Sleep, hunger, alertness: The body’s natural processes are regulated throughout the day by our internal clock. But what happens when the body’s clock gets out of sync? Biologist Dr. Dominic Landgraf is studying this question — with the goal of improving the treatment of common diseases.
Dominic Landgraf’s body clock is a bit out of sync right now. “I got up at 5:15 a.m. today,” he says, adjusting his glasses and setting a cup of coffee down on the table. Sleep disorder, a research experiment, or just a morning person? He shakes his head: “No, we have two small children who often wake up very early.” Now that he is a family man, part of his research has crept into his daily life. These days, Landgraf has firsthand experience of how exhausting it is when the circadian rhythm gets out of balance. “Luckily, I was already more of a morning person, so I adapted pretty quickly.”
The circadian rhythm is what we often call our internal or biological clock. It regulates the body’s processes — such as sleep, temperature, hunger, digestion, metabolism, and hormones — in a roughly 24-hour cycle. “It’s really fascinating how universal its influence is,” says the biologist. “From entire ecosystems to individual organisms, organs, cells, or molecules — our body clock is ticking along at every level.”
Light and darkness are among the most important factors regulating the body's internal clock. If the day-night rhythm changes—for example, during travel across multiple time zones—it can throw the body off balance.
© IMAGO / U. Stamm / Future ImageIn fact, without this internal clock, we would be lost: We would constantly have to react spontaneously to events that repeat themselves every day. Being unprepared would be stressful and inefficient, and a lot of processes that are not supposed to happen at the same time would get in each other’s way. “The stress hormone cortisol, for example, needs to be elevated during the day and would prevent us from falling asleep at night. Conversely, the sleep hormone melatonin should only rise at night and would make us tired during the day,” explains Landgraf. But because the body knows roughly when we need to sleep, eat, or be alert, it orchestrates hormones and processes accordingly. For the same reason, different areas of the brain are active at night than during the day. “So, from an evolutionary perspective, it’s a real advantage that we have an internal clock,” says Landgraf.
Dominic Landgraf
So, how does the body find its rhythm? The most important daily timing indicators are light and dark, as well as meals, and physical activity too. Also, age and life circumstances (such as having children who wake up early) can influence our internal clock over the long term.
The body clock is already well researched: The suprachiasmatic nucleus — the central pacemaker of our sleep–wake cycle — located in the brain is very well known, as are the so-called clock genes, which control the circadian rhythm at the molecular level. Indeed, the 2017 Nobel Prize in Medicine was awarded for decoding these genes. So, what remains to be explored? “Quite a lot,” says Landgraf, who is most interested in two aspects: the health consequences of having a disrupted circadian rhythm, and how to stabilize the circadian rhythm with treatment.
Shift work, particularly night shifts, is a prominent example of working against the body’s internal clock and is associated with an increased risk of numerous diseases.
© IMAGO / Gottfried CzepluchScientists have long known that chronotherapies can be effective. But why that is and what exactly happens in the body remains largely unexplored. Knowledge on the subject tends to be anecdotal to date. “That makes such therapeutic approaches less accepted in medicine,” says Landgraf. Often, they are not taken seriously or are even dismissed as esoteric. And that is what he wants to change with his work. “My goal is to ensure that more research finds its way into clinical practice and thus reaches patients.” The biologist is convinced that the circadian rhythm is a therapeutic lever that holds enormous potential.
Dominic Landgraf
There is extensive data to support this assumption. The data shows that circadian system disruptions increase the risk of diseases such as cancer, diabetes, depression, obesity, and high blood pressure. People who work shifts or have a genetic predisposition are particularly at risk; shift workers, for example, have a five times higher risk of obesity and type 2 diabetes. “It’s also interesting to note that mental and metabolic disorders often occur together — such as depression, obesity, and diabetes.”
