Author: Satchin Panda, PhD

Seven links between circadian disruption and disease

How do we figure out if a disease has something to do with circadian rhythm? There are many ways to connect circadian rhythm disruptions to a given disease, some are very obvious and straightforward, whereas others require a careful look. We can group these connections into seven bins. While connections between circadian disruption and metabolic disease are supported by multiple lines of evidence, connections to other diseases are often supported by only one or two studies. Yet, this latter connection should not be ignored, as they provide important clues about how to prevent or more effectively treat these diseases.

1. Heritable circadian disorders in humans. There are certainly rare, congenital diseases (heritable) that cause abnormal rhythms in the sleep-wake cycle. In this era of genetic testing, whenever we think of a disease we instinctively ask: Did I inherit a bad gene from my parents?  To date, we have characterized at least a dozen genes that constitute the molecular clock in every cell, and several genes that encode circadian-regulated hormones or their receptors. It is therefore natural to ask: How many people have mutations in these genes, and what happens to these people? The intersection between human genetics and circadian rhythms is a rapidly growing area of research. There are a few clear examples diseases that disturb the normal cycle of sleep-wake, including Smith-Magenis syndrome (SMS), Prader-Willie syndrome, familial advanced sleep-phase syndrome (FASPS), and delayed sleep phase syndrome (DSPS). But these are very rare conditions. Some children born with SMS tend to stay awake during the night and are sleepy and irritable during the day. In fact, some may even have high levels of melatonin during the day and low levels at night. Some Prader-Willie patients also have an abnormal sleep-wake cycle, staying awake late into the night. As the name suggests, people with FASPS tend to go to bed very early and are morning larks, while individuals with DSPS tend to be night owls. Some individuals with FASPS or DSPS may carry mutations in circadian clock genes. Similarly, some individuals who feel rested after only 5 hours of sleep (short sleepers) may carry a mutation in a gene that shows daily rhythm.
2. Disease susceptibility of circadian mutant animals. Starting from the famous period mutation in fruit flies, there are numerous examples of animals that harbor mutations in circadian clock genes. These mutant animals were initially studied to understand circadian rhythm defects. But, over time it became apparent that they also suffer from an array of diseases. For example, mice carrying mutations that alter the function of circadian clock genes (clock, bmal1, cry1, cry2, per1, per2, rev-erbs, rors) often show diseases of metabolism. Many of these mutant mice exhibit abnormal metabolism of sugar, fat, and amino acids. As a result, they develop various metabolic diseases, including type 2 diabetes, atherosclerosis, increased adiposity, and fatty liver disease. Some of these mutants also have a dysfunctional immune system and therefore suffer from elevated levels of inflammation. Some circadian mutant animals show sign of early aging, brain inflammation, and mania. Similarly, animals that lack the blue light sensor melanopsin show signs of depression.
3. Disease prevalence among shift workers. People who work night shifts, or rotate between day and night shifts, have higher incidences of a number of diseases compared to people who typically work the day shift. These diseases range from obesity and diabetes to diseases of the colon, infections, and certain types of cancer. This observation was a smoking gun for connecting circadian rhythm disruption (in this case due to work habit or lifestyle) to disease. However, many argue that shift workers are exposed to other confounding factors – they may not have access to the same types of food as day-time workers. They may not have time to exercise. However, even after controlling for these confounds, there is a significant connection between shift work and diseases. Some of these connections have also been studied in controlled clinical conditions.
4. Controlled clinical studies. When the circadian rhythms of healthy human volunteers are intentionally disrupted, they show early signs of disease. In a few controlled studies, healthy human volunteers have been invited to clinical laboratories where they live for several days or a few weeks under medical supervision. When these volunteers are asked to sleep less or change their sleep-wake cycle, as if they are on a night shift or rotating shift work, they show early signs of some diseases. For example, sleep-deprived volunteers may begin to eat more than they need, may exhibit slightly elevated blood sugar, or may show an abnormal hormonal response to a bolus of glucose. These are early signs of metabolic diseases that offer another line of evidence that circadian rhythm disruption increases our chance of getting sick. Of course, we cannot keep healthy volunteers in the clinic for months or years to determine if they ultimately develop fatty liver disease, obesity, digestive disease, or cancer. That would be unethical. For these reasons, laboratory animals such as fruit flies or rodents are sometimes subject to shift work-like conditions under the supervision of veterinarians, pathologists, and scientists.
5. Chronic circadian disruption studies in animals. Animals subjected to chronic circadian rhythm disruption are predisposed to the disease. Sometimes, animals that have normal circadian clock genes and normal circadian rhythms are placed in conditions that disrupt their circadian clocks (e.g., a nighttime lamp, or a light:dark cycle that simulates a transatlantic flight or rotating shiftwork). These perturbations affect their circadian clock genes, as well as everything the clock genes control. Within a few days or weeks, the animals under simulated shiftwork become overweight and show early signs of heart disease, increased inflammation, fatty liver disease, and even cancer. Some of these animals also become prone to pathogenic infection, and female often develop reproductive issues.
6. Therapeutic effects of restored rhythms. Restoring daily rhythm of light:dark, feeding:fasting, or sleep:wake can alleviate disease symptoms. The simple everyday experience for many people is that when they dim or turn off the lights in the evening, they sleep better. Conversely, being exposed to bright light during short winter days improves mood and reduces depression. Cancer patients who maintain a regular bedtime and get enough sleep recover faster and experience less severe adverse effects of cancer treatment. Finally, as our lab has shown, maintaining a daily rhythm of feeding and fasting – an eating pattern called time-restricted feeding (TRF) – can prevent or reverse obesity, metabolic diseases, heart disease, and even certain diseases of the brain. While many of these observations are in animals, these animal studies have offered clear molecular links that can be further examined in human studies of TRF.
7. Circadian rhythms in disease symptoms. Some disease symptoms exhibit daily fluctuations in severity, indicating that treatments strategies should take into account circadian rhythms. Many autoimmune diseases, including eczema, asthma, and diseases of the gut such as acid reflux, becomes more severe at night. Similarly, inflammatory diseases, such as rheumatoid arthritis, are most painful early in the morning. These time-of-the-day fluctuations in disease severity indicates that the underlying pathology has a circadian component, which should be kept in mind when attempting to prevent or treat these diseases. For example, clinical studies are now finding anti-inflammatory medications taken late at night are better at controlling joint pain from rheumatoid arthritis than the same medication taken in the morning.

The science of circadian rhythm is a relatively new and growing field. As more clinicians and scientists become interested in this area of research, we will learn more about how circadian rhythm disruptions predispose us to various diseases, and how certain lifestyle choices (e.g., timing of food consumption, activity, sleep, exercise, and medication) can be used to prevent or cure diseases – from simple gut discomfort to life-threatening forms of cancer.