Carina Yiu ’23 and Delaney McKinstry ’23 (M.S.)

Circadian Rhythms 

Imagine turning off your daily alarm, and refraining from that afternoon cup of coffee to keep you awake after you start to feel tired. Imagine yourself with no ensuing assignment deadline, or 5am task awaiting you, filling you with fear or excitement. Now you may wonder, how exactly would we wake up without a blaring phone or how would we fall asleep without exhausting our bodies nearly to the breaking point every night. Our bodies are actually much more complex than we think. Imagine the instructions to build and maintain our bodies are compiled into a book – a very long and convoluted book, known as our genetic code. And one chapter in this book has instructions written for setting an internal clock, known as our central circadian rhythm. Simply put, our circadian rhythm tells our brain that it is time to be awake in the presence of light, and asleep in the presence of dark. 

These rhythms are driven primarily by two proteins, called CLOCK and BMAL1 (figure 1)1,2. How exactly do they set this internal clock? We can think about these proteins as working a repetitive yet critical 9-to-5 job. Throughout the course of the normal day, during their so-called “shift,” CLOCK and BMAL1 work to read different parts of our genetic code. As they read this code, they are activating various metabolic, cellular, and physiological functions necessary for proper human function during the day. When CLOCK and BMAL1 have worked for many hours, and it is nearing night time and the close of their “shift,” two different proteins known as PER and CRY take over for the night shift and read different parts of the book, activating different physiological processes. By the time morning comes around again, it is once again time for the CLOCK and BMAL1 to take over, and so on. This recurrent cycle of switching from these daytime to nighttime proteins allows them to directly influence circadian control.   

Epigenetic and Nutritional Influences 

You may wonder what influences changes to our normal circadian rhythms, because as we know, every single person does not wake up at the crack of dawn, nor fall asleep soon after it gets dark out. Similarly, you may have experienced jet lag when traveling to a new time zone. And if you have, you’ve probably noticed that slowly over time, your body becomes accustomed to the new time zone. What drives this? Well, in part this acclimation is influenced by something called epigenetics. Epigenetics are basically changes to the way our genetic code is read, without making permanent changes to this code.

Imagine someone has placed bookmarks and highlighted specific sections to read. Imagine that they’ve also crossed out some of the chapters in the book, so they are harder to read. And they’ve done so with erasable markers and pens, so the parts intended to be read and not to be read can continue to change! There are certain proteins which we might say add bookmarks to certain pages or highlight certain sentences. There are other proteins which work to hide certain parts of our genetic code from being read. This means that there are dynamic changes happening within our bodies and brains constantly, and our physiology is not a product of our DNA alone.

What we eat and when we eat has a big impact on physiological changes through different readings of our genetic code. The study of nutrition’s impact on epigenetics is called nutri-epigenetics. Let’s take a further look into how changes in our genetic code may alter our sleep-wake cycles and visa-versa.

As mentioned before, our circadian rhythm is regulated in part by environmental stimuli, which can disrupt normal circadian rhythmicity. Changes to the typical daylight-driven order of the biochemical, physiological, and behavioral circadian rhythms may increase risk of disease onset (e.g. obesity).3 Some examples include unusual periods of the light/dark cycle, eating at abnormal times or emotional eating, and jet lag. Recent research has found that epigenetics and nutrition are indeed highly interconnected with our circadian rhythms. In one study performed on 60 women, researchers found a direct quantitative correlation between epigenetic modifications of the CLOCK protein mentioned earlier and obesity. They found that these changes were associated with several obesity-inducing behaviors such as snacking frequently, eating when bored, and eating from large packages.4

This is just one example of the interplay between epigenetics, nutrition, and circadian rhythms. To understand how exactly our dietary habits may influence dynamic genomic changes to our internal clock, we looked at how what and when we eat as well as our gut microbiome affects our central circadian rhythm, as well as the health implications of circadian disruptions. 

It is probably no surprise to hear that what we eat has direct effects on our health and how we feel. But what we eat is not the only important factor: when we eat also has a big influence on our daily energy levels and sleep patterns. 

