Advanced Glycation End Products

Recent research shows that advanced glycation end products (AGEs) are a causative factor in many degenerative diseases – including almost all of the diseases associated with aging. AGEs have been linked to Alzheimer’s, heart disease, diabetes, chronic kidney disease, wrinkles and loss of skin elasticity, and more.

Like most topics covered here on Genetic Lifehacks, both genetic susceptibility and lifestyle interact to cause the problems associated with AGEs. This article will dig into the genetic susceptibility and then discuss the lifehacks that can help to mitigate any susceptibility. In fact, one specific type of advanced glycation end product has been shown to be highly determined by genetics.[ref]

Advanced Glycation End Products:

The term AGEs (advanced glycation end products) refers to a lipid or protein being glycated, which means that a sugar or aldehyde binds with the protein or lipid. It is a general term that is applied to a bunch of different molecules, but the basic premise is that certain byproducts of glycolysis (producing energy from sugar) can bind with a protein or fat in the body and alter it permanently.

AGEs naturally occur in the body as a result of normal metabolism. You can also consume AGEs in foods,  and their production can depend on how you cook the food.

The problems with advanced glycation end products develop when an excess is produced by the body, along with consuming a diet high in AGEs.

First, a quick food example of AGEs to give you a picture of what is going on…  When you throw a steak on the grill or brown a pork chop in a hot pan, advanced glycation end products form in the process of browning of the meat. This is known as a Maillard reaction – and it is what makes grilled meat and vegetables taste great and smell delicious. This Maillard reaction is producing advanced glycation end products in the food. Think about uncooked bacon versus the taste, feel, and smell of cooked bacon – a big part of the deliciousness is the production of AGEs. It also causes the proteins to transform, linking together to create nice, crispy bacon.

Grilled meat makes a great mental image, but AGEs also form within the body under normal conditions. In fact, the majority of advanced glycation end products come from this natural formation process in the body rather than from food.

So let me go into the formation of AGEs in the body first and then discuss ways to prevent the formation of AGEs in foods in the Lifehacks section at the end.

Where do advanced glycation end products come from in the body?

Glucose is the main fuel that your body uses for energy. (Yes, you can use fat for energy also if you are in ketosis. Stick with me here, even if you are a low carb fanatic.)

We get glucose from consuming carbohydrates, which are broken down in the body into simple sugars. The body can also create glucose via a process called gluconeogenesis, but this isn’t a big source of glucose under normal circumstances.

Inside all of your cells, glucose is converted into energy in the form of ATP.

When glucose is used in the cell for glycolysis, it goes through a multistep process to break the glucose molecule (C6H12O6) into two pyruvate molecules plus a hydrogen ion. This process releases energy that is stored in the ATP molecule. In high school biology, it is usually just noted that glycolysis is the process of splitting the glucose molecule, forming two pyruvates and two ATP. But there are actually a bunch of intermediate steps along the way.

One of the intermediate steps of glycolysis forms glyceraldehyde-3 phosphate, which can spontaneously form methylglyoxal (MGO). Methylglyoxal is a ‘key precursor of the AGEs’. [ref]

Why are AGEs a problem?

The body has a hard time getting rid of advanced glycation end products. When a protein is bound to a carbohydrate, its structure is altered in such a way that the enzymes that would normally act on the protein can no longer break it down. Thus, the altered proteins can build up in the body. [ref]

Getting rid of AGEs is especially a problem in collagen and elastin, which have a slow turnover rate. It is also a problem when glycated proteins cross-link and form large proteins. The proteins have to be eliminated, mainly through the kidneys.

Another reason that AGEs are a problem is that they can stimulate the AGE receptor (known as RAGE), which signals for a cascade of inflammatory events.[ref]

Three problems with AGES: 1) they can build up because they are hard to eliminate; 2) they trigger inflammation through their receptor; 3) they cause protein structure to be altered.

AGEs as a causal factor of aging.

If you consider aging a disease, then it makes sense to look for the causes of that disease called aging. In general, aging usually involves a loss of fitness – low muscle mass, easy injuries, increased risk of chronic diseases. These all tie together with the increased cellular damage that happens over time. This accumulated cellular damage then causes a bunch of problems — including excess AGEs.[ref]

It can be argued that one of the causal factors of aging is your body accumulating more and more advanced glycation end products. AGEs = Aging. [ref]

For example, I mentioned AGEs forming in collagen above… Collagen is a protein that is an abundant component of bones, ligaments, skin, and muscles.

When AGEs accumulate in the collagen proteins in joints, muscles, and bone, they play a role in causing arthritis, muscle loss, and osteoporosis. All are associated with both aging and higher levels of AGEs.[ref]

The cross-linked proteins, such as in collagen in a tendon, can increase stiffness and make it more prone to tearing. Think about the problems of a twisted ankle with a tendon tear when older vs when you were a kid.[ref]

This increased cross-linking in AGEs also shows up in the skin. As AGEs increase with age, you get wrinkles, thinner skin. and less elasticity.[ref]

What causes excess AGEs in the body?

More AGEs are produced under conditions of oxidative stress. When too many reactive oxygen species (ROS) are present in a cell, it causes oxidative stress. Not only does this trigger the body’s antioxidant defenses to be produced, but the excess ROS can also escalate the production of the precursors for AGEs. This happens through increased lipid peroxidation and glycoxidation reactions, which causes more of the reactive products (like methylglyoxal) that bind with proteins to form AGEs.[ref]

More AGEs are also produced when blood sugar levels are high. Diabetes is a disease of high blood glucose levels. This excess of glucose makes it more available and thus likely for AGEs to form.  A lot of the complications of diabetes, such as cardiovascular disease, retina problems, and kidney problems, are actually caused by the accumulation of AGES.[ref]

Preventing the formation of AGEs in the body:

The glucose metabolites that react to form AGEs can be stopped by multiple ways in the body. In fact, the body naturally has several ways to combat AGEs, and the key is to promote this along with decreasing production.

The enzymes glyoxalase I and II are tasked by the body to break down methylglyoxal, one of the main precursors for the production of AGEs in the body. Methylglyoxal can be formed as a side-product during glycolysis.

Decreased levels of glyoxalase I (GLO1 gene) are associated with higher AGEs in the plasma of hemodialysis patients. Another study found that upregulating the GLO1 gene (animal study) prevented AGEs formation in the presence of high blood glucose levels.[ref]

What does it take to make glyoxalase? Glutathione, one of the body’s main antioxidants, is a cofactor of glyoxalase. Low levels of glutathione can reduce the activity of glyoxalase 1.[ref]

Taking this one step further, the Nrf2 pathway stimulates glutathione production in the cells. It has been shown in recent studies that activating the Nrf2 pathway can stop the formation of AGEs by eliminating methylglyoxal.[ref]

Often when thinking of advance glycation end products the mind jumps to the idea that eating sugar is entirely to blame: Glycolysis is a glucose-based pathway, and the side-products of glycolysis (especially methylglyoxal) increase AGEs. High levels of glucose in the blood do increase AGEs. But one of the ketone bodies formed when eating a low-carb diet is acetone, and acetone can also be converted using the CYP2E1 enzyme into methylglyoxal.[ref][ref]

AGEs and RAGEs…

Essentially, we have two things going on here with AGEs.

First, we don’t want a build-up of AGEs in general. They are hard for the body to get rid of, and they are making my skin look old. In a general sense, we can prevent this by keeping glucose levels low and boosting glyoxalase.

Second, we don’t want a lot of AGEs to bind with the receptor for advanced glycation end products (RAGE), which causes inflammation. (more below on this…)

Genetics comes into play here, with some people having more of a problem with this than others. In other words, some people who have genetic variants in the receptor for AGEs are going to be more susceptible to the negative consequences of AGEs.

RAGEs:

RAGE stands for the receptor for advanced glycation end-products. It is coded for by AGER gene. When AGEs bind to the receptor, it triggers inflammation.

RAGEs are called a multi-ligand receptor, which means that multiple molecules can bind to it. They are located on the cell membrane in a bunch of different cell types including endothelial cells, immune system cells, muscle cells, and neurons.

RAGEs and Inflammation:

When AGEs (or another molecule) activate a RAGE receptor on the cell membrane, it transmits a signal that increases the body’s immune response. For example, in endothelial cells, which line the blood vessels, activation of the RAGE receptors causes the expression of the proinflammatory cytokines IL-1a, IL-6, and TNF-alpha. It also causes the formation of proteins needed for clotting, vasoconstriction, and cellular adhesion. [ref] This all adds up to inflammation in the blood vessels, higher blood pressure, and cardiovascular disease.

Diseases associated with RAGE activation include “inflammatory diseases, rheumatic or autoimmune diseases, infectious diseases, diabetes, metabolic syndrome and its complications, obesity, insulin resistance, hypertension, atherosclerosis, neurological diseases such as Alzheimer’s disease, cardiovascular diseases, pulmonary diseases such as chronic obstructive pulmonary disease (COPD), and cancer.” [ref]  (Yes, that is pretty much every chronic disease that I can think of — and all are associated with aging.)

Activation of RAGE (cell membrane receptor) causes an increase in reactive oxygen species as well as the increase in inflammatory cytokines.  It also downregulates the cholesterol transporters, ABCA1 and ABCG1. This is important in neurodegenerative diseases. [ref]

RAGEs and Glyoxalase-1 interact:

As I talked about above, the enzyme glyoxalase breaks down one of the precursors for AGEs (methylglyoxal). Researchers have found that the receptor for advanced glycation end products also regulates glyoxalase. In animal studies, when the researchers delete the RAGE gene (AGER gene), the animals no longer accumulate methylglyoxal. [ref]

RAGEs in Alzheimer’s:

I mentioned above that RAGE is a multi-ligand receptor, which just means that there are multiple molecules that can bind to it. In addition to AGEs, amyloid-beta is another molecule that can bind to RAGE. Amyloid-beta is produced in the brain, and the accumulation is one of the hallmarks of Alzheimer’s disease.

The inflammatory signaling from binding with RAGE exacerbates the neurodegeneration in Alzheimer’s disease. Glyoxalase 1 is initially upregulated in the early stages of Alzheimer’s. But eventually, due to glutathione depletion, the overall activity of glyoxalase 1 is reduced. [ref]

Soluble RAGEs:

There are two forms of RAGE, a soluble and a full-length form that is the receptor on the cell membrane. In contrast to the membrane receptor form, the soluble form of RAGE doesn’t signal for inflammation. It is thought that soluble RAGE acts as a decoy receptor and is protective against the accumulation of amyloid-beta [ref][ref]

One example of how soluble RAGE acts to decrease AGEs can be found in osteoarthritis. People with osteoarthritis have significantly lower levels of soluble RAGE in their synovial fluid (fluid in the joint). [ref]

Basically, you want more of the soluble form of RAGE. If soluble RAGE is floating around, it can bind with AGEs (or other molecules) and prevent them from binding to the RAGE receptor that is on the cell membrane which activates inflammation.

 


Genetic variants that impact RAGEs:

AGER gene: codes for the receptor for AGEs

Check your genetic data for G82S  rs2070600 (23andMe v5; AncestryDNA):

  • C/C: normal risk
  • C/T: decreased soluble RAGE; increased risk of Alzheimer’s disease; increased risk of diabetic retinopathy with diabetes; increased risk of RA;
  • T/T: significantly decreased soluble RAGE [ref][ref]; increased risk of Alzheimer’s disease [ref]; increased risk of diabetic retinopathy with diabetes[ref]; higher levels of insulin resistance, TNF-alpha, and CRP; increased risk of rheumatoid arthirits[ref]

Check your genetic data for rs1800624  -374T>A (23andMe v4, v5; AncestryDNA):

  • A/A: normal risk
  • A/T: increased AGER expression (Increased RAGE);[ref] increased risk of several types of cancer[ref]; increased risk of cardiovascular disease in Caucasians with T2D
  • T/T: *increased AGER expression (Increased RAGE);[ref] increased risk of several types of cancer[ref]; increased risk of cardiovascular disease in Caucasians with T2D [ref]

*Given in the plus orientation to match 23andMe, AncestryDNA

Check your genetic data for rs184003 1704G>T (23andMe v5; AncestryDNA):

  • C/C: normal
  • A/C: slightly increased risk of diabetes, increased risk of diabetic retinopathy in people with diabetes; increased risk of coronary artery disease;
  • A/A: slightly increased risk of diabetes, increased risk of diabetic retinopathy in people with diabete[ref]; increased risk of coronary artery disease [ref]

GLO1 gene: codes for glyoxalase I enzyme.

Check your genetic data for rs1130534 (23andMe v5):

  • A/A: decreased enzyme activity [ref]; increased risk of retinitis pigmentosa [ref]
  • A/T: decreased enzyme activity [ref]; increased risk of retinitis pigmentosa [ref]
  • T/T: *normal

*Given in the plus orientation to match 23andMe, AncestryDNA

 


Lifehacks:

The big question here is…

How do you lower advanced glycation end products?

There are several ways to decrease AGEs both through the way that you cook your food, balancing your blood glucose levels, and boosting your body’s natural detoxification system.

