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13 Hacks in Keeping a Circadian Rhythm + Zeitgebers

Written by Puya Yazdi, MD | Last updated:
Medically reviewed by
Genius Labs Science Team | Written by Puya Yazdi, MD | Last updated:

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When the circadian rhythm is disrupted, our ability to get quality sleep will suffer. But it isn’t just about sleep – the circadian rhythm is a key player in many aspects of health including stress, energy levels, and even weight control. Read on to learn more about the science behind keeping a healthy and balanced circadian rhythm.

For an executive summary of this post, read:

Top 25 Methods For Better Sleep and Circadian Rhythm Entrainment.

What is the Circadian Rhythm?
The Circadian Rhythm In Pictures

File:Biological clock human.svg

4.3.18 bioklok

About the Circadian Rhythm

Here’s a simple way to think about the circadian rhythm: the body has thousands of processes going on at any given moment. Many of these processes function better in concert with other processes – just like in a symphony, where different sounds work better with other sounds.

These processes have a certain rhythm or flow. Scientists think the body conducts this orchestra with clock genes, which get activated in many cells in the body in a synchronized way.

Research over the past few decades has recognized the importance of disrupted circadian biology in obesity, though this is still an active area of research [1].

Scientists believe that circadian biology likely also has a massive influence on energy balance and metabolism [2].

Some studies suggest that many hormone receptors have been observed to exhibit circadian rhythms of expression [2].

The daily timing of food intake has itself been shown to affect body weight regulation in mammals through the regulation of genes that control metabolism. This phenomenon has yet to be studied in humans [2].

But in particular, clock genes seem to control NAD+/SIRT1. According to some theories, low levels of these proteins have been linked with mitochondria that don’t work well, which may cause people to feel tired and have slower metabolism [2].

Many variations in genes of the circadian rhythm are being researched as potential factors that may raise the risk of diabetes [2].

Thus, it seems that if a person’s circadian rhythm is off, their quality of sleep will suffer considerably.

Is the circadian rhythm actually more important than sleep and how does it impact health and weight loss? Let’s take a look at the basic scientific concepts tied to it to get some answers.

Protein Recycling/Autophagy

At the protein level, a healthy cell will progress through a daily cycle of alternating metabolic states directed by the circadian system, with proteins going through cycles of being synthesized and degraded [3].

Science suggests that, during periods of fasting, cells release nutrients for recycling and remove damaged or unnecessary organelles (cellular structures). This is known as autophagy. In the liver and other tissues, this timely progression is controlled by the body’s circadian clocks [3].

Part of circadian modulation of autophagy includes establishing particular phases of day or night when the neurons are more susceptible to aggregation and mitochondrial dysfunction, and potentially this would be exacerbated by circadian and/or sleep disturbance which would reduce the daily peak capacity for autophagy (autophagy works via circadian expression of the transcription factor C/EBPβ) [3].

Zeitgebers or Circadian Cues

A zeitgeber or time giver is a biological cue for the time of day. Researchers believe that our bodies need these clues to know when to synchronize different activities.

The most significant zeitgeber is the light-dark cycle. The environmental information goes through the retina and the retinohypothalamic tract to the Suprachiasmatic nucleus in the hypothalamus [3].

Other zeitgebers include temperature, tides, social contact, and food availability, among others [3].

Scientists point out that there is the “central clock” in the hypothalamus, which has light as the predominant zeitgeber, and there are “peripheral clocks” in cells outside the brain, such as in the liver [3].

Feeding/starving cycles are considered to be dominant zeitgebers for many peripheral clocks [3].

Food metabolites such as glucose and/or feeding-related hormones such as glucagon and insulin have been proposed as likely candidates for phase setting of peripheral clocks [3].

Given the multitude of signals able to generate circadian rhythms in tissue culture cells, it is likely that a variety of different pathways are also used to synchronize peripheral clocks [3].

Below is a list of factors that may support a healthy circadian rhythm, according to limited research. The focus of this post is scientific–our aim is to outline the latest research about the circadian rhythm.

However, if you suffer from insomnia or a seriously disrupted circadian rhythm, it’s important to see a doctor to get an accurate diagnosis and treatment.