The Timing of Food Intake and Nutrition

Given that a wide variety of physiological and metabolic changes (e.g. sleep/wake cycles, eating behavior, hormone levels) are dependent on the time of day, it’s understandable that our circadian clock is highly interconnected with our metabolism and nutrition. So how exactly does the timing of when we eat impact the way our genetic code is read? Let’s think about our core internal clock machinery discussed previously: the proteins CLOCK and BMAL1. Remember how we talked about these proteins going to work every morning and reading different parts of our genetic code? We mentioned that these daily readings essentially switch on various metabolic processes necessary for normal functioning throughout the day. For example, CLOCK and BMAL1 were found to have some influence on the NAD-salvage pathway, a key pathway in our body’s method of breaking down food into energy (figure 2).5 This means they may have a significant influence on the rate of our metabolism.

  

Why is this important? Because food, once it’s broken down, is what supplies our body with fatty acids and these NAD-salvage pathway products. Think about these proteins working in a cyclic fashion, like we just discussed. Now consider the possibility that you can change the pattern or length of these cycles through our diet or sleep habits. By changing the composition or timing of our food intake, we can influence the activation of these epigenetic and transcriptional control systems in either a positive or negative way. 

Circadian Nutrition Studies 

This is supported by studies in mice with one study showing that altered feeding times are correlated with the development of metabolic syndrome and obesity, suggesting that a consistent eating schedule is beneficial for reducing disease risks. Another study looked into the importance of food timing by implementing a time-restricted feeding schedule; this is when a subject is given its food supply for a discrete window of time each day. This study showed that when mice are restricted to eating during a certain timeframe, they have a 50% decrease in liver fat content, but there was no effect on their total daily caloric consumption.6 From this, we can assume that the timing of food consumption, specifically a time-restricted feeding schedule, may improve your metabolism. Even when fed high-fat diets, the main difference in health outcomes resulted from the difference in food availability window. Mice with unlimited food availability have worse metabolic health outcomes compared to those on time-restricted diets, supporting the idea that the consistency of a feeding schedule has an impact on health, even more so than by the food content itself, which may come as a surprise. 

As for studies in humans, those are more scarce, but one in particular identifies a correlation between eating patterns and obesity; showing that weight gain is inversely associated with breakfast consumption.7 Another study addresses the correlation between sleep, time of calorie consumption, and risk of obesity. Those that sleep less than five hours or have a midpoint of sleep later than 5:30am, and consume more calories later in the day, have a significantly higher risk of developing obesity.8 More correlational studies show that time-delayed eating patterns are positively associated with increased body mass index (BMI).9 All of this is to say that eating late in the day comes with the risk of developing obesity, but further evidence is needed to support this (figure 3). 

Gut Microbiota Rhythms 

Now to change gears slightly, we are going to look at the influences our central circadian rhythms have on our gut microbiome. If you are unfamiliar with the idea of this microbiome, it essentially describes how our gut consists of trillions of healthy microscopic organisms and their DNA, which help out with our metabolism and digestion. Not only do our circadian rhythms influence microorganism populations in our gut, but it has been found that these microorganisms actually have their own rhythms as well, which are regulated by our diet and the timing of when we eat. While a big influence on our central circadian rhythm is light, our gut microbiota have no way to sense changes in light and dark environments; which is why they must rely on timing of eating as a primary rhythmic pacemaker.10

Our microbiota rhythms are regulated by time of eating, and may be disrupted by irregular eating schedules or eating late at night (figure 4). Through altering the timing of our eating, we may alter the availability of nutrients such as carbohydrates, fats, proteins, vitamins, minerals, etc. The availability of these nutrients may epigenetically alter metabolic structure and function within our gut, either by changing the size of these microbiota populations or the processes they carry out.11 This essentially means that your eating patterns have a big influence on the ability of microbiota to carry out essential processes such as energy harvesting, cell growth, DNA repair, and detoxification.12 

One study looked at how some of the gut bacteria involved in the breakdown of consumed saturated fats are affected by a high fat diet.13 We mentioned this energy harvesting pathway earlier known as the NAD-salvage pathway. Here, we can see how the microbiota’s own cyclic rhythms are intertwined with our central internal clock. Under this high fat diet, the regulation of the microbiota circadian rhythms was thrown off balance, which disrupted the ability for them to help us digest our food.14 Basically, a high fat diet decreased the ability of these gut microbiota to break down these saturated fats. One of the products of fat breakdown in the intestines are “short-chain fatty acids”. When this fat breakdown is not happening efficiently, the gut cannot produce enough short-chain fatty acids as are required for optimal brain function and digestion.

