How natural supplements can change circadian gene expression

Did you know that some supplements change the expression of your core circadian clock genes? Your core circadian rhythm genes are foundational to your health, and some supplements alter that rhythm.

I find the idea of using natural supplements to alter your circadian gene expression to be pretty cool! And thus, something that I need to understand and exploit to benefit my health and longevity. I’m going to outline the science behind this and then explain how you also can use this knowledge to alter your gene expression and hack your own circadian rhythm.

Need a reason to keep reading (other than this just being cool stuff)? Here are the possible benefits of controlling circadian rhythm: better mental health, better blood glucose control, prevention of dementia/ Alzheimer’s, quality sleep, and overall well-being…

Using supplements to alter circadian gene expression:

First, let me explain what I mean by gene expression.  Your genes are sections of your DNA that code for proteins.  Not all genes are being translated into proteins all the time in cells.  Instead, your cells have ways to turn on and off gene translation so that the right amount of a protein is available at the right time. Altering gene expression means that the gene is being translated into the protein when it normal wouldn’t be — or vice-versa. To put it simply, it is like turning on or off a gene.

Background on circadian rhythm:

(Just skip this part if you are already a circadian expert!)

Your circadian rhythm is the approximately 24-hour cycle of various biological activities that go on each day.  Some obvious examples include your sleep/wake cycle or when you get hungry and eat each day.  Slightly less obvious examples include your body temperature changes over the course of a day and the rhythm of hormones such as cortisol and melatonin.

Taking a look under the hood, so to say, shows that the body has thousands of internal activities that oscillate over the course of the 24-hour day.

All of this is driven by a molecular core circadian clock that is located in a region of your hypothalamus called the suprachiasmatic nucleus.  In this brain region, the levels of a pair of core circadian clock proteins rise during the day and then are suppressed at night as another pair of clock proteins rise during the night.

The two human proteins that are considered to be the ‘positive arm’ of the molecular circadian clock are known as CLOCK and BMAL1. The other side of the equation contains the proteins called Period (PER1/2) and Cryptochrome (CRY1/2). [ref]

Researchers can sample the amount of these proteins that are available at a specific time and can plot when the CLOCK and BMAL1 proteins are high or low, and then when the CRY and PER proteins are high or low.

This oscillation over 24 hours makes up your core circadian clock.

Researchers talk about the amplitude of the clock genes — how much of the protein is created at the peak time. They also talk about the period of the clock genes – the time between when those peaks occur.

So the main genetic players in the core circadian clock are CLOCK, BMAL1, CRY1/2, and PER1/2. In addition, there is a secondary regulatory loop where the  REVERBa and RORa genes are also important.  These are both retinoic acid (vitamin A) related genes.

How is this rhythm set?

Every living thing has a built-in circadian rhythm. It is fundamental to life.

For living creatures that live for more than 24-hours, this circadian rhythm generally lasts for around 24-hours (circa – about; dien – a day). But if the natural rhythm of a person or animal is off by 15 or 20 minutes a day, there has to be a way to reset it and keep everything functioning in concert.

Light from the sun resets the core circadian rhythm each day in almost every living thing, from plants to animals.

For humans, light from the sun hits receptors in the retina of the eye. This signal sets the circadian rhythm within the suprachiasmatic nucleus and it stops the production of melatonin in the pineal gland.

Prior to electric lighting (so, for billions of years!), the only light was from sunlight during the day and soft firelight (candles, lanterns, fireplace) or moonlight at night. The receptors in our eyes are stimulated at ~479nm wavelengths of light, which is in the blue spectrum.

Fast forward millions of years to modern life with bright light to be found 24-hours a day from our electric lightbulbs – but especially the blue lights from our TV, laptops, cell phones, etc.

You can see where I’m going with this…  Blue light at night is screwing with our circadian rhythm — and the circadian rhythm of all the animals that live near our homes and cities.

Beyond Light and Darkness:

I’ve optimized my circadian rhythm as much as possible by blocking blue light at night, sleeping in the dark, and through getting sunlight each morning. (Read more: Blocking blue light; Circadian Genes and Mood; www.CircadianLifehacks.com) Basically, I’ve reset myself to be in alignment with daylight and darkness…

The benefits of those three things have made an outstanding difference for me when it comes to sleep, mood, energy, and overall health.

But what if there is more? What if manipulating circadian gene expression can do even more than adjusting my life to the natural rhythm of the sun has done.

Peripheral Circadian Rhythms

I’ve given a simplified overview here of the circadian systems — core circadian clock that is set by sunlight. Realistically, it gets more complex than that. There are secondary systems that synchronize and affect the core circadian clock.

