Did you know that about 1 in 5 people will deal with an anxiety disorder at some point in life? From generalized anxiety to separation anxiety to panic disorder – there are underlying physiological and genetic factors involved.
This article covers genetic variants related to anxiety disorders. This is a big topic, and new research is coming out all the time. The information here is presented for educational/informational purposes. Which means… learn all that you can about the physiological and genetic reasons for anxiety disorders, but do talk with your doctor before making any medical decisions.
(Members: Read the enhanced member’s article with your genetic data included.)
The lifetime risk of anxiety disorder is over 20%. If you’re dealing with anxiety, you are not alone!
‘Anxiety disorder’ is a general term that can include generalized anxiety, panic disorders, social anxiety, PTSD, phobias, and more. This is a complex group of disorders with various ways of presenting, but there are some underlying biological similarities in their causes. [ref]
Social anxiety disorder is really common and affects up to 10% of the population. People with social anxiety disorder have severe enough anxiety in social situations to cause behavioral alterations in order to avoid some social situations. This can lead to stress or an inability to function well in society. [ref]
Generalized anxiety disorder (GAD) is a condition in which people worry more than normal about everyday things. People with GAD may feel on edge, irritable, tense and they may have problems sleeping well.
People with panic disorder have a sudden onset of anxiety. They have physical symptoms of acute fear such as feeling like they can’t breathe, trembling, dizziness, and an increased heart rate. [source]
Genetics plays a role in anxiety disorders, with the heritability estimated to be up to 50%. The other half of the picture here is environmental and lifestyle factors.[ref]
The big takeaway here is that anxiety disorders have a genetic component, for most people. And that the genetic component causes a physical alteration in the way the brain works or in the physiological response to stress.
Knowing your genetic ‘kryptonite’ may help you to find the right solution to your anxiety problems.
Researchers investigate how genes influence the risk of a disease/condition through several methods: One way is to first assume that genes in a certain pathway are important, and then investigate those variants in detail. Another way is to do a ‘Genome-wide association study’ (GWAS), which looks at all the genes in people with a disease to see which variants differ from a control group. A final approach is to look at how specific variants interact with lifestyle factors to influence disease risk. All of these methods have their pros and cons, and often all of the different methods end up being used by different research groups investigating a topic.
Let’s take a look at specific genes that are linked to anxiety disorders:
One gene that is linked with anxiety in multiple studies is the ADORA2A gene. ADORA2A codes for the adenosine 2A receptor, which is important in the way that the brain works.
Adenosine is an important biological compound that is made up of an adenine molecule and a d-ribose sugar molecule. It is found in every cell in the body. Adenine is a nucleotide (the “A” in your DNA raw data). D-ribose is the sugar that makes up part of the DNA molecule (deoxyribonucleic acid).
Adenosine also may sound familiar because it is part of the ATP molecule (adenosine triphosphate).
In the brain, adenosine is important in the way that the neurons work. It helps to fine-tune the way that neurons communicate, and it also helps to balance the inhibitory and excitatory neurons.[ref]
Adenosine levels in the brain increase over the course of the day. This higher level of adenosine is what causes you to feel sleepy at night – called the homeostatic sleep drive.
Caffeine works to make you feel awake by binding to the adenosine receptor and blocking it so that the adenosine can’t attach to it. Genetic variants in the adenosine receptor alter people’s response to caffeine.
Animal studies are great for showing exactly how a gene works. Mice have greatly increased anxiety when researchers knock down the ADORA2A (adenosine receptor) gene expression. They also had an increased heart rate, increased platelet aggregation, and altered pain response, because adenosine is important in a lot of different functions in the body. [ref]
But what about in humans? There is a common genetic variant in the ADORA2A gene that alters its function. An fMRI study found that ADORA2A variant carriers had increased connectivity between two regions of the brain: the prefrontal cortex and the insula (part of the cerebral cortex). [ref]
One more way ADORA2A variants impact the risk of anxiety disorder is through the impact on the startle response and the maladaptive emotional reactivity.[ref]
All in all, this paints a picture of the adenosine receptor being important in how neurons communicate. Alterations in this pathway may cause people to be on alert, startling more easily and jittery (especially with high caffeine).
Oxytocin is a hormone and a neuropeptide that researchers link to both emotional functioning and social empathy. Oxytocin is also released in women in large quantities in childbirth and during breastfeeding and is part of the mother-child bonding. (For anyone who has been induced in childbirth, this is done using oxytocin or Pitocin.)
Anyone who has had kids understands that there is a connection where a mother can recognize their own baby’s cry. In fact, oxytocin is a big part of a mother’s neuroendocrine response to their baby’s crying. Researchers study this by brain imaging using an fMRI on mothers listening to crying babies. [ref] It is a built-in, physiological response based on oxytocin.
Going beyond mother-infant bonding, oxytocin, in general, plays a role in social attachment and trust. In fact, if you give normal adults oxytocin intranasally (up the nose), there is a substantial increase in trust amongst people, which increases the benefits of social interaction.[ref] If you want to get into the geeky details on what brain imaging shows with intranasal oxytocin, here is a new study illustrating the fMRI changes in activity levels in certain areas of the brain. It’s pretty cool…
Stressful situations cause the body to increase oxytocin, which acts quickly to decrease anxiety. But oxytocin creates an anti-anxiety effect only under stressful conditions.[ref] In other words, boosting oxytocin when you’re not stressed doesn’t change anything. It is only a ‘chill pill’ in situations that have your body on alert.
Adult separation anxiety is a disorder linked in several studies with oxytocin levels and oxytocin receptor genetic variants. It is characterized by feeling anxious when separated from a loved one or even a pet.[ref] [article]
Serotonin is a neurotransmitter that is involved in mood. This pathway is a common target of antidepressant and antianxiety medications known as SSRIs. Serotonin is also important in gut motility and in sleep (as the precursor for melatonin).
Researchers still have a lot of questions about how serotonin works in anxiety. The key may be that serotonin acts differently in situations of fear or panic, compared to situations that cause general anxiety. [ref][ref]
Several genetic variants in serotonin-related pathways have been linked to PTSD, which is classified as an anxiety disorder.
Brain-derived neurotrophic factor (BDNF) has multiple functions in the brain including neuroplasticity and potentiating neurotransmitter function. Basically, it helps grow new neurons and helps neurotransmitters work better.
BDNF genetic variants are linked with an increased risk of depression and anxiety, but the common variants in this gene also interact with other genes and with stress in changing the risk for depression. The Val66Met variant (listed below) has been investigated in over a thousand studies. The Met allele carriers have reduced BDNF activity. [ref][ref]
A recent animal study tested the theory that BDNF genetic variants interact with stress as a ‘two-hit’ combo for impacting mood and brain function. The researchers gave normal mice and BDNF reduced mice (Val/Met heterozygous mice) a stress hormone (cortisol) in their water. Then they tested the effects of different environments. Mice that were housed in an enriched environment (toys, tunnels, more open housing, exercise, mazes, etc) did not have brain changes in the BDNF + stress hormone mice. But the female mice in a non-enriched environment that were exposed to the ‘two-hits’ had changes in spatial memory, maze performance, and the hippocampus. [ref]
The HPA axis (hypothalamus-pituitary-adrenals) controls the body’s cortisol release in times of stress. Cortisol is released by the adrenals when you are exposed to physical or mental stressors. This system works great when you are being chased by a tiger once in a while, but chronically elevated cortisol is linked to a number of health problems including depression.
Altered cortisol levels with low cortisol and a stronger negative feedback loop are found in people with PTSD. While the research is still ongoing, there seems to be a subset of people for whom altered cortisol response is at the root of either their anxiety or depression. [ref]
The body’s baseline level of cortisol rises and falls in a circadian rhythm over the course of 24-hours. Having this rhythm in sync with the rest of the body is important for both physical and mental health.
