internal clock

Scientists Want to Align Your Internal Clock Because Timing Is Everything

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internal clock

In life, timing is everything.

Your body’s internal clock — the circadian rhythm — regulates an enormous variety of processes: when you sleep and wake, when you’re hungry, when you’re most productive. Given its palpable effect on so much of our lives, it’s not surprising that it has an enormous impact on our health as well. Researchers have linked circadian health to the risk of diabetes, cardiovascular disease, and neurodegeneration. It’s also known that the timing of meals and medicines can influence how they’re metabolized.

The ability to measure one’s internal clock is vital to improving health and personalizing medicine. It could be used to predict who is at risk for disease and track recovery from injuries. It can also be used to time the delivery of chemotherapy and blood pressure and other drugs so that they have the optimum effect at lower doses, minimizing the risk of side effects.

However, reading one’s internal clock precisely enough remains a major challenge in sleep and circadian health. The current approach requires taking hourly samples of blood melatonin — the hormone that controls sleep — during day and night, which is expensive and extremely burdensome for the patient. This makes it impossible to incorporate into routine clinical evaluations.

My colleagues and I wanted to obtain precise measurements of internal time without the need for burdensome serial sampling. I’m a computational biologist with a passion for using mathematical and computational algorithms to make sense of complex data. My collaborators, Phyllis Zee and Ravi Allada, are world-renowned experts in sleep medicine and circadian biology. Working together, we designed a simple blood test to read a person’s internal clock.

Listening to the Music of Cells

The circadian rhythm is present in every single cell of your body, guided by the central clock that resides in the suprachiasmatic nucleus region of the brain. Like the secondary clocks in an old factory, these so-called “peripheral” clocks are synchronized to the master clock in your brain, but also tick forward on their own — even in petri dishes!

Your cells keep time through a network of core clock genes that interact in a feedback loop: When one gene turns on, its activity causes another molecule to turn it back down, and this competition results in an ebb and flow of gene activation within a 24-hour cycle. These genes in turn regulate the activity of other genes, which also oscillate over the course of the day. This mechanism of periodic gene activation orchestrates biological processes across cells and tissues, allowing them to take place in synchrony at specific times of day.

The circadian rhythm orchestrates many biological processes, including digestion, immune function, and blood pressure, all of which rise and fall at specific times of the day. Misregulation of the circadian rhythm can have adverse effects on metabolism, cognitive function, and cardiovascular health.
The circadian rhythm orchestrates many biological processes, including digestion, immune function, and blood pressure, all of which rise and fall at specific times of the day. Misregulation of the circadian rhythm can have adverse effects on metabolism, cognitive function, and cardiovascular health.

The discovery of the core clock genes is so fundamental to our understanding of how biological functions are orchestrated that it was recognized by the Nobel Committee last year. Jeffrey C. Hall, Michael Rosbash, and Michael W. Young together won the 2017 Nobel Prize in Physiology or Medicine “for their discoveries of molecular mechanisms controlling the circadian rhythm.” Other researchers have noted that as many as 40 percent of all other genes respond to the circadian rhythm, changing their activity over the course of the day as well.

This gave us an idea: Perhaps we could use the activity levels of a set of genes in the blood to deduce a person’s internal time — the time your body thinks it is, regardless of what the clock on the wall says. Many of us have had the experience of feeling “out of sync” with our environments — of feeling like it’s 5:00 a.m. even though our alarm insists it’s already 7:00 a.m. That can be a result of our activities being out of sync with our internal clock — the clock on the wall isn’t always a good indication of what time it is for you personally. Knowing what a profound impact one’s internal clock can have on biology and health, we were inspired to try to gauge gene activity to measure the precise internal time in an individual’s body. We developed TimeSignature: a sophisticated computational algorithm that could measure a person’s internal clock from gene expression using two simple blood draws.

Designing a Robust Test

To achieve our goals, TimeSignature had to be easy (measuring a minimal number of genes in just a couple blood draws), highly accurate, and — most importantly — robust. That is, it should provide just as accurate a measure of your intrinsic physiological time regardless of whether you’d gotten a good night’s sleep, recently returned from an overseas vacation, or were up all night with a new baby. And it needed to work not just in our labs but in labs across the country and around the world.

