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.

Key Points

• 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.

• Brain-related disorders
  

  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 release^7-9.
  • 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.

• Heart disease
  

  Multiple studies have linked the circadian clock to optimal heath function, particularly involving changes in blood pressure or response to drugs like aspirin^12-13. Various conditions are included in this category, such as unhealthy blood pressure, accelerated heart aging and increased resting heart rate¹⁴.

• Sleep disorders 

  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,

• Light therapy 

  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 axis^15-16.

• Melatonin supplements

  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.

• Botanical therapies  

  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.

• Non-botanical supplements

  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 body^22-24.
  • 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 others^25-26.
  • 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 awakening^28-30.

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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