How the Circadian Rhythm Affects Sleep, Wakefulness, and Overall Health

By Dr. Nina Mikirova, Director of Research

Life on earth has evolved under the daily rhythm of light and dark. Metabolic, physiological and behavioral processes exhibit 24-hour rhythms in most organisms, including humans.

Light is one of the most potent environmental cues that enable the organisms to adapt to the 24-hour environmental LD cycle. Photic signals are delivered from the eye to the suprachiasmatic nucleus (SCN) via the retino-hypothalamic tract, thereby mediating the entrainment of the circadian clock system.

This regulation is driven by a small region in the anterior hypothalamus of the brain, termed as the “circadian clock.” This clock spontaneously synchronizes with the environmental light-dark cycle, thus enabling all organisms to adapt to and anticipate environmental changes. As a result, the circadian clock actively gates sleep and wakefulness to occur in synchrony with the light-dark cycles. Indeed, our internal clock is our best morning alarm clock, since it shuts off melatonin production and boosts cortisol secretion and heart rate 2-3h prior awakening.

The internal circadian clock and sleep-wake homeostasis regulate and organize human brain function, physiology and behavior so that wakefulness and its associated functions are optimal during the solar day and that sleep and its related functions are optimal at night. The maintenance of a normal phase relationship between the internal circadian clock, sleep-wake homeostasis and the light-dark cycle is crucial for nominal neurobehavioral and physiological function in humans. The circadian timing system influences food intake behavior, activity of the gastrointestinal system, and several aspects of glucose and lipid metabolism.

In fact, the internal biological timekeeping and the sleep-wake systems are important regulators of neuroendocrine, metabolic, renal, cardiovascular, and neurobehavioral function. Disturbed circadian rhythms are known to be closely related to many diseases, including sleep disorders. The circadian clock system regulates daily rhythms of physiology and behavior, such as the sleep-wake cycle and hormonal secretion, body temperature and mood. Sleep disorders include chronic insomnias associated with an endogenous clock which runs slower or faster than the norm sleep phase syndrome, periodic insomnias due to disturbances in light perception (non-24-hour sleep-wake syndrome and sleep disturbances in blind individuals) and temporary insomnias due to social circumstances (jet lag and shift-work sleep disorder).

According to the Centers for Disease Control and Prevention and the Institute of Medicine of the National Academies, insufficient sleep has become a public health epidemic. Approximately 50-70 million adults (20 years or older) suffer from some disorder of sleep and wakefulness, hindering daily functioning and adversely affecting health and longevity.

Treatment of circadian rhythm disorders, whether precipitated by intrinsic factors (e.g., sleep disorders, blindness, mental disorders, aging) or by extrinsic factors (e.g., shift work, jet-lag) has led to the development of a new type of agents called ‘chrono-biotics’, among which melatonin is the prototype. The term ‘chrono-biotic’ defines as a substance capable of shifting the phase of the circadian time system thus re-entraining circadian rhythms. Melatonin administration synchronizes the sleep-wake cycle in blind people and in individuals suffering from delayed sleep phase syndrome or jet lag, as well in shift-workers.

Melatonin is synthesized from tryptophan and is intensively secreted into the blood only in darkness (nighttime) by the pineal gland. Melatonin is not only the most reliable marker of internal circadian phase but also a potent sleep-promoting and circadian phase regulatory agent in humans. The hormone melatonin is commonly used as a marker of internal biological time representing the phase of the master circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus in mammals.  Humans typically initiate sleep shortly after the circadian rise in plasma melatonin levels and awaken shortly after the circadian fall in plasma melatonin levels. In humans, sleep efficiency is best during the biological night when melatonin levels are high.

The effect of melatonin on sleep is probably the consequence of increasing sleep propensity (by inducing a fall in body temperature) and of a synchronizing effect on the circadian clock (chrono-biotic effect).

In several studies successfully employed the timely use of three factors (melatonin treatment, exposure to light, physical exercise) to hasten the resynchronization after trans-meridian flights comprising 12-13 time zones, from an average of 8-10 days to about 2 days.

Daily melatonin production decreases with age, and in several pathologies, attaining its lowest values in Alzheimer’s dementia patients.  Due to decreased melatonin production, about 45% of dementia patients have severe disruptions in their sleep-wakefulness cycle.

Cardiac rhythm, melatonin and cancer risk: does light at night compromise physiologic cancer protection by lowering serum melatonin levels?

Light is the primary stimulus to the disruption and resetting of pacemaker, which is expressed in changing melatonin rhythms. Melatonin production in humans decreases when people are exposed to light at night. Since melatonin shows potential oncostatic action in a variety of tumors, it is possible that lowered serum melatonin levels caused by exposure to light at night enhance the general tumor development.

It has been estimated that about 20% of working people work in the shift system. This estimate concerns health service employees and policemen among others. The shift work causes permanent conflict “of biological clock” with required working hours. The work in the night hours is less effective and triggering the increased tiredness.

Cancer is the second leading cause of death in industrialized countries like the United States, where a significant proportion of workers engage in shift work, making a hypothesized relation between light exposure at night and cancer risk relevant. Observational studies support an association between night work and cancer risk. The potential primary culprit for this observed association is the lack of melatonin, a cancer-protective agent whose production is severely diminished in people exposed to light at night.