A mismatch between our internal time and our daily activities may raise the risk of disease.
A mismatch between our internal time and our daily activities may raise the risk of disease.

To develop the gene signature biomarker, we collected tens of thousands of measurements every two hours from a group of healthy adult volunteers. These measurements indicated how active each gene was in the blood of each person during the course of the day. We also used published data from three other studies that had collected similar measurements. We then developed a new machine learning algorithm, called TimeSignature, that could computationally search through this data to pull out a small set of biomarkers that would reveal the time of day. A set of 41 genes was identified as being the best markers.

Surprisingly, not all the TimeSignature genes are part of the known “core clock” circuit — many of them are genes for other biological functions, such as your immune system, that are driven by the clock to fluctuate over the day. This underscores how important circadian control is — its effect on other biological processes is so strong that we can use those processes to monitor the clock!

Using data from a small subset of the patients from one of the public studies, we trained the TimeSignature machine to predict the time of day based on the activity of those 41 genes. (Data from the other patients was kept separate for testing our method.) Based on the training data, TimeSignature was able to “learn” how different patterns of gene activity correlate with different times of day. Having learned those patterns, TimeSignature can then analyze the activity of these genes in combination to work out the time that your body thinks it is. For example, although it might be 7 a.m. outside, the gene activity in your blood might correspond to the 5 a.m. pattern, indicating that it’s still 5 a.m. in your body.

Many genes peak in activity at different times of day. This set of 41 genes, each shown as a different color, shows a robust wave of circadian expression. By monitoring the level of each gene relative to the others, the TimeSignature algorithm learns to ‘read’ your body’s internal clock.
Many genes peak in activity at different times of day. This set of 41 genes, each shown as a different color, shows a robust wave of circadian expression. By monitoring the level of each gene relative to the others, the TimeSignature algorithm learns to ‘read’ your body’s internal clock. 

We then tested our TimeSignature algorithm by applying it to the remaining data, and demonstrated that it was highly accurate: We were able to deduce a person’s internal time to within 1.5 hours. We also demonstrated our algorithm works on data collected in different labs around the world, suggesting it could be easily adopted. We were also able to demonstrate that our TimeSignature test could detect a person’s intrinsic circadian rhythm with high accuracy, even if they were sleep-deprived or jet-lagged.

Harmonizing Health With TimeSignature

By making circadian rhythms easy to measure, TimeSignature opens up a wide range of possibilities for integrating time into personalized medicine. Although the importance of circadian rhythms to health has been noted, we have really only scratched the surface when it comes to understanding how they work. With TimeSignature, researchers can now easily include highly accurate measures of internal time in their studies, incorporating this vital measurement using just two simple blood draws. TimeSignature enables scientists to investigate how the physiological clock impacts the risk of various diseases, the efficacy of new drugs, the best times to study or exercise, and more.

Of course, there’s still a lot of work to be done. While we know that circadian misalignment is a risk factor for disease, we don’t yet know how much misalignment is bad for you. TimeSignature enables further research to quantify the precise relationships between circadian rhythms and disease. By comparing the TimeSignatures of people with and without disease, we can investigate how a disrupted clock correlates with disease and predict who is at risk.

Down the road, we envision that TimeSignature will make its way into your doctor’s office, where your circadian health could be monitored just as quickly, easily, and accurately as a cholesterol test. Many drugs, for example, have optimal times for dosing, but the best time for you to take your blood pressure medicine or chemotherapy may differ from somebody else.

Previously, there was no clinically feasible way to measure this, but TimeSignature makes it possible for your doctor to do a simple blood test, analyze the activity of 41 genes, and recommend the time that would give you the most effective benefits. We also know that circadian misalignment — when your body’s clock is out of sync with the external time — is a treatable risk factor for cognitive decline; with TimeSignature, we could predict who is at risk, and potentially intervene to align their clocks.