Also… never smoke. Tobacco smoke increases AGEs in the lining of the arteries, LDL cholesterol, the lens of the eye, and collagen in the skin. Basically, one reason smoking causes wrinkles, high blood pressure, and cataracts is due to increased AGEs.  Second-hand smoke is also a problem. [ref][ref]

Dietary choices to decrease consumption of AGEs:

Foods that are high in AGEs include meats cooked with high, dry heat. Going beyond steak or grilled chicken, AGEs also form in any food that contains proteins and fats and is browned. Cheese also contains higher levels of AGEs.  One study explains that the ‘order of dietary AGEs levels in foods is found to be beef>cheeses>poultry>pork>fish>eggs’. Lower amounts of AGEs are found in uncooked foods and cooked fruits, vegetables, and whole grains. Milk is also low in AGEs (but cheese is high).  In addition to broiled meats, oils that are heated to a high temperature and roasted nuts are also high in AGEs. [ref]

Studies show that AGEs are partially absorbed in the intestines from foods at a rate of 10 – 30%. The studies, though, are only looking at some of the AGEs in foods because it is difficult to figure detect and quantify all of the different types. [ref]

Carbohydrates generally contain the lowest amount of AGEs [ref]. But… carbs also tend to increase blood glucose levels the most. Finding a balance between foods that are low in AGEs yet don’t spike your glucose levels is important.

Carbohydrates such as bread, though, that are heated to the point of browning have higher AGEs in the browned portion (the crust).[ref] Perhaps those picky kids who don’t eat the crust on bread actually have the right idea.

If you are a soda drinker, the types of soda with caramel additives (brown sodas, like Pepsi and Coke) have higher levels of AGE precursors than clear sodas (like Sprite).[ref]

Putting this into practice:

  • Cut back on the grilled meat and foods cooked at high heat.
  • Swap out some of your grilled recipes for crockpot (low and slow) recipes.
  • Eat more vegetables, cooked or raw.
  • Decrease or eliminate fried foods, and don’t go overboard on roasted nuts.
  • Combine your grilled or pan-fried meats with foods high in polyphenols (e.g. have some Broccoli slaw alongside your BBQ).
  • Consider sous-vide for your steaks? Or perhaps the reverse sear method (and go light on the sear!)

Polyphenols and supplements that block the formation of AGEs:

Just as there are different types of AGEs, different natural compounds that block the formation of specific AGEs in the body. Your best bet may be to stack multiple ways of blocking the formation of AGEs in the body — along with a diet that is low in AGES.

Berberine is a plant-based supplement that is known for lowering blood glucose levels.  It has been shown in animal studies to inhibit AGEs formation. [ref]  You can get berberine on Amazon or at your local health food store.  Note that is may also reduce blood pressure a bit – something to keep in mind if you are already on medication for high blood pressure.

Quercetin is a natural compound found in fruits and vegetables. It has been shown in animal studies and cell studies to decrease the formation of AGEs. [ref]  Quercetin has also been shown in animal studies to increase GLO1 (glyoxalase 1) levels and also increase glutathione levels.[ref] You can get quercetin as a supplement in addition to consuming it in foods. Studies show that quercetin is not all that well absorbed as a supplement, but adding a little fat to it may help absorption.[ref]

Resveratrol decrease RAGE expression in diabetic rats. [ref]  It also helps decrease AGE accumulation in diabetic rats.[ref]  The dosages of resveratrol were higher than what you can get from drinking wine… (I know that you were thinking that you would just have some wine alongside your grilled steak.) It is available as a supplement. Note that it can also decrease blood pressure.

NAD+ boosters, such as nicotinamide riboside (NR) and NMN, may protect against the damage caused by AGEs.[ref]  You can read all about NAD+, genetics, and why I think it is important here. And you can get NR (combined with resveratrol) or NMN on Amazon or at other health food stores.

Glutathione is a cofactor of glyoxalase 1. Your body naturally produces glutathione as an antioxidant. You can get it as a supplement or work on activating the Nrf2 pathway.

Sulforaphane, which is found in broccoli sprouts and cruciferous vegetables, has been shown to reduce the production of advanced glycation end products. [ref] You can get high levels of sulforaphane from growing broccoli sprouts or via a supplement.

Aspirin reduces RAGEs. This may be one way that low dose aspirin is protective against heart disease. [ref][ref][ref]  If you have questions or concerns about aspirin, talk with your doctor.

Curcumin and Gingerol have been shown in a mouse study to decrease the effects of AGEs in muscle cells. Curcumin works through trapping methylglyoxal.[ref][ref] Eat your curry with some ginger?

Hesperidin is a flavonoid found in citrus fruits that can help upregulate glyoxalase 1. It does this by activating the Nrf2 pathway. [ref] You can get hesperidin as a supplement.

Exercise?

Studies in rats show that exercise helps to decrease AGEs in old rats. But the human studies show conflicting results on whether exercise is beneficial or not for AGEs. [ref]  Some studies show that staying active, in general, is correlated with lower AGEs. [ref]

Sleep Well!

Perhaps as important as eating a diet with healthy vegetables is sleeping well.  Getting adequate sleep was shown in a study of Japanese adults found that sleep deprivation may increase the formation of AGEs.[ref]

Men with sleep apnea have higher circulating levels of AGEs and insulin resistance. [ref] And sleep apnea also increases RAGE.[ref]

 

References:

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Baig, M. H., Jan, A. T., Rabbani, G., Ahmad, K., Ashraf, J. M., Kim, T., … Choi, I. (2017). Methylglyoxal and Advanced Glycation End products: Insight of the regulatory machinery affecting the myogenic program and of its modulation by natural compounds. Scientific Reports, 7(1), 5916. https://doi.org/10.1038/s41598-017-06067-5
Chaudhuri, J., Bains, Y., Guha, S., Kahn, A., Hall, D., Bose, N., … Kapahi, P. (2018). The role of advanced glycation end products in aging and metabolic diseases: Bridging association and causality. Cell Metabolism, 28(3), 337–352. https://doi.org/10.1016/j.cmet.2018.08.014
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Chen, Y.-J., Kong, L., Tang, Z.-Z., Zhang, Y.-M., Liu, Y., Wang, T.-Y., & Liu, Y.-W. (2019). Hesperetin ameliorates diabetic nephropathy in rats by activating Nrf2/ARE/glyoxalase 1 pathway. Biomedicine & Pharmacotherapy, 111, 1166–1175. https://doi.org/10.1016/j.biopha.2019.01.030
Daborg, J., von Otter, M., Sjölander, A., Nilsson, S., Minthon, L., Gustafson, D. R., … Zetterberg, H. (2010a). Association of the RAGE G82S polymorphism with Alzheimer’s disease. Journal of Neural Transmission, 117(7), 861–867. https://doi.org/10.1007/s00702-010-0437-0
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Nishimoto, S., Koike, S., Inoue, N., Suzuki, T., & Ogasawara, Y. (2017). Activation of Nrf2 attenuates carbonyl stress induced by methylglyoxal in human neuroblastoma cells: Increase in GSH levels is a critical event for the detoxification mechanism. Biochemical and Biophysical Research Communications, 483(2), 874–879. https://doi.org/10.1016/j.bbrc.2017.01.024
Patel, S. H., Yue, F., Saw, S. K., Foguth, R., Cannon, J. R., Shannahan, J. H., … Carroll, C. C. (2019). Advanced Glycation End-Products Suppress Mitochondrial Function and Proliferative Capacity of Achilles Tendon-Derived Fibroblasts. Scientific Reports, 9. https://doi.org/10.1038/s41598-019-49062-8
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Restless Leg and Periodic Limb Movement Disorder: Genetics and Solutions

Twitchy legs, restless sleep…  That urge to move your legs at night or being woken up with your leg moving rhythmically — both take a toll on sleep quality. And good sleep is foundational for overall health and wellbeing.

I’m going to dive into the genetics of restless leg syndrome and periodic limb movement disorder to show how the root cause can affect the treatment options.  No magic bullet cures here… but perhaps some options that you haven’t yet tried.

RLS and PLMD

Restless leg syndrome (RLS) is characterized by a feeling that you have to move your legs, usually at night when you are in bed. In some people it can also affect the need to move the arms also.  Restless leg is estimated to affect between 4 and 14% of adults.  It is most prevalent in older women, but it can affect both men and women at any age.

Periodic Limb Movement Disorder (PLMD)  causes repetitive jerking motions in the foot/leg or in the hands/arm. In contrast to RLS, PLMD is more prevalent in men than women.[ref]  PLMD is also called or Periodic Limb Movements in Sleep (PLMS).

RLS and PLMD overlap for a lot of people, but they can also exist on their own. Much of the research groups the two topics together, and genetically they may have a common cause.

In a study of older men, restless leg syndrome was associated with a higher mortality rate, even when controlling for a bunch of other variables. [ref]

Is RLS genetic?

Twin studies show that there is a strong genetic element to RLS, but there are also some environmental factors that add to the risk for it.  [ref]

Often when researchers don’t really understand the root cause of a condition they will use Genome Wide Assocation Studies (GWAS) to see if they can detect which genetic variants and which genes are involved.  It is an approach that takes away any preconceived notions of why a disease occurs, but it can also at times give red-herrings.

In 2007, genome-wide studies found that the BTBD9 and MEIS1 genes were linked with an increased risk of both restless leg syndrome and periodic limb movement disorder.  [ref][ref]  Numerous studies have been conducted since then in an effort to replicate the findings and figure out why those two genes are so important to RLS and PLMD.

Why these genes?

Almost all the studies agree that BTBD9 and MEIS1 are important in restless leg and periodic limb movement disorder, but the question for many researchers is ‘why?”

MEIS1 gene function:

The MEIS1 gene codes for a homeobox protein that is involved in turning on and off genes during the development of a fetus – specifically in the development of the limbs. It also is thought to be involved in neurodevelopment and is expressed in the substantia nigra – the region of the brain involved in dopamine production. MEIS1 is also thought to be involved in the formation of blood cells. [ref]

The susbstantia nigra is the region of the brain that causes the dopamine-related issues in Parkinson’s disease. This is important in RLS and PLMD because the prescription medications that are often used are Parkinson’s medications.

People with Parkinson’s are at an elevated risk of also having RLS. [ref] But is restless leg a precursor or predictor of Parkinson’s disease? The research doesn’t really show that, but there are a lot of confounders, such as disturbed circadian rhythm and dopaminergic medication intake, in trying to figure this out.[ref]

Interestingly, MEIS1 mice that have only half of the normal gene function are restless and move a lot more (16% more) as normal mice. The mice weren’t anxious, they just moved more, traveled longer distances, and were a little speedier.[ref]

Other studies show that decreased MEIS1 causes changes to the cholinergic neurons in the region of the brain that controls voluntary movement (striatum). [ref]

BTBD9 gene function: 

The BTBD9 gene codes for a protein “which modulates transcription, cytoskeletal arrangement, ion conductance and protein ubiquitination”. Let me break that down a little bit…

If you delete the BTBD9 gene, it alters neurotransmission in the animal. A recent study shows that mice without the BTBD9 gene had enhanced brain activity in the striatum, which is part of the basal ganglia which controls voluntary movement.  The neurons in this area are mostly dopaminergic neurons that contain either dopamine 1 receptors or dopamine 2 receptors. (See my article on dopamine receptors for more info). The study showed that lacking BTBD9 caused enhanced activity and excitability in these dopaminergic neurons in the striatum. Of note, these are calcium-dependent neurons that are inhibited by GABA. These mice without BTBD9 were more active when they should be resting, had disturbed sleep, and were more sensitive to temperature.[ref]

To sum up – increased excitability in the neurons that control movement when there isn’t enough BTBD9.  This caused more activity when the mice should be sleeping — and don’t forget the thermal sensitivity…

Human brain imaging studies:

Is there anything different about the brains of people with RLS or PLMD?

MRI, PET scans, and SPECT scans have all been done to look at the brains of people with RLS.  Some people (but not all) with RLS have lower iron stores that show up on MRI’s. Many of the other studies were inconclusive or had contradictory results. A study that looked at the results of several different types of brain scans came to the conclusion that there could be an evening and night time dopamine deficit in the striatum due to increased daytime receptor function. [ref] There is an overall circadian rhythm to dopamine production, and it is naturally lower at night and higher during the daytime.

Iron and RLS:

A number of studies point to low iron in the brain being a contributing factor in some people with RLS.  This is based on studies that show that people with RLS are more likely to have low cerebrospinal fluid ferritin.  Most studies, though, show that serum ferritin levels don’t differ in people with RLS. [ref]

Not everyone with restless leg has low iron levels. Researchers have investigated to see if genetic variants that cause high iron (HFE gene) are protective against RLS, but the conclusion was that the mutations that give people high iron levels are not protective against restless leg.[ref]

Thus, while iron may be part of the picture for RLS, it isn’t the whole story by far.

Dopamine and RLS:

In addition to the genetic connections with dopaminergic neuron function, there are a couple of other things that point to dopamine being really important in RLS and PLMD.

Commonly, doctors will treat RLS and PLMD with dopamine agonist medications that are traditionally used for Parkinson’s disease (a low dopamine disease).  These medications are effective for some people, but they come with side effects. For example, Sinemet is a dopamine agonist often prescribed with a long list of side effects.