Previously, humans tended to conduct their daily activities according to the sun’s cycle: rising at sunrise and going to bed at sunset. Such sleep rhythms appear not only to be more natural, but also to be essential for a variety of physiologic functions in humans, such as body temperature, excretion, and the production of hormones.

Melatonin, for example, follows a very distinct pattern of production, which is very closely linked to the individual’s circadian rhythm, following light exposure. Environmental lighting powerfully alters physiologic release of melatonin, which typically peaks in the middle of the night: a profound melatonin reduction was observed in humans after 2 weeks of intermittent nightly exposure to light.

Thus, novel hypotheses were generated, proposing that the diminished function of the pineal gland might promote the development of breast cancer in humans. One of the initial theories supporting that a diminished function of the pineal gland might promote the development of cancer hypothesized that melatonin suppression may lead to an increase in levels of reproductive hormones, particularly oestradiol, thereby increasing the growth and proliferation of hormone-sensitive cells in the breast.

Observational studies have supported that theory, indicating that women in occupations that expose them to light at night do experience a higher risk of breast cancer. Interestingly, blind women, who do not have the ability to experience lower melatonin levels because of their supposed lack of receptivity to light, have a lower incidence of breast cancer.

Studies fairly consistently report meaningful increases in breast cancer risk among postmenopausal women exposed to shift work. Two retrospective studies of flight attendants with occupational exposure to light at night linked the employment time to an increased risk of breast cancer.

Two nationwide record linkage studies and a retrospective case–control study associated night work with an approximately 50% higher risk of breast cancer.

Finally, the Nurses’ Health Study, the only prospective study published that evaluated the association, observed a positive association of extended periods of rotating night work and breast cancer risk (more than 30 years of rotating night work ).   In this study, nightwork was defined as the total number of years during which the nurses had worked rotating night shifts with at least three nights per month, in addition to days and evenings in that month. During10 years of follow-up, 2441 incident cases of breast cancer were documented among 78,562 women. A positive association between the numbers of years a woman had worked on rotating night shifts and breast cancer risk was observed.

Among postmenopausal women, the relative risk for breast cancer, controlling for all the major risk factors for breast cancer, was moderately increased after 1–14 and 15–29 years of rotating nightshift work, and was further increased for those nurses who worked the night shift for 30 or more years, with similar risks for premenopausal women. Thus, in sum, observational studies seem to support the hypothesis that night work increases the risk for breast cancer.

Light at night and other cancers

Only few observational studies have addressed the relationship between shift work and cancers, other than breast cancer. Early suggestions for an increased cancer risk related to shift work arose from two mortality studies that were conducted among male shift workers to assess the influence of shift work upon total and cause-specific mortality, with suggestions for an increased cancer mortality related to shift work.  One study reported an increased risk of colon and rectum cancer in the cohort of female radio and telegraph workers. Another study did not report the risks for colorectal cancer among the female Icelandic flight attendants, but describe an elevated risk for tumors of the lymphatic system.

The Nurses’ Health Study Cohort was used to explore the association between nightwork and colorectal cancer; 602 women were diagnosed with incident of colorectal cancer during the 10 years of follow-up. In these analyses, women who worked 15 or more years on rotating night shifts were at a higher risk of colorectal cancer than were women who never worked rotating night shifts.

Cancer-Protective Effects of Melatonin

In recent years, an overwhelming amount of research has been devoted to exploring the cancer-protective properties of the hormone melatonin. Today, many of the oncostatic properties of melatonin have been fairly well described, and evidence from experimental studies strongly suggests a link between melatonin and tumor suppression.

In vitro studies, although not entirely consistent, give support to a reduction in the growth of malignant cells of the breast and other tumor sites by both pharmacological and physiologic doses of melatonin.

In rodent models, exogenous melatonin administration exerts anti-initiating and oncostatic in various chemically induced cancers.

Melatonin is believed to have antimitotic activity by its direct effect on hormone-dependent proliferation through interaction with nuclear receptors. Another explanation is that melatonin increases the expression of the tumor-suppressor genep53. Cells lacking p53 have been shown to be genetically unstable and thus more prone to tumors.

In vitro studies do support not only an effect of melatonin on breast cancer, but also on other tumors. In fact, to date, melatonin has been shown to be oncostatic for a variety of tumor cells in experimental carcinogenesis.

Reports show that melatonin exhibits a growth-inhibitory effect on endometrial and ovarian carcinoma cell lines, Lewis lung carcinoma, prostate tumor cells, and intestinal tumors.

Furthermore, today, several clinical trials confirm the potential of melatonin, either alone or in combination with standard therapy regimens, to generate a favorable response in the treatment of human cancers.

Given the evidence from experimental studies supporting the general oncostatic property of melatonin, we therefore speculate that exposure to light at night not only has an impact on breast cancer risk, but also may increase the risk of other cancers, primarily through the melatonin pathway. This has been posed previously without much further attention from the scientific community, but most recent evidence from observational studies supports such a link.