Research shows that people with panic disorder have higher overnight cortisol levels and they have an exaggerated response to novel stressors. [ref]
In severe anxiety or panic disorder, people often feel like they are short of breath or suffocating. Interestingly, people with panic disorder also have a heightened sensitivity to carbon dioxide. Most people, when inhaling higher percentages of carbon dioxide don’t have a response, but in people with panic disorder, inhaling a higher than normal amount of CO2 can actually trigger a panic attack. [ref]
Increasing the CO2 levels in the blood increases the acidity (lower pH). Researchers theorize that a chemical sensor for the detection of pH levels in the amygdala is involved. In mouse studies, inhaled CO2 drops the pH in the amygdala and causes fear behaviors. This is mediated by the acid-sensing ion channel-1a subunit (coded for by the ACCN2 gene in humans). [ref][ref]
This section gets specific on genetic variants of the pathways discussed above. Note that there are other genetic variants that could also impact these pathways. The variants included below are found in 23andMe or AncestryDNA data and also have multiple studies to back up the assertions. (In other words – I left out some variants that had conflicting data or research that wasn’t replicated.)
ADORA2A gene: adenosine receptor 2A
Check your genetic data for rs5751876 (23andMe v4, v5; AncestryDNA):
OXTR gene: codes for the oxytocin receptor
Check your genetic data for rs53576 (23andMe v4, v5; AncestryDNA):
Check your genetic data for rs5443 (23andMe v4, v5; AncestryDNA):
SLC6A4 gene: serotonin transporter:
Check your genetic data for rs140701 (23andMe v4; AncestryDNA):
BDNF gene: brain-derived neurotrophic factor
Check your genetic data for rs6265 (23andMe v4, v5; AncestryDNA):
FKBP5 gene codes for a chaperone protein that regulates the sensitivity of the glucocorticoid receptor (GR). (HPA axis, cortisol response)
Check your genetic data for rs1360780 (23andMe v4, v5, AncestryDNA):
CHCR1 gene: codes for the corticotropin-releasing hormone receptor, which is involved in the signaling for cortisol release.
Check your genetic data for rs110402 (23andMe v5, AncestryDNA)
ACCN2 gene: codes for a protein important in sensing CO2 levels in the brain
Check your genetic data for rs10875995 (23andMe v4; AncestryDNA):
Check your genetic data for rs685012 (AncestryDNA):
The following are solutions that may work for the specific genetic variants. Everyone is different, of course. Use your best judgment and talk with your doctor if you are under a doctor’s care for anxiety.
If you carry the ADORA2A receptor variant and drink beverages containing caffeine, try cutting down on caffeine to see if it helps with your anxiety.
Caffeine at low doses has been shown to help some people with anxiety, so cutting out coffee all together may not be the right move. If you’re a coffee drinker, try switch to half decaf/half regular, and decrease caffeine levels to less than 150mg per day.[ref]
Experiment with different levels of caffeine – your sweet spot may be less than 150mgs. It takes time for the adenosine receptors to adjust, so give this experiment a week or more to see if it decreases your anxiety. In my opinion, the best way to know if something is working is to track the results. So be deliberate in noting the amount of caffeine you drink in a day and also what you feel that your anxiety level was by the end of the day.
Understanding the way that social interaction and empathy are important to you personally, may help you to modify your interactions. If you carry the G/G allele and you have anxiety when separated from loved ones, you may want to see about boosting oxytocin levels at times when you feel anxious.
Here are a couple of ways to raise oxytocin levels:
If you carry the BDNF variants, you may want to experiment with boosting your BDNF levels on a long-term basis.
Sunlight: Exposure to sunlight or bright light during the day increases BDNF levels. [ref] Go outside!
Animal studies show that increased branch chain amino acid (BCAA) intake promoted BDNF growth and made the animals less anxious and more resilient to stress. This was shown to affect the same pathway that exercise affects, but that adding BCAA to exercise didn’t have a synergistic effect.[ref] Thus, it may be worthwhile to experiment with increasing BCAAs on days that you don’t exercise to see if there is an effect on anxiety.
Lion’s Mane mushroom extract has been shown to increase BDNF levels. [ref] Lion’s mane is available as a supplement, or you may be able to find fresh lion’s mane mushrooms as your farmer’s market (they taste like lobster!).
Bacopa increases BDNF expression when given chronically. [ref] Bacopa is an herbal supplement that has been used for thousands of years in India. It is known for its positive effect on memory and cognition.
Ashwagandha, an ancient medicinal herb, has been shown in multiple clinical trials and research studies to reduce cortisol. One study, for example, tested 300 mg/twice a day vs. placebo. After 8 weeks, cortisol was reduced by an average of 22%. Weight also went down for the Ashwagandha group. [ref] [ref]
Holy Basil shown in animal studies to inhibit cortisol release. You can get Holy Basil as a supplement or drink it as Tulsi tea. [ref ]
Sleep is important in cortisol response. A recent study showed that getting more sleep the night before lead to a decreased stress response during the morning and afternoon, but that effect wore off by evening.[ref ] So you need good quality sleep and a good quantity of sleep, every single night.
If you carry the genetic variants related to cortisol levels and anxiety, it may be time to take a hard look at how much stress you deal with every day…
Read more about the lifehacks for modifying cortisol levels.
Carriers of the ACCN2 gene variants may want to look into the different types of breathing therapy. Look into hypoventilation therapy or talk with your doctor about your options here. [ref]
Other options investigate may include left nostril breathing (yoga) or Wim Hof breathing.[ref] Undertake these with help from an expert, though, in case the altered breath training triggers a panic attack.
Seasonal Affective Disorder (SAD) is characterized by recurrent depression with a change in the season usually in fall/winter for most. Scientists think this is possibly due to an aberrant response to light – either not enough brightness to the sunlight or not enough hours of light. Your genes play a big role in this responsiveness to light.
Lithium + B12
For some people, low-dose, supplemental lithium orotate is a game-changer when combined with vitamin B12. But other people may have little to no response. The difference may be in your genes.
HPA Axis Dysfunction:
Cortisol is a hormone produced by the adrenal glands in times of stress, and it also plays many roles in your normal bodily functions. It is a multi-purpose hormone that needs to be in the right amount (not too high, not too low) and at the right time. Your genes play a big role in how likely you are to have problems with cortisol.
With COVID-19 all over the news, many people have now heard the term ARDS bandied about. Acute respiratory distress syndrome (ARDS) is a very serious condition that a minority of people with COVID-19 develop. This is the reason, though, that everyone is discussing ‘flattening the curve’ as a way to decrease the number of patients on ventilators in the ICU at one time.
This is article explains what happens to the body in ARDS, and it goes into the genetic variants that increase or decrease the risk of ARDS (due to all causes – not just COVID-19).
The intent here is to educate and inform – not to stress anyone out. There is a multitude of factors that influence the risk for ARDS with COVID-19, and genetics is only one part of the ARDS picture.
Acute Respiratory Distress Syndrome (ARDS) is a condition in which critically ill patients have acutely lowered oxygen levels, fluid in the lungs, and a need for positive pressure ventilation. ARDS is due to an uncontrolled inflammatory response injuring the lung tissue. [ref]
This syndrome was first defined in 1967, with updates periodically to the diagnosis criteria. The 2012 ARDS diagnosis definition includes that respiratory failure occurs without being explained by heart function and that oxygenation is needed at specific levels. [ref]
The most common causes of ARDS are pneumonia, sepsis, aspiration, and major trauma. The mortality rate is high for people with ARDS – from 35 – 36% mortality, depending on the severity.
Inside the lungs, you have the major airways (bronchi) that branch off into secondary bronchi. At the end of all the branching are alveoli – little sacks that are filled with air and surrounded by capillaries. This is where the exchange of oxygen and carbon dioxide takes place. Oxygen enters the bloodstream and carbon dioxide leaves.
These alveoli are lined with two types of epithelial cells that form a very tight barrier that only allows the passage of carbon dioxide and oxygen gasses. These tight junctions between the cells are important and created by specific proteins to create the bonds.
In ARDS, the epithelial cells lining the alveoli are no longer as tightly bound together, allowing them to be filled with fluid that leaks in from surrounding tissue. Once the alveoli are filled up, air can’t be exchanged. This causes both a decrease in oxygen and a buildup of carbon dioxide. [ref]
This is why just giving a patient more oxygen when they have ARDS doesn’t do any good. The alveoli aren’t able to make the exchange with the capillaries any more. Mechanical ventilation is needed in order to reopen and stabilize the alveoli.