You may try the additional strategies listed below if you and your doctor determine that they could be appropriate. None of these strategies should ever be done in place of what your doctor recommends or prescribes.

1) Block Out Light at Night

According to some theories, getting rid of blue light at night is critical to a healthy circadian rhythm. Green light seems to have some melatonin blocking effects as well, so that’s why red glasses are considered to be ideal [4].

Some studies suggest that even red light at night increases alertness even though it doesn’t inhibit melatonin release like blue light, showing that melatonin suppression might not be required for light-induced nighttime alertness [5].

On the other hand, remember that blue-light-blocking glasses aren’t marketed as medical devices, which means that their claims are not regulated by the FDA.

There are no valid clinical trials to support the use of these glasses or other means of blocking out blue light in humans – all findings come from animal studies and can’t be extrapolated to humans.

In animals, light at night alters daily patterns of cortisol and clock proteins [6, 7]. It has been suggested that nighttime light also alters circadian clocks in humans, though large-scale studies are lacking [8].

Scientists are investigating whether blue light destroys the DHA in eyes, which hypothetically disrupts the signal to the hypothalamus (SCN) [9].

Other researchers suggest that a mere 5 lux of light (a tiny amount) can disrupt the circadian rhythm in mice [10]. The amount of light that may have the same effect in humans is unknown. Bright light devices are around 10,000 lux and direct, bright sunlight is around 100,000 lux.

Therefore, a low level of light may be present in your room even if you shut your lights off but have a night light, or if you are getting light from outside at night, which is the case if you live in a city.

According to some hypotheses, low levels of light may alter core circadian clock rhythms in the hypothalamus. These changes were associated with time alterations in eating and increased weight gain in mice, but such mechanisms remain unexplored in humans [11].

In one study, people who had delayed phase sleep syndrome (and likely people who are “night owls”) experienced lower melatonin levels in response to light at night [12].

Additionally, one study suggested that people with light colored eyes (light-eyed Caucasians), may be more susceptible to melatonin suppression by blue light than people with darker eyes (dark-eyed Asian). Further research is needed to verify these findings [13].

User Experiences

The opinions expressed in this post (under “user experiences”) are solely those of the users who may or may not have medical or scientific training. Their reviews do not represent the opinions of SelfHacked. SelfHacked does not endorse any specific product, service, or treatment.

Do not consider user experiences as medical advice. Never delay or disregard seeking professional medical advice from your doctor or another qualified healthcare provider because of something you have read on SelfHacked. We understand that reading individual, real-life experiences can be a helpful resource, but it is never a substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.

Some people say that when they keep to strictly blocking out all blue and green light at night, others find their behavior odd. Some people advise that “you have to make a calculation if your health is worth it, and you can mitigate weirdness in various ways.”

One person said that if your partner isn’t on board, it will be tough. They were dating someone who was on board with this because they knew it would be difficult otherwise.

Another person said that it’s mandatory to block out blue light after the sun goes down.

Some recommend the Orange Glasses to be worn when the sun starts going down. They say you can wear them starting in the afternoon if you wish when you’re indoors, but that’s anecdotally typically reserved for people who are ready to undergo a strict routine.

People say that another good idea is to have Blackout Curtains, especially if you live in a city. That way, no light whatsoever gets into the bedroom. Some also use a sleep mask, if need be.

Those who have a night-shift job mention that orange glasses are important.

Certain people say that if you need to go outside, you should wear red glasses and a hat/cap to block artificial lighting from above.

Joe says he wears red glasses for at least 2 hours before bed. He says that he turns off all artificial lighting and uses orange bulbs at night. He feels that if he gets any kind of light at night that isn’t filtered, it will throw off his circadian rhythm (including “light bombs” that come from outside).

Joe also uses the popular f.lux program to block out blue light–he uses the f.lux program all day.

Plus, he uses Twilight and Bluelight Filter for Android. Jailbroken iPhones can have f.lux installed. Otherwise, he hasn’t found programs in the IOS app store yet.

Joe mentions that he uses Red Sheets that block blue and green to cover iPad or other screens. He actually put these on his windows to block out stray lights from outside because in NYC light bombs are the norm.