Dancing to the circadian rhythm: NHLBI researcher finds new genes for body’s internal clock

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Might lead to better understanding of sleep disorders, heart disease, and more

If you feel energized or tired around the same time each day, or routinely get up early or stay up late—the familiar ‘early riser’ or ‘night owl’ syndrome—you are witnessing, in real time, your circadian rhythm at work. That’s the 24-hour internal body clock which controls your sleep/wake cycle.

Circadian rhythms have long fascinated researchers—decades ago three of them marked a critical milestone when they discovered the molecular components behind that mysterious timing cycle. For this game-changing finding, the trio recently was awarded the 2017 Nobel Prize in Physiology or Medicine. Since their discovery researchers have come to know that the circadian clock affects not just sleep, but hormone production, eating habits, body temperature, heart rate, and other biological functions.

Yet, for all these advances, scientists still know relatively little about the clock’s genetic underpinnings. Now a team of NHLBI researchers is working to change that with the discovery of scores of new genes they say have a profound impact on the circadian rhythm. These researchers say these genes could hold the key to a new understanding of a wide range of health conditions, from insomnia to heart disease, and perhaps pave the way for new treatments for them.

Dr. Susan Harbison holding a sleep monitor
NHLBI researcher Dr. Susan Harbison displays a device used to record sleep and activity in fruit flies.

“We all ‘dance’ to the circadian rhythm,” said Susan Harbison, Ph.D., an investigator in the NHLBI’s Laboratory of Systems Genetics, who is among an elite cadre of scientists studying the complex genetics of the biological clock. “Quietly, this clock influences our body and our health in ways that are just now being understood.”For sure, the studies are slowly unfolding. For example, long-term night shift work has been associated with an increased risk of high blood pressure, obesity, and heart disease. Some studies have shown a link between circadian rhythm changes and cancer.  And a recent study by researchers in France found that heart surgery is safer in the afternoon than in the morning, a phenomenon they attribute to the body’s circadian clock having a better repair mechanism in the afternoon than in the morning.

Now, thanks to Harbison and her research team, new insights into why some people experience longer or shorter periods of wakefulness or sleepiness than others—and what it might mean for a host of health conditions—could be on the horizon.

To explore this line of research more deeply, Harbison is working with a favorite laboratory model of sleep researchers: Drosophila melanogaster, the common fruit fly.  While this little fly may seem like an unlikely choice, it turns out to be an appropriate stand-in for humans.

“The clock mechanisms regulating circadian rhythm in humans and fruit flies are remarkably similar,” Harbison said. “They both have biological rhythms of about 24 hours. In fact, the genes involved in mammalian circadian rhythms were first identified in flies.”

Previous studies by other researchers had identified approximately 126 genes for circadian rhythms in fruit flies.  In recent studies using a natural population of flies, Harbison’s group estimates that there are more than 250 new genes associated with the circadian clock, among the largest number identified to date.  Many of the genes appear to be associated with nerve cell development—not surprising, she said, given the wide-ranging impact of circadian rhythms on biological processes.

In addition to finding this treasure trove of clock-related genes, Harbison’s group also found that the circadian patterns among the flies were highly variable, and that some of the genes code for variability in the circadian clock. Some flies had unusually long circadian periods—up to 31 hours—while others had extremely short circadian periods of 15 hours.  In other words: Just like people, there were ‘early risers’ and ‘night owls’ and long sleepers and short sleepers among the fruit flies.

“Before we did our studies, there was little attention paid to the genes responsible for variability in the circadian period,” noted Harbison, who is also looking at environmental factors that might influence these genes, such as drugs like alcohol and caffeine. “We now have new details about this variability, and that opens up a whole new avenue of research in understanding what these genes do and how they influence the circadian clock.”

See description
This graph shows rest and activity patterns for two different fruit flies. The graph on the left shows the rest and activity of a fly with a normal circadian period (about 24 hours). Vertical blue bars show the fly's activity during the day (yellow horizontal bars) and night (black horizontal bars). The graph on the right shows the rest and activity of a fly with an abnormal circadian period (about 31 hours). The abnormal pattern is similar to an individual with a circadian rhythm disorder. Graphic courtesy of Susan Harbison, NHLBI.

