How drugs that hack our circadian clocks might one day improve our health
They could help us overcome the toll that jet lag and shift work have on our bodies.
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We've got more than one biological clock. Beyond the one that marches onwards as we age, the circadian clock that sits in our brains keeps our bodies in rhythm. This clock helps control when we wake, eat, and sleep.
But there’s more to it than that. It also controls the finer aspects of how our bodies work, by influencing hundreds of molecular clocks throughout our cells and organs. There are clocks that regulate metabolism, for example, and others that control how genes make proteins. So it’s not surprising that disruptions to our circadian rhythms—from jet lag or shift work, for example—can wreak havoc on our health.
Now scientists are working on ways to tailor treatments to our circadian rhythms. Drugs that specifically target the clocks themselves are being explored in the lab. Will we one day be able to hack our circadian clocks to improve our health?
Circadian clocks don’t tick forward so much as loop through cycles over a 24-hour period. They are essentially clusters of genes and proteins that work together. Some genes might make proteins during the day, for example. When enough of these proteins have been made, they block the genes from making more overnight. Once levels of these proteins drop too low, the genes switch back on again in the morning. And so the cycle continues.
These cycles are controlled internally, by what’s known as a “master clock” in the brain’s hypothalamus. This clock is thought to synchronize all the others. And while it sets its own rhythm, it is influenced by how much light enters our eyes, when we eat and sleep, and other aspects of our behavior.
Molecular clocks have been found to affect many biological functions. One study in mice found that 43% of the animals’ genes follow some kind of circadian rhythm. Most genes seem to make more proteins during “rush hours” just before dawn and dusk.
It’s tricky to do the same research in people, but we do know that plenty of human genes work in a similar way. Our hormones and immune cells seem to show circadian patterns, fluctuating throughout the day.
Even our microbiomes seem to cycle over the course of a day. When scientists analyzed stool samples from volunteers, they found that some types of gut bacteria seem to be more abundant during the day, while others are more abundant at night. The relative abundance of Bacteroidetes bacteria—which can break down starches and fibers in the gut—was 6% higher at night, for example. It’s not yet clear what this means for our health, but curiously, these patterns seem to be disrupted in people with obesity and type 2 diabetes.
Both those conditions are more common in people who work night shifts, who also have an increased risk of cardiovascular disease and cancer. Again, it’s difficult to work out exactly how much of this risk can be blamed on a disrupted circadian rhythm, but research suggests that working overnight can shift the timing of when some genes make proteins. Some of these are proteins that are important for the immune system—particularly those that help kill cancer cells.
Given all this, it’s no surprise that the hunt is on for tools to realign our circadian rhythms. Some people swear by melatonin or light therapy, and you can influence your own rhythms by changing the timing of your meals and sleep. But scientists are after drugs that can target our molecular clocks directly.
Take KL001, for example. This compound affects a protein called CRY. Clock genes can switch on the production of CRY, and high levels of the protein can in turn switch off the clock genes.
KL001 works to keep levels of CRY protein high, which can affect the length of the circadian period. This can have a knock-on effect on genes in the liver that also run to a circadian rhythm. It can even control how liver cells make glucose, according to research on cells in a dish. In theory, a drug like this could help limit the effects of shift work on metabolic health, and potentially lower the risk of diabetes.
Unfortunately, we are likely some way off from being able to do this in people. But that doesn’t mean it isn’t a tantalizing idea worth investigating. In the meantime, we might be able to tailor existing treatments to people on the basis of their individual circadian rhythms.
While we all roughly follow a diurnal 24-hour cycle, there are variations. It is thought that people tend to fall into “chronotypes,” which roughly determine when they wake up, feel alert, and sleep. Basically, you’re a morning person or an evening person. If we can find ways to more accurately determine how a person cycles through a day at the molecular level, we might be able to work out the best time to deliver medicines or perform surgery, say some researchers.
Considering how long some of these ideas have been around, it’s a little disappointing that we haven’t made more progress. But it’s a vital area of research. We’ve probably all experienced the effects of a misaligned circadian rhythm. Jet lag can be brutal. Working late can leave you feeling rough and groggy the next day. We know that staring at screens at night is bad for us, but how many of us can honestly say we don’t check our phones last thing at night or first thing in the morning?
We already know we should be switching off our phones as bedtime approaches, and avoiding artificial light overnight. Going to bed at a regular time and getting enough sleep is another pretty obvious way to maintain good circadian health. At least it happens to be the best time of year for making resolutions …
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