Each tissue or organ in the body also has its own circadian rhythm – called peripheral circadian clocks. For example, your liver has an internal timing system so that it knows when you are probably going to eat and drink. The liver then produces enzymes that will probably be needed for breaking down food and toxins at the time that you normally eat. Say that you get up each morning at 6 am and drink your first cup of coffee at 6:30 every morning. Your liver will produce the enzymes needed for metabolizing caffeine (CYP1A1) in anticipation of your cup of coffee.

To some extent, your peripheral clock genes in your organs need to be aligned with your core circadian clock. Dysregulation, or getting out of sync, may be one driver of a lot of modern chronic diseases.

 

Supplements that affect circadian gene expression:

Jiao-Tai-Wan increases CRY1/2:
A traditional Chinese medicine herbal blend called Jiao-Tai-Wan has been shown to affect circadian rhythm. The herbal blend contains Thizome coptidis and Cortex cinnamomi (Chinese cinnamon). It traditionally is used for insomnia, but it also helps decrease insulin resistance and increase weight loss. A recent study shows that Jiao-Tai-Wan upregulates the CRY1 and CRY2 proteins as well as downregulating inflammatory proteins. [ref]

Interestingly, genetic variants in the CRY2 gene are linked to an increased risk of obesity and higher fasting blood glucose levels. (Circadian Genes and Weight)

Passionflower Extract increases circadian gene expression:
Passionflower has been used for anxiety and anxiety-related sleep disorders for centuries. A study shows that passionflower extract increases the amplitude of PER1/2 and CRY1 gene expression in the liver, but it doesn’t shift the phase of when the genes are expressed. In the brain (of mice), passionflower extract increased the expression of BMAL1 and CLOCK. Interestingly, it also caused a change in cortisol levels – decreasing the levels when they should be low, but not affecting the peak levels. [ref]

Passionflower extract is available on Amazon as a supplement* and as a tea.  It is also very easy to grow and a nice vine to add to your garden.

NAD+ increases PER1:
Increasing NAD+ levels has been shown in animal studies to increase PER1 gene expression and also to reduce weight gain. [ref]

The supplements NR (nicotinamide riboside) and NMN (nicotinamide mononucleotide) have been shown in both animal and human studies to increase NAD+ levels.  (Article with all the background and studies on this: NAD+ Reversing Aging? Overview of NR and NMN )

You can get Nicotinamide Riboside* and NMN on Amazon or through your local health food store.

Berberine:
Berberine is a component of several different plants that have been traditionally used as natural medicines. It is known for regulating blood glucose levels. A recent cell study looked at the effects of berberine on adipose tissue. The study showed that berberine upregulated FGF21 (important in glucose regulation) through increasing BMAL1.[ref]

Berberine is available online and through your local health food store.  It may also lower blood pressure in addition to lowering blood glucose levels, so check with your doctor if you are on any prescription meds.

Reveratrol:
Fatty liver disease decreases the expression of CLOCK and BMAL1. Resveratrol has been shown in cell studies to restore BMAL1 expression in liver cells that are treated with fatty acids. Other studies have shown that resveratrol also normalizes the rhythm of CLOCK and PER2 in addition to BMAL1 in animals fed an obesogenic diet. [ref][ref]

Additionally, resveratrol has been shown to reverse the negative effects on circadian rhythm from acrylamide.[ref] When food is browned through a Maillard reaction (e.g. french fries, toast), it can form acrylamide, which has been shown in several studies to downregulate circadian genes in both the liver and brain as well as causing cognitive deficits. [ref] Acrylamide is also found in cigarette smoke.

Resveratrol is found in grapes and wine (in low levels) or can be taken as a supplement.

Nobiletin increases PER2:
Nobiletin is a flavonoid found in citrus fruits. It has been fairly well studied in its effect on circadian rhythm. Specifically, it increases the amplitude and lengthens the period for PER2.

There is a Life Extension Foundation supplement called Circadian Sleep. It includes both 1.5mg of melatonin and 50 mg of nobiletin.  That is the only supplement that I’ve seen that contains nobiletin…

Lithium:
Lithium carbonate has been used in high doses for decades as a prescription medication for bipolar disorder. Lithium orotate, though, is available in low doses as a supplement.

