, Klein C, Ortmans S, Seunes C, Potelle C. Daytime variation of perioperative myocardial injury in cardiac surgery and its prevention by Rev-Erbα antagonism: a single-centre propensity-matched cohort study and a randomised study. The Lancet. 2018 Jan 6;391(10115):59-69. Read it!
- Curtis AM, Cheng Y, Kapoor S, Reilly D, Price TS, FitzGerald GA. Circadian variation of blood pressure and the vascular response to asynchronous stress. Proceedings of the National Academy of Sciences. 2007 Feb 27;104(9):3450-5. Read it
- Thosar SS, Butler MP, Shea SA. Role of the circadian system in cardiovascular disease. The Journal of clinical investigation. 2018 Jun 1;128(6):2157-67. Read it!
- Figueiro MG, Rea MS. Short-wavelength light enhances cortisol awakening response in sleep-restricted adolescents. International journal of endocrinology. 2012;2012. Read it!
- Paul MA, Gray GW, Lieberman HR, Love RJ, Miller JC, Trouborst M, Arendt J. Phase advance with separate and combined melatonin and light treatment. Psychopharmacology. 2011 Mar 1;214(2):515-23. Read it!
- Vural EM, Van Munster BC, De Rooij SE. Optimal dosages for melatonin supplementation therapy in older adults: a systematic review of current literature. Drugs & aging. 2014 Jun 1;31(6):441-51. Read it!
- Leach MJ, Page AT. Herbal medicine for insomnia: A systematic review and meta-analysis. Sleep medicine reviews. 2015 Dec 1;24:1-2. Read it!
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- Song CH, Kim YH, Jung KI. Associations of zinc and copper levels in serum and hair with sleep duration in adult women. Biological trace element research. 2012 Oct 1;149(1):16-21. Read it!
- Zhang HQ, Li N, Zhang Z, Gao S, Yin HY, Guo DM, Gao X. Serum zinc, copper, and zinc/copper in healthy residents of Jinan. Biological trace element research. 2009 Oct 1;131(1):25-32. Read it!
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