So what causes the epithelial cells lining the alveoli to be damaged and no longer tightly joined together? There are a variety of different causes including:[ref]
When the epithelial cells are initially damaged, the body produces an immune response – sending in neutrophils and monocytes in to kill the pathogens. But this inflammatory response also damages the epithelial cells further. This is a second wave of damage that occurs in the lungs, due to our own immune response.
Capillaries leaking fluid: During ARDS, the capillaries surrounding the alveoli also play a role. The immune response causes increased permeability in the blood vessels, allowing plasma to leak out. This causes increased fluid around the alveoli, which combines with the decrease in epithelial cell barrier to flood the alveoli with fluid.
Finally, there is a long road to healing. The inflammatory response must be tamped down and the damaged lung tissue must be repaired. The recovery period can be extensive, with the patients continuing to have shortness of breath with exertion. [ref]
Looking at the genetic variants that increase the risk for ARDS is one way of knowing the pathways involved in this syndrome. Researchers can measure what is going on in the blood when someone has ARDS, and they can look at animal research models to see what goes on specifically in the alveoli. But genetics research can also show exactly which inflammatory molecules and which cellular junction molecules are involved both in the initial cascade of symptoms as well as the final steps needed to turn the corner and heal. Certain genetic variants are linked to an increased risk of having ARDS, and other variants are linked to a poorer outcome if someone has ARDS.
Vascular endothelial growth factor (VEGF) is produced in the cells that make up blood vessels (endothelial cells). They cause increased blood vessels to form and also mediate the permeability, or leakiness, of the blood cells. So while VEGF can be a part of the problem with fluid building up around the lungs, it can also be part of the repair process when the injured lungs are healing.[ref]
Genetic variants in the VEGF gene can cause a person to create more or less VEGF during normal circumstances. These variants are also linked to poor outcomes in ARDS.
Plasma levels of angiopoietin-2 (ANG2) are linked to increased endothelial permeability, allowing fluid to move out of the capillaries. Animal models show that increasing ANG2 causes a disruption of the epithelial barrier and causes lung injury. [ref]
TNF-alpha is a pro-inflammatory cytokine released for both acute infection and in chronic inflammation. Levels of TNF-alpha are increased in lung infections and COPD. [ref]
Interleukin-17 is another pro-inflammatory cytokine that is involved in amplifying inflammatory response by recruiting more monocytes and neutrophils to an area. Higher IL-17 is linked to an increased risk of ARDS. [ref]
Another part of the innate immune system is the complement system, which is activated to enhance the body’s ability to clear out microbes as well as damaged cells. Mannose-binding lectin is one way of activating the complement system. Low levels of mannose-binding lectin, due to an MBL2 genetic variant, increases the risk for septic shock and ARDS. [ref] [ref]
On the other hand, the overall picture on mannose-binding lectin and activation of the complement system isn’t entirely clear for the SARS coronavirus infections. Animal models here show that blocking the activation of the complement system lead to better outcomes for SARS coronavirus. [ref]
Currently, medical professionals use therapy such as specific rates of ventilation and conservative fluid strategies to stop ARDS. The trials for pharmacological therapies are ongoing and target the inflammatory response. Additionally, trials using mesenchymal stem cells hold promise as well. [ref][ref][ref][ref][ref] There is hope for future treatments to reverse the course of ARDS.
For most people, COVID-19 infection will be asymptomatic or cause mild symptoms.
So what is the trigger for causing some people, mainly elderly people with co-morbidities, to progress to ARDS?
First, let’s take a look at the co-morbidities, or underlying health conditions, linked to COVID-19, especially in the elderly, include: [ref]
The virus that causes COVID-19 is now named SARS-CoV2, and it enters cells in the body through a receptor called ACE2 (angiotensin-converting enzyme 2). Cells in the lower respiratory tract have the ACE2 receptors on their surface. This allows the passage of the virus into the lung cells. [ref]
There are a number of different viral recognition receptors in the body that recognize the virus and then trigger MyD88 (below in the genetics section), which activates NF-κB, interferons, and several different inflammatory cytokines (also in the genetics section). This innate immune response needs to be regulated so that it doesn’t overwhelm the body. The infected lung cells are targeted, and if the initial infection isn’t cleared out, it can trigger “a series of immune responses and the production of cytokine storm in the body, which may be associated with the critical condition of COVID-19 patients.” [ref]
Initial data is showing that among COVID-19 patients that required ICU care, over 30% of them presented with ARDS. [ref]
So why are elderly people more prone to respiratory infections and pneumonia in general? According to the statistics from the 2017-2018 flu season, between 61,000 and 80,00 people (mostly elderly) died of the flu in the United States. Worldwide, there are about 200 million cases of viral community-acquired pneumonia every year, with children and the elderly being hit hardest. [ref]
The elderly are hit hard by the flu and cold viruses due to frailty, an inability to clear mucous well, and decline in the initial immune response. Senescence is the term applied to cells that are no longer functioning and needing to be cleared out of the body. Cellular senescence increases in older people, including senescence of immune cells (immunosenescence). This is one cause of the decrease in the ability of the immune system to clear out a viral infection quickly. “Infection is the primary cause of death in one third of individuals aged 65 years and over.” [ref]
Below are some of the genetic variants that research has shown to impact either susceptibility to ARDS or mortality in ARDS. These variants are linked with ARDS in general studies, not specific to COVID-19. Note that there are other genetic variants that influence ARDS (not found in 23andMe or AncestryDNA), so this is only giving you part of the genetic picture.
VEGFA gene: code for vascular endothelial growth factor which both increases the permeability of blood vessels (leakiness), but is also important for recovery from ARDS with repair and growth of blood vessels
Check your genetic data for rs3025039 936C>T (23andMe v4, v5; AncestryDNA):
ANGPT2 gene: codes for ANG2, which increases the permeability (leakiness) of blood vessels
Check your genetic data for rs2442608 (23andMe v4; AncestryDNA):
Check your genetic data for rs2442630 (23andMe v5):
Check your genetic data for rs2515475 (23andMe v4):
MBL2 gene: codes for mannose-binding lectin, which activates part of the immune response. Low levels are generally linked with an increased risk of infections.
Check your genetic data for rs1800450 (23andMe v4, v5; AncestryDNA):
MyD88 gene: codes for a key activator of pro-inflammatory cytokines (NF-κB, TNF-alpha, and IL-6)
Check your genetic data for rs7744 (23andMe v4; AncestryDNA):
TNF gene: codes for TNF-alpha, important inflammatory cytokine
Check your genetic data for rs1800629 308G>A (23andMe v4, v5; AncestryDNA):
Note that a different study found a decreased risk of getting ARDS in children with sepsis with the rs1800629 A-allele[ref]. The increased TNF-alpha production perhaps may be a risk factor in adults, but not children or elderly patients. More studies are needed to know for sure.
IL17 gene: codes for interleukin-17, an inflammatory cytokine
Check your genetic data for rs2275913 (23andMe v4, v5; AncestryDNA):
NAMPT gene: codes for a rate-limiting enzyme in the NAD+ salvage pathway. It acts as a modulator in the immune system. [ref]
Check your genetic data for rs9770242 -1001T>G (23andMe v4; AncestryDNA):
Normally in a Genetic Lifehacks article, this is where you would find a bunch of ‘lifehacks’ to modify the risk from the variants listed above. But that isn’t appropriate here… I don’t want to take a chance on leading anyone down the wrong path.
Your genetic variants shape your immune system and give you superpowers against some pathogens – and perhaps more susceptible to others.
Your circadian rhythm influences your immune response. Learn how this rhythm controls white blood cell production and why melatonin is important in protecting against viral and bacterial infections.
Have you ever woken up to excruciating pain in your big toe or ankle? If so you may be one of the millions of people worldwide with gout. In fact, a study from 2008 showed that about 8.3 million Americans had gout. Men are affected at about 3 times the rate as women. [ref]
When your body breaks down purines, a type of biological molecule, the eventual by-product of the process is uric acid. And just like it sounds like – uric acid is a normal part of the urine.