Too much dopamine in the brain can cause psychosis, and atypical antipsychotic drugs block the dopamine receptors.  It turns out that a side effect of some of the atypical antipsychotics is that they can cause or aggravate RLS. [ref]


Genetic variants linked to RLS and PLMD:

MEIS1 gene:

Check your genetic data for rs2300478 (23andMe v4, v5; AncestryDNA):

  • G/G: greater than 1.7x risk of RLS, increased sympathovagal balance during N3 sleep stage[ref][ref]; increased risk of PLMD [ref] low MEIS1 gene expression[ref]
  • G/T: 1.7x risk of RLS, increased risk of PLMD
  • T/T: normal risk of RLS

Check your genetic data for rs12469063 (AncestryDNA only):

  • G/G: increased risk of PLMD [ref]; increased risk of RLS[ref] low MEIS1 gene expression[ref]
  • A/G: somewhat increased risk of PLMD and RLS;
  • A/A: normal risk of RLS, PLMD

 

BTBD9 gene:

Check your genetic data for rs3923809:  (23andMe v4, v5; AncestryDNA):

  • A/A: increased risk of PLMD [ref]; increased risk of RLS [ref]1.9x risk of PLMD without RLS, serum ferritin levels decreased  26%  [ref]
  • A/G: somewhat increased risk of RLS and PLMD, serum ferritin levels decreased 13%
  • G/G: normal risk of RLS

Check your genetic data for rs9357271 (23andMe v4, v5; AncestryDNA):

  • C/C: lower risk (<0.63) of RLS  [ref]
  • C/T: slightly lower risk of RLS
  • T/T: normal risk of RLS; increase PLMD risk[ref]

PTPRD gene

Check your genetic data for rs1975197 (23andMe v4, v5; AncestryDNA):

  • A/A: increased (1.8x) risk of RLS  [ref]; increased risk of PLMD [ref]
  • A/G: increased risk of RLS and PLMD
  • G/G: normal risk of RLS

MAP2K5 gene:

Check your genetic data for rs6494696 (23andMe v4; AncestryDNA):

  • G/G: increased risk of PLMD (most common allele) [ref]
  • C/G: decreased risk of RLS
  • C/C: decreased risk of RLS [ref]

GABA Receptors:

A study of patients with restless leg found that GABA receptor variants may affect restless leg syndrome. GABA is the main inhibitory neurotransmitter — it keeps the neurons from being overexcited.[ref]

Check your genetic data for rs2229940 (23andMe v4, v5; AncestryDNA):

  • G/G: normal
  • G/T: earlier age of onset for RLS
  • T/T: earlier age of onset for RLS[ref]  (also, faster motor reaction times [ref])

Lifehacks:

Iron: There is a statistical link between low iron (in the brain) and restless leg syndrome. And a subset of RLS patients improved with additional iron. Before you start supplementing with iron, you really need to do a blood test to see what your iron levels are. Iron is definitely one mineral you don’t want to go overboard with!  Talk with your doctor about getting an iron panel run – or order one yourself through UltaLab Tests or another online lab test ordering service.  If you do order your own lab tests, check around for coupon codes and specials. For example, on UltaLab Tests, if you wait a minute on the page they usually pop up a coupon.

According to the MayoClinic, all you need to do is take a warm bath, have good sleep habits, get some daily exercise, and cut back on caffeine…  (not sure how helpful that advice will be for you).

Acupuncture: A randomized-controlled trial of acupuncture plus gabapentin vs gabapentin alon found that sleep quality increased for those people getting acupuncture with their gabapentin. [ref]  Another study of acupuncture alone concluded that it ‘might help’, but the data doesn’t show a lot of improvement. [ref]

l-dopa: A small trial of l-dopa for RLS/PLMD in children with ADHD, l-dopa was found to improve restless leg syndrome. [ref] It also has been shown to help with RLS in people with chronic kidney disease. [ref]

You can get l-dopa in an herbal form by taking mucuna pruriens, which is an herbal supplement high in l-dopa. It is available on Amazon or at your local health food store. There aren’t any studies that I can find on using mucuna pruriens for RLS.  Here is the Examine.com article on mucuna pruriens, if you want to read more about it.

Magnesium: A small study found that magnesium supplement before bed cut the incidence of PLMD in half.  [ref]

Hypoxia – low oxygen: There are several studies pointing to peripheral hypoxia (low oxygen in the legs, arms) as being a contributing factor in RLS and PLMD. One study found that PLMD symptoms were worsened by sleeping at high altitude. [ref] Another study found poor endothelial function in people with RLS.[ref] And another study found lower oxygen levels just in the legs of patients with RLS.

Exercise may help with low oxygen levels in the legs. A recent study on a small group of patients with both restless leg and peripheral artery disease found that frequent, low-intensity exercise helped reduce symptoms. [ref] Other studies also point to exercise (possibly) helping with restless leg. [ref]  Yoga was shown in one small (10 people) study to help with restless leg symptoms. [ref]

Whole-body vibration: A study tested whether blood flow would be increased using whole-body vibration. The results showed that skin blood flow in the legs did not increase — but that whole-body vibration did help with RLS. [ref]

References:

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Bollu, P. C., Yelam, A., & Thakkar, M. M. (2018). Sleep Medicine: Restless Legs Syndrome. Missouri Medicine, 115(4), 380–387.
Ferini-Strambi, L., Carli, G., Casoni, F., & Galbiati, A. (2018). Restless Legs Syndrome and Parkinson Disease: A Causal Relationship Between the Two Disorders? Frontiers in Neurology, 9. https://doi.org/10.3389/fneur.2018.00551
Li, Y., Wang, W., Winkelman, J. W., Malhotra, A., Ma, J., & Gao, X. (2013). Prospective study of restless legs syndrome and mortality among men. Neurology, 81(1), 52–59. https://doi.org/10.1212/WNL.0b013e318297eee0
Rizzo, G., Li, X., Galantucci, S., Filippi, M., & Cho, Y. W. (2017). Brain imaging and networks in restless legs syndrome. Sleep Medicine, 31, 39–48. https://doi.org/10.1016/j.sleep.2016.07.018
Sarayloo, F., Dion, P. A., & Rouleau, G. A. (2019a). MEIS1 and Restless Legs Syndrome: A Comprehensive Review. Frontiers in Neurology, 10. https://doi.org/10.3389/fneur.2019.00935
Sarayloo, F., Dion, P. A., & Rouleau, G. A. (2019b). MEIS1 and Restless Legs Syndrome: A Comprehensive Review. Frontiers in Neurology, 10. https://doi.org/10.3389/fneur.2019.00935
The Role of BTBD9 in Striatum and Restless Legs Syndrome. (n.d.). Retrieved November 7, 2019, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787346/
Ylikoski, A., Martikainen, K., & Partinen, M. (2015). Parkinson’s disease and restless legs syndrome. European Neurology, 73(3–4), 212–219. https://doi.org/10.1159/000375493
Aggarwal, Shilpa, et al. “Restless Leg Syndrome Associated with Atypical Antipsychotics: Current Status, Pathophysiology, and Clinical Implications.” Current Drug Safety, vol. 10, no. 2, 2015, pp. 98–105.
Bollu, Pradeep C., et al. “Sleep Medicine: Restless Legs Syndrome.” Missouri Medicine, vol. 115, no. 4, 2018, pp. 380–87.
Connor, James R., et al. “Iron and Restless Legs Syndrome: Treatment, Genetics and Pathophysiology.” Sleep Medicine, vol. 31, 2017, pp. 61–70. PubMed, doi:10.1016/j.sleep.2016.07.028.
England, Sandra J., et al. “L-Dopa Improves Restless Legs Syndrome and Periodic Limb Movements in Sleep but Not Attention-Deficit-Hyperactivity Disorder in a Double-Blind Trial in Children.” Sleep Medicine, vol. 12, no. 5, May 2011, pp. 471–77. PubMed, doi:10.1016/j.sleep.2011.01.008.
García-Martín, Elena, et al. “Missense Gamma-Aminobutyric Acid Receptor Polymorphisms Are Associated with Reaction Time, Motor Time, and Ethanol Effects in Vivo.” Frontiers in Cellular Neuroscience, vol. 12, Jan. 2018. PubMed Central, doi:10.3389/fncel.2018.00010.
Haba-Rubio, José, et al. “Prevalence and Determinants of Periodic Limb Movements in the General Population.” Annals of Neurology, vol. 79, no. 3, Mar. 2016, pp. 464–74. PubMed, doi:10.1002/ana.24593.
Hornyak, M., et al. “Magnesium Therapy for Periodic Leg Movements-Related Insomnia and Restless Legs Syndrome: An Open Pilot Study.” Sleep, vol. 21, no. 5, Aug. 1998, pp. 501–05. PubMed, doi:10.1093/sleep/21.5.501.
Innes, Kim E., et al. “Efficacy of an Eight-Week Yoga Intervention on Symptoms of Restless Legs Syndrome (RLS): A Pilot Study.” Journal of Alternative and Complementary Medicine (New York, N.Y.), vol. 19, no. 6, June 2013, pp. 527–35. PubMed, doi:10.1089/acm.2012.0330.
Jiménez-Jiménez, Félix Javier, et al. “Gamma-Aminobutyric Acid (GABA) Receptors Genes Polymorphisms and Risk for Restless Legs Syndrome.” The Pharmacogenomics Journal, vol. 18, no. 4, 2018, pp. 565–77. PubMed, doi:10.1038/s41397-018-0023-7.
—. “Gamma-Aminobutyric Acid (GABA) Receptors Genes Polymorphisms and Risk for Restless Legs Syndrome.” The Pharmacogenomics Journal, vol. 18, no. 4, 2018, pp. 565–77. PubMed, doi:10.1038/s41397-018-0023-7.
Kemlink, D., et al. “Replication of Restless Legs Syndrome Loci in Three European Populations.” Journal of Medical Genetics, vol. 46, no. 5, May 2009, pp. 315–18. PubMed, doi:10.1136/jmg.2008.062992.
Kim, Min Seung, et al. “Impaired Endothelial Function May Predict Treatment Response in Restless Legs Syndrome.” Journal of Neural Transmission (Vienna, Austria: 1996), vol. 126, no. 8, Aug. 2019, pp. 1051–59. PubMed, doi:10.1007/s00702-019-02031-x.
Lamberti, Nicola, et al. “Restless Leg Syndrome in Peripheral Artery Disease: Prevalence among Patients with Claudication and Benefits from Low-Intensity Exercise.” Journal of Clinical Medicine, vol. 8, no. 9, Sept. 2019. PubMed Central, doi:10.3390/jcm8091403.
Lyu, Shangru, et al. “The Role of BTBD9 in Striatum and Restless Legs Syndrome.” ENeuro, vol. 6, no. 5, Oct. 2019. PubMed Central, doi:10.1523/ENEURO.0277-19.2019.
Mitchell, Ulrike H., et al. “Decreased Symptoms without Augmented Skin Blood Flow in Subjects with RLS/WED after Vibration Treatment.” Journal of Clinical Sleep Medicine: JCSM: Official Publication of the American Academy of Sleep Medicine, vol. 12, no. 7, 15 2016, pp. 947–52. PubMed, doi:10.5664/jcsm.5920.
Moore, Hyatt, et al. “Periodic Leg Movements during Sleep Are Associated with Polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD.” Sleep, vol. 37, no. 9, Sept. 2014, pp. 1535–42. PubMed Central, doi:10.5665/sleep.4006.
—. “Periodic Leg Movements during Sleep Are Associated with Polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD.” Sleep, vol. 37, no. 9, Sept. 2014, pp. 1535–42. PubMed Central, doi:10.5665/sleep.4006.
—. “Periodic Leg Movements during Sleep Are Associated with Polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD.” Sleep, vol. 37, no. 9, Sept. 2014, pp. 1535–42. PubMed, doi:10.5665/sleep.4006.
—. “Periodic Leg Movements during Sleep Are Associated with Polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD.” Sleep, vol. 37, no. 9, Sept. 2014, pp. 1535–42. PubMed Central, doi:10.5665/sleep.4006.
Raissi, Gholam Reza, et al. “Evaluation of Acupuncture in the Treatment of Restless Legs Syndrome: A Randomized Controlled Trial.” Journal of Acupuncture and Meridian Studies, vol. 10, no. 5, Oct. 2017, pp. 346–50. PubMed, doi:10.1016/j.jams.2017.08.004.
Rizzo, Giovanni, et al. “Brain Imaging and Networks in Restless Legs Syndrome.” Sleep Medicine, vol. 31, Mar. 2017, pp. 39–48. PubMed Central, doi:10.1016/j.sleep.2016.07.018.
Sarayloo, Faezeh, et al. “MEIS1 and Restless Legs Syndrome: A Comprehensive Review.” Frontiers in Neurology, vol. 10, Aug. 2019. PubMed Central, doi:10.3389/fneur.2019.00935.
—. “MEIS1 and Restless Legs Syndrome: A Comprehensive Review.” Frontiers in Neurology, vol. 10, Aug. 2019. PubMed Central, doi:10.3389/fneur.2019.00935.
—. “MEIS1 and Restless Legs Syndrome: A Comprehensive Review.” Frontiers in Neurology, vol. 10, Aug. 2019. PubMed Central, doi:10.3389/fneur.2019.00935.
Song, Yuan-Yuan, et al. “Effects of Exercise Training on Restless Legs Syndrome, Depression, Sleep Quality, and Fatigue Among Hemodialysis Patients: A Systematic Review and Meta-Analysis.” Journal of Pain and Symptom Management, vol. 55, no. 4, 2018, pp. 1184–95. PubMed, doi:10.1016/j.jpainsymman.2017.12.472.
Stefani, Ambra, et al. “Influence of High Altitude on Periodic Leg Movements during Sleep in Individuals with Restless Legs Syndrome and Healthy Controls: A Pilot Study.” Sleep Medicine, vol. 29, Jan. 2017, pp. 88–89. ScienceDirect, doi:10.1016/j.sleep.2016.06.037.
Stefansson, Hreinn, et al. “A Genetic Risk Factor for Periodic Limb Movements in Sleep.” The New England Journal of Medicine, vol. 357, no. 7, Aug. 2007, pp. 639–47. PubMed, doi:10.1056/NEJMoa072743.
—. “A Genetic Risk Factor for Periodic Limb Movements in Sleep.” New England Journal of Medicine, vol. 357, no. 7, Aug. 2007, pp. 639–47. Taylor and Francis+NEJM, doi:10.1056/NEJMoa072743.
Thireau, Jérôme, et al. “MEIS1 Variant as a Determinant of Autonomic Imbalance in Restless Legs Syndrome.” Scientific Reports, vol. 7, 20 2017, p. 46620. PubMed, doi:10.1038/srep46620.
Trenkwalder, C., et al. “L-Dopa Therapy of Uremic and Idiopathic Restless Legs Syndrome: A Double-Blind, Crossover Trial.” Sleep, vol. 18, no. 8, Oct. 1995, pp. 681–88. PubMed, doi:10.1093/sleep/18.8.681.
Winkelmann, Juliane, et al. “Genome-Wide Association Study of Restless Legs Syndrome Identifies Common Variants in Three Genomic Regions.” Nature Genetics, vol. 39, no. 8, Aug. 2007, pp. 1000–06. PubMed, doi:10.1038/ng2099.
Xiong, Lan, et al. “MEIS1 Intronic Risk Haplotype Associated with Restless Legs Syndrome Affects Its MRNA and Protein Expression Levels.” Human Molecular Genetics, vol. 18, no. 6, Mar. 2009, pp. 1065–74. PubMed Central, doi:10.1093/hmg/ddn443.
Yang, Qinbo, et al. “Family-Based and Population-Based Association Studies Validate PTPRD as a Risk Factor for Restless Legs Syndrome.” Movement Disorders : Official Journal of the Movement Disorder Society, vol. 26, no. 3, Feb. 2011, pp. 516–19. PubMed Central, doi:10.1002/mds.23459.