Harbison says that for most people, disruptions to the circadian clock have a temporary effect, as occurs with daylight saving time or jet lag from overseas travel, when a person may experience short-term fatigue as they adjust to a time change or new time zone. But for some, disruptions to the clock are associated with chronic health effects, as occurs with night shift workers. Others who suffer from certain circadian rhythm disorders— such as delayed sleep phase disorder—may find it extremely difficult to fall asleep at a desired time.

“The clock architecture is not set in stone and is not a ‘one size fits all’ device,” she noted. “What we’re finding is that the effect of disrupting the circadian clock differs depending on the genetic makeup of the individual. Just as human height and other traits are variable, the same is true of circadian traits among different individuals.”

In the future, Harbison hopes that these newly identified genes might ultimately be linked to specific disease processes in humans. Her findings could lead to the discovery of new biomarkers for diagnosing circadian disorders and lay the groundwork for new treatments for sleep and circadian disorders in humans.

Internal ‘clock’ makes some people age faster and die younger – regardless of lifestyle

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Study could explain why even with healthy lifestyles some people die younger than others, and raises future possibility of extending the human lifespan

“You get people who are vegan, sleep 10 hours a day, have a low-stress job, and still end up dying young,” said the biostatistician who led the research.
“You get people who are vegan, sleep 10 hours a day, have a low-stress job, and still end up dying young,” said the biostatistician who led the research.

Scientists have found the most definitive evidence yet that some people are destined to age quicker and die younger than others – regardless of their lifestyle.

The findings could explain the seemingly random and unfair way that death is sometimes dealt out, and raise the intriguing future possibility of being able to extend the natural human lifespan.

“You get people who are vegan, sleep 10 hours a day, have a low-stress job, and still end up dying young,” said Steve Horvath, a biostatistician who led the research at the University of California, Los Angeles. “We’ve shown some people have a faster innate ageing rate.”

A higher biological age, regardless of actual age, was consistently linked to an earlier death, the study found. For the 5% of the population who age fastest, this translated to a roughly 50% greater than average risk of death at any age.

Intriguingly, the biological changes linked to ageing are potentially reversible, raising the prospect of future treatments that could arrest the ageing process and extend the human lifespan.

“The great hope is that we find anti-ageing interventions that would slow your innate ageing rate,” said Horvath. “This is an important milestone to realising this dream.”

Horvath’s ageing “clock” relies on measuring subtle chemical changes, in which methyl compounds attach or detach from the genome without altering the underlying code of our DNA.

His team previously found that methyl levels at 353 specific sites on the genome rise and fall according to a very specific pattern as we age – and that the pattern is consistent across the population. The latest study, based on an analysis of blood samples from 13,000 people, showed that some people are propelled along life’s biological tramlines much quicker than others – regardless of lifestyle.

“We see people aged 20 who are fast agers and we look at them 20 years later and they are still fast agers,” said Horvath. “The big picture here is that this is an innate process.”

The scientists found that known health indicators, such as smoking, blood pressure and weight, were still more valuable in predicting life expectancy in the 2,700 participants who had died since the study began, but that their underlying aging rate also had a significant effect.

In a fictional example, the scientists compare two 60-year-old men, Peter, whose ageing rate ranks in the top 5% and Joe, whose rate is in the slowest 5%. If both are smokers and have stressful jobs, Peter is given a 75% chance of dying in the next 10 years compared to a 46% chance for Joe.

This is not the first time that scientists have observed so-called epigenetic changes to the genome with age, but previously these were put down to wear-and-tear brought about by environmental factors, rather than indicating the ticking of an internal biological clock.

Wolf Reik, a professor of epigenetics at the University of Cambridge who was not involved in the work, said: “It now looks like you get a clock given to you when you’re young. It gets wound up and the pace it’s ticking at is dictated by this epigenetic machinery.”

“I’m sure insurance companies are already quite interested in this kind of thing,” he added.

Horvath said he has no plans to market the test, which costs around $300 per sample in his lab, but admits he has run his own blood through the analysis.