This biological process of breaking down purines and thus creating uric acid occurs for both purines created in the body and due to dietary factors. While it is easy to point the finger at the dietary component (alcohol, fructose, meat, and seafood), the purines produced in the body is a big part of your uric acid levels.
Almost all other mammals actually go one step further when metabolizing purines, and they break down the uric acid into allantoin. Humans and higher primates don’t make that final enzyme to convert uric acid into allantoin. (Dalmations also have a genetic defect that causes them to excrete uric acid instead of allantoin.) Researchers theorize that uric acid is important in humans, and possibly takes the place of ascorbic acid (which humans and higher primates also don’t produce). Uric acid acts as a potent antioxidant in the serum, but can act as a pro-oxidant at certain levels and inside cells. [ref][ref]
Purines are a class of biological molecules that include the nucleotides adenine and guanine – the A’s and G’s in your DNA. You naturally have some cells in the body that are broken down each day. Cellular turnover is high in certain tissues (like the intestines and skin) and low in other tissues (like the brain) – but the net effect is that your body breaks down cellular components, including DNA and RNA, all the time.
Guanine and adenine are broken down through a multistep process that eventually creates xanthine, which is acted on by the enzyme xanthine oxidase to form uric acid. (This is important in how gout drugs work.)
Lab ranges may vary a bit on uric acid as far as what is considered normal vs. high. Basically, there comes a point when crystals will form when the concentration of uric acid gets too high.
The normal reference range for uric acid is:
In blood, uric acid crystals start to form at 6.8 mg/dL. [ref] (I have no idea why the normal range for men goes a little higher than the point of crystals forming… )
Normally, about 70% of uric acid is disposed of each day via the kidneys, with the rest being excreted through feces.[ref] High uric acid levels are mainly driven by inefficient renal excretion. [ref]
The levels of uric acid in the body are primarily due to a person’s rate of turnover of cells as well as the rate of excretion and reabsorption in the kidneys. [ref]
In addition to someone’s natural rate of uric acid production and excretion, the following can influence uric acid levels:
There are two ways of looking at high uric acid levels:
The third phenotype here is a combination of both creating two much uric acid along with not excreting enough. [ref]
Figuring out which genetic variants you carry that impact these pathways may help you to determine the best method of decreasing uric acid levels – for you.
The kidneys excrete the majority of uric acid and are the regulators of uric acid levels in the body. They control the balance through reabsorbing uric acid using the urate transporter 1 (SLC22A12 gene) and using the glucose transporter 9 (SLC2A9 gene).[ref]
Lab ranges may vary a bit on uric acid as far as what is considered normal vs. high. Basically, there comes a point when crystals will form when the concentration of uric acid gets too high.
The normal reference range for uric acid is:
In blood, uric acid crystals start to form at 6.8 mg/dL. [ref] (I have no idea why the normal range for men goes a little higher than the point of crystals forming… )
Gout is a painful, acute arthritis condition that is caused when crystals of uric acid accumulate in the joints. Uric acid crystals can also form in the capillaries and skin, but for most people, the first onset of gout is heralded by pain and swelling in the big toe.
Genetics plays a big role in gout, with heritability being estimated at 73% (which is high!). [ref]
Gout occurs with high uric acid levels, but that level at which gout occurs varies a lot from person to person.
Getting more detailed:
High levels of uric acid for long periods of time causes the growth of monosodium urate crystals in and around the joints. These crystals are asymptomatic at first, but they can be seen on ultrasound. The acute episodes of pain are thought to be caused by crystals moving from the cartilage surface into the space in the joint. Ouch! If uric acid remains elevated, the crystals keep forming and periodically moving into the joint space – leading to chronic gout that can damage the joint. [ref]
Another component of the pain of gout is the increase of inflammation due to the monosodium urate crystals.
Xanthin oxidase inhibitors, such as allopurinol and febuxostat, lower urate levels and help to prevent gout attacks.[ref]
Lifestyle interventions, such as dietary changes, have also been shown to be effective in lowering gout risk. See the Lifehacks section below.
Gout is not a new health problem, although it is on the increase. It was written about as far back as the ancient Egyptians and by Hippocrates. In the 1800s, gout was treated with lithium salts, since lithium binds to urate to make it more soluble. And this was (is) commonly used in studies when giving the test subjects uric acid. In fact, this is how lithium came to be used for bipolar disorder. A psychiatrist in 1949 started treating bipolar patients with lithium carbonate after noticing that lab animals were calmer after being treated with lithium plus uric acid. [ref]
The majority of people with high uric acid levels actually do not have gout. A study based on data from 2008 found that 3.9% of US adults had gout, while over 21% of adults had high uric acid levels. This study defined hyperuricemia as serum urate levels of >5.7 mg/dl for women and >7 mg/dl for men.
There are a lot of association studies that show that people with high uric acid also are more likely to have ‘co-morbidities’ or other health conditions. Questions remain, though, as to whether there is causation involved – for example: do high uric acid levels cause high triglycerides or do high triglycerides cause high uric acid. [ref] Is high uric acid just a byproduct (perhaps due to diet) or is it playing a role in causing chronic disease?
Obesity is one co-morbidity that occurs at a higher rate in people with higher uric acid. Some studies indicate that obesity causes high serum uric acid. [ref] Other studies indicate that high uric acid levels cause an increase in obesity. [ref] In fact, some researchers theorize that humans found it to be an advantage to have higher uric acid levels because it promoted fat accumulation, something that was helpful for survival throughout history. [ref]
Interestingly, there seems to be a U-shaped curve for uric acid levels and BMI, with the lowest uric acid found in women with a BMI of 21.3 and men with a BMI of 19.1. [ref]
While the complete picture isn’t clear here, obesity combined with higher uric acid levels is associated with a greater risk of high blood pressure than either condition separately. [ref]
High uric acid levels are linked with a greater risk of heart problems. A study showed that cardiac patients with uric acid levels >8mg/dL had a more than 4-fold increase in the 2-year risk of cardiac mortality. The trend on this seemed to be fairly linear, with people with uric acid >8 at the highest risk for death, uric acid between 7 and 8 still at elevated risk – down to people with uric acid less than 6 being at the lowest risk for cardiac mortality. [ref] Again – I’m not sure that causality is proven here as to whether uric acid increases heart problems or whether heart disease (and heart cell death) increases uric acid.
A really interesting study looked at the effects of giving uric acid to healthy people who had normal levels of uric acid. Giving the people uric acid, of course, raised their uric acid levels. The test subjects then were given a fast-food type meal that contained 900 calories and 50 grams of fat. The researchers then tested their inflammatory markers at 2-hour intervals. This was then compared with the same meal given a couple of days later – but with lowered uric acid levels. The results showed that high uric acid, combined with the high-fat fast-food meal, causes a significant increase in the inflammatory cytokine, IL-6.
Like most things in the body, there seems to be a sweet spot for uric acid – neither too high nor too low. Uric acid does act as a potent antioxidant in the serum, and it is thought to contribute about 60% to the plasma antioxidant capacity in the body.[ref]
Studies show that uric acid levels are lower in people with Parkinson’s disease, and that high uric acid levels are protective against Parkinson’s. [ref][ref] There is also a link between quicker progression in Alzheimer’s with low uric acid. And people with higher uric acid levels are at a reduced risk of Alzheimer’s. [ref]
The following genetic variants have been linked with gout.
ABCG2 gene codes for the ATP-binding cassette transporter G2. There are multiple ATP-binding cassette (ABC) transporters in the body, and they generally move substances across the cell membrane. Researchers and drug manufacturers are particularly interested in several of the ABC genetic variants because they can cause medications (including chemotherapy drugs) to be transported back out of a cell. [ref]
The ABCG2 transporter also is most important in the excretion of uric acid in the intestines. Genetic variants that decrease ABCG2 are associated with increased uric acid levels. While the majority of uric acid is excreted by the kidneys, about a third still gets excreted through the intestines. So decreasing this pathway shifts the burden of excretion to the kidneys. [ref] The genetic variants that impact this pathway may be more of a problem for someone with diminished kidney function. [ref]
Check your genetic data for rs2231142 (23andMe v4, v5; AncestryDNA):
Check your genetic data for rs72552713 (23andMe v4, v5; AncestryDNA):
SLC2A9 gene: codes for GLUT9, a urate transporter in the kidneys that is facilitated by glucose and fructose [ref] Variants here account part of the variation seen in uric acid levels in a healthy population.[ref]
There are quite a few SLC2A9 variants that are linked to a decreased risk of gout — alternatively, you could consider the more common genotype at a higher risk of gout.