Research shows that lithium affects BMAL1 expression through inhibiting GSK3.  [ref] Other research shows that lithium upregulates PER2 expression.[ref] It has also been shown to lengthen the period of peripheral clock gene expression (in mice). [ref]

DHA (fish oil) supplements affect BMAL1:
The omega-3 fatty acid DHA has been shown in cell studies on neurons to affect BMAL1. The study found that palmitate (an often inflammatory saturated fat) altered the period of BMAL1 expression, but that DHA could protect the cells from that negative effect. [ref] This study hints that some of the negative effects of palmitic acid may be due to disruption fo BMAL1.

Supplements that affect circadian rhythm without affecting gene expression:

Lion’s Mane:
A recent animal study shows that Lion’s mane mushroom extract (Hericium erinaceus) alters the sleep/wake activity timing without altering the core circadian clock genes. The study found that the animals that were given the lion’s mane extract were active earlier in their normal activity period and then also went to sleep earlier. This didn’t affect the expression of the PER genes or BMAL1 (which were the two circadian genes investigated in the study).  [ref]

If you are working to shift your circadian rhythm in a way that you naturally get up and are active a little earlier, perhaps Lion’s Mane would help.  Four Sigmatic Lion’s Mane coffee may be getting my brain going in more than one way!

Curcumin:
A cell study looked at the anti-cancer effects of curcumin, based on the timing of consumption. The thought behind this is that curcumin can induce cell death in cancer cells, and it also may be useful in combination with chemotherapy drugs. The study found that low-dose curcumin treatment given 6-11 hours before peak PER2 expression was most effective in killing cancer cells.  [ref]

This was just a cell study – so the timing of curcumin treatment in humans still needs to be researched. I’ve included it here, not as a definitive time for taking curcumin, but rather as an example of how timing matters and may change depending on what outcome you are wanting.

Lifehacks:

If you know that you have a condition that is caused by circadian disruption (diabetes, mood disorders, weight problems, sleep problems), then the first step is getting your circadian rhythm on track with daylight and darkness. While it really is as simple as sleeping in the dark and being outside in the daylight, the reality of modern life is that isn’t simple for everyone.

I suggest starting with a week-long experiment using blue-light blocking glasses at night (for two to three hours before bedtime) and also getting outside in the morning sunlight.

When you have your circadian rhythm dialed into night and day, then the next step could be to experiment with the timing of supplements.

So what does all of the above research mean?  Should you take resveratrol in the morning and lithium at night?

To be honest, I don’t have solid answers here – and I would bet that the answer is NOT the same for everyone. I do know that genetic variants impact how long it takes for supplements to enter your system and how long they are available before being excreted.

Self-experimentation:

Instead of this being a ‘how-to’ guide, I hope that you will take the information presented in this article and use it as a starting point for your own investigations.

For example, if you take lithium orotate, experiment with taking it in the morning vs. in the evening and see if you notice an effect on sleep or mood.

Another example, passionflower extract is usually used at night for sleep, but its effects on CLOCK and BMAL1 make me wonder if taking it in the morning would be beneficial for some people.

A word of caution: The research on how circadian rhythm dysregulation affects depression and bipolar disorder is fairly solid. If you struggle with mood, talk with your doc and/or involve your family/friends in any experiments you do to alter your circadian rhythm. While it may seem like a minor change, altering light, sleep timing, and other ways of changing circadian rhythm can be more powerful than even heavy-duty medications. [study][study][study]

Keep in mind when experimenting with circadian rhythm effects that you need to plan on experimenting for several days for each ‘variable’ to really make a difference. Personally, I like to track sleep parameters using my Oura ring.  If you are trying to reverse diabetes, you may want to track blood glucose levels or other markers. If you are working to stabilize mood, then try just keeping a journal (digital or in a notebook) to keep track of how you feel in the morning or night — along with whatever variable (supplement, light, meal timing), you are varying.

Post in the comments below (or send me a message via the contact page) if you have experimented with altering circadian rhythm using supplements.

 

*Links to Amazon are for illustrative purposes and not necessarily an endorsement of that brand. Check the reviews and go with the product that you think is best.