Mutations common in Ashkenazi Jewish populations

How to check your genetic data for ashkenazi jewish mutations

Ashkenazi Jews are descendants of Jewish communities that were established mainly in Eastern Europe along the Rhine River around the 12th century AD. The Ashkenazi Jewish people traditionally married within their community, and genetic mutations that naturally cropped up within the population have been studied extensively.[ref]

Why are Ashkenazi Jews at a higher risk for certain genetic diseases?

People who are of Ashkenazi Jewish ancestry are at a higher risk of certain genetic diseases. This is in part due to historically marrying fairly strictly within their own community. But there is also confirmation bias involved here — a lot of the genetic mutations are known and linked with Ashkenazi ancestry due to more studies being done on the population. Other population groups that didn’t marry much outside of their community also have inherited genetic mutations, but most population groups aren’t as well studied or well known. [ref]

A word of caution:
The genetic data from 23andMe, AncestryDNA, etc. is not guaranteed to be clinically accurate (for the most part). Errors are possible…  When it comes to figuring out if I should eat more green vegetables or cut down on sugar, I don’t worry about the statistical possibility of errors in direct-to-consumer genetic testing. For something that is important, getting a clinical-grade test done before making any medical decisions is necessary.

Also keep in mind that errors are possible in the genetics research and that I could have a typo on this page (yes, I will double-check everything!). The mutations listed below are currently marked ‘pathogenic’ or ‘likely pathogenic’ in ClinVar.

This compilation of common Ashkenazi Jewish mutations only covers part of the known mutations. Additionally, people who are not of Ashkenazi Jewish ancestry can also carry these mutations (of course!).

The column labeled ‘risk allele’ contains the letter (A, C, G, T) corresponding to the nucleotide base that represents the mutation. For the most part, these are diseases that require two mutations to actually have the disease.  So what you are checking for here is to see if you carry one copy of the mutation and are thus a carrier for the disease.

List of common Ashkenazi Jewish mutations:

Disease: Gene: RS ID Risk allele: Available in:
Familial adenomatous polyposis 1 risk
(10% lifetime risk of colon cancer)
APC rs1801155 A 23andMe v4, v5; AncestryDNA [ref]
Hyperapobetalipoproteinemia (high lipid levels) LPL rs268 G 23andMe v4, v5;  AncestryDNA [ref]
Spongy degeneration of central nervous system ASPA rs28940574 A 23andMe v4, v5;  AncestryDNA [ref]
Spongy degeneration of central nervous system ASPA rs28940279 C 23andMe v4, v5;  AncestryDNA [ref]
Brugada syndrome SCN5A rs137854603 T  AncestryDNA [ref]
21-hydroxylase deficiency CYP21A2 rs6476 A 23andMe v4;  AncestryDNA [ref]
Deafness GJB2 rs72474224 T 23andMe v4;  AncestryDNA [ref]
Deafness GJB2 rs35887622 C 23andMe v5;  [ref]
Deafness GJB2 rs28931594 (i6011365) T 23andMe v4;  [ref]
Deafness GJB2 rs104894401 (i5001992) T 23andMe v4;  AncestryDNA [ref]
Deafness LOXHD1 rs75949023 T 23andMe v5;  AncestryDNA [ref]
Dihydropyrimidine dehydrogenase deficiency DPYD rs3918290 T 23andMe v4, v5;  AncestryDNA [ref]
Dyskeratosis congenita WRAP53 rs281865548 T 23andMe v5;  AncestryDNA [ref]
S-cone syndrome; Goldmann-Favre NR2E3 rs28937873 A 23andMe v4, v5;  AncestryDNA [ref]
Factor XI deficiency F11 rs121965064
(i4000399)
C 23andMe v4, v5;  AncestryDNA [ref]
Factor XI deficiency F11 rs121965063
(i4000398)
T 23andMe v4, v5;  AncestryDNA [ref]
Familial dysautonomia IKBKAP rs111033171
(i4000334)
G 23andMe v4, v5;  AncestryDNA [ref]
Familial hyperinsulinemia ABCC8 rs151344623 T 23andMe v4, v5;  [ref]
Fructose Intolerance ALDOB rs1800546 G 23andMe v4, v5;  AncestryDNA [ref]
Galactosemia GALT rs111033773 T 23andMe v4, v5;  AncestryDNA [ref]
Glycogen storage disease G6PC rs1801175
(i3002486)
T 23andMe v4;  AncestryDNA [ref]
Homocysteinuria CBS rs5742905 G 23andMe v4;   [ref]
Apolipoprteinemia MTTP rs146064714 T 23andMe v5;  AncestryDNA [ref]
Butyryl-dehydrogenase deficiency ACADS rs61732144 T 23andMe v4, v5;  AncestryDNA [ref]
Pigmented nodular adrenocortical disease PDE11A rs76308115 A 23andMe v4, v5;  AncestryDNA [ref]
Franconi anemia FANCC rs104886456
(i4000336)
A 23andMe v4, v5;  AncestryDNA [ref]
Hermansky-Pudlak HPS3 rs201227603 A 23andMe v4, v5;  AncestryDNA [ref]
Primary hyperoxaluria HOGA1 rs138207257 T 23andMe  v5;  AncestryDNA [ref]
Gait ataxia DARS2 rs142433332 C 23andMe v4, v5;  AncestryDNA [ref]
Mucolipidosis MCOLN1 rs104886461 G 23andMe v4;  AncestryDNA [ref]
Leber congenital amaurosis LCA5 rs121918165 A  23andMe v4, v5;  AncestryDNA [ref]
Retinitis pigmentosa DHDDS rs147394623 G  23andMe v5;  AncestryDNA [ref]

BRCA1 and BRCA2 mutations and Ashkenazi ancestry.

I have deliberately not included the BRCA1 and BRCA2 mutations here. 23andMe does offer information on a few of the BRCA1 and BRCA2 in their health reports, but do be aware that the report doesn’t include all of the possible mutations. In my opinion, if you have a reason to suspect a BRCA1/2 mutation, you should go with a company that offers a complete screening of those genes and talk with someone knowledgable about the mutation risk.

What does it mean to be a carrier of a genetic disease?

If you are a carrier of one copy of a mutation of an autosomal recessive genetic disease, you will usually have few symptoms of the disease. Autosomal recessive diseases (such as most of those listed above) require two copies of the mutation in order to have the disease.

Interestingly, now that so many people have done genetic testing, researchers are realizing that many genetic diseases that are caused by a single gene mutation can exhibit different phenotypes – or symptoms/traits of the disease. It isn’t quite so cut-and-dried as we learned in high school biology with Punnet squares and Mendel’s peas.

Can carriers of a mutation have symptoms?

For diseases that require two copies of the mutation, people with only one copy of the mutation usually have one functioning copy of the gene. Depending on the disease, some people with one copy of a mutation will have mild symptoms related to the mutation. This article in Nature explains how large genetic studies have shown that there is a range of symptoms for many genetic diseases, and that carriers can exhibit mild symptoms.

Another great review of this topic is from the American Journal of Human Genetics. In it, the authors explain how other genes generally modify the effects of genetic disease-causing mutations. This causes a range of phenotypes for almost all genetic diseases (except for albinism)

Take cystic fibrosis for example. A study in JAMA showed that carriers of one cystic fibrosis mutation were much more likely to have chronic rhinosinusitis. Similarly, a study in Nature showed that carriers of one cystic fibrosis mutation can sometimes be diagnosed with mild cystic fibrosis. In fact, over a quarter of mild cystic fibrosis patients only carried one copy of a mutation.

More to read:

Familial Mediterranean Fever: Often misdiagnosed!

Short-chain Acyl-CoA Dehydrogenase Deficiency

Building Up Iron: Check your genes to see how iron affects your health

 

 

Motivation to exercise? It’s genetic

A new study in the journal Behavioral Brain Research paints a fascinating picture of why some people are more motivated to exercise. The study looked at the dopaminergic system to see how people’s genetic variants could alter the ‘reinforcing value’ of exercise.

The majority of people in the US are too sedentary, and 90% of Americans don’t meet the government’s recommendation for physical activity. (In the appendix of the ‘Dietary Guidelines,’ there is a recommendation by the US Department of Health and Human Services that adults need 2 1/2 hours/week of moderate-intensity aerobic exercise and two days/week of strength training.)

According to the researchers, one factor in adhering to the guidelines is “the reinforcing value of exercise relative to a competing alternative behavior”.  In other words, would you rather exercise, or do something else…

The study looked at 178 adults (average age 27) who wore activity trackers. The participants also rated how much they liked different exercises and sedentary activities.

The researchers investigated 23 different genetic variants – ranging from FTO (obesity-related variants) to ACE (muscle/heart disease) to dopamine variants.

Study results: 

The study found four genetic variants to be related to exercise reinforcement and exercise intensity.

The first variant is related to motivation to exercise.  It is a dopamine receptor variant in the ANKK1 gene that affects the dopamine 2 receptor.  This variant is well studied in relation to addiction, weight gain, ADHD, and suicide risk (read the whole article on dopamine receptor variants).

The results showed that this dopamine related variant was involved in the reinforcement value for exercise — or, in other words, whether people felt that the reward of exercising was greater than doing other non-physical activities such as watching TV, playing video games, etc.

Check your genetic data for rs1800497 (23andMe v4, v5; AncestryDNA):

  • A/A: (DRD2*A1/A1)  lower reinforcement value for exercise.
  • A/G: (DRD2*A1/A2) normal reinforcement value for exercise
  • G/G: (DRD2*A2/A2) normal, most common;

The other three genetic variants were linked with the intensity of exercise.

The CNR1 gene codes a cannabinoid receptor variant that has also been associated in other studies with exercise tolerance.  The cannabinoid receptors are involved in pain tolerance.

Check your genetic data for rs6454672 (23andMe v4 only):

  • C/C: normal exercise tolerance
  • C/T: normal exercise tolerance
  • T/T: greater tolerance for higher intensity exercise

The LEPR gene codes for the leptin receptor.  Leptin is a hormone that signals for satiety and for energy homeostasis.

Check your genetic data for rs12405556 (23andMe v5; AncestryDNA):

  • T/T: greater tolerance for exercise intensity
  • G/T: greater tolerance for exercise intensity
  • G/G: less tolerance for exercise intensity

The GABRG3 gene codes for a GABA receptor that has been associated with exercise tolerance in previous studies. It is thought to decrease pain signaling.