Check your genetic data for rs6449213 (23andMe v4, v5; AncestryDNA):
Check your genetic data for rs7442295 (23andMe v4, v5; AncestryDNA):
Check your genetic data for rs12510549 (23andMe v4; AncestryDNA):
Check your genetic data for rs12498742 (23andMe v4, v5; AncestryDNA):
Check your genetic data for rs16890979 (23andMe v4 only):
Check your genetic data for rs1014290 (23andMe v4; AncestryDNA):
Check your genetic data for rs10805346 (23andMe v5; AncestryDNA):
SLC22A12 gene codes for the urate transporter 1 (URAT1), which is a key player in uric acid reabsorption in the kidneys.
Check your genetic data for rs475688 (23andMe v4; AncestryDNA):
Check your genetic data for rs780094 (23andMe v4, v5; AncestryDNA):
SLC28A2 gene: codes for an intestinal transporter that transports dietary purines into the body. Increased uptake of dietary purines could increase the risk for gout, depending on the diet.
Check your genetic data for rs2271437 (23andMe v5 only):
Your doctor can order a uric acid test for you if you suspect you have gout.
If for some reason you can’t order the test through your doctor, you can order it yourself online in the US through Ulta Lab tests and other online lab test ordering companies. (UltaLabs Tests price – $18) This is also a good option if you are trying different lifestyle interventions and want to track the results.
It is always interesting to see how researchers create an animal model of a human condition. To create high uric acid levels, researchers simply give rats 10% fructose in their water. [ref]
In humans, there is a strong relationship between the intake of fructose and uric acid levels. When fructose is metabolized in the liver, it is broken down through a multistep process. When there is too much fructose consumed at once (e.g. drinking a large soda that contains high-fructose corn syrup), one of the components of the metabolism process can build up in the liver. This stimulates purine degradation, which produces uric acid. [ref]
Not all studies agree on the role that fructose plays in uric acid –including a large meta-analysis of controlled trials.[ref]
It may be the amount of fructose consumed at one time that is the key here, with larger amounts overwhelming the liver.[ref] Moderating fructose consumption and not consuming larger amounts at one time may be key here.
ABCG2 variant carriers:
Carriers of the ABCG2 variant rs2231142 T-allele have decreased ABCG2.
Chicory has been shown in studies to decrease serum uric acid levels via increasing the expression of ABCG2 in the intestines.[ref] Chicory is often consumed as a hot beverage, similar to coffee.
On the other hand, a high consumption of fructose decreases ABCG2 levels in the intestines (animal study). [ref]
SLC22A1 (urate transporter 1) variant carriers:
Citrus flavonoids – specifically nobiletin, hesperetin, and naringenin – have been shown in cell studies to inhibit SLC22A1.[ref]
Orange juice is the most common source of the citrus flavonoids in the diet.
Hesperetin and orange juice have also been shown in animal studies to inhibit xanthine oxidase (the enzyme allopurinol acts on). [ref]
SLC28A2 variant carriers:
This gene codes for a transporter that is involved in the absorption of purines from foods. A low intake of dietary purines may work well to mitigate the impact of this variant.
Foods that are highest in purine include (mg/100g) [ref]:
A recent animal study found the hydroxytyrosol, a component of olive leaves and olive oil, decrease uric acid levels and also moderated the levels of ABCG2, SLC22A1 (URAT1), and SLCA9 (GLUT9). [ref]
A meta-analysis of 19 studies on diet and gout found that higher intake of the following foods increases the risk of gout (listed from greatest impact to lowest):[ref]
The following foods are shown in multiple studies to decrease the risk of gout:
Quite a few clinical trials, dating back to the 70s, show that supplemental vitamin C decreases uric acid levels in people with high uric acid. The studies used a range of doses from 500mg/day to 3 g/day. [ref][ref][ref] The only study that I could find that concluded that vitamin C has no effect was one that had the control arm taking allopurinol… [ref]
A randomized, double-blinded, placebo-controlled crossover trial found that 500mg/day of quercetin decreased uric acid levels in men who had high-normal levels at baseline.[ref]
Tart cherry juice was recently shown to have no effect on uric acid or gout flares, although previous studies had indicated there could be a benefit.[ref]
Let’s take fexofenadine (Allegra) for example. You have watery eyes and a drippy nose during spring allergy season and take some Allegra to help with the symptoms. Once swallowed, that medication is dissolved, absorbed, and then transported to the cells where it is going to act. Plus, it has to stay inside of those target cells.
Staying inside the cells – instead of the medicine being transported right back out of the cell – is where genetics comes in to play here.
Certain medications and toxins are transported back out of cells by an ATP-binding cassette transporter protein encoded by the ABCB1 gene.
In the epithelial cells that line your intestines, the ABCB1 proteins are involved in pumping substances back into the intestinal lumen. So imagine if you take an Allegra, it dissolves, gets absorbed, and then part of that gets pumped back into the intestines to be eliminated.
Genetic variants in ABCB1 affect how much stays in the cells vs getting eliminated (through intestines, bile, urine). In general, it is a good thing for the body to get rid of a substance that it thinks might be toxic.
While an allergy medication not working well for you isn’t really a bid deal, the real problem comes when trying to keep chemotherapy drugs inside of cancer cells. Thus, this gene has been studied in depth for drug that treat cancer.
ABCB1 gene (multidrug resistance protein, p-glycoprotein):
The genetic variant known as rs1045642 or C3435T has been extensively studied in regards to response to quite a few different drugs. Those who have the AA genotype (23andMe orientation) have less of an efflux (outward flow) of certain drugs — meaning that less of the drug is transported back out of the cell by the ABCB1 transporter. [ref]
Less of a drug transported out of the cell usually indicates a higher effectiveness of the drug for that individual. The variant, AA, is fairly common with about 25% of Caucasians carrying it (less frequent in Asian populations).
Check your genetic data for rs1045642 C3435T (23andMe v.4 only)
Check your genetic data for rs1128503 C1236T (23andMe v4, v5; AncestryDNA):
Note that the two SNPs above, rs1045642 and rs1128503, are almost always inherited together. In some studies you may see one or the other rs id referred to. [ref]
If you carry one of the variants above, you may be wondering what you can do to increase the effectiveness of your allergy medicine during this pollen season.
A natural inhibitor of ABCB1 is piperine, a substance found in black pepper. Studies have shown that piperine increases the effectiveness of fexofenadine (Allegra) by about 2-fold. [ref] [ref] Of course, check with your doctor if you have any questions about this or other medications.
Our immune system’s response varies over the course of 24-hours. At certain times, we may be more resilient to fighting off viruses; at other times of the day, we may be more susceptible to pathogens.
For anyone who has traveled across multiple time zones, this altered immune response won’t come as much of a surprise. How many times have you adjusted to jet lag, just to end up with a cold or not feeling well? Similarly, you are at an increased risk of getting sick when staying up late – pulling that all-nighter before finals or working the night shift once in a while.
This article covers the background information on how your circadian rhythm and timing is important in your body’s immune response in general — and the response to viruses such as COVID-19 and the flu. Just want to know about COVID-19? Jump ahead to that section.
The term circadian comes from Latin, circa diem, meaning about a day. Humans – and actually all animals and plants – have a built-in clock system that controls bodily functions across the course of 24-hours.
The first thing that comes to mind for circadian rhythms is usually the sleep/wake cycle. Humans (and diurnal animals) are naturally awake during the day and sleep about 8 hours at night.