2) Do Not Eat Large Meals Late at Night

Night-eating habits have been linked with metabolic syndrome, obesity, circadian rhythm disruption, and other health problems [14].

However, a recent review suggested that eating at night is only detrimental in people who have large meals. Small healthy meals (~150 kcals) were not seen as harmful, which was especially true in healthy people and in those with obesity who also regularly exercise. Additional research is needed [15].

User Experiences

Anecdotally, people say that not eating a meal at least 3 hours before bed helps and that restraining from food for 4 hours may be even better.

This is usually because many people don’t feel like they have control over the amount of food they eat late at night, and skipping this nighttime meal is a safer option than overeating.

Some people suggest increasing daytime calories to reduce hunger before bed or at night.

Joe says that, on the rare days when he misses to eat until later, he uses 1tbsp Ghee, 1tbsp Raw honey, and 1 tbsp Collagen before bed.

He mentions that, in the beginning, it may help to have some honey before bed, but that most people following the lectin avoidance diet and keeping to a circadian rhythm quickly get used to avoiding nighttime meals.

Joe thinks it’s a good idea to up your calories of lectin free foods and seafood, especially for breakfast. According to him, you will not get tired if you only eat 12 ounces of wild salmon and no carbs or oils (unless you have an allergy).

Joe also has the vast majority of his calories and especially protein in the morning and afternoon.

He says that protein can jump-start his metabolic rate and this is better close to the time he wakes up.

He advises against having your biggest meal for supper (last meal), as is common in the US.

People might have their largest meal for supper because they might not want to be fatigued in the day or more likely because they don’t have time to eat in the morning. Joe says it’s time to change this.
Joe also suggests constructing your meal size based on if you get hungry before bed or in the middle of the night. If you’re hungry before bed or you wake up in the middle of the night because of hunger, he thinks this means you didn’t eat enough in your last meal or in the day in general.

He usually fasts for 12-14 hours a day because he will stop eating at about 7 PM and eat breakfast at maybe 8 AM. This fluctuates.

3) Getting Outside First Thing in the Morning

Scientists claim that light helps entrain our circadian rhythm. This entrainment normally happens during the natural 24h solar day, over the course of which day turns into night [16, 17].

Based on animal studies, scientists suggest that bright light exposure during the daytime enhances the nighttime melatonin and activates the immune response [18].

Plus, spending more time being active outdoors is good for overall health.

It may be a good idea to get outside first thing in the morning. This will help you get natural sunlight to support and “reset” your daily rhythm.

Joe also uses a dawn simulator and a bright light device when he is not getting bright light in the morning.

Bright light devices are large. Yu can put them at your workstation if you use your computer first thing in the morning.

Joe also has a portable Bright Light Device to put on a cap. He uses an EMF Cap with it for a maximum of 15 minutes. He emphasizes that if you can get outside within a half hour every day, then you don’t need any device–you’re much better off getting outside.

4) Getting As Much Sunlight In The Day

Studies have suggested that melatonin is more easily suppressed in the winter than the summer by light in Japanese people [19]. Scientists say that this might be because not having enough bright light in the day predisposes people to circadian disruption with light at night, though large-scale human studies are needed to confirm this hypothesis.

In one small study, people who are “night owls” (later chronotypes) exposed only to natural sunlight had a more significant change in the time they went to sleep. They went to bed earlier, becoming more similar to early birds (earlier chronotypes) [8].

See this video in which this researcher mentions how the sun is important for setting the circadian rhythm.

5) Going to Bed and Waking Up At The Same Time

Irregular sleep-wake patterns have been associated with delayed circadian rhythms and lower academic performance in 61 undergraduate students. Keeping a regular sleep-wake cycle may support healthy sleep and a balanced circadian rhythm [20, 21].

Joe says he’s pretty bad when it comes to this, but he’s working on going to bed at the same time as a tool for programming his circadian rhythm.

6) Reduce Psychological Stress

The body’s circadian rhythm and stress response are tightly tied. Research suggests that psychological stress will throw off a healthy circadian rhythm [22].

Stress hormones (CRH, cortisol) may have the effect of delaying the circadian rhythm. Some scientists suspect that this is why night owls are more of an “anxious phenotype,” though this hypothesis remains unproven [23, 23].