Check your genetic data for rs8036270 (23andMe v4; AncestryDNA):

  • G/G: greater tolerance for exercise intensity
  • A/G: greater tolerance for exercise intensity
  • A/A: less tolerance for exercise intensity

 

Concluding thoughts:

It is always interesting to see the genetic pathways that are involved in a topic. If you would rather sit on the couch and play video games rather than working out at the gym, perhaps you can blame your dopamine receptors. And if you don’t work out hard because it hurts, well – blame your GABA or cannabinoid receptors.

Perhaps understanding the reason why you don’t want to exercise will motivate you to get beyond that and start working out more :-)

High blood pressure due to AGTR1 gene variants

Blood pressure isn’t something that you think much about – unless your doctor is harping about it being high or low.  The CDC statistics, though, make a pretty compelling argument that a lot of us should be thinking about blood pressure. The CDC estimates that about 1/3 of US adults have high blood pressure – and that it contributes to more than 410,000 deaths each in the US in a year. [ref] That is a lot…

High blood pressure has several contributing factors, and genetics is one of them.  There are quite a few genes that influence blood pressure, but I’m only going to focus on the angiotensin I receptors here.

High blood pressure (hypertension):

Researchers, doctors, public health officials, etc all seem to have different ways of defining high blood pressure. In general, the following blood pressure ranges are what are used in most studies:

Systolic (top number):
120-139mmHg ‘high normal’; over 140mmHg is considered high or hypertension

Diastolic (bottom number):
80-89 mmHg ‘high normal’ [ref]; over 90 mmHg is considered high.

The Mayo Clinic explains that high blood pressure can be due to the amount of blood pumped and the amount of resistance – or constriction – in the arteries.[ref]

Your body’s blood pressure is a tightly regulated system that depends on a lot of factors.

For some interesting reading on the topic of high blood pressure and heart disease, I recommend Dr. Malcolm Kendrick’s blog series on what causes heart disease.

Angiotensin II – a vasoconstrictor:

Angiotensin is a hormone that is part of the renin-angiotensin-aldosterone system (RAAS) of blood pressure regulation. To increase blood pressure, angiotensin II causes the blood vessels to constrict, thus upping the pressure.

Angiotensin I is a precursor hormone that is converted into angiotensin II by the ACE enzyme (angiotensin-converting enzyme). Stopping that conversion of angiotensin I into II by blocking the ACE enzyme decreases blood pressure.  ACE inhibitors are a commonly used type of blood pressure medication. (See article on ACE gene variants)

For angiotensin II to constrict blood vessels (and increase blood pressure) it must bind to its receptor. The AGTR1 gene codes for the angiotensin II receptor type-1.  Common genetic variants increase the expression of the angiotensin II receptor 1 (AGTR1) gene — thus causing blood pressure to increase when there is abundant angiotensin II.


Genetic variants:

AGTR1 gene:  Angiotensin II receptor type-1

Check your genetic data for rs5186 A1166C (23andMe v4, v5; AncestryDNA):

  • A/A: normal variant; decreased risk of chronic kidney disease [ref]
  • A/C: increased angiotensin II receptors;  increased risk of higher blood pressure[ref]
  • C/C: increased angiotensin II receptors; a 2 to 7-fold increased risk of high blood pressure[ref][ref][ref], increased risk of fatty liver, insulin resistance[ref]

Note that the increased risk of high blood pressure seems to be the greatest in Caucasian populations.  Some studies of other population groups find a smaller increase in the risk of high blood pressure[ref] or even no statistical risk. [ref]

Other studies on this variant show that the rs5186 A/C or C/C genotype is associated with:

  • an increased risk of psoriasis [ref]
  • left ventricular dysfunction (3-fold increased risk) [ref]
  • increased relative risk of endometrial cancer [ref]
  • an increased risk of metabolic syndrome in males [ref]
  • in pregnancy, an increased risk of hypertensive disorders (pre-eclampsia) [ref][ref]

Other AGTR1 genetic variants (less impactful but perhaps adding to above risk):

Check your genetic data for rs3772622 (23andMe v4, v5; AncestryDNA):

  • T/T: normal
  • C/T: increased risk of fatty liver disease in people
  • C/C:  almost 2-fold increased risk of fatty liver disease [ref], in people with cardiovascular disease[ref]

Check your genetic data for rs1492078 (23andMe v4; AncestryDNA):

  • T/T: decreased risk of kidney cancer [ref]
  • C/T: normal risk of kidney cancer
  • C/C: normal risk of kidney cancer

 


Lifehacks:

High-fat diet?  Some studies suggest that a high-fat diet, in part, increases the rs5186 impact on blood pressure. [ref] If you have high blood pressure and carry the risk allele for rs5186, try experimenting with a lower-fat diet to see if it decreases your blood pressure.

Sodium intake: You may be assuming that salt consumption would interact with this genetic variant… (I did!)  But I could only find one research study that looked at salt sensitivity and the AGTR1 gene. It showed no interaction. [ref]

Blood pressure meds: The commonly prescribed blood pressure medications losartan and valsartan act on the AGTR1 receptor, as do other angiotensin receptor blockers (ARBs).

Natural angiotensin-receptor blockers include:[ref]

*Note that you don’t want to go overboard with high doses of supplemental potassium at one time. That said, there are many studies pointing to increased potassium in the diet being very helpful for hypertension. [ref]  Here is a complete list of potassium-containing foods. 

Also, if you are on blood pressure medication, check with your doctor before adding in any of the natural supplements that lower blood pressure. The interaction could cause your blood pressure to go too low.

 

*Amazon affiliate links are not an endorsement of a specific brand, rather for you to check out available supplements and decide on the best options for yourself.

The Interaction Between BDNF and Serotonin

The more I learn about genetics, the more I appreciate how intricate and complex we humans are as a biological system. What do I mean by this? Most of the genetic variants, or SNPs, that people carry don’t have a huge impact on their own. The impact comes in the combination of gene variants — or the interaction of a variant with the environment (toxins, stress, sleep, diet, pathogens, etc).

This article digs into a combo of genetic variants that affect the way that serotonin works in the brain. A new brain imaging study shows that a combo of BDNF and serotonin receptor variants change brain function.

Let’s get into some background science and then go into how BDNF and serotonin work together.

Background on BDNF:

You may think that you only have the brain cells that you were born with.  Perhaps your parents told you this when you were a teenager to prevent you from drinking :-)

However, research now shows that you can actually add brain cells in certain areas of your brain, especially in the hippocampus. You can also increase the connections between the neurons, increasing the plasticity of the brain.

BDNF is the key to producing more neurons.

BDNF stands for brain-derived neurotrophic factor.  It is a type of protein called a neurotrophin.  BDNF works in several ways:

  • BDNF encourages new neuronal growth from stem cells
  • it protects neurons from injury and cell death
  • it improves neuronal function (important in learning and mood)

To improve the way the neurons function, BDNF binds to receptors that are located in the synapses between neurons. It helps to potentiate, or increase, the signal from one neuron to the next.

In addition to being found in the brain, BDNF is also found in the peripheral nervous system – helping muscle nerves to function well.  This connection with muscles is one way that exercise increases BDNF.

Studies on BDNF show:

  • Chronic stress causes a decrease in BDNF. [ref]
  • Low BDNF is linked to Alzheimer’s disease[ref] and Parkinson’s[ref][ref]
  • People with depression usually have lower levels of BDNF.[ref][ref][ref]
  • Mothers with postpartum or during pregnancy depression have low BDNF[ref] and elderly people with depression also have low BDNF. [ref]
  • Low BDNF is linked to obesity.[ref]

BDNF doesn’t necessarily act alone in causing diseases. It often interacts with other neurotransmitters or cytokines. For example, a recent study found that in people with schizophrenia, lower BDNF levels correlated with higher IL-2 (interleukin-2) levels.  IL-2 is an inflammatory cytokine that is part of the immune system.[ref]

BDNF Genetic Variant:

There is one really well studied genetic variant in the BDNF gene. (Literally, thousands of studies on it…) It is knowns as the Val66Met (rs6265) variant.

Check your genetic data for rs6265 (23andMe v4, v5; AncestryDNA):

  • T/T:  decreased BDNF[ref] referred to in studies as Met/Met
  • C/T: somewhat decreased BDNF, referred to as Val/Met
  • C/C: normal BDNF, referred to as Val/Val

The T allele (decreased BDNF in the brain) is linked in studies to:

  • decreased hippocampus volume if exposed to early life stress[ref]
  • altered learning and recall [ref][ref]
  • more likely to be overweight[ref]
  • increased anxiety and altered response to antidepressants [ref]
  • less likely to respond to citalopram and escitalopram (Celexa and Lexapro, antidepressants).[ref] Note that this doesn’t mean that those antidepressants absolutely won’t work, just that a larger proportion of people carrying the T allele didn’t respond compared with people carrying the C/C genotype

Not all studies show that the rs6265 T allele has an effect on depression or anxiety.[ref]  There are a lot of conflicting studies that muddy the water…  It isn’t as simple as T-allele = bad brain. 

First, there are lifestyle factors that increase or decrease BDNF (more on these in the Lifehacks section below).  Second, there are other genetic variants that are important. Such as serotonin gene variants…

Background on Serotonin:

Serotonin is often thought of as a happy neurotransmitter and is linked to feelings of wellbeing. (Serotonin does a lot of things, not just in the brain. But here I’m just focusing on its role as a brain neurotransmitter.)

Tons of research has been done showing that there is a link between serotonin and depression.  To sum up the research: depression and serotonin are probably linked, somehow. Yep, pretty wishy-washy for decades of research. Again, it doesn’t seem like there are simple answers here such as simply increasing serotonin to cure depression.

Serotonin works as a neurotransmitter to transmit signals in a variety of neurons in the brain. It is released by a neuron into the synapsis and then binds to the next neuron to cause the signal to be transmitted.

Whole books could be (and have been) written on serotonin and depression.  Instead of getting too deep into the weeds here, I’m going to dive into one specific serotonin receptor…

HTR1A Serotonin Receptor:

The serotonin receptor known as 5-HT1A is coded for by the HTR1A gene. Here, I’m just going to call it the serotonin 1A receptor.  (There are a bunch of different serotonin receptors that do different things in the body.)

Basically, serotonin gets released by one neuron into the space (synapse) next to the beginning of the next neuron. Then serotonin binds to receptors on the next neuron, triggering a reaction that sends the signal along. The receptors are specific to serotonin — in this case, we’re talking about the serotonin 1A receptor.

BDNF is also active in the brain and potentiates the release of serotonin.[ref] It gives it a boost. Like adding nitrous to your car. OK, maybe not that big of a boost.

Research shows that the serotonin 1A receptor variant is linked to depression. A new study now points to an interaction between the serotonin receptor variant and the BDNF variant when it comes to depression.

Check your genetic data for rs6295 (23andMe v4, v5):

  • C/C: normal risk of depression*
  • C/G: linked with an increased risk of depression
  • G/G: linked with an increased risk of depression in most (but not all) studies [ref]

* Given in plus orientation to match 23andMe data

A meta-analysis that looked at several different studies on rs6295 found that it was linked with an increased risk of depression in Asian populations.[ref] Not all studies agree, of course. [ref]

How BDNF and Serotonin and Genetic variants combine:

The key to the increased risk of depression and anxiety disorders due to the serotonin 1a receptor and BDNF variants may be the combination of the risk alleles.

A recent study looked at the combined effects of carrying both the serotonin 1a receptor (rs6295) variant and the BDNF rs6265 variant.  [ref]

The study used PET scan imaging of the brains of people with affective disorders (depression, bipolar, anxiety disorders) and at least three copies of the variant alleles (combos of rs6295 G-alleles and rs6265 T-alleles).  The brain imaging showed that the risk variants altered the serotonin 1a receptor binding in ways associated with affective disorders.


Lifehacks:

There are several different ways that you can increase BDNF levels:

Exercise has been shown in multiple studies to reliably increase BDNF levels.  It is thought that this is one way that exercise decreases depression for some people. [ref]  Specifically, aerobic activity or endurance-type exercises are best for increasing BDNF. [ref]

Lion’s Mane mushroom extract has been shown to increase BDNF levels. This makes sense in context with all of the studies showing the neuroprotective effects of Lion’s Mane. [ref]  Lion’s mane is available as a supplement on Amazon and also combined with coffee (one of my personal favorites:-). You also may be able to find fresh Lion’s mane mushrooms at your local farmer’s market. They are quite tasty!

Anthocyanins, a flavonoid found in blueberries, have been shown in animal studies to increase BDNF in the brain. The levels used were similar to adding more blueberries into the diet or taking a blueberry supplement. [ref]  Yes, there are blueberry supplements available online, but blueberries are delicious and easy to add into your diet…

Milk thistle increases BDNF in depressed rats. [ref]

Dopamine Receptor Genes

Dopamine is a powerful player in our cognitive function – impacting mood, movement, and motivation. Genetic variants in the dopamine receptors influence addiction, ADHD, neurological diseases, depression, psychosis, and aggression.