Over the last two decades, researchers have uncovered the genes that control this built-in clock and discovered that many of the body’s functions happen in a rhythmic fashion. For example, we don’t produce the enzymes needed for breaking down different foods during the night when we are normally sleeping. It turns out that 10 to 40% of our cellular functions are under circadian clock control.[ref]
Our circadian rhythm isn’t exactly 24-hours, and the body uses outside signals to reset the clock each day. Sunlight is the synchronizer of the core circadian clock. The sun comes up every morning… every single day throughout the history of the earth.
In humans, the core circadian pacemaker is located in the hypothalamus, right in the mid-part of the brain. It is called the suprachiasmatic nucleus (SCN).
The signal that sets that core circadian clock is a specific wavelength of light hitting the eyes. In the retina, you have rods and cones for color and night vision. Additionally, the retina contains non-image forming photoreceptors with melanopsin. These receptors directly signal to the suprachiasmatic nucleus (SCN) to reset the circadian clock.
The melanopsin receptors are triggered, or excited, by light in the blue wavelengths. Prior to electric lights, the only exposure that we had to light in the blue wavelengths was due to sunlight (firelight, candlelight has very little light in the blue wavelengths).
This causes a mismatch in modern times with bright electric lights and blue wavelengths at night battling our evolutionarily conserved mechanism of resetting the circadian clock. Many research studies show the impact of blue light exposure at night on both melatonin and our circadian rhythm. (article)
Different tissues and organs throughout the body have their own clock mechanism. These ‘peripheral clocks’ control the rhythm of expression of genes – the creation of different cellular enzymes and proteins – in tissues such as the skin, liver, pancreas, heart, and adrenal glands.
The liver is geared up and ready to produce enzymes needed to breakdown food (or medicine) at the time of day that you normally eat. Your skin produces different enzymes during the day for battling UV exposure and for making vitamin D. And your vitamin D levels rise and fall in a circadian pattern as well, with a peak mid-day. One study indicates that 25-OH D levels (the commonly tested vitamin D component) can change up to 20% over a 24-hour period. (Something to keep in mind the next time you get blood work done.) [ref][ref]
The key with these peripheral clocks is that they are also affected by your core circadian pacemaker (the SCN) in the hypothalamus. The core circadian clock interacts with the peripheral circadian clocks – and this whole system needs to be in sync for optimal wellness.
For example, the adrenal glands release glucocorticoids, e.g. cortisol, in a rhythm that is (ideally) in sync with the body’s core circadian rhythm. The hypothalamus, where the suprachiasmatic nucleus is located, also directly controls the rhythm of the glucocorticoids. The HPA axis – hypothalamus-pituitary-adrenals axis – receives input directly from the suprachiasmatic nucleus, which receives input from the natural light/dark cycle of the sun. [ref][ref]
Why am I using the HPA axis as an example here? Because the HPA axis is also very important in the body’s immune response…
Key fighters in your body’s defense against pathogens include macrophages and lymphocytes. Macrophages are a type of large white blood cell that patrols and engulfs foreign pathogens, cellular debris, and cancer cells. They are found throughout the body. Lymphocytes, which are found in the lymph, are another type of white blood cell and include T-cells and B-cells.
B-cells are made in the bone marrow, and macrophages are also formed from bone marrow stem cells.
Researchers have found that there is an innate circadian rhythm to the production of macrophages, B-cells, and T-cells. White blood cells are released from the bone marrow at the beginning of the rest phase (night time for humans). This leads to a peak serum circulation for these immune cells in the rest period. [ref] During the day, these immune cells then migrate into the body’s tissues where they will do their job, defending against pathogens as well as normal cellular cleanup.[ref]
Cortisol levels, as well as inflammatory cytokines, peak during the beginning of the active phase (first thing in the morning). [ref]
You can see where I’m going here — the overnight period of rest (aka sleep) is vital for your body’s immune function the next day.
Not only is there a rhythm to the production of new white blood cells, but within the cells, there is also a circadian rhythm. T-cells, a type of white blood cell produced in the thymus, have a circadian rhythm within the cell. These oscillations are controlled in part by BMAL1, a core circadian clock gene. [ref] Macrophages also exhibit their own internal clock, which affects the production of cytokines in the cells. [ref]
So basically, there is a rhythm to when there are more circulating white blood cells in the body — plus there is a rhythm within the cells as to when they have maximum cytokine production.
That is one headline that I never thought I would write :-)
Animal studies show that time of day matters a lot in both herpes and flu viral replication. The mice that infected just before the rest phase (just before mouse bedtime ;-) had a 10-fold greater viral replication than the mice that were infected at the start of their active phase. Moreover, in mice that had the BMAL1 (core circadian clock) gene knocked out, the mice had higher viral replication no matter what time they were infected with either herpes simplex 1 or the flu. [ref]
A cell study showed that PER2 helps to counteract hepatitis C viral replication. PER2 is a core circadian gene that is highly expressed at night in humans. [ref]
In healthy people, there is a circadian rhythm to pulmonary function. Research shows that people’s lungs work better during the day (best around noon) and function is at the lowest in the wee hours of the morning (usually around 4 am). [ref][ref]
In a viral model of acute airway disease, animal studies show that circadian rhythm is also important. Researchers gave mice jet-lag (messed with their circadian rhythm by changing the lighting) and found that the mice had increased susceptibility to viral bronchitis and increased replication of the virus. The same study showed that deleting the BMAL1 gene (core clock gene) also caused increased susceptibility to airway problems due to viruses. [ref]
To sum this up – a circadian rhythm that is out of sync, such as due to traveling across time zones or suddenly staying up several hours later than normal, causes a greater susceptibility and worsened response to a virus that causes bronchitis. It is thought that this is a similar mechanism to the time-of-day differences in asthma and COPD problems.
Patients with COPD (chronic obstructive pulmonary disease, emphysema) are at a much higher risk of problems with the flu, rhinovirus, RSV, and coronavirus. Research shows that 50-70% of acute problems (i.e. go to the doctor/hospital type of problems) in COPD are due to viral infections. The circadian decrease in lung capacity (FVC) that happens in the early hours of the morning coincides with emergency room visits for people with COPD. [ref]
Researchers modeled COPD in mice using chronic cigarette smoke exposure. Then they exposed the mice influenza A. Not surprisingly, the mice with chronic cigarette exposure had a worse response to the flu than the control mice that were not smokers. When the mice were exposed to the flu, the non-smoker mice had somewhat altered circadian rhythm (active vs rest cycle), but the cigarette smoke-exposed mice had a significant alteration to their activity vs rest cycle. In fact, they were just as active during the day as they were at night. (mice are nocturnal…) The researchers found that the core circadian rhythm gene expression was altered in the lungs of mice exposed to the flu, and that the changes in gene expression were much greater in the cigarette smoke-exposed mice. [ref]
You may be thinking that vaping is the answer here… It turns out that e-cigarettes also alter the core circadian clock genes in the lungs. [ref]
A study (in humans) looked at the rhythm of immune cell production and the rhythm of cytokines (Il-6, TNF-alpha, and IL-IB) for the study participants during a normal day-oriented schedule and then after three days of working the night shift. For the normal day-oriented schedule, there were two peaks: a peak in the night-time production of the cytokines and another peak in the day due to a higher proportion of immune cells in the tissues.
When the study participants underwent three days of having a night-oriented schedule (i.e. working the night shift), the cytokine production peak was partly shifted, but the peak in the proportion of immune cells didn’t shift. So part of the immune rhythm shifted to the new schedule – but part of it didn’t. The study concludes “This led to a desynchronization of rhythmic immune parameters, which might contribute to the increased risk for infection, autoimmune diseases, cardiovascular and metabolic disorders, and cancer reported in shift workers.” [ref]
It isn’t only a one-way street here where the human circadian rhythm is the only thing that matters in fighting off pathogens. It goes both ways — some pathogens can alter the host circadian rhythm and thus cause worsening of the disease.