Joe thinks it’s not only about psychological stress. According to him, anything that activates the HPA axis or stress response is included. Here is a list of dozens of HPA triggers.

7) Sync Your Exercise Routine

Some research suggests that exercise acts similar to sunlight, it helps entrain the circadian rhythm and is normally practiced during daylight. Exercise likely also promotes the production and release of melatonin, which commonly improves sleep quality [24].

Some blogs suggest that people should not exercise 4 hours before going to bed. Others say that exercising at ~5 pm can be ideal for sleep, but that exercising at 9 pm and going to sleep at 11 pm isn’t good. However, there’s no evidence to back up any of these opinions.

In fact, research suggests it may be best to sync the time of the day when you exercise to your circadian rhythm. “Early birds” may feel better if they exercise first thing in the morning, but “night owls” may want to exercise later in the day [24].

One study found that exercising early in the morning enhanced sleep quality, which in turn led to greater reductions in blood pressure during the night. Other studies found the opposite, suggesting that exercising in the evening is a better way to lower nighttime blood pressure. More research is needed to clarify these mixed findings [24].

Remember, regular, moderate exercise is good for your sleep, heart, and overall health. If you’re not sure how or when to exercise, see a qualified fitness professional to get some guidance.

8) Get Enough Nutrients

Eat a healthy diet high in whole foods, vegetables, and fiber. Diets high in fat or sugar have been shown to alter circadian clock function [25].

Additionally, selenium and proper methylation may be important for circadian functioning. Scientists are investigating how the following nutrients affect the circadian rhythm:

The effects of these supplements on the circadian rhythm in humans has not been investigated.

Supplements have not been approved by the FDA for medical use. Supplements generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective. Speak with your doctor before supplementing.

9) Be Warm Enough (But Not Too Warm) At Night

Body temperature normally drops at night. Limited research suggests that heat exposure increases wakefulness and decreases slow wave sleep and rapid eye movement (REM) sleep. But both excessively high and low temperatures can disturb sleep [27].

Some people like to have a thick blanket to snuggle on at night, regardless of the season. Depending on the temperature in your room, this may make you too warm and potentially disturb your circadian rhythm. Make sure that you are warm enough at night, but try not to overdo it.

Anecdotal (Joe’s tips):

The following tips are Joe’s personal experience. They are not based on clinical research.

10) Go to Bed Early

You want to ideally go to sleep at 10 PM and wake up at 6 AM. You don’t want to go to bed at 12 PM like I do.

I am working on this, with some limited success. I seem to be able to go to bed earlier, but the key for me is to do it EVERY DAY, not just most days.

I find I’m most successful when I aim to get to bed at 9 and then I end up getting in bed at 11. When I aim for 11, I get to bed at 1.

11) Get Rid of Chronic Inflammation, Oxidative stress, Mitochondrial Dysfunction or Hypoxia

If you have chronic oxidative stress, inflammation, hypoxia or mitochondrial issues, then see a doctor to get a diagnosis and treatment.

Each of these may disturb your circadian rhythm and they are also increased by a disturbed circadian rhythm, creating a bad vortex.

For me, food lectins were most significant in giving me inflammation and disrupting my circadian rhythm, but this was far from the only trigger.

Your mitochondria are supposed to be more active in the day and you’re supposed to utilize oxygen, which results in superoxide. Bursts of superoxide will help you create new mitochondria.

When your mitochondria are working well, you will build up healthy levels of ATP and NAD+ levels, which are important for energy utilization and metabolism.

Healthy levels of these will allow you to be alert and energized in the day and tired by nightfall.

How?

The mitochondria create ATP. ATP converts to cyclic AMP, which is a critical messenger molecule for so many cellular processes.

cAMP is needed for the regulation of glycogen, sugar, and lipid metabolism.

The phosphates from ATP activate proteins that act directly on the cell’s ion channels.

Through PKA/CREB, it leads to the production of gene products.

The following hormones also require adequate cAMP levels to function optimally: FSH, LH, ADH (V2=kidneys), TSH, CRH, hCG, ACTH, MSH, PTH, GHRH, Glucagon, and Calcitonin.