Please keep in mind as you read this article that I’m not a neuroscientist — instead, I’m just consolidating the research and translating it into something that is (hopefully) easier to read and apply.  If you are under psychiatric care, do talk with your doctor before making any changes to anything you are currently doing.

What is dopamine?

Let’s start with the basics here. Dopamine acts as a neurotransmitter in the brain, transmitting a signal from one neuron to the next. It is a monoamine neurotransmitter, and also a catecholamine.  A monoamine just means that it contains a single amine group – and this is important in the way that it is regulated in the brain

Dopamine is derived from the amino acid tyrosine, which is converted to L-dopa and then to dopamine.

Dopamine is involved in:

  • Movement
  • Reward
  • Memory
  • Lactation
  • Attention
  • Sleep regulation

It acts on the dopamine receptors to cause motion and emotion.

Motion:
Dopamine is important in how the brain controls movement, and it needs to be balanced. Too much dopamine leads to more movement – such as tics and involuntary movement. Too little dopamine leads to less movement – such as in Parkinson’s.

Emotion:
Dopamine is also important in emotions.  Excess dopamine leads to euphoria, hallucination, and psychosis. Dopamine causes conditioning – for example,  learning either not to do something (via punishment) or learning to do something through reward. Not enough dopamine leads to anhedonia – that feeling of not caring about anything.

Prolactin:
Dopamine also functions within the hypothalamus and pituitary gland to affect hormones.  Specifically, dopamine inhibits prolactin. Without enough dopamine, it can lead to amenorrhea (lack of periods) in women and impotence and gynecomastia (moobs) in males.

Where is dopamine made?

There are two small regions deep in the brain where dopamine is made – the substantia nigra and the ventral tegmental area. From there, it travels via tracts to other areas of the brain.

What do the dopamine receptors do?

Dopamine doesn’t do anything by itself – it needs to bind with a receptor to cause an action. There are five different dopamine receptors in humans. They are coded for by the DRD1 through DRD5 genes. The receptors are responsible for the slightly different effects of dopamine in the various brain regions.

DRD1 receptor:

The most common dopamine receptor in the brain is DRD1. It is found in several regions of the brain including the neostriatum, basolateral amygdala, cerebral cortex, hypothalamus, and thalamus.

The DRD1 receptor is linked to the effects of alcohol consumption. Blocking the DRD1 gene decreases the alcohol-seeking behavior in animal studies. It also decreases heroin and cocaine seeking-behavior. [ref]

Working memory – short term memory needed for thinking and speaking – depends on the DRD1 receptors in the prefrontal cortex. Interestingly, working memory as considered to have a strong genetic component based on the DRD1 gene variants. [ref]

DRD2 receptor:

The DRD2 receptor is less abundant in the cerebral cortex than the DRD1 receptors, but it is abundant in other areas of the brain with dopaminergic neurons.

Both agonists and antagonists of the DRD2 receptor have been shown in animal studies to decrease alcohol and opiate consumption. The studies show that higher levels of either an agonist (something that stimulates the receptor) or antagonist (something that blocks the receptor) alter the addictive response. [ref]

DRD3 receptor:

The DRD3 receptor is found in the ventral striatum and other limbic areas. In humans, there are low amounts of the DRD3 receptors found in the cortical regions. This differs from other species and is a good reminder that animal studies may not be totally applicable to humans. [ref]

The DRD3 receptor has a higher affinity for dopamine (>20-fold higher than DRD2 receptors). This means that dopamine is more likely to bind with the DRD3 receptors, and high levels of dopamine will prompt the brain to make more DRD3 receptors. This ability to change with fluctuating dopamine levels makes the DRD3 receptor critical in dopamine-related functions and cognition.[ref]

DRD4 receptor:

This dopamine receptor is found at lower levels than DRD1 through DRD3.   It is found in the retina, cerebral cortex, amygdala, hypothalamus, and pituitary. The DRD4 receptor hasn’t been shown to be all that important in alcohol, opiate, or cocaine addiction.  [ref]

DRD5 receptor:

The DRD5 receptor is very similar to the DRD1 receptor, and they are often located together. There seems to be a lot more research on DRD1, but often substances that bind to DRD1 also bind to DRD5. [ref]

How does dopamine relate to addiction?

Addiction to drugs causes a compulsive drug-seeking behavior. The dopamine system is involved in the rewarding effects of drugs, and a lot of addictive drugs increase dopamine levels in certain regions of the brain. It has been known since the 1990s that blocking dopamine transmission takes away the reward effects of some addictive substances, such as cocaine and amphetamines. [ref]

There are three theories on how dopamine is related to addiction. First, is that the extra dopamine produced by addictive substances trains the brain through the reward system. It is the idea that the brain learns to like the drug, or makes it a habit. The second theory is that addictive substances change the brain circuits, making them hypersensitive.  Third, researchers theorize that there is an imbalance between dopamine and other neurotransmitters. [ref]

Diseases associated with abnormal dopamine levels:

There are several diseases that are associated with altered dopamine.

  • Parkinson’s disease – not enough dopamine due to degradation of the dopamine-producing area of the brain (substantia nigra)
  • Tics / Tourettes – excess striatal dopamine due to GABAergic network dysfunction [ref]
  • Psychosis – excess dopamine
  • Schizophrenia – excess dopamine in some areas of the brain (causes hallucinations) and not enough in others [ref]
  • Addiction – caused in part by repeated surges in dopamine (reward) and increased dopamine receptors
  • ADHD -associated with low dopamine function in certain areas of the brain [ref]
  • Bipolar affective disorder –  high dopamine during mania which elevated DRD2 and DRD3 receptors, coupled with reduced dopamine during depression [ref]
  • Anorexia – decreased reward (dopamine) for food along with other neurotransmitter imbalances [ref]

 


Dopamine receptor genetic variants:

DRD1 gene:

Check your genetic data for rs4532 (23andMe v4, v5; AncestryDNA):

  • C/C:  increased risk of nicotine dependence [ref]; increased risk of treatment-resistant schizophrenia[ref]; better response accuracy in complex tasks [ref];
  • C/T: increased risk of nicotine dependence [ref]; somewhat increased risk of treatment-resistant schizophrenia[ref]
  • T/T: normal

Check your genetic data for rs5326 (23andMe v4, v5; AncestryDNA):

  • T/T: decreased DRD1 in certain brain areas; increased risk of heroin addiction [ref]; poorer cognition and worse strategic planning[ref]
  • C/T: increased risk of schizophrenia[ref] poorer cognition and worse strategic planning[ref]
  • C/C: normal/most common

Check your genetic data for rs686 (23andMe v4, v5; AncestryDNA):

  • A/A: most common genotype; more DRD1 expression
  • A/G: intermediate DRD1 expression
  • G/G: less DRD1 expression [ref]; decreased risk of rapid opioid dependence [ref]

DRD2 gene:

Check your genetic data for rs6277 (23andMe v4, v5; AncestryDNA):

  • A/A: increased D2 receptor binding potential; increased susceptibility to stuttering [ref]; decreased risk of schizophrenia in Caucasians [ref]; better avoidance learning from negative outcomes[ref]; better rule-based learning[ref]
  • A/G: common genotype in Caucasians
  • G/G: most common worldwide;  poorer performance on working memory test[ref]; decreased cognitive ability in older adults (compared to AA) [ref]

Check your genetic data for rs1801028*  (23andMe v4; AncestryDNA):

  • G/G: normal, most common (Ser)
  • C/G: may not respond as well to risperidone; increased risk of schizophrenia[ref]
  • C/C: (Cys) may not respond as well to risperidone; increased risk of schizophrenia[ref]

*given in plus orientation to match 23andMe, AncestryDNA data

The following variant is known as the DRD2 TaqI A variant, located in the ANKK1 gene. It is thought to be linked with a polymorphism in the DRD2 gene that affects its function.[ref]

Check your genetic data for rs1800497 (23andMe v4, v5; AncestryDNA):

  • A/A: (DRD2*A1/A1) reduced number of dopamine binding sites[ref] increased risk of opioid dependence [ref]; increased BMI (susceptibility to food reward) [ref]; higher consumption of fried food [ref]; poorer working memory[ref]; increased suicide risk[ref]; increased risk of PTSD[ref] increased ADHD in males[ref]
  • A/G: (DRD2*A1/A2) increased risk of opioid dependence; reduced number of dopamine binding sites; increased BMI (susceptibility to food reward) [ref]; higher consumption of fried food [ref] poorer working memory[ref]; increased risk of PTSD;
  • G/G: (DRD2*A2/A2) normal, most common; aerobic exercise increases motor learning [ref]

DRD3 gene:

Check your genetic data for rs6280 Ser9Gly (23andMe v4, v5; AncestryDNA):

  • C/C: poorer executive function (psychosis patients)[ref], much better response to risperidone (antipsychotic used in autism)[ref]; increased risk of alcohol dependence [ref] decreased risk of bipolar disorder[ref]
  • C/T: better response to risperidone (antipsychotic)
  • T/T: normal (most common in most populations)

DRD4 gene:

Check your genetic data for rs1800955 (23andMe v4 only):

  • C/C: more likely to be a novelty seeker, more impulsive[ref]; more likely to smoke [ref]; more likely to take risks in ski/snowbording[ref]; possibly less likely to become addicted to heroin[ref]
  • C/T: somewhat more likely to be a novelty seeker; more likely to smoke
  • T/T: most common

COMT gene:

The COMT gene codes for the enzyme that breaks down dopamine and other catecholamine neurotransmitters. A common variant can decrease or increase the speed at which this enzyme works.

  • The G allele (Val) has higher COMT enzymatic activity, causing a more rapid breakdown of the neurotransmitters and thus lower levels of dopamine. In most populations, the G allele is the most common.[ref]
  • The A allele (Met) has lower COMT enzyme activity and thus higher levels of dopamine.  This variant of the COMT enzyme is said to have lower activity because it breaks down faster at normal body temperature.[ref]

Check your genetic data for rs4680 (23andMe v.4 and v.5):

  • G/G: higher COMT activity, lower dopamine & norepinephrine, higher pain tolerance (Val)
  • A/G: intermediate COMT activity
  • A/A: 40% lower COMT activity, higher dopamine & norepinephrine, lower pain tolerance (Met)

SLC6A3 gene:

This gene codes for the dopamine transporter, known as DAT1. Below are just a couple of the variants in DAT1 — perhaps I’ll follow up with a longer article on this soon.

Check your genetic data for rs27072 (23andMe v.4 and v.5):

  • C/C: normal / most common genotype;
  • C/T: increased risk of bipolar disorder; increased risk of early smoking onset;
  • T/T: increased risk of bipolar disorder [ref]; increased risk of early smoking onset[ref];

 


Lifehacks:

Again – let me caution that you don’t want to experiment with your neurotransmitters if you are under psychiatric care without talking with your doctor. Do more research, talk with your doctor/health care practitioner, and know what you are doing before you mess around here.

Diet – get enough protein to produce dopamine:
Dopamine is produced by converting the amino acid tyrosine into l-dopa and then dopamine. The body produces tyrosine from phenylalanine, which you get from your diet. You can also get tyrosine from foods. A diet that includes enough protein-rich foods (containing tyrosine/phenylalanine) is needed for dopamine production.   [ref]

There have been several studies looking at the cognitive response in people who ate a diet lacking phenylalanine and tyrosine for a day. The results show that the acute decrease in dopamine changes response to timing, decreased functional connectivity in the brain, and slowed reaction time.[ref][ref][ref]

Decreasing Dopamine:

Natural dopamine receptor antagonists (blocks the receptor):

In general, atypical antipsychotic medications are antagonists of the DRD2 receptor. This makes sense when you think about too much dopamine causing hallucinations, euphoria, etc — things associated with a psychotic break.

Yohimbine is derived from the bark of an African tree, P. yohimbe,  and traditionally used as an aphrodisiac (although human studies don’t really back that up). It is marketed as a supplement and used for weight loss.  It acts on the adrenergic receptors, serotonin receptors, and is also an antagonist of the DRD2 and DRD3 receptors.  [ref]  Yohimbine is also used in animal studies to cause anxiety… so you may want to watch out for this as a side effect. [ref]

Ningdong granule is a traditional Chinese medicine preparation used for Tourette’s syndrome.  It has been shown to regulate extracellular dopamine and also decrease binding to DRD2. [ref]

Natural ways to reduce dopamine:

Lithium?
An animal study showed that chronic lithium treatment  – similar to prescription levels of lithium rather than supplemental lithium orotate –  were able to blunt an anticipated spike in dopamine. This was thought to be one way that lithium may be effective in mania, which should be a high dopamine state.[ref]  Other studies, though, show that lithium increases dopamine following a TBI.[ref]

Ketogenic diet:
At least in rats, a ketogenic diet reduced the effects of daily cocaine injections.[ref]  This is obviously not a study that is going to be repeated in humans…

In kids with epilepsy, when they went on a ketogenic diet to control the seizures, their dopamine metabolites decreased. [ref]

Increasing dopamine:

Natural dopamine receptor agonists:

L-theanine has been shown in animal studies to activate the DRD1/DRD5 receptors.  Theanine is a component of green tea and is also sold as a supplement. 

