New research by John O’Neill, in the LMB’s Cell Biology Division, and Kenneth Wright, at the University of Colorado, has revealed the mechanism by which caffeine affects the human body clock. The body’s internal clock affects many aspects of human health and disease, such as when we feel sleepy, how we metabolise food, and even when in the day we observe the best athletic and cognitive performance. This circadian (roughly daily) rhythm operates in every single cell of the body, turning different genes on and off at different times of day to allow us to best anticipate the external cycle of night and day. Disruption of this daily internal rhythm, during shift work or through repeated jet lag, significantly increases the risk of various cancers as well as cardiovascular disease, type 2 diabetes and neurodegenerative disorders such as Alzheimer’s disease. It is known that caffeine counteracts some of the effects of sleepiness and makes it easier to stay awake, but until now no one had looked at whether there is also an effect on the internal circadian body clock.
Kenneth Wright’s group carried out in vivo experiments in which volunteers were placed in laboratory conditions so that their internal body clock could be observed. Each person lived in the laboratory for 49 days (without a clock, or any knowledge of external night and day). They were given caffeine or a placebo, and dim or bright light (the bright light was a control, since bright light at night also delays the human circadian clock). Melatonin is the main sleep hormone and is released from the pineal gland at night to make you feel sleepy. By observing the timing of the evening melatonin surge they showed that taken 3 hours before bedtime, the same amount of caffeine that you would find in a double espresso delays the normal rise in melatonin, equivalent to being jet-lagged by about an hour.
To understand how caffeine elicits its effects, in parallel, John’s group carried out in vitro experiments with human cells. Remarkably caffeine has the same effect on the circadian clockwork in human cells, cultured in a petri dish, as can be observed in whole humans. They found that caffeine in the cell growth media delayed the cellular clock by several hours. By comparing the effect of caffeine with more specific drugs they established that perturbation of adenosine receptor signalling, but not ryanodine receptor or phosphodiesterase activity, is enough to account for caffeine’s effects. Caffeine is already established to oppose the action of adenosine, a common metabolite, and adenosine receptors are found throughout the body. Using siRNA knockdown to reduce the levels of each adenosine receptor in turn, only when adenosine A1 receptors were targetted did the researchers observe reduced effects of caffeine on the cellular timekeeping. The A1 receptor is the most abundant receptor in the human brain, therefore this new work suggests a simple explanation for how caffeine has its effects on our internal body clock.
Caffeine is the world’s most widely consumed psychoactive drug, being the main drug in drinks such as coffee, tea and Coca-Cola. Caffeine’s wake-promoting effects are well established and the finding that caffeine influences human circadian physiology may have implications for the pathophysiology and perhaps treatment of some circadian sleep-wake disorders. For example, beyond increasing daytime exposure to sunlight and reducing evening exposure to electrical light, avoiding evening caffeine may help to treat problematic delayed sleep timing through circadian as well as established wakefulness-sleep mechanisms. Properly timed caffeine use may also be of benefit with respect to shifting circadian timing, potentially assisting with circadian adaptation to large phase delays required when flying across many time zones westward, as well as sustaining wakefulness until bedtime in the new time zone. Trials are needed to test the latter, and it will be important to monitor for caffeine-induced sleep disruption under such conditions, which could worsen jet lag.
This work was funded by the MRC, the Wellcome Trust, the NIH and the Howard Hughes Medical Institute in collaboration with the Biological Sciences Initiative and Undergraduate Research Opportunities Program at the University of Colorado Boulder.