References:

Furuta, Shoko, Rika Kuwahara, Eri Hiraki, Koichiro Ohnuki, Shinobu Yasuo, and Kuniyoshi Shimizu. 2016. “Hericium Erinaceus Extracts Alter Behavioral Rhythm in Mice .” Biomedical Research 37 (4): 227–32. https://doi.org/10.2220/biomedres.37.227.
Greco, James A., Johanneke E. Oosterman, and Denise D. Belsham. 2014. “Differential Effects of Omega-3 Fatty Acid Docosahexaenoic Acid and Palmitate on the Circadian Transcriptional Profile of Clock Genes in Immortalized Hypothalamic Neurons.” American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 307 (8): R1049–60. https://doi.org/10.1152/ajpregu.00100.2014.
Huang, Wen-Ya, Xin Zou, Fu-Er Lu, Hao Su, Chu Zhang, Yan-Lin Ren, Ke Fang, et al. 2018. “Jiao-Tai-Wan Up-Regulates Hypothalamic and Peripheral Circadian Clock Gene Cryptochrome and Activates PI3K/AKT Signaling in Partially Sleep-Deprived Rats.” Current Medical Science 38 (4): 704–13. https://doi.org/10.1007/s11596-018-1934-x.
Jagannath, Aarti, Lewis Taylor, Zeinab Wakaf, Sridhar R. Vasudevan, and Russell G. Foster. 2017. “The Genetics of Circadian Rhythms, Sleep and Health.” Human Molecular Genetics 26 (R2): R128–38. https://doi.org/10.1093/hmg/ddx240.
Kripke, Daniel F, Caroline M Nievergelt, EJ Joo, Tatyana Shekhtman, and John R Kelsoe. 2009. “Circadian Polymorphisms Associated with Affective Disorders.” Journal of Circadian Rhythms 7 (January): 2. https://doi.org/10.1186/1740-3391-7-2.
Li, Jian, Wei-Qun Lu, Stephen Beesley, Andrew S. I. Loudon, and Qing-Jun Meng. 2012. “Lithium Impacts on the Amplitude and Period of the Molecular Circadian Clockwork.” PLoS ONE 7 (3). https://doi.org/10.1371/journal.pone.0033292.
Li, Jing, Liping Wei, Caicai Zhao, Junyi Li, Zhigang Liu, Min Zhang, and Yutang Wang. 2019. “Resveratrol Maintains Lipid Metabolism Homeostasis via One of the Mechanisms Associated with the Key Circadian Regulator Bmal1.” Molecules 24 (16). https://doi.org/10.3390/molecules24162916.
Putker, Marrit, Priya Crosby, Kevin A. Feeney, Nathaniel P. Hoyle, Ana S.H. Costa, Edoardo Gaude, Christian Frezza, and John S. O’Neill. 2017. “Mammalian Circadian Period, But Not Phase and Amplitude, Is Robust Against Redox and Metabolic Perturbations.” Antioxidants & Redox Signaling 28 (7): 507–20. https://doi.org/10.1089/ars.2016.6911.
Roh, Eun, Gil Myoung Kang, So Young Gil, Chan Hee Lee, Seongjun Kim, Dugu Hong, Gi Hoon Son, and Min-Seon Kim. 2018. “Effects of Chronic NAD Supplementation on Energy Metabolism and Diurnal Rhythm in Obese Mice.” Obesity 26 (9): 1448–56. https://doi.org/10.1002/oby.22263.
Sarma, Ashapurna, Vishal P. Sharma, Arindam B. Sarkar, M. Chandra Sekar, Karunakar Samuel, and Michael E. Geusz. 2016. “The Circadian Clock Modulates Anti-Cancer Properties of Curcumin.” BMC Cancer 16 (1): 759. https://doi.org/10.1186/s12885-016-2789-9.
Shinozaki, Ayako, Kenichiro Misawa, Yuko Ikeda, Atsushi Haraguchi, Mayo Kamagata, Yu Tahara, and Shigenobu Shibata. 2017. “Potent Effects of Flavonoid Nobiletin on Amplitude, Period, and Phase of the Circadian Clock Rhythm in PER2::LUCIFERASE Mouse Embryonic Fibroblasts.” PLoS ONE 12 (2). https://doi.org/10.1371/journal.pone.0170904.
Tan, Xintong, Ling Li, Jia Wang, Beita Zhao, Junru Pan, Leran Wang, Xiao Liu, Xuebo Liu, and Zhigang Liu. 2019. “Resveratrol Prevents Acrylamide-Induced Mitochondrial Dysfunction and Inflammatory Responses via Targeting Circadian Regulator Bmal1 and Cry1 in Hepatocytes.” Journal of Agricultural and Food Chemistry 67 (31): 8510–19. https://doi.org/10.1021/acs.jafc.9b03368.
Toda, Kazuya, Shoketsu Hitoe, Shogo Takeda, Norihito Shimizu, and Hiroshi Shimoda. 2017. “Passionflower Extract Induces High-Amplitude Rhythms without Phase Shifts in the Expression of Several Circadian Clock Genes in Vitro and in Vivo.” International Journal of Biomedical Science : IJBS 13 (2): 84–92.


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