Sleeping sickness is a tropical disease that more than 10,000 people per year will contract in sub-Saharan Africa. It is caused by the parasite Trypanosoma brucei. The reason this truly terrible disease is called “African sleeping sickness” is that the parasite causes people to have altered sleep/wake cycles. Researchers in 2018 found that the parasite actually disrupts the body’s normal circadian rhythm. It causes altered sleep/wake cycles and body temperature cycles by shortening the period of the core circadian clock. [ref]
Studies also show that viruses such as herpes simplex virus 1affect the transcription of different genes including the core circadian genes, CLOCK and BMAL1. [ref]
A study of canine coronavirus (not the same strain as COVID-19) showed that the viral infection caused changes to sirtuin expression. Sirtuins, specifically SIRT1, can act within the nucleus to turn on and off other genes. SIRT1 is important in cell defense and the resistance to cell death (apoptosis). SIRT1 is an NAD+ dependent protein. [ref] (Read more about SIRT1 and NAD+)
Melatonin is a hormone produced in large quantities by the pineal gland at night. Melatonin levels rise in the evening hours, peak at night, and then are suppressed during the daytime by exposure to blue light. In addition to being important for circadian rhythm, melatonin is also produced in small amounts in cells throughout the body all day. It acts as an intracellular antioxidant and also as an immunomodulator.
Melatonin from the pineal gland is vital to the immune system – and also affected by the immune system. It is a two-way street. Interferon-gamma has been shown in studies to increase melatonin production, and other immune system signals can suppress melatonin. Research studies on sepsis show that melatonin may be beneficial for reducing excessive cytokine production and restoring mitochondrial function. Many animal studies show that melatonin enhances immune function prior to stimulation, but it may also tamp down an excessive immune response.[ref] [ref][ref]
In other words, melatonin is needed before getting sick to keep your immune system up and running well, and once you are sick, melatonin may keep your immune system function at the right level.
Melatonin as an antiviral:
Melatonin has been shown in viral infection to reduce mortality and delay disease onset in infected animals. In animal studies using stressed-out mice given West Nile virus, melatonin prior to infection and continued 10 days after infection reduced mortality and the virulence of the disease. Melatonin was proposed in research studies as being helpful for the Ebola virus.[ref] [ref][ref]
Unfortunately, melatonin production from the pineal gland declines with aging as the pineal gland calcifies. The decreasing melatonin levels with age are thought to be one of the causes for declining health in old age. [ref]
Being generally more susceptible to viruses at night may have you re-thinking your plans to go out in crowded bars or concerts late at night during flu season. If you think about it, prior to electric lights, people were more likely to gather in crowds – and thus need their immune system on high alert – during daylight hours. It makes sense that our immune system would ‘restock’ and produce more white blood cells overnight when people are normally sleeping and not interacting and spreading germs.
The declining melatonin levels with age may contribute to the susceptibility of older people to pathogens including the season flu viruses and COVID-19. (Melatonin isn’t the only part of the immune system that changes with age, of course, but it does seem to play a big role in overall immune function.)
If you do get sick with either the flu or COVID-19 and need hospitalization, the constant lights and noises in hospitals can be really hard on your circadian rhythm. You may want to have a sleep mask and earplugs on hand.
The alterations to circadian rhythm functions in the lungs from cigarette smoke and vaping may increase the risk for a more severe respiratory infection. While most of us know that smoking isn’t good, the changes in clock genes due to vaping may be pretty important here as well. [ref][ref]
As you get older, NAD+ levels decline. While there is still a lot of research to be done on this topic, the interaction between NAD+, SIRT1, and circadian rhythm may be important in preventing illness, especially respiratory illnesses. This research paper has a good overview of how NAD+ and SIRT1 interact with the circadian system in airway diseases. (Genetic Lifehacks article on boosting NAD+)
A new study, published on March 16, 2020, investigated the pathways utilized by the coronavirus that causes COVID-19 and cross-referenced this with FDA approved drugs. One of the drugs suggested by this pathway analysis is melatonin. From the study: “The antioxidant effect of melatonin makes it a putative candidate drug to relieve patients’ clinical symptoms in antiviral treatment, even though melatonin cannot eradicate or even curb the viral replication or transcription61,62. In addition, the application of melatonin may prolong patients’ survival time, which may provide a chance for patients’ immune systems to recover and eventually eradicate the virus. As shown in Fig. 5e, melatonin indirectly targets several HCoV cellular targets, including ACE2, BCL2L1, JUN, and IKBKB.” [ref]
The animal studies on viruses show that melatonin before and during viral infection may help. You can boost your own production of melatonin by blocking blue light at night. Wearing blue light blocking glasses has been shown to increase melatonin production by 50% within a week.[ref] Bright light during the day, such as going outside, increases melatonin production at night. [ref]
Melatonin production decreases with age due to calcification of the pineal gland. Depending on your age, you may want to investigate whether supplemental melatonin is right for you. If you go the supplement route, look for time-release melatonin to better mimic the natural production of melatonin. The immediate-release formulas are cleared from your body rather quickly.
It makes sense that our immune system’s circadian rhythm can impact the effectiveness of vaccines. A vaccine gives a small amount of a pathogen so that your body will mount an immune response and then remember that pathogen.
A study in the UK looked at the timing of vaccines for the annual flu vaccine in adults over age 65. People getting the H1N1 vaccine had a significantly greater antibody response if they were vaccinated in the morning vs. the afternoon. But that same study showed that the H3N2 vaccine didn’t have a response difference between morning and afternoon vaccines. [ref]
A lot more research needs to be done on this topic, but it may turn out that there are certain times of the day that are better for getting your seasonal flu vaccine – or for getting your coronavirus vaccine next year.
Keeping your circadian rhythm on track is important for your ability to fight off pathogens. Burning your candle at both ends or jet-lag from travel leaves you more susceptible to viral and bacterial infections.
Is sleeping well, blocking blue light at night, and getting sunlight during the day a magic pill to prevent all diseases? Of course not. But when your circadian rhythm is out of sync, you are going to be more susceptible than you would be otherwise.
Viral Immunity & Your Genes
Your genetic variants shape your immune system and give you superpowers against some pathogens – and perhaps more susceptible to others.
Vaccinations and MTHFR
Taking an in-depth look at the research and evidence about vaccinations and MTHFR… Learn about what the studies show regarding a link (or – spoiler alert – lack lack of a link) between the MTHFR variant and vaccines.
Aging brings with it a myriad of health issues including an increased risk of diabetes, heart disease, cancer, and neurodegenerative diseases. A supplement that can mitigate the root cause of some of these age-related conditions is a very alluring idea. But does the research back it up?
This article delves into the recent research on a natural compound called fisetin that may prove to be a key anti-aging component. Or… it could be just one more way to keep mice healthy. Read through the research and decide for yourself whether fisetin is worth trying or is something to keep an eye on for the future.
Fisetin is a natural flavonol found in several types of fruits and vegetables. It is being studied for a variety of health benefits including preventing complications from diabetes to heart disease, and as a longevity compound. Fisetin has been shown in several recent studies to clear out senescent cells, which holds a lot of promise for healthy aging.
This article probes the evidence for using fisetin as a longevity compound and explores the research on supplemental fisetin’s health benefits. We will also explore the timing and dosages of fisetin used in clinical trials. Finally, you will be able to draw your own conclusions as to whether there is sufficient evidence for using fisetin at this time.
At the end of a cell’s life, a cell becomes senescent, giving off signals that it needs to be removed by the immune system. The chemical signals that it gives off are pro-inflammatory cytokines, so it becomes a source of low-level inflammation. Senescent cells are sometimes called ‘zombie cells‘ because they aren’t quite dead, but they are no longer functioning cells.
The process of cellular senescence is a natural part of the cell cycle, and it is important in both wound healing and in stopping cells from becoming cancerous. You want a cell that is damaged (or cancerous) to stop the cell cycle and hang out a flag saying that it is time to be killed off and recycled.
Cellular senescence is triggered by a number of circumstances including[ref]:
Younger people with a good immune system have no problem clearing out senescent cells, and this process of cell-cycle arrest and clearing out cellular insults works well. Just as it is supposed to.
The number of senescent cells increases with age. Older people often have a problem clearing out all of the senescent cells, and this is directly linked to some of the diseases associated with aging.
