Circadian Rhythms: Genes at the Core of Our Internal Clocks

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.

It turns out that we also have circadian cycles (peripheral clocks) in most organs such as the liver, pancreas, and fat cells. These peripheral rhythms drive cyclical production of proteins in our organs. One example of why this is important is the research being done on the timing of chemotherapy drugs based on the circadian rhythm of enzymes produced in the liver. [study]

Not to be left out, our gut microbiome also has a circadian rhythm, and disruption of our circadian rhythm can disrupt the microbial rhythm. [study]

Getting a little Geeky…
There is some pretty cool terminology involved in chronobiology (a nifty term for the study of biological rhythms) that you will want to be familiar with before digging into the research papers on the topic.  The part of the hypothalamus that controls the central clock is called the “suprachiasmatic nucleus” (SCN), which sounds a little sci-fi to me.  And the external environmental inputs, like the time the sun rises or lights at night, are known as zeitgebers.  Some things are named more predictably, like one gene controlling circadian rhythms which is called the CLOCK gene ( an acronym for Circadian Locomotor Output Cycles Kaput).

It is probably not a big surprise that our core circadian rhythm is set by sunlight since night/day rhythms can be seen in all animals.  In a nutshell, light from the sun in the short, blue wavelengths hits receptors in the eye (intrinsic photosensitive retinal ganglion cells) which signals to the suprachiasmatic nucleus synchronizing the circadian 24-hour cycle.

There are two factors that can mess up our circadian rhythms:  light at night (specifically, blue wavelengths ~450-480nm) and lack of sunlight in the morning.  Add to that the individual genetic variants that affect our clock gene functions and you can begin see the importance of this topic.

So what happens when our circadian rhythms go askew?  The effects can be far ranging and include increased risk for the following: diabetes, cardiovascular disease, certain cancers, mood disorders, and obesity.  The amount of scientific research coming out on the topic in the past few years is astounding.  While not talked about much in the mainstream press, the evidence is strong enough that in 2007 the IARC (cancer research arm of the World Health Organization) listed chronic exposure to light at night as a possible carcinogen.

Quick Recap:
Circadian rhythm is at the base of good health.
Blue wavelengths set circadian rhythm.
Sunlight in the morning is good; blue light in evening alters the circadian system.

Genetic Variants in Clock Genes:

The CLOCK and BMAL1 (ARNTL) genes are the core clock genes that target and turn on other genes. They are regulated and turned off by rising levels of the cryptochromes, CRY1 and CRY2,  and the period genes, PER1, PER2, and PER3.[ref]  This forms the daily feedback loop of rising CLOCK and BMAL1 that are then inhibited by rising levels of CRY and PER giving a 24-hour rhythm.

CLOCK gene variants:

One well-studied variant of CLOCK is rs1801260 (G is the minor allele for 23andMe orientation, also known as 3111T/C ) with quite a variety of effects:

  • Carriers of the G allele have higher activity in the evening, delayed sleep onset, and less overall sleep time on average.  [ref][ref]
  • A 2016 study looked at body temperature changes, activity and position in a group of women based on carriers of the G allele. They found that those with the minor allele had higher evening activity, and different body temperature variations over a day leading to a conclusion of ‘less robust circadian rhythm’.  [ref]
  • Carriers of the G allele had higher BMI and less weight loss on a calorie restricted diet in a study of obese patients[ref]. They also lose less weight after bariatric surgery.[ref]
  • Those with the G allele had slower gastric motility.[ref]
  • G allele carriers had higher resistance to weight loss, lower intake of total carbohydrates and monounsaturated fat, and high intake of saturated fat.  Ghrelin (hunger hormone) concentrations were also higher. [ref] [ref] [ref]
  • Blood pressure circadian rhythms are lower in those carrying the G allele [ref]
  • In those with bipolar disorder, the G allele is associated with increase manic episodes [ref]

Check your 23andMe results for rs1801260 (v.4 and v.5):

  • GG: higher activity in the evening, possible delayed sleep onset, risk for obesity
  • AG: somewhere in between
  • AA: normal

Another CLOCK gene variant, rs11932595 (G is the minor allele), has also been found to affect circadian function:

Check your 23andMe results for rs11932595 (v.4 and v.5):

  • GG: somewhat increased risk of miscarriage, risk of male infertility
  • AG: somewhat increased risk of miscarriage, risk of male infertility
  • AA: normal, longer sleep duration

Studies show:

  • Sleep duration for those with the AA genotype is likely to be longer [ref]
  • Those with the minor allele were less likely to have non-alcoholic fatty liver disease. [ref] and sleep disturbance in depression [study]
  • An increased risk of miscarriage was found for those with AG, GG[ref]
  • An increased risk (1.9x) for male infertility for those with the G allele.[ref]

BMAL1 (ARNTL gene):
BMAL1 binds with CLOCK to increase the production of the PER and CRY circadian genes.  One of the BMAL1 variants, rs3816358 (A is the minor allele), has been studied in reference to breast cancer risk, cardiovascular disease risk, and diabetes risk.

Check your 23andMe results for rs3816358 (v.4 only):

  • AA: less of a risk of breast cancer than other shift workers [ref]
  • AC: less of a risk of breast cancer than other shift workes
  • CC: regular risk of breast cancer compared with other shift workers


rs7950226
(A is the minor allele)

  • increased risk of diabetes and gestational diabetes [ref] [ref]

PER1 gene:
PER1 codes for the ‘period circadian protein homolog 1’ protein which, along with CRY (below), is the other half of the core genes involved in our circadian rhythm.