Cyclic AMP turns on PKA, which converts ATP into AMP, which ends up converting to adenosine.

Adenosine builds up throughout the day and causes you to feel tired as the day goes on. Orexin also has a sharp drop off and you feel like you need to go to sleep.

If your mitochondria aren’t working, you don’t produce optimal levels of ATP, cyclic AMP, AMP, and adenosine.

You need adequate oxygen for your mitochondria to work well.

Chronic inflammation and/or oxidative stress will cause your mitochondria to slow and you won’t utilize oxygen well. Low oxygen will lengthen your electron transport chain and cause increased superoxide per ATP produced (Kruse).

12) Increase Cyclic AMP (cAMP) Right After Awakening

cAMP resets the circadian rhythm. If you take forskolin, which is claimed to help with weight loss, take it right when you wake up.

Exercise also increases cAMP, so it’s not a bad idea to wake up and do some push-ups or take a quick sprint.

13) Take Most Supplements in the Morning

I think that almost all herbal or other supplements should be taken in the morning or afternoon.

The exceptions are raw honey, magnesium, glycine, herbs meant to put you asleep (valerian, passion flower) and perhaps a few others. Unless you have a clear reason to use it at night, use it in the morning or afternoon.

I used to support some supplements to make you drowsy before bed, but I am now careful. I use them only when people suffer from insomnia.

Other

Music and socializing are zeitgebers, which can indicate it’s daytime, so keep these to the earlier parts of the day (or restrict at night).

Oxygen can also reset the circadian rhythm and help jet lag [28].

If you use an oxygen concentrator or hyperbaric machine, it should be done in the AM or afternoon.

Anything that increases NAD+/SIRT1 should be done in the morning/afternoon.

Circadian Rhythm

AsianJPharm_2011_5_1_1_80057_f3

Of Hormones

In the morning, light on the retinas signals the SCN to shut off melatonin [29].

Prolactin is secreted early after sleep onset and rises through the night [30].

GHRH spikes at about midnight while growth hormone gets released a bit later.

TRH spikes at 3-4 AM, followed by TSH, T4, and T3.

Metabolism is lowest at about 4 AM and this corresponds to our lowest body temperature.

Toward the end of the sleep phase, before early morning, the renin-angiotensin system kicks up. This increase causes aldosterone to also increase (before cortisol rises) [31].

Cortisol spikes at 6 AM. CRH and ACTH precede the cortisol spike by an hour or so.

Aldosterone and cortisol both cause a blood pressure spike.

VIP is highest at 6 AM and lowest at 6 PM.

In lean people, ghrelin rises rapidly at midnight and peaks about 2:30 AM, but not in obese people, where it stays flat [32].

This burst of ghrelin stimulates growth hormone.

Ghrelin continues to be high until the morning. Ghrelin stimulates NPY in the hypothalamus increasing our desire and ability to eat a lot more. Melatonin is known to acutely decrease ghrelin.

Light at night can disturb the ghrelin release [33].

Leptin rises as the day goes on and peaks at midnight and is at the lowest point between 9AM-12PM. The timing of your meals affects when you have a peak of leptin [34].

Leptin makes NPY decline normally, but if one is leptin resistant this does not occur and appetite is out of control at the brain level.

Testosterone secretion peaks at about 9 AM. This is preceded by FSH and LH secreted at about 6 AM.

At 6:30 PM we see our highest blood pressures due to changes in atrial natriuretic factor and antidiuretic hormone (ANF, ADH).

Of Disease

Some evidence suggests that heart attacks often occur in the morning. Epileptic seizures peak in the late afternoon. Asthma attacks get worse and more deadly between 11 PM and 3 AM [29].

In the morning, the immune system may be overactive, inflaming airways in asthma sufferers and swelling arthritic joints [29].

Blood pressure and heart rate start increasing in the morning due to cortisol [29].

Heart attacks and strokes peak at around 9 AM, partly because of the higher blood pressure [29].

Also, a substance called PAI-1, which makes blood clot more readily, peaks around 6:30 AM [29].

GERD may be higher at night. Stomach acid production peaks between 10 PM and 2 AM [29].