One example of how a lack of sufficient short-chain fatty acids affects gut health is that it may lead to increased inflammation in the gut.15 These fatty acids have anti-inflammatory effects, a process they carry out through epigenetic mechanisms.16 Earlier, we talked about how our genetic code can be thought of  like a long book, filled with specific parts highlighted and crossed out. These short-chain fatty acids work to dynamically highlight parts of our DNA from being “read”, which results in making proteins to fight inflammation, by helping restore balance in the gut during trauma, stress, or infection.17

To summarize, these findings suggest that through disrupted nutritional intake (in this case a high fat diet),  the circadian rhythms of microbiota may be disrupted, leading to changes in the way DNA is read and ultimately in increased inflammation and further dysregulation of microbiota rhythms. While this is just one example of nutri-epigenetic interactions with circadian rhythms, it illustrates how nutrition and circadian rhythms are intricately connected through epigenetics.

Additionally, the lack of these short-chain fatty acids may disrupt communication between our primary metabolic clock and the gut.18 It is important that the rhythms in our gut are aligned with our central pacemaker, which regulate our primary circadian rhythms. Disruption of this alignment may cause higher risks for poor health.

Health Risks Increased by Circadian Disruption

There have been studies demonstrating higher risks of health problems associated with disruptions in circadian rhythms, including breast and prostate cancer, obesity, cardiovascular disease, and psychiatric and neurodegenerative problems.19 The association is most often seen in “night owls”, and may be partially explained by eating late at night, close to the time of sleeping. As we eat very close to the time we rest for the night, we may – without realizing it– be uncoupling our gut microbiome rhythms from our central circadian rhythms.  

When the microbiome’s rhythmicity is disrupted and anti-inflammatory bacteria decrease, our bodies are put at a higher risk for inflammation-mediated diseases. Earlier, we talked about a high fat diet as a potential cause for this rhythmic disruption. This is not the only possible cause, however. Both environmental and genetic factors may increase susceptibility. For example, alcohol consumption can also lead to gut microbiome disruption through gene modification (more specifically, through DNA methylation),20 which may cause circadian disruption and increase risk of inflammatory disease, through affecting genes involved in circadian rhythms. 

Disruption of gut microbiome rhythms are not the only way in which nutriepignetic changes may increase health risks and disease prevalence. Interestingly, circadian regulation also turns out to play an important role in reproductive biology. Disturbances to circadian synchrony have been shown to have major implications for reproductive health. Studies in mice with mutations in CLOCK or BMAL1 showed ovulation timing problems,21 irregular estrous cycles,22 a lower number of eggs,23 and an increased miscarriage risk. One paper showed that removing BMAL1 resulted in infertility in both males and females.24 Looking to literature on studies in humans, we find an association between night shift work and earlier menopause among women under 45.25 What we can take from this is that dysregulation to our normal circadian rhythms can potentially lead to fertility and reproductive issues, and that you should avoid behaviors that cause disruptions to the circadian clock. Some examples include not doing night-shift work and avoiding disruptions to the typical sleep-wake cycle. 

Implications 

So, you might be thinking, “what does this all mean”, or “how can I use this information to improve my sleep health”? Well, one thing to keep in mind is that these studies are relatively recent and there is still a lot more research to be done. That being said, one thing is clear: in order to maximize our body’s potential, it is important to be mindful of nutritious and time-conscious eating. Developing these habits is easier said than done, but there are some things you can do, and your body will thank you later, when it feels more well rested and your mind feels more focused. Trying to reduce the temptation to have a “midnight snack,” for example, is one straightforward step you can take towards healthier sleep habits. Remember, your body and brain essentially “communicate” with each other through chemical signals and dynamic readings of your genetic code: your brain, which thinks it is almost time to rest for the night, could be confused by your body telling it that, “actually, no– we just got an influx of food energy, it’s time to wake up and do things!”.

Let’s think back to the idea of jet lag. If you have ever experienced it, you know that your body and internal circadian clock naturally adjusts, and one day you just wake up and feel like you could’ve been in this time zone for your entire life. This is all regulated by our brain communicating with our body and visa-versa, and in this case, meal timing is the preferred method of communication.