Natural dopamine boosters:

Sugar causes the release of dopamine.  Research shows this is both from the taste of sugar and from the nutrition (energy) from sugar.[ref]  You know how you read headlines stating that sugar is just like cocaine in the brain — well it turns out that isn’t really correct.  Sugar affects dopamine in different areas of the brain (natural reward areas) than cocaine does.  [ref]

Gingko biloba increases dopamine levels (in rat brains). The effect was seen after chronic (14-day) administration of the gingko. [ref][ref]  Perhaps this is why Ginkgo Biloba is thought to increase memory…  You can get gingko at your local health food stores or on Amazon.

Bacopa is an herbal supplement that is marketed as helping with brain function.  In rats, bacopa decreased serotonin and increased dopamine.  It has also been shown in studies to potentially help with dementia and Parkinsons. [ref] You can get bacopa at health food stores or on Amazon. 

Mucuna pruriens, aka velvet beans, have traditionally been cultivated as a vegetable in Asia, Africa, and the Pacific Islands. Mucuna prurien extract is high in l-dopa, the precursor to dopamine, and it has been used as a natural treatment for Parkinson’s. [ref] You can get a concentrated extract as a supplement — or perhaps you can find velvet beans at an ethnic grocery store in your area?

 

More to read/watch:

Serotonin: How your genes affect this neurotransmitter

 

 

References:

Aguiar, Sebastian, and Thomas Borowski. “Neuropharmacological Review of the Nootropic Herb Bacopa Monnieri.” Rejuvenation Research, vol. 16, no. 4, Aug. 2013, pp. 313–26. PubMed Central, doi:10.1089/rej.2013.1431.
Baetu, Irina, et al. “Commonly-Occurring Polymorphisms in the COMT, DRD1 and DRD2 Genes Influence Different Aspects of Motor Sequence Learning in Humans.” Neurobiology of Learning and Memory, vol. 125, Nov. 2015, pp. 176–88. ScienceDirect, doi:10.1016/j.nlm.2015.09.009.
—. “Commonly-Occurring Polymorphisms in the COMT, DRD1 and DRD2 Genes Influence Different Aspects of Motor Sequence Learning in Humans.” Neurobiology of Learning and Memory, vol. 125, Nov. 2015, pp. 176–88. ScienceDirect, doi:10.1016/j.nlm.2015.09.009.
Balestri, Martina, et al. “Genetic Modulation of Personality Traits: A Systematic Review of the Literature.” International Clinical Psychopharmacology, vol. 29, no. 1, Jan. 2014, pp. 1–15. PubMed, doi:10.1097/YIC.0b013e328364590b.
Bolton, Jennifer L., et al. “Association between Polymorphisms of the Dopamine Receptor D2 and Catechol-o-Methyl Transferase Genes and Cognitive Function.” Behavior Genetics, vol. 40, no. 5, Sept. 2010, pp. 630–38. PubMed, doi:10.1007/s10519-010-9372-y.
Bombin, Igor, et al. “DRD3, but Not COMT or DRD2, Genotype Affects Executive Functions in Healthy and First-Episode Psychosis Adolescents.” American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics: The Official Publication of the International Society of Psychiatric Genetics, vol. 147B, no. 6, Sept. 2008, pp. 873–79. PubMed, doi:10.1002/ajmg.b.30710.
Byrne, Kaileigh A., et al. “Dopaminergic Genetic Polymorphisms Predict Rule-Based Category Learning.” Journal of Cognitive Neuroscience, vol. 28, no. 7, July 2016, pp. 959–70. PubMed Central, doi:10.1162/jocn_a_00942.
Can, Adem, et al. “Chronic Lithium Treatment Rectifies Maladaptive Dopamine Release in the Nucleus Accumbens.” Journal of Neurochemistry, vol. 139, no. 4, Nov. 2016, pp. 576–85. PubMed Central, doi:10.1111/jnc.13769.
—. “Chronic Lithium Treatment Rectifies Maladaptive Dopamine Release in the Nucleus Accumbens.” Journal of Neurochemistry, vol. 139, no. 4, Nov. 2016, pp. 576–85. PubMed Central, doi:10.1111/jnc.13769.
Carlson, Shaun W., and C. Edward Dixon. “Lithium Improves Dopamine Neurotransmission and Increases Dopaminergic Protein Abundance in the Striatum after Traumatic Brain Injury.” Journal of Neurotrauma, vol. 35, no. 23, 01 2018, pp. 2827–36. PubMed, doi:10.1089/neu.2017.5509.
Chang, Yun-Hsuan, et al. “Genetic Variants of the BDNF and DRD3 Genes in Bipolar Disorder Comorbid with Anxiety Disorder.” Journal of Affective Disorders, vol. 151, no. 3, Dec. 2013, pp. 967–72. ScienceDirect, doi:10.1016/j.jad.2013.08.017.
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—. “Association between Polymorphisms of DRD2 and DRD4 and Opioid Dependence: Evidence from the Current Studies.” American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics: The Official Publication of the International Society of Psychiatric Genetics, vol. 156B, no. 6, Sept. 2011, pp. 661–70. PubMed, doi:10.1002/ajmg.b.31208.
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Hildebrand, Patricia, et al. “Effects of Dietary Tryptophan and Phenylalanine-Tyrosine Depletion on Phasic Alertness in Healthy Adults – A Pilot Study.” Food & Nutrition Research, vol. 59, 2015, p. 26407. PubMed, doi:10.3402/fnr.v59.26407.
James, Morgan H., et al. “Cued Reinstatement of Cocaine but Not Sucrose Seeking Is Dependent on Dopamine Signaling in Prelimbic Cortex and Is Associated with Recruitment of Prelimbic Neurons That Project to Contralateral Nucleus Accumbens Core.” International Journal of Neuropsychopharmacology, vol. 21, no. 1, Nov. 2017, pp. 89–94. PubMed Central, doi:10.1093/ijnp/pyx107.
Kang, Seung-Gul, et al. “DRD3 Gene Rs6280 Polymorphism May Be Associated with Alcohol Dependence Overall and with Lesch Type I Alcohol Dependence in Koreans.” Neuropsychobiology, vol. 69, no. 3, 2014, pp. 140–46. PubMed, doi:10.1159/000358062.
Kehr, J., et al. “Ginkgo Biloba Leaf Extract (EGb 761®) and Its Specific Acylated Flavonol Constituents Increase Dopamine and Acetylcholine Levels in the Rat Medial Prefrontal Cortex: Possible Implications for the Cognitive Enhancing Properties of EGb 761®.” International Psychogeriatrics, vol. 24 Suppl 1, Aug. 2012, pp. S25-34. PubMed, doi:10.1017/S1041610212000567.
Le-Niculescu, H., et al. “Convergent Functional Genomics of Anxiety Disorders: Translational Identification of Genes, Biomarkers, Pathways and Mechanisms.” Translational Psychiatry, vol. 1, no. 5, May 2011, p. e9. PubMed Central, doi:10.1038/tp.2011.9.
Levran, Orna, et al. “Overlapping Dopaminergic Pathway Genetic Susceptibility for Heroin and Cocaine Addictions in African Americans.” Annals of Human Genetics, vol. 79, no. 3, May 2015, pp. 188–98. PubMed Central, doi:10.1111/ahg.12104.
Li, Lizhuo, et al. “The Association Between Genetic Variants in the Dopaminergic System and Posttraumatic Stress Disorder: A Meta-Analysis.” Medicine, vol. 95, no. 11, Mar. 2016, p. e3074. PubMed, doi:10.1097/MD.0000000000003074.
Ling, Daijun, et al. “Association between Polymorphism of the Dopamine Transporter Gene and Early Smoking Onset: An Interaction Risk on Nicotine Dependence.” Journal of Human Genetics, vol. 49, no. 1, 2004, pp. 35–39. PubMed, doi:10.1007/s10038-003-0104-5.
Mang, Cameron S., et al. “Exploring Genetic Influences Underlying Acute Aerobic Exercise Effects on Motor Learning.” Scientific Reports, vol. 7, no. 1, 21 2017, p. 12123. PubMed, doi:10.1038/s41598-017-12422-3.
Martinez, Luis A., et al. “A Ketogenic Diet Diminishes Behavioral Responses to Cocaine in Young Adult Male and Female Rats.” Neuropharmacology, vol. 149, 01 2019, pp. 27–34. PubMed, doi:10.1016/j.neuropharm.2019.02.001.
Mohammadi, Hiwa, et al. “Relationship between Serum Homovanillic Acid, DRD2 C957T (Rs6277), and HDAT A559V (Rs28364997) Polymorphisms and Developmental Stuttering.” Journal of Communication Disorders, vol. 76, Dec. 2018, pp. 37–46. PubMed, doi:10.1016/j.jcomdis.2018.08.003.
Naß, Janine, and Thomas Efferth. “Pharmacogenetics and Pharmacotherapy of Military Personnel Suffering from Post-Traumatic Stress Disorder.” Current Neuropharmacology, vol. 15, no. 6, Aug. 2017, pp. 831–60. PubMed Central, doi:10.2174/1570159X15666161111113514.
Nyman, Emma S., et al. “Sex-Specific Influence of DRD2 on ADHD-Type Temperament in a Large Population-Based Birth Cohort.” Psychiatric Genetics, vol. 22, no. 4, Aug. 2012, p. 197. journals.lww.com, doi:10.1097/YPG.0b013e32834c0cc8.
Nymberg, Charlotte, et al. “DRD2/ANKK1 Polymorphism Modulates the Effect of Ventral Striatal Activation on Working Memory Performance.” Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, vol. 39, no. 10, Sept. 2014, pp. 2357–65. PubMed, doi:10.1038/npp.2014.83.
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Snips about SNPs: Diabetes and TCF7L2

Diabetes is usually blamed on eating the wrong foods, but your genes play a big role in your susceptibility to the disease.

The TCF7L2 (transcription factor 7-like 2) gene codes for a protein that activates many genes involved in type 2 diabetes,  including glucagon-like peptide 1 GLP1. Genetic variants are associated with a decreased or impaired beta-cell function. It is one of the best-studied genes with regard to diabetes risk. [ref][ref]

Check your genetic data for rs7903146 (23andMe v4, v5; AncestryDNA):

  • T/T: 2-fold increased risk of diabetes, decreased beta-cell function[ref][ref]
  • C/T: increased risk of diabetes
  • C/C: normal

Check your genetic data for  rs12255372 (23andMe v4, v5; AncestryDNA):

  • T/T: increased risk of diabetes[ref][ref]
  • G/T: increased risk of diabetes
  • G/G: normal

Want to learn more about genetics and diabetes risk factors? Check out this article!

 

*SNP stands for Single Nucleotide Polymorphism, which is when one of the nucleotide bases (the A, C, G, or Ts) is replaced by a different nucleotide base in a gene. 

Want more quick bits about your genes? Read through all the Snips about SNPs

Autoimmune Disease Genetic Risk Factors: CTLA-4 Gene

Autoimmune diseases are caused by your immune system targeting and attacking cells in your body. This can result in a number of different problems:  joint pain (rheumatoid arthritis), scaly, thick skin (psoriasis), hypothyroidism (Hashimoto’s), and more. It is often difficult to get a solid diagnosis with autoimmune conditions since the symptoms overlap with other conditions.

This article covers just one genetic cause of increased susceptibility to several different autoimmune diseases. Keep in mind that genetic variants just add to the susceptibility to autoimmune diseases — there is usually an additional factor that triggers the disease.

CTLA-4 and Autoimmune Diseases:

The CTLA4 gene codes for a protein that is important in the immune system. It acts as a checkpoint that can downregulate your immune system response. CTLA4 is active in regulatory T cells (Tregs), which are the part of the immune system that maintains your tolerance to self-antigens. [ref][ref]

Basically, you want a powerful response from your immune system when you are exposed to a pathogen that causes a disease – pneumonia, West Nile virus, cholera, measles, flu… But you don’t want an out of control immune system.

Your body needs to control your immune response when it isn’t needed. Checks and balances.  The Treg cells are the checks that keep your immune system from going out of control and attacking your own cells.

One way in which the body needs to deactivate the immune response is during pregnancy.  Think about it — a mother’s body has an organism with foreign DNA growing in it. There has to be a system in place to keep the mother’s body from attacking the fetus. Immune checkpoint molecules (CTLA4 is one of them), keeps the maternal immune system from attacking the fetus. [ref]

When researchers decrease the amount of CTLA-4 in mice, it causes autoimmunity.[ref]

Autoimmune conditions associated with CLTA-4  include:

  • Graves’ disease (TSH-receptor autoantibodies cause hyperthyroidism)
  • Hashimoto’s disease (hypothyroidism)
  • Rheumatoid arthritis [ref]
  • Type 1 diabetes[ref]
  • Lupus[ref]
  • Vitiligo
  • Multiple Sclerosis[ref]
  • Celiac disease [ref]
  • Myasthenia gravis

Keep in mind, though, that autoimmune conditions aren’t solely caused by decreased CTLA-4. This is just one player in the autoimmune profile.