“I’m currently 48 and the test indicated I was 5 years older, which I wasn’t too pleased about,” he said, but adds that for an individual factors like blood pressure and smoking were more decisive. “My innate ageing rate is too fast to become a centenarian, but otherwise I’m not too worried about it.”

The study, published in the journal Aging, suggests that accelerated ageing rather than simply a riskier lifestyle could explain why men die younger. Even by the age of five, Horvath said, the different speeds of aging between genders was apparent and by the age of 40 a biological age gap of 1-2 years opens up. “Women always age a little bit more slowly than men,” he said. “It’s not lifestyle it’s this innate ageing process that favours women.”

A week’s worth of camping synchs internal clock to sunrise and sunset, CU-Boulder study finds.

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Spending just one week exposed only to natural light while camping in the Rocky Mountains was enough to synch the circadian clocks of eight people participating in a University of Colorado Boulder study with the timing of sunrise and sunset.

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The study, published online today in the journal Current Biology, found that the synchronization happened in that short period of time for all participants, regardless of whether they were early birds or night owls during their normal lives.

“What’s remarkable is how, when we’re exposed to natural sunlight, our clocks perfectly become in synch in less than a week to the solar day,” said CU-Boulder integrative physiology Professor Kenneth Wright, who led the study.

Electrical lighting, which became widely available in the 1930s, has affected our internal circadian clocks, which tell our bodies when to prepare for sleep and when to prepare for wakefulness. The ability to flip a switch and flood a room with light allows humans to be exposed to light much later into the night than would be possible naturally.

Even when people are exposed to electrical lights during daylight hours, the intensity of indoor lighting is much less than sunlight and the color of electrical light also differs from natural light, which changes shade throughout the day.

To quantify the effects of electrical lighting, a research team led by Wright, who also is the director of CU-Boulder’s Sleep and Chronobiology Laboratory, monitored eight participants for one week as they went about their normal daily lives. The participants wore wrist monitors that recorded the intensity of light they were exposed to, the timing of that light, and their activity, which allowed the researchers to infer when they were sleeping.

At the end of the week, the researchers also recorded the timing of participants’ circadian clocks in the laboratory by measuring the presence of the hormone melatonin. The release of melatonin is one of the ways our bodies signal the onset of our biological nighttime. Melatonin levels decrease again at the start of our biological daytime.

The same metrics were recorded during and after a second week when the eight participants—six men and two women with a mean age of 30—went camping in Colorado’s Eagles Nest Wilderness. During the week, the campers were exposed only to sunlight and the glow of a campfire. Flashlights and personal electronic devices were not allowed.

On average, participants’ biological nighttimes started about two hours later when they were exposed to electrical lights than after a week of camping. During the week when participants went about their normal lives, they also woke up before their biological night had ended.

After the camping trip—when study subjects were exposed to four times the intensity of light compared with their normal lives—participants’ biological nighttimes began near sunset and ended at sunrise. They also woke up just after their biological night had ended. Becoming in synch with sunset and sunrise happened for all individuals even though the measurements from the previous week indicated that some people were prone to staying up late and others to getting up earlier.

“When people are living in the modern world—living in these constructed environments—we have the opportunity to have a lot of differences among individuals,” Wright said. “Some people are morning types and others like to stay up later. What we found is that natural light-dark cycles provide a strong signal that reduces the differences that we see among people—night owls and early birds—dramatically.”

Our genes determine our propensity to become night owls or early birds in the absence of a strong signal to nudge our internal circadian clocks to stay in synch with the solar day, Wright said.

The new study, which demonstrates just how strong of a signal exposure to natural light is, offers some possible solutions for people who are struggling with their sleep patterns. For example, people who naturally drift toward staying up late may also find that it’s more difficult to feel alert in the morning—when melatonin levels may indicate they’re still in their biological nighttimes—at work or in school.

To combat a person’s genetic drift toward later nights, exposure to more sunlight in the morning and midday could help nudge his or her internal clock earlier. Also, dimming electrical lights at night, forgoing late-night TV and cutting out screen time with laptops and other personal electronic devices also may help internal circadian clocks stay more closely attuned with the solar day, Wright said.

Source: http://www.eurekalert.org