Circadian Rhythm Genes: Our Internal Clocks

Key takeaway:
~ Your circadian rhythm is a fundamental part of health and wellness.
~ Disruption to circadian rhythm gene expression is causal for chronic diseases
~ Genetic variants in core circadian genes can help you understand how and why circadian rhythm optimization may be important for you.

What is circadian rhythm?

Circadian Rhythms: The Unsung Heroes of Our Biological Symphony

Circadian rhythms are the intrinsic biological patterns that orchestrate our physiological processes. For example, the master clock in our brains regulates the sleep-wake cycle across a 24-hour period, governed by primary ‘clock’ genes.

Our biological molecular clock, called the core circadian clock, sets the rhythm of literally thousands of our genes over the course of about 24 hours.

Recent discoveries, however, extend beyond this central clock. Peripheral clocks exist in various organs like the liver, pancreas, and even in fat cells. These peripheral rhythms are crucial for the timely production of proteins in these organs.

The gut microbiome, too, participates in this rhythmic dance, exhibiting its own circadian fluctuations. Disruptions in our circadian rhythms can, in turn, upset this microbial balance, illustrating the interconnectedness of our body’s systems. [ref]

Diving into Chronobiology

The hypothalamus is the region of the brain that houses the suprachiasmatic nucleus (SCN), the conductor of our central circadian rhythm.

Environmental cues like sunrise, meal timing, temperature, and exposure to artificial lighting, termed ‘zeitgebers,’ play pivotal roles in synchronizing these rhythms.

Sunlight’s role is paramount in setting our core circadian rhythm. Specifically, short, blue wavelengths of sunlight interact with intrinsic photosensitive retinal ganglion cells in the eye, signaling the SCN and synchronizing our 24-hour cycle.

Until the advent of modern electric lights, particularly LED and fluorescent lights, the only time we were exposed to light in the blue wavelengths (around 450-480nm) was during daylight.

Two significant disruptors of circadian rhythms are nighttime blue light exposure (around 450-480nm) and insufficient morning sunlight. Coupled with individual genetic variants affecting clock gene functions, these factors underscore the complexity and importance of circadian rhythms.

The Genetic Machinery Behind Circadian Rhythms

The core of circadian rhythm regulation lies in an intricate network of genes and their protein products. Central to this are the CLOCK and BMAL1 genes. These genes encode proteins that form a complex, initiating the transcription of other circadian genes, such as PER (Period) and CRY (Cryptochrome).

During the day, CLOCK and BMAL1 proteins bind together and promote the expression of PER and CRY genes. The proteins produced by these genes gradually accumulate in the cell’s cytoplasm and, as night approaches, they form a complex that moves back into the nucleus. This complex inhibits the activity of the CLOCK-BMAL1 complex, thereby reducing their own production in a negative feedback loop.

To simplify:

CLOCK and BMAL1,  influence biological activities during the daytime.

PER and CRY control the nighttime half of the rhythm.

As PER and CRY proteins degrade over time, their inhibition on CLOCK-BMAL1 diminishes, allowing the cycle to start again. This feedback loop is approximately 24 hours, aligning with the Earth’s day-night cycle.

Period and Amplitude of  Circadian rhythm:

When it comes to the circadian clock genes, researchers like to use terminology like ‘period’ and ‘amplitude’. Let’s take BMAL1 as an example: the levels will rise and then fall (amplitude) over the course of 24 hours (period).

It is easier to picture this if you visualize the amount of BMAL1 rising and falling like a sine wave:

Regulation by Post-Translational Modifications

Post-translational modifications of circadian proteins play a pivotal role in maintaining the precision of the circadian clock. Phosphorylation, for instance, regulates the stability and activity of circadian proteins. Kinases and phosphatases add and remove phosphate groups, respectively, influencing the timing of the feedback loop.

Setting the circadian clock.

For humans, the average circadian clock runs about 15 minutes longer than 24 hours. But we aren’t all average, and the circadian period varies between a few minutes less than 24 hours to about a half-hour longer.[ref].

To keep us on track, the body has a built-in clock setting mechanism — exposure to light.

Imagine if your clock ran at about 24.5 hours instead of 24. Within a week, you would be about seven hours out of sync.

They’ve done studies with people kept in caves or bunkers, and with no outside light, this does happen.

Below is a graph from a recent study where the participant stayed in a bunker for 9 days. The first two days and the last two days, he had lights available to turn on when he wanted. During days 3 through 7, a dim light was constantly turned on. As you can see, sleep timing (in yellow) and sleep duration changed a lot throughout the week. (CC image) [ref]

While light is the main way the body resets the circadian clock, food timing and temperature changes can also make an impact.

What about melatonin?

Often referred to as the ‘sleep hormone’, melatonin levels rise at night when it is dark. It is a key molecule in circadian rhythm signaling.

Animal studies specifically show that melatonin is part of regulating some of the core clock genes. In fact, without melatonin, the PER1 gene doesn’t rise and fall rhythmically.[ref]

Melatonin is produced by the pineal gland in large amounts at night due to the lack of light. Exposure to artificial light at night significantly decreases overnight melatonin levels.

During the day, melatonin levels should be low – decreased by the bright light. In people with depression, research shows that melatonin levels are often higher than they should be during the day. This is possibly due to indoor lighting not suppressing the melatonin levels enough in an individual (hyposensitivity due to the low light).[ref]

When Rhythms Go Awry

Disrupted circadian rhythms have far-reaching implications, increasing risks for diabetes, cardiovascular diseases, certain cancers, mood disorders, and obesity. The burgeoning volume of research in recent years has been remarkable. This has prompted the IARC (International Agency for Research on Cancer, part of the WHO) to classify chronic exposure to light at night as a potential carcinogen since 2007.

Circadian rhythms are the natural biological rhythms that shape our biology.  Most people know about the master clock in our brain that keeps us on a wake-sleep cycle over 24 hours.  This is driven by our master ‘clock’ genes.

Quick Recap: Circadian rhythms are foundational to optimal health. Morning sunlight sets the rhythm, while evening blue light can disrupt it. Understanding and respecting these natural cycles, along with recognizing the role of genetic differences, is vital for maintaining health and preventing disease.

Lifehacks: Optimizing Circadian Rhythm

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Circadian Rhythm and Mood Disorders
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Circadian Rhythm and Weight Loss
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 Updated and revised Dec 2017, Aug. 2018