I mentioned above that cells hang out a flag when they become senescent. The ‘flag’ that senescent cells wave when they need to be killed off and recycled is a chemical signal of inflammatory cytokines. When senescent cells aren’t cleared quickly, this can leads to local inflammation and neighboring cells also becoming senescent. This secretion of inflammatory cytokines by senescent cells is known as ‘senescence-associated secretory phenotype’ (SASP).[ref] Stopping this low-grade inflammation is one goal in longevity science.
Clearing out senescent cells has been shown in animal studies to prevent the onset of age-related diseases. This increases healthspan (number of years of healthy living), as well as increasing lifespan (in animals). [ref]
The animal studies on this are pretty cool, and they clearly show that a buildup of senescent cells is one major aspect of the diseases of aging. Human studies on longevity are harder to fund and take a much longer time (of course).
Targeting senescent cells, likewise, seems to be an effective way to combat some of the problems of aging. [ref]
There are two pathways through which increased senescent cells could lead to the chronic diseases of aging:
Why don’t senescent cells die? In addition to the SASP signals that are calling for the cell to stop dividing and be destroyed through apoptosis, senescent cells also upregulate something called the senescent-cell anti-apoptotic pathway (SCAP). This pathway prevents apoptosis, or the clearing out of cells.
Senolytics are compounds that target and clear out senescent cells. They do this by targeting the SCAP pathway. Senolytics are a relatively new concept, with the first studies on them published in 2015. This concept of being able to clear out senescent cells in aging has prompted a lot of interests, and a bunch of studies have been published on senolytics in the past few years. [ref]
Initial work with senolytics focused on the similarities between cancer cells that don’t divide and senescent cells. This led researchers to experiment with a chemotherapy drug called dasatinib. Further research showed that dasatinib plus quercetin, a natural compound found in fruits and vegetables, was even more effective at clearing senescent cells and increasing healthspan (animal studies).[ref][ref
Fisetin has been shown in several promising new studies to act as a senolytic.
A study investigating natural senolytic compounds found that fisetin was the most effective flavonoid for reducing senescent markers — and more potent than quercetin. The study also showed that fisetin increased the lifespan and healthspan of mice. Of note here is that the mice were given fisetin starting when they were 85 weeks of age, which is equivalent to 75-years-old for a human.[ref]
That same animal study showed the fisetin, when given at a high dose for a few days, was able to clear out 25-50% of senescent cells in different organs. [ref]
A different cell study showed that fisetin causes cell death (apoptosis) in certain types of senolytic cells including endothelial cells. It was not shown to be a senolytic for lung fibroblast cells. [ref]
I want to note here that while the animal studies on fisetin as a senolytic are very promising, the human studies are not yet complete. This is all really new research.
Fisetin has been shown to act both as a direct antioxidant and to also increase the body’s antioxidant system via activating glutathione. Fisetin’s actions as an antioxidant may have important implications for reducing age-related neurodegenerative diseases.[ref]
Cell studies show that fisetin may reduce amyloid-beta, the protein that accumulates in the brain with Alzheimer’s. The study showed the reduction fisetin to be similar to the reduction due to melatonin [ref]. (Read more about melatonin and Alzheimer’s)
Cell studies and animal studies also show that fisetin inhibits microglial
Advanced glycation endproducts (AGEs) are another natural occurrence that both increases with age and can increase the problems with the diseases of aging. Methylglyoxal is a breakdown product in the body that can react to form advanced glycation end products. This can lead to complications in diabetes, such as diabetic retinopathy. (Read more about AGEs and genetic variants)
Fisetin has been shown in animal studies to decrease the formation of methylglyoxal. Fisetin was shown to upregulate the Nrf2 pathway, increasing glutathione which reduces methylglyoxal levels. The animal studies in mice bred to be diabetes showed that fisetin didn’t change blood glucose levels or alter weight, but it did reduce the complications of diabetes such as kidney disease. The mice that had consumed fisetin (0.05% of their diet) had decreased levels of oxidative stress and reduced the formation of advanced glycation endproducts.[ref]. One thing to note here is that fisetin reduced AGEs and oxidative stress in the mouse models of diabetes — but it didn’t have an effect on normal mice with normal levels of AGEs and oxidative stress.
Other animal studies do show a decrease in blood glucose levels with fisetin, which may indicate that it should be investigated further for diabetes prevention or treatment.[ref]
In cell studies, fisetin has been shown to inhibit mast cells from releasing inflammatory cytokines (IL-31, IL1B, IL4, IL6, TNF-alpha, and NF-κB) along with inhibiting histamine release. [ref] [ref] [ref] Another study shows that fisetin inhibits mast cell activation due to stimulation from T-cells. [ref]
While I am not finding any human trials using fisetin as a mast cell stabilizer, the animal studies on this are intriguing.
Please bear in mind that animal studies and cell studies don’t always show the same results in human studies.
As a senolytic:
There are currently a couple of phase 2 clinical trials underway by the Mayo Clinic using fisetin in older people as a senolytic. No results have been posted yet, though. Both of the clinical trials used a dosage of 20mg/kg/day for two days. [ref] [ref] This would be equivalent to 1,600mg/day for someone who weighs 175 lbs.
A 2018 clinical trial of fisetin administered via IV after a stroke concluded that “Fisetin dramatically improved the treatment outcomes of the patients with stroke in the delayed OTT [onset-to-treatement time] strata, as revealed by lower NIHSS scores.” The clinical trial used a one-time treatment of 0.9mg/kg given via IV followed by 7 days of 100mg of fisetin per day. [ref]
As an antioxidant:
A 2012 clinical trial investigated freeze-dried strawberry powder to see if it could prevent pre-cancerous lesions of the esophagus from progressing. The results showed that the higher dosage of 60g/day (for 6 months) of freeze-dried strawberries had the potential for preventing esophageal cancer. [ref] Strawberries contain the highest amount of fisetin of any fruit or vegetable – along with other vitamins and micronutrients.[ref]
A clinical trial in colorectal cancer patients showed that fisetin (100mg/day) given along with their chemotherapy significantly reduced IL-8 and hs-CRP, which are markers of inflammation.[ref]
Bioavailability and Timing:
Senolytics are usually used in brief periods of time – often for a few days per month or quarterly. Senescence is an important bodily function, and clearing out senescent cells continually is not usually recommended. All of this is fairly new research, so there doesn’t seem to be a consensus yet on the most effective timing of senolytics.
Fisetin is not very water-soluble, and studies show that fisetin encapsulated in micelles (surrounded by fat) may be more effective. [ref]
The study referenced above on the combination of melatonin and fisetin is interesting. It may be that fisetin is more effective when taken at night — possibly depending on your goals for the compound.[ref]
It is always important to keep in mind interactions between any prescription medications and supplements, even herbal supplements that seem safe. A recent study showed that fisetin inhibits CYP2C8, a liver enzyme that is important in the metabolism of several drugs. (More information on CYP2C8 and genetic variants).
Another study showed that fisetin may moderately inhibit CYP2C19, CYP2C9, and CYP1A2.[ref] CYP2C19 is notable in that it is the only enzyme that converts Plavix into the active form of the drug that inhibits clotting. (Read more about CYP2C19 genetic variants and Plavix.)
Fruits and vegetables contain small amounts of fisetin. Strawberries are by far the largest dietary source of fisetin with 160mg in a kg of strawberries.
Rhus verniciflua stokes, which is known as a Korean herbal supplement, contains fisetin as one of its active components. Notably, it also contains urushiol, which is what causes the skin reaction in poison ivy. Studies on Rhus verniciflua stokes with urushiol removed show that is may have positive pharmacological properties. It contains about 2% fisetin. [ref]
There are a lot of interesting animal and cell studies on fisetin which show a lot of promise as far as a senolytic and as a possible cancer therapeutic (for certain types of cancer). But… there is a lack of human trials that make it difficult to know if the results of animal studies will hold true for humans. Lots of things look good in animal studies.
The human studies on fisetin at lower levels as an antioxidant seem promising as well.
If you want to learn more about fisetin as a senolytic and read user comments on trying fisetin both at lower and higher dosages, check out fightaging.org’s article.