Checkpoint inhibitors in cancer:

The flip side of this CTLA-4 story is that inhibiting CTLA-4 is now a powerful tool in cancer therapy for certain types of cancers. Taking away the brakes on the immune system – decreasing that checkpoint for downregulating the immune system – allows the body to have a better shot at destroying cancer cells.


Genetic variants in the CLTA4 gene:

Genetic variants that decrease the function of the CTLA4 can could cause an increased immune system response.

Check your genetic data for rs231775 49A/G (23andMe v4, v5; AncestryDNA):

  • A/A: normal risk of autoimmune conditions
  • A/G: increased risk of autoimmune conditions, decrease CTLA4 expression; increased risk of Grave’s [ref]; increased risk of Hashimoto’s; increased risk of myasthenia gravis;
  • G/G: increased risk of autoimmune conditions, decrease CTLA4 expression; increased risk of Grave’s [ref]; increased risk of Hashimoto’s [ref]; increased risk of myasthenia gravis [ref]; decreased mortality risk in sepsis patients[ref]; increased risk of type 1 diabetes[ref]

 

Check your genetic data for rs3087243 60C/T (23andMe v4, v5; AncestryDNA):

  • A/A: normal risk of autoimmune conditions
  • A/G: increased risk of autoimmune conditions, decrease CTLA4 expression; increased risk of Grave’s [ref]; increased risk of myasthenia gravis [ref]; slightly increased risk of type 1 diabetes, celiac
  • G/G: increased risk of autoimmune conditions, decrease CTLA4 expression; increased risk of Grave’s [ref]; increased risk of myasthenia gravis [ref]; slightly increased risk of type 1 diabetes[ref][ref]; reduced tumor growth in breast cancer[ref]; celiac [ref]

One study showed that a combination of carrying each of the above risk alleles increased the risk of autoimmune disease almost 5-fold. [ref]


Lifehacks:

If you have an autoimmune condition, your doctor can best guide you in the new immune suppression medications on the market today.

Diet:

The autoimmune paleo diet has been effective for many people with autoimmune diseases. A clinical trial of the autoimmune paleo diet showed good results for women with Hashimoto’s thyroiditis. [ref]

Dr. Terry Wahl’s also has a dietary protocol that has been shown to be effective in multiple sclerosis patients.[ref]

Both of those diets focus on fresh vegetables and fruits, high-quality meats and proteins, and avoid gluten, dairy, and eggs.

Vitamin D:

Active vitamin D levels (1,25 (OH)2D3) can increase the expression of CTLA-4. [ref] This may be part of the connection between low vitamin D and an increased risk for many autoimmune conditions.

What can you do to raise your vitamin D levels?  First, you should check to see if your levels are low. Your doctor may be willing to run this for you or you can order your own test-  UltaLab Tests – 1,25(OH)D test (insurance won’t pay if you order your own). Sun exposure on as much skin as possible, but not so long as to get sunburned or skin damage. [ref] If you go the vitamin D supplement route, a lot of the cheap vitamin D supplements contain soybean oil. Personally, I like the idea of coconut oil-based vitamin D supplements instead.

DHA:

DHA is an omega-3 fatty acid found in fish oil.  One study shows that DHA upregulated CTLA-4. [ref] If you are low in DHA, consider adding more fish to your diet or taking a fish oil supplement.

cAMP:

Studies show that substances that upregulate cyclic adenosine monophosphate (cAMP) cause an upregulation of CTLA-4.  Cholera toxin is one substance that is used in studies, but not something that I would recommend as a ‘lifehack’ :-)[ref]

cAMP is important in regulating blood sugar, glycogen, and using fat for fuel. Forskolin is a supplement derived from the Indian Coleus plant. It also is used in research to increase cAMP and increase CTLA-4.[ref]

Curcumin and resveratrol are two more natural supplements that have been shown to upregulate cAMP. [ref]

Raising cAMP does more, though, than just upregulate CTLA4. It is a second-messenger within cells that is important for a bunch of different biological responses. Thus, it may or may not be an effective way to decrease symptoms in an autoimmune condition.

 

More to read:

 

References:

Abbott, Robert D., et al. “Efficacy of the Autoimmune Protocol Diet as Part of a Multi-Disciplinary, Supported Lifestyle Intervention for Hashimoto’s Thyroiditis.” Cureus, vol. 11, no. 4, Apr. 2019, p. e4556. PubMed, doi:10.7759/cureus.4556.
Benmansour, Jihen, et al. “Association of Single Nucleotide Polymorphisms in Cytotoxic T-Lymphocyte Antigen 4 and Susceptibility to Autoimmune Type 1 Diabetes in Tunisians.” Clinical and Vaccine Immunology: CVI, vol. 17, no. 9, Sept. 2010, pp. 1473–77. PubMed, doi:10.1128/CVI.00099-10.
—. “Association of Single Nucleotide Polymorphisms in Cytotoxic T-Lymphocyte Antigen 4 and Susceptibility to Autoimmune Type 1 Diabetes in Tunisians.” Clinical and Vaccine Immunology: CVI, vol. 17, no. 9, Sept. 2010, pp. 1473–77. PubMed, doi:10.1128/CVI.00099-10.
Fathima, Nusrath, et al. “Association and Gene-Gene Interaction Analyses for Polymorphic Variants in CTLA-4 and FOXP3 Genes: Role in Susceptibility to Autoimmune Thyroid Disease.” Endocrine, vol. 64, no. 3, June 2019, pp. 591–604. PubMed, doi:10.1007/s12020-019-01859-3.
Fellows Maxwell, Kelly, et al. “Lipid Profile Is Associated with Decreased Fatigue in Individuals with Progressive Multiple Sclerosis Following a Diet-Based Intervention: Results from a Pilot Study.” PloS One, vol. 14, no. 6, 2019, p. e0218075. PubMed, doi:10.1371/journal.pone.0218075.
Ferrari, Davide, et al. “Association between Solar Ultraviolet Doses and Vitamin D Clinical Routine Data in European Mid-Latitude Population between 2006 and 2018.” Photochemical & Photobiological Sciences: Official Journal of the European Photochemistry Association and the European Society for Photobiology, Sept. 2019. PubMed, doi:10.1039/c9pp00372j.
Goske, Maruthi, et al. “CTLA-4 Genetic Variants (Rs11571317 and Rs3087243): Role in Susceptibility and Progression of Breast Cancer.” World Journal of Oncology, vol. 8, no. 5, Oct. 2017, pp. 162–70. PubMed, doi:10.14740/wjon1046w.
Houcken, Juliane, et al. “PTPN22 and CTLA-4 Polymorphisms Are Associated With Polyglandular Autoimmunity.” The Journal of Clinical Endocrinology and Metabolism, vol. 103, no. 5, 01 2018, pp. 1977–84. PubMed, doi:10.1210/jc.2017-02577.
Jeffery, Louisa E., et al. “Vitamin D Antagonises the Suppressive Effect of Inflammatory Cytokines on CTLA-4 Expression and Regulatory Function.” PloS One, vol. 10, no. 7, 2015, p. e0131539. PubMed, doi:10.1371/journal.pone.0131539.
Kailashiya, Vikas, et al. “Role of CTLA4 A49G Polymorphism in Systemic Lupus Erythematosus and Its Geographical Distribution.” Journal of Clinical Pathology, vol. 72, no. 10, Oct. 2019, pp. 659–62. PubMed, doi:10.1136/jclinpath-2019-206013.
Karami, Jafar, et al. “Genetic Implications in the Pathogenesis of Rheumatoid Arthritis; an Updated Review.” Gene, vol. 702, June 2019, pp. 8–16. PubMed, doi:10.1016/j.gene.2019.03.033.
Li, Fang, et al. “Association of CTLA-4 Polymorphisms with Increased Risks of Myasthenia Gravis.” Annals of Human Genetics, vol. 82, no. 6, 2018, pp. 358–69. PubMed, doi:10.1111/ahg.12262.
—. “Association of CTLA-4 Polymorphisms with Increased Risks of Myasthenia Gravis.” Annals of Human Genetics, vol. 82, no. 6, 2018, pp. 358–69. PubMed, doi:10.1111/ahg.12262.
—. “Association of CTLA-4 Polymorphisms with Increased Risks of Myasthenia Gravis.” Annals of Human Genetics, vol. 82, no. 6, 2018, pp. 358–69. PubMed, doi:10.1111/ahg.12262.
Li, Jinghong, et al. “Regulation of Cytotoxic T Lymphocyte Antigen 4 by Cyclic AMP.” American Journal of Respiratory Cell and Molecular Biology, vol. 48, no. 1, Jan. 2013, pp. 63–70. PubMed, doi:10.1165/rcmb.2012-0155OC.
Liu, J., and H. X. Zhang. “Association between the Rs3087243 Polymorphism and Risk for Diabetes: A Meta-Analysis.” Genetics and Molecular Research: GMR, vol. 12, no. 4, Dec. 2013, pp. 6344–50. PubMed, doi:10.4238/2013.December.6.1.
Lo, Bernice, and Ussama M. Abdel-Motal. “Lessons from CTLA-4 Deficiency and Checkpoint Inhibition.” Current Opinion in Immunology, vol. 49, Dec. 2017, pp. 14–19. PubMed, doi:10.1016/j.coi.2017.07.014.
Mewes, Caspar, et al. “The CTLA-4 Rs231775 GG Genotype Is Associated with Favorable 90-Day Survival in Caucasian Patients with Sepsis.” Scientific Reports, vol. 8, no. 1, 11 2018, p. 15140. PubMed, doi:10.1038/s41598-018-33246-9.
Miko, Eva, et al. “Immune Checkpoint Molecules in Reproductive Immunology.” Frontiers in Immunology, vol. 10, Apr. 2019. PubMed Central, doi:10.3389/fimmu.2019.00846.
Mitsuiki, Noriko, et al. “What Did We Learn from CTLA-4 Insufficiency on the Human Immune System?” Immunological Reviews, vol. 287, no. 1, 2019, pp. 33–49. PubMed, doi:10.1111/imr.12721.
Mohammadzadeh, Adel, et al. “CTLA-4, PD-1 and TIM-3 Expression Predominantly Downregulated in MS Patients.” Journal of Neuroimmunology, vol. 323, 15 2018, pp. 105–08. PubMed, doi:10.1016/j.jneuroim.2018.08.004.
Riccomi, Antonella, et al. “Modulation of Phenotype and Function of Human CD4+CD25+ T Regulatory Lymphocytes Mediated by CAMP-Elevating Agents.” Frontiers in Immunology, vol. 7, 2016, p. 358. PubMed, doi:10.3389/fimmu.2016.00358.
Safavifar, Farnaz, et al. “Augmented CAMP Signaling by Co-Administration of Resveratrol and Curcumin: A Cellular Biosensor Kinetic Assessment.” Iranian Journal of Public Health, vol. 48, no. 7, July 2019, pp. 1310–16.
Saleh, Hatem Mohamed, et al. “The CTLA4 -819 C/T and +49 A/G Dimorphisms Are Associated with Type 1 Diabetes in Egyptian Children.” Indian Journal of Human Genetics, vol. 14, no. 3, Sept. 2008, pp. 92–98. PubMed, doi:10.4103/0971-6866.45001.
Tu, Yaqin, et al. “Association between Rs3087243 and Rs231775 Polymorphism within the Cytotoxic T-Lymphocyte Antigen 4 Gene and Graves’ Disease: A Case/Control Study Combined with Meta-Analyses.” Oncotarget, vol. 8, no. 66, Nov. 2017, pp. 110614–24. PubMed Central, doi:10.18632/oncotarget.22702.
—. “Association between Rs3087243 and Rs231775 Polymorphism within the Cytotoxic T-Lymphocyte Antigen 4 Gene and Graves’ Disease: A Case/Control Study Combined with Meta-Analyses.” Oncotarget, vol. 8, no. 66, Nov. 2017, pp. 110614–24. PubMed Central, doi:10.18632/oncotarget.22702.
—. “Association between Rs3087243 and Rs231775 Polymorphism within the Cytotoxic T-Lymphocyte Antigen 4 Gene and Graves’ Disease: A Case/Control Study Combined with Meta-Analyses.” Oncotarget, vol. 8, no. 66, Nov. 2017, pp. 110614–24. PubMed Central, doi:10.18632/oncotarget.22702.
—. “Association between Rs3087243 and Rs231775 Polymorphism within the Cytotoxic T-Lymphocyte Antigen 4 Gene and Graves’ Disease: A Case/Control Study Combined with Meta-Analyses.” Oncotarget, vol. 8, no. 66, Nov. 2017, pp. 110614–24. PubMed Central, doi:10.18632/oncotarget.22702.
Walker, Lucy S. K. “EFIS Lecture: Understanding the CTLA-4 Checkpoint in the Maintenance of Immune Homeostasis.” Immunology Letters, vol. 184, 2017, pp. 43–50. PubMed, doi:10.1016/j.imlet.2017.02.007.
Yessoufou, Akadiri, et al. “Docosahexaenoic Acid Reduces Suppressive and Migratory Functions of CD4+CD25+ Regulatory T-Cells.” Journal of Lipid Research, vol. 50, no. 12, Dec. 2009, pp. 2377–88. PubMed, doi:10.1194/jlr.M900101-JLR200.

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.