Is your body clock important?
Absolutely. Just ask any morning lark who lives with a night owl, or vice versa.
But it’s much more complicated than that, researchers are finding.
At the University of Pennsylvania, Carsten Skarke, research assistant professor of medicine, and his colleagues are exploring numerous aspects of our body clocks – they’ve coined the term chronobiome – including how a better understanding might affect medical treatments.
We recently spoke to Skarke, the Robert L. McNeil Jr. Fellow in Translational Medicine at the Institute for Translational Medicine and Therapeutics, about his work.
What, exactly, is the chronobiome?
It’s a new term we created. Chronos is Greek, and it means time. Biome has been used to describe habitats on earth. When it comes to the human body, we have different biorhythms, which have gotten a lot of traction over the past 10 years. Taking this idea, we put together the word chronobiome.
Depending on the time of day, you see different abundances of breakdown products, different levels of activities, within body systems. A classic example is cortisol, a hormone that has many functions in our bodies. It is more abundant in the morning than the evening. Another one is melatonin, which is high in the evening and low in the morning. Typically, it accumulates two hours before people’s bedtime and facilitates sleep. These signals and the time of when they are high, or when they are low, the entirety of this, we call the chronobiome.
Why is it important?
Most people know a lot about how time of day influences their well-being. Everyone is familiar with jet lag. That is an acute form of disrupting someone’s chronobiome. We know that if someone is doing shift work for a decade or two, the risk for cardiovascular disease and other diseases increases dramatically. That is a chronic form of disrupting someone’s biological rhythm.
Today, we light up our cities. The strongest signal from the environment to keep us in the correct biological rhythm is light. So if you live in a city with streetlights and if you don’t use blinds, your body gets disrupted.
And then, over the last 10 years, more and more people started using smartphones and similar devices. These emit blue light, which signals to your body that it’s day. There is increasing literature showing that if you read from a device before you go to bed, and you hold it very close to your eyes, that also disrupts your biological rhythms. You will have trouble going to sleep.
But if you go into medicine, you encounter very little time data. It’s rarely taken into account. For example, many data bases and tissue banks and collections of biospecimens have not been annotated by time, meaning the time of collection has not been written down.
So we are at a phenomenal point of time. Over the last two decades, the circadian clock, its molecular mechanism, has been teased out. We have a good understanding of these rhythms -- why something is high in the morning and low in the evening. They are interconnected. They have feedback loops, feedforward loops. That is a pretty complicated regulatory system. It has been elucidated in fruit flies and in mice. Now is the perfect time to translate all that knowledge into us humans.
An immediate benefit that comes to mind is drug treatment. There are several ideas in that field. One is that it matters when a drug is given to a patient. We want to get the largest benefit for the patient, and the lowest risk of any side effects. One very nice example we already know about is cholesterol-lowering drugs, statins. There, the evidence points to giving these drugs in the evening. We know the cholesterol-making enzymes in the human body are most active during the night, so it makes sense to give the drug that inhibits the making of cholesterol before you go to sleep.
Are you looking more broadly at the human chronobiome, or is an individual’s chronobiome important, as well?
At the end of the day, we’re interested in an individual’s chronobiome. That brings up the area of personalized medicine. How can you adapt the treatment according to the patient’s particular need?
About a year ago, a French group did a study where they compared aortic valve replacement surgeries done in the morning versus the afternoon. They looked at the subsequent days and weeks to see which group — the morning or the afternoon group — fared better in terms of cardiovascular events. They found out that patients operated on in the afternoon fared better. But if you were to look at the different chronotypes of these patients individually, the molecular times might have been different. My 4 p.m. may be different from your 4 p.m. So there is another opportunity, when we understand someone’s molecular time, or biological time, to adjust treatments or interventions.
How are you studying this?
This had not been done before, so we started with a small pilot. We chose six healthy volunteers. They were all male because often, in biology, you will see differences between women and men. We wanted to reduce this variability.
We used smartphone apps to collect data on communication, on mobility, on what they ate. A GPS function told us when they traveled and how much distance was traveled. Another domain was activity, so we used research-grade Fitbits that gave us 60 signals each second. That also gave us a view into sleep -- how long the volunteers slept, how well they slept, how much they woke up. Each data point had a time and date attached to it.
We also measured clinical readouts -- blood pressure, heart rate. Twice a day, in the morning and evening, we collected many biospecimens -- blood, urine, saliva -- to look at certain metabolites, proteins, gene expression, and into the microbiome, the bacteria residing in our gut and mouth.
One important point: We intervened in the lives of our volunteers as little as possible. We wanted to measure the chronobiome in the wild, as we called it.
What have you learned so far, and where do you go from here?
We found that between 5 to 6 percent of the metabolites differed between morning and evening. Also, the bacteria differed from morning to evening. What that told us is that despite the fact that the six healthy volunteers followed their individual lives and schedules, and that introduces a lot of variability, we still were able to pick up time-of-day-dependent differences in the metabolites and bacteria.
Now we want to look at 200 healthy volunteers. That will give us a much richer data set. We also will be able to address the difference between women and men. We can specifically look for certain signals that are stronger in women than in men and vice versa. We also want to look at age. We know that the expression of the circadian clock tapers off as you age. The rhythms are less strong. We will follow people for a year, so then we also will be able to see if season makes a difference. We know that there are seasonal affective disorders, but we want to look at that at a much deeper level.
We have so many approved drugs at our hands, and all these drugs come with certain benefits and some side effects. The big hope is that we can find a way to synchronize the time of treatment with the molecular time of the patient. That means that the unique body time of a particular patient matters, and that there is a benefit in thinking, “When should a certain drug be administered?”