A study in 2012 found that a variant, rs7221412, altered the natural timing of activity. Those with the AA genotype may naturally wake up about an hour earlier than those with GG, while AG falls in the middle.

Check your 23andMe results for rs7221412 (v.4 only):

  • AA: one hour earlier peak in circadian rhythm, more like to wake earlier [ref] [Article]
  • AG: peak was midway between AA and GG
  • GG: one hour later peak in circadian rhythm, more likely to wake later

PER2 gene:
A recent study looked at the expression of clock genes after weight loss and found that PER2 expression was increased after weight loss. [ref]

Check your 23andMe results for rs2304672 (v.4 only):

  • CC: associated with abdominal obesity, snacking, stress with dieting [ref] higher lipids [ref]
  • CG: associated with abdominal obesity, snacking, stress with dieting, higher lipid levels
  • GG: normal type (23andme orientation)

CRY2 gene:
A study of obese and lean women tracked their clock gene expressions in fat tissue over a 24-hour period.  The study found that CRY2 and REV-ERB  ALPHA are up-regulated in obesity over a 24-hour period.  [ref]

For rs7123390, postmenopausal women with AA had half the risk of estrogen and progesterone receptor-negative breast cancer.  [ref]

NR1D1 (REV-ERB Alpha)

rs2314339 (T is the minor allele)

  • REV-ERB alpha is associated both with a circadian mechanism and the biological action of lithium carbonate.  For bipolar disorder, those with at least one copy of the T allele were 3.5x less likely to improve on lithium carbonate therapy.  [ref]
  • Minor allele (T) carriers are less likely to be abdominally obese. [ref]

rs2071427 (T is the minor allele)

  • The minor allele, T, is associated with higher risk of obesity and higher BMI. [ref]

Other genes:

FTO is a gene with variants that are associated with increased risk of obesity (nicknamed the fatso gene).  A 2015 study found that FTO deficient mice had robust circadian locomotor activity rhythms, while “Overexpression of FTO represses the transcriptional activation by CLOCK and BMAL1.”[ref]  Other studies have shown that over-expression of FTO leads to increased body fat.[ref]


Lifehacks:

Blocking Blue Light:
Blue light at night has a big effect on your circadian rhythms. (Read my melatonin article).  Blocking blue light in the evening for a few hours before bed with blue-blocking glasses is one solution that will have multiple positive benefits on sleep and circadian rhythm. Get some inexpensive orange safety goggles and wear them every evening. Or upgrade to some nicer looking blue-blocking glasses. This seriously makes a difference in sleep quality and circadian function.

Sleep in the dark:
Even dim light at night can affect the body.  A study found that after two weeks with dim light during their dark cycle, “mice gained significantly more mass, reduced whole-body energy expenditure, increased carbohydrate over fat oxidation, and altered temperature circadian rhythms.” [ref]  So get some light blocking curtains, put electrical tape on any LED charger lights, and sleep in true darkness.

Time your meals right:
When you eat may matter more than what you eat:  “we recently showed that the timing of the main meal was predictive of weight loss during a 20-week dietary intervention and that this effect was independent from total 24-h caloric intake. The importance of caloric distribution across the day on weight loss therapy was supported by a recent 12-week experimental study showing that subjects assigned to high caloric intake during breakfast lost significantly more weight than those assigned to high caloric intake during the dinner.”[ref]  Another study showed that for bariatric surgery patients, those who ate their main meal later in the day were much more likely to be poor responders and lose less weight. [ref]

For those with melatonin receptor variants, eating dinner earlier can significantly decrease the risk of type 2 diabetes!

Intermittent fasting or restricted feeding time would also be something to explore.  Mouse studies on restricting feeding time to a four-hour window resulted in less weight gain, even though equal calories were eaten.  Possibly more importantly, it reset some of the circadian rhythm markers in those mice.  [ref]

Ketogenic Diet alters circadian system:
A mouse study looked at the effects of a ketogenic diet on clock genes.  It found that: “Clock genes showed delayed rhythms under KD. In the brain of KD-fed mice, amplitudes of clock genes were down-regulated, whereas 6-fold up-regulation was found in the liver. The metabolic state under KD indicates reduced satiety in the brain and reduced anabolism alongside increased gluconeogenesis in the liver.”  The study also found that the ketogenic diet “led to 1.5-fold increased levels of blood glucose and insulin.”  [ref]  There are other studies as well on the circadian rhythm changes induced by a ketogenic diet [ref]

NAC:
N-acetyl-cysteine (NAC) reversed the effects of BMAL1 deficiency in mice in regards to aging and oxidative stress.  Additionally, “Bmal1-deficient mice that received NAC weigh less than the corresponding control animals drinking regular water”, but they also drank less water.[ref]  This may be something to look into more as far as the timing of when it is best to take NAC.

Final thoughts:
There is an incredible amount of research coming out about the impacts of disruptions to our circadian rhythms, which has convinced me that this is one of the most important bases for good health.  Significant increases in the risk for breast and prostate cancer have been tied to being exposed to light at night, as well as increased risk of metabolic syndrome and diabetes.  While I’m not ready to go back to using candles for illumination in the evening, I am rocking the orange glasses every evening and sleeping like a rock each night.  Plus I’ve moved my evening meal earlier (5:30  or 6 pm) and cut out snacking at night to give my body the signal that the day is done.

More to read:

 

Originally published on July 2016.  Updated and revised Dec 2017.

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