These disease clusters are precisely the ones that he and his team have studied in detail, starting in the laboratory. In animal experiments, they were able to confirm that mice whose clock genes had been disabled or had had their day–night rhythm manipulated were more prone to behavior that looked like depression, as well as obesity and diabetes, than mice whose circadian rhythm was intact. When the genes were reactivated or the light was synchronized with the day–night rhythm, the symptoms improved or disappeared entirely. “The more rhythms we restored, the better the mice fared,” says Landgraf.
In laboratory experiments, mice with a disrupted day-night rhythm were more likely to exhibit depression-like behavior, obesity, and diabetes than mice with an intact circadian rhythm.
© LMU / Jan GreuneMeanwhile, his Emmy Noether–funded junior research group has also conducted two pilot studies with humans. The results are promising: The first study examined how eating meals at set intervals affects body weight and mood. “First we analyzed the participants’ individual rhythm and then we set the time window within which they were allowed to eat,” says Landgraf, explaining the setting.
Within 6 weeks, the strictly scheduled meals led to weight loss in many participants, improved their mood and sleep quality, and gave them a greater sense of self-efficacy. “The body had learned to adjust to the regular meals and to optimally prepare the metabolism for them at these times,” explains Landgraf. Under such conditions, for example, an increase in the hormones and enzymes important for digestion can be measured in the blood as much as an hour before eating. The amazing thing is that although there was no mention of how much and what food they should eat, and the participants were told to eat until they were full and not to cut anything out of their diet, they lost weight.
In a second study, the biologist investigated whether clinical withdrawal could be made easier for people with alcohol dependency by prescribing a fixed day–night rhythm. These individuals, too, often suffer from co-occurring conditions; addiction frequently goes hand in hand with depression, for example. Once again, the results were remarkable: In the group with a fixed daily schedule, only just over ten percent of the participants had one or two relapses. In the control group, by contrast, more than half of the participants experienced numerous relapses. Depression also improved significantly in the group with a fixed daily schedule. “Of course, further research and larger studies are needed. But the pilot studies have reinforced our belief that we are on the right track,” says Landgraf.
In other words, the potential for practical application is enormous. “Stabilizing the circadian rhythm could be a low-threshold and virtually side-effect-free approach to supporting the treatment of various diseases,” says Landgraf. For example, such measures could be systematically integrated into the treatment of diabetes, obesity, depression, or addiction.
Dominic Landgraf
And for everyday life, is it worth paying attention to circadian balance to prevent illness? “Absolutely,” says Landgraf, pointing out that the body benefits above all from regularity. If it fits into your daily routine, plan your sleep and meal times for roughly the same time each day.
When daily life stays on rhythm, the body benefits too: Regular sleep and mealtimes strengthen the circadian rhythm and can help prevent diseases.
© IMAGO / imagebrokerEspecially if you have a medical history, such as a genetic predisposition to depression, obesity, or diabetes. But as a healthy person, you don’t have to overdo it: Temporary disruptions, like from jet lag or a night out, are no big deal. And, if you eat breakfast at 8 a.m. during the week, you can still sleep in on the weekend. However, if your breakfast is significantly delayed as a result, it makes more sense to wait until your usual lunchtime to eat.
It’s important to note that not everyone has the same rhythm. There are different chronotypes — such as early birds (‘larks’) and night owls, meaning people who are more productive in the morning or the evening. But daily life doesn’t necessarily have to interfere with that, because the circadian rhythm is not set in stone: “You can certainly modify it to a certain extent by changing your habits, especially since most people fall somewhere in between,” says Landgraf. He has done it himself. Since having his children, he’s gone from being a ‘lark’ to being a ‘super-lark’; starting his day at 5:00 a.m. doesn’t throw him off his rhythm anymore — “I just go to bed at 9:30 p.m. now.”
Dr. Dominic Landgraf led the Emmy Noether junior research group ‘Circadian clocks as modulators of metabolic cormorbidity in major depressive disorders’ at the Department of Psychiatry and Psychotherapy, LMU University Hospital, beginning in 2017.
Read more articles from LMU's research magazine in the online section and never miss an issue by activating the magazine alert!