Metabolism and Oxidative Stress

Metabolism/mitochondrial production of energy, the sun, and detoxification of food-derived toxins create free radicals in the daytime, which then elicit an antioxidant response in a cyclic manner throughout the day (but oxidative states are focused in the daytime and antioxidant response at night) [35].

In the late afternoon and on we see more antioxidant gene expression [35].

During daylight hours, we see increased Nrf2 gene expression, and at 6 PM, we see a peak in NRF2 protein [35], which some scientists call the body’s core antioxidant defense system.

Some researchers suggest that circadian disruption is tied to higher levels of oxidative stress [35].

PPAR alpha and gamma, proteins implicated in metabolism, are also active in the day and are controlled by CLOCK/BMAL1 [35].

Scientists posit that when the cellular clock is disrupted, it results in a deficiency of NAD+ because NAMPT, the enzyme that makes NAD, is controlled by clock proteins – BMAL1 is especially important for this [36]. Less NAD+ leads to a reduction of SIRT3, which is necessary for metabolism and mitochondrial function [37].

The Immune System

Some part of your immune system is elevated in the day and some at night. TNF, IL-1, IL-2, IL-6, and IFNy are elevated, in part because of melatonin [38].

TNF–α, IL-2, and IFN-γ likely work in part by inducing slow wave sleep, which makes us more resistant to infections [38].

T cell numbers and its reactivity were stable during the daytime, whereas a significant increase was observed in the late evening and early morning hours [38].

Scientists think this may be associated with why people with arthritis have “morning stiffness of joints,” because of these aspects of the immune system peak from midnight to early in the morning [38].

Cytokines, such as TNF, can change the circadian rhythm, so the effects are bidirectional [39].

Per2, which peaks toward the early evening, increases natural killer cell activity [40].

Weight Control, CLOCK & MBAL1 genes

Mice who eat at the wrong time (when it’s dark for humans) gained more weight, despite the absence of any significant differences in calorie intake or activity over the course of the experiment. [2] Scientists suggest their metabolism shifted, but similar mechanisms have not been explored in humans.

Limited studies suggest that a disrupted circadian rhythm is why shift workers are at increased risk of obesity. Large-scale studies are needed [41].

Mice deficient in the core circadian CLOCK gene develop obesity. These mice have reduced levels and a flat rhythm of orexin, a neurotransmitter that increases energy metabolism [2].

Mice deficient in another circadian gene (Bmal1) had defects in insulin secretion, both at base levels and in response to glucose stimulation. These mice were highly susceptible to diabetes [2].

Fat cells also need BMAL1 to develop [42].

When mice were bred without BMAL1, they lost weight [43].

The effects of BMAL1 and BMAL1 deficiency on weight loss in humans are unknown.

I see both excessively thin and obese people having circadian rhythm problems. The obese people might have a problem with the CLOCK gene and the thin people might have an issue with BMAL1.

Overall, a BMAL1 deficiency fits with the thin phenotype client who has sleep problems and can’t gain weight.

In mice, deficiency of BMAL1 leads to increased ROS levels in several tissues [44, 35], which is an issue my clients deal with.

Adequate BMAL1 is needed for the production of vasopressin [45], which is something low in my clients.

Having too little BMAL1 will ruin your sleep. Many of my clients have sleep problems.

Adequate BMAL1 is needed for the production of hypoxia-inducible factors [45], which is something that I’d guess would be low for my clients because they often have low EPO, which needs HIF [46].

A BMAL1 deficiency may also correlate with higher LDL cholesterol levels because BMAL1 (and CLOCK) may be needed to increase LDL receptor genes, which swallow up LDL [45].

Mice bred without BMAL1 are infertile, small in stature, age quickly, and have progressive pains in joints and are more sleepy and less active (less overall locomotor activity) than normal mice [45].

BMAL1 (and CLOCK) increases gene production of NAMPT [36], which is crucial in converting niacin (also called nicotinamide) to NAD [47], which is what puts the pedal to the metal of metabolism. So less BMAL1 may imply less NAD+, slower metabolism, and energy production [36].

NAD+ is needed for SIRT1 [48], which increases orexin 2 receptors [49], which is important for wakefulness [50].