References

  1. Adamovich, Yaarit, Liat Rousso-Noori, Ziv Zwighaft, Adi Neufeld-Cohen, Marina Golik, Judith Kraut-Cohen, Miao Wang, Xianlin Han, and Gad Asher. “Circadian clocks and feeding time regulate the oscillations and levels of hepatic triglycerides.” Cell metabolism 19, no. 2 (2014): 319-330. https://doi.org/10.1016/j.cmet.2013.12.016
  2. Asher, Gad, and Paolo Sassone-Corsi. “Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock.” Cell 161, no. 1 (2015): 84-92. https://doi.org/10.1016/j.cell.2015.03.015
  3. Baron, Kelly G., Kathryn J. Reid, Andrew S. Kern, and Phyllis C. Zee. “Role of sleep timing in caloric intake and BMI.” Obesity 19, no. 7 (2011): 1374-1381. https://doi.org/10.1038/oby.2011.100
  4. Boden, Michael J., Tamara J. Varcoe, Athena Voultsios, and David J. Kennaway. “Reproductive biology of female Bmal1 null mice.” Reproduction 139, no. 6 (2010): 1077-1090. https://doi.org/10.1530/REP-09-0523
  5. Chaix, Amandine, Amir Zarrinpar, Phuong Miu, and Satchidananda Panda. “Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges.” Cell metabolism 20, no. 6 (2014): 991-1005. https://doi.org/10.1016/j.cmet.2014.11.001
  6. Chen, Linlin, Huidan Deng, Hengmin Cui, Jing Fang, Zhicai Zuo, Junliang Deng, Yinglun Li, Xun Wang, and Ling Zhao. “Inflammatory responses and inflammation-associated diseases in organs.” Oncotarget 9, no. 6 (2018): 7204. ​​10.18632/oncotarget.23208
  7. Colles, S. L., J. B. Dixon, and Paul Edmond O’Brien. “Night eating syndrome and nocturnal snacking: association with obesity, binge eating and psychological distress.” International journal of obesity 31, no. 11 (2007): 1722-1730.https://doi.org/10.1038/sj.ijo.0803664
  8. Huang, Wenyu, Kathryn Moynihan Ramsey, Biliana Marcheva, and Joseph Bass. “Circadian rhythms, sleep, and metabolism.” The Journal of clinical investigation 121, no. 6 (2011): 2133-2141. 10.1172/JCI46043
  9. Li, Ruiwen, Shuting Cheng, and Zhengrong Wang. “Circadian clock gene plays a key role on ovarian cycle and spontaneous abortion.” Cellular Physiology and Biochemistry 37, no. 3 (2015): 911-920.https://doi.org/10.1159/000430218
  10. Stock, D., J. A. Knight, J. Raboud, M. Cotterchio, S. Strohmaier, W. Willett, A. H. Eliassen, B. Rosner, S. E. Hankinson, and E. Schernhammer. “Rotating night shift work and menopausal age.” Human reproduction 34, no. 3 (2019): 539-548.https://doi.org/10.1093/humrep/dey390
  11. Timlin, Maureen T., Mark A. Pereira, Mary Story, and Dianne Neumark-Sztainer. “Breakfast eating and weight change in a 5-year prospective analysis of adolescents: Project EAT (Eating Among Teens).” Pediatrics 121, no. 3 (2008): e638-e645.https://doi.org/10.1542/peds.2007-1035
  12. Voigt, R. M., C. B. Forsyth, S. J. Green, P. A. Engen, and A. Keshavarzian. “Circadian rhythm and the gut microbiome.” International review of neurobiology 131 (2016): 193-205. https://doi.org/10.1016/bs.irn.2016.07.002
  13. Zhao, Xianlin, Shifeng Zhu, Juan Li, Dan Long, Meihua Wan, and Wenfu Tang. “Epigenetic changes in inflammatory genes and the protective effect of cooked rhubarb on pancreatic tissue of rats with chronic alcohol exposure.” Biomedicine & Pharmacotherapy 146 (2022): 112587. https://doi.org/10.1016/j.biopha.2021.112587

Featured Image Source

Brooke Wolford, N. H. G. R. I. I. R. T. A. F. and L. F. (n.d.). Humans adapted to life at different latitudes by tuning their circadian \”clocks\”. Genome.gov. Retrieved December 31, 2022, from https://www.genome.gov/27559632/humans-adapted-to-life-at-different-latitudes-by-tuning-their-circadian-clocks