Biological clocks are known to schedule sleep and changes in alertness, mood, strength and blood pressure, but recent studies suggest they are also deeply involved in mental health
Prof Foster will deliver a public lecture on “The rhythms of life” at the Physiological Society on Monday 7.30-8.30pm BST. Watch a livestream below
Our lives are ruled by time and we use time to tell us what to do. But the digital alarm clock that wakes us in the morning and the wrist-watch that tells us we are late for a meeting are not the clocks I mean. Our biology dances to a profoundly more ancient beat that probably started to tick early in the evolution of all life.
Embedded within the genes of us, and almost all life on Earth, are the instructions for a biological clock that marks the passage of approximately 24 hours. Biological clocks, or “circadian clocks” (circa “about”, diem “a day”), help time our sleep patterns, alertness, mood, physical strength, blood pressure and much more.
Under normal conditions, we experience a 24-hour pattern of light and dark, and our circadian clock uses this signal to align biological time to the day and night. The clock is then used to anticipate the differing demands of the 24-hour day and fine-tune physiology and behaviour in advance of the changing conditions. Body temperature drops, blood pressure decreases, cognitive performance drops and tiredness increases in anticipation of going to bed. Before dawn, metabolism is geared up in anticipation of increased activity when we wake.
But what generates these 24-hour rhythms? At the base of the brain within the anterior hypothalamus is a cluster of about 50,000 neurons known as the suprachiasmatic nuclei, or SCN. If this region of the brain is destroyed, say as a result of a tumour, then 24-hour rhythms are lost and physiology becomes randomly distributed across the day.
The finding that isolated SCN neurons show close to 24-hour rhythms in electrical activity demonstrated that the basic mechanisms that generate this internal day must be the product of a molecular process, and to date, approximately 14-20 genes and their protein products have been linked to the generation of this clock. Indeed, small changes in these genes have been linked to the morning and evening preferences of individuals who describe themselves as “larks” or “owls”.
The first assumption was that the cells of the SCN impose 24-hour rhythms of physiology and behaviour on the rest of the body. However, the discovery that isolated cells from almost any organ have clock genes and show patterns of 24-hour biology has led to a major shift in our understanding. It now seems that the SCN acts as the “master clock”, coordinating the activity of billions of individual cellular clocks across the body.
But it is important to stress that the molecular clock is not exactly 24-hour, but a bit longer. This means that unless we experience a daily dawn/dusk cycle the body clock drifts out of synchrony with the solar day, and in practice this would mean we would get out of bed later and later each day. The adaptive value of the circadian system is then lost – and this state has been termed “sleep and circadian rhythm disruption”, or SCRD.
Studying how light regulates the circadian system to prevent SCRD led to the remarkable finding that the eye has another light-sensing system, quite different from the rods and cones of the retina that allow us to build an image of our world. About 1% of the cells that form the optic nerve are directly sensitive to light. These photosensitive retinal ganglion cells (pRGCs) detect the dawn/dusk cycle and send projections to the SCN and force the molecular clock to be exactly 24-hour.
This discovery redefined our clinical definition of blindness. We can lose our rods and cones because of genetic disease, but the pRGCs can still function. So visual blindness does not always have to mean clock blindness. Slowly, in eye hospitals across the world, people with visual loss but with intact pRGCs are being advised to seek out sufficient daytime light to ensure their SCN is properly adjusted to the solar day. Otherwise they will experience SCRD for the rest of their lives.
But SCRD is much more than feeling sleepy at an inappropriate time. SCRD promotes multiple illnesses, including abnormal metabolism; reduced immunity; increased stress; and abnormal processing of information by the brain. We have known for years that shift workers tend to have higher rates of type two diabetes, heart disease, infection, cancer and mental illness, and are more prone to accidents, and recent studies have linked these illnesses directly to SCRD.
Severe SCRD is also a feature of mental illness. Conditions such as schizophrenia, bipolar disorder and depression all show SCRD, along with the ill health that arises from this disruption. This association between mental illness and SCRD is usually assumed to be linked to medication or some other ill-defined influence such as social isolation.
However, recent studies have shown that genes linked to mental illness are also involved in the generation of circadian rhythms and sleep, while some clock genes have also been shown to influence the development of certain specific mental illnesses. This new insight of common and overlapping mechanisms is not only telling us much about the biology of these processes, but is also informing the development of new treatments for these severely debilitating conditions.
The recent advances in our understanding of the brain mechanisms that generate and regulate sleep and circadian rhythms, and a growing appreciation of the broad health problems associated with SCRD, represents a truly remarkable opportunity to develop novel evidence-based treatments and interventions that will transform the health and quality of life of millions of individuals across a broad spectrum of illnesses.
The potential impact is extraordinary, yet in most five-year medical degrees the subject of sleep and circadian rhythms will be considered in perhaps one or two lectures. Now there’s a fact to sleep on …
Russell Foster is professor of circadian neuroscience at the University of Oxford, head of the Nuffield Laboratory of Ophthalmology, and director of the Sleep and Circadian Neuroscience Institute. He is a co-author of Sleep – A Very Short Introduction with Stephen Lockley