Having less BMAL1 will result in less SIRT1 protein and activity [51].

Having less BMAL1 will also lower PPAR alpha [52].

Histaminergic neurons are silent during sleep, and start firing after waking. Histamine, made by the enzyme histidine decarboxylase (HDC), enhances wakefulness.

Mice that don’t have BMAL1 in histamine cells have more fragmented sleep, prolonged wakefulness at night, shallower sleep depth (Less SWS or N3), hindered recovery sleep after sleep deprivation, and impaired memory [53].

BMAL1 is lower in people with Bipolar [45].

BMAL1 increases muscle production [54] – through MYOD1 [55].

BMAL1 increases the Nrf2 antioxidant protein, which decreases oxidative stress. The free radicals cause pancreatic beta cells to malfunction and decrease insulin release [56].

BMAL1 inhibits mTOR [57].

BMAL1 increases hair growth. Mice deficient in BMAL1 had a delay in hair regrowth after shaving [58].

BMAL1 controls certain kinds of inflammatory monocyte [59].

BMAL1 increases the circadian genes Per1, Per2, Rev-erbα, and Dbp)

BMAL1 increases genes involved in hormone production, including Star, Cyp19a1, Cyp11a1, Hsd3b2, and Lhcgr [60].

Cyp11a1 makes a protein (Cholesterol side-chain cleavage enzyme) that converts cholesterol to pregnenolone [61].

Star is the rate-limiting step for hormone production. It transports cholesterol to the inner mitochondrial membrane to be transformed into pregnenolone. Recently, it has been found to play a role in creating bile as well [62].

Hsd3b2 plays a crucial role in the synthesis of all classes of hormonal steroids. This gene is predominantly expressed in the adrenals, ovaries and the gonads [63]. The HSD3B2 gene provides instructions for making the 3β-HSD enzyme, which is necessary for the production of progesterone, testosterone and ultimately cortisol, aldosterone, and estrogens.

CYP19A1 is a gene that makes aromatase, the enzyme that transforms testosterone to estradiol.

In the male, the LHCGR has been identified on the Leydig cells that are critical for testosterone production and support sperm production. LHCGR is also important for female fertility as well [64].

BMAL1 (and CLOCK) is also important for GnRH receptors in the pituitary gland [65]. This receptor receives the signal from the hypothalamus (GnRH) to produce LH and FSH.

BMAL1 increases the nerve growth factor receptor which can bind to NGF, BDNF, NT-3, and NT-4. This can mediate neuron cell survival.

BMAL1 plays an important role in adult hippocampal neurogenesis by regulating neural stem/progenitor cells (NSPCs). This ties various neurological/psychological disorders linked to adult neurogenesis and circadian rhythm [66].

BMAL1 increases MAOA [67].

BMAL1 (and CLOCK) increases PGC-1a&b [55] and SIRT1 [68].

BMAL1 (and CLOCK) represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) [57].

People with Gestational Diabetes have lower BMAL1 [69].

About the Author

Puya Yazdi

MD
Dr. Puya Yazdi is a physician-scientist with 14+ years of experience in clinical medicine, life sciences, biotechnology, and nutraceuticals.
As a physician-scientist with expertise in genomics, biotechnology, and nutraceuticals, he has made it his mission to bring precision medicine to the bedside and help transform healthcare in the 21st century.He received his undergraduate education at the University of California at Irvine, a Medical Doctorate from the University of Southern California, and was a Resident Physician at Stanford University. He then proceeded to serve as a Clinical Fellow of The California Institute of Regenerative Medicine at The University of California at Irvine, where he conducted research of stem cells, epigenetics, and genomics. He was also a Medical Director for Cyvex Nutrition before serving as president of Systomic Health, a biotechnology consulting agency, where he served as an expert on genomics and other high-throughput technologies. His previous clients include Allergan, Caladrius Biosciences, and Omega Protein. He has a history of peer-reviewed publications, intellectual property discoveries (patents, etc.), clinical trial design, and a thorough knowledge of the regulatory landscape in biotechnology.He is leading our entire scientific and medical team in order to ensure accuracy and scientific validity of our content and products.

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