Always tired? Genetic reasons for fatigue

Do you constantly feel tired, even when you know you slept well? Exhausted. Drained. Unable to function.

Fatigue is a debilitating condition that plagues many people, and research now points to the root cause of fatigue: elevated inflammatory cytokines.

This article digs into the new studies showing that inflammation causes the brain to alter our behavior. Genetics research fills in the details on why and how inflammatory cytokines cause fatigue. Understanding your genetic susceptibility to fatigue may help you to target the underlying causes.

Fatigue has a neuroimmune root cause:

Kind of like pornography, we all recognize what fatigue is, even if it is sometimes hard to define and quantify. Fatigue is overwhelming tiredness, but not the same type of tiredness that you get from lots of physical activity or from lack of sleep. It can be temporary or long-lasting.

But what causes fatigue? Why does it last, even when you rest enough?

Understanding why you feel fatigue from a physiological standpoint may set you on the path towards conquering it.

Fatigue in the physically ill patient is one of the most common and earliest non-specific symptoms of disease and can persist long after the medical condition has resolved.[ref]

Inflammation as a (the?) cause of fatigue:

Inflammation-induced fatigue is the concept that higher levels of inflammatory cytokine production cause the feeling of fatigue, aka chronic inflammation.

Fatigue is a totally normal response to inflammation: when your immune system is kicking into higher gear, this usually means you’re sick or wounded. And when you are sick or wounded, you should want to lie down and rest.

This fatigue response to inflammation is something that all sick or hurt animals experience.

“…the behavior of sick animals and people is not a maladaptive response or the effect of debilitation, but rather an organized, evolved behavioral strategy to facilitate the role of fever in combating viral and bacterial infections.”[ref]

But what if you aren’t sick or hurt? Chronically elevated inflammatory cytokines can trigger the same pathways that cause you to feel fatigued when you’re ill.

As one study puts it: “…sickness behaviour is not an accident of chronic inflammatory diseases but an adaptive program used during immune activation. Unfortunately, this program is switched-on considerably too long, during chronic conditions, sometimes lifelong.”

Fatigue is all in your head (neuroinflammation):

Researchers have found that the brain is the “central regulator of fatigue perception”.[ref]

Inflammatory cytokines signal an inflammatory response in the body, but how do elevated cytokines impact the brain?

Elevated levels of cytokines in the body cannot easily get past the blood-brain barrier. Instead, the peripherally elevated cytokines can signal to the brain through a couple of pathways.

  • The vagal nerve passes along the ‘inflammation’ signal to the brain from the abdomen.
  • The trigeminal nerve is responsible for the brain knowing about infections in the teeth and oral cavity.
  • At high enough levels, some inflammatory cytokines can gain access to the brain through transporters at the blood-brain barrier.[ref]

Getting specific: What is chronic inflammation?

I’ve seen inflammation written about in vague terms on almost every alternative health or natural medicine type of website. Usually, the articles encourage eating the right diet (whatever ‘right’ diet is being promoted) or buying their supplements.

I will go into a little more depth here on the specifics of the inflammatory cytokines – and then revisit all of these in the genetic variants section below.

Inflammatory cytokines elevated in fatigue:

Known causes of fatigue include elevated levels of:

  • interleukin-1α (IL-1α, IL1A gene)
  • interleukin-1β (IL-1β, IL1B gene),
  • tumor necrosis factor-α (TNF-α, TNF gene)
  • interleukin-6 (IL-6, IL6 gene).[ref]
  • interferon-gamma and kynurenine (IDO gene)

Additionally, the NLRP3 inflammasome can cause an increase in several of the inflammatory cytokines.

Interleukin 1:

Interleukin 1 is part of the innate immune response. There are two main players here: IL-1alpha (IL-1α) and IL-1beta (IL-1β).

IL-1α is released when cells die, and it is present on the surface of immune system cells such as monocytes and B cells.

IL-1β is produced only in specific immune cells, including monocytes, macrophages, and dendritic cells. When either of the IL-1 proteins binds to the IL-1 receptor, it causes a cascade of inflammatory events to happen.[ref]

Elevated IL-1 in the brain directly leads to ‘sickness behavior’, including fever and sleep. These behavior changes are due to altered dopamine synthesis via disruption of a precursor (BH4). Serotonin production can also decrease due to a shift in tryptophan to be used for kynurenine production. Reduced dopamine means that you aren’t motivated to do anything, and reduced serotonin may mean that you are less social and a little more irritable. AKA -Fatigue.

TNF-alpha:

TNF-alpha (tumor necrosis factor alpha) is a pro-inflammatory cytokine produced by macrophages, monocytes, and other cells.  When a lot of TNF-alpha is produced by a cell, it is a signal that causes the cells to undergo cell death. Great when needed to destroy a tumor cell, but too much TNF-alpha is also linked to Alzheimer’s, Parkinson’s, psoriasis, arthritis, septic shock, and COPD.[ref]

There are two sides to TNF-alpha, though. When it docks with tumor necrosis factor receptor 1 (TNFR1 receptor), it initiates a whole cascade of inflammatory events including NF-kB activation or cell death. But there are also cases when TNF-alpha acts to modulate or reduce the immune response through binding to the TNFR2 receptor.

Elevated TNF-alpha levels are thought to be causal – or at least part of the cause – in neurodegenerative disorders such as Alzheimer’s, ALS, and Parkinson’s.[ref]

TNF-alpha inhibitor drugs are available and used for several chronic diseases. Side effects are the big drawback to these drugs, such as increased infections, fungal overgrowth, and potential increased cancer risk. For example, thalidomide is a TNF-alpha reducing drug with a wide range of side effects, including severe birth defects.[ref]

Interferon-gamma and Kynurenine:

Interferon-gamma is a pro-inflammatory cytokine that is activated to fight off viral infections. It is the body’s first line of defense against certain viruses, and you need a good response to knock out a virus.

But elevated interferon-gamma also shifts tryptophan metabolism away from serotonin/melatonin and towards the kynurenine pathway. It can result in higher levels of the neurotoxic metabolite quinolinic acid and a reduction in serotonin and melatonin.[ref]

NLRP3 inflammasome:

Activation of the NLRP3 inflammasome causes an increase in other inflammatory cytokines such as IL-1B and IL-18.  Basically, it revs up the immune response when activated by pathogens (such as viruses) or damage to cells (wounds, radiation, DNA or RNA that isn’t inside a cell where it should be, and misfolded proteins).

Chronic activation of NLRP3 is associated with atherosclerosis, MS, and diabetes.[ref][ref][ref]. Animal studies show that NLRP3 activation and its subsequent increase in IL-1B causes significantly more fatigue than without NLRP3.[ref]

Sources of chronic inflammation:

So what causes the elevation of these inflammatory cytokines all the time? Many reasons include autoimmune diseases, chronic conditions, sleep problems, stress, and exposure to environmental toxicants.

Chronic diseases and autoimmune conditions that involve chronic inflammation and fatigue include:[ref]

  • Rheumatoid arthritis, with 50% or more reporting severe fatigue[ref][ref]
  • Sjögren’s syndrome – higher Il-1 levels and fatigue[ref]
  • Diabetes – 40% reporting fatigue[ref]
  • Cancer- higher IL-1B and TNF-alpha linked to fatigue levels[ref][ref]
  • Depressive disorder
  • Multiple Sclerosis
  • Parkinson’s disease
  • Chronic liver disease[ref]
  • NAFLD[ref]
  • Inflammatory Bowel Disease[ref]
  • chronic infections[ref]

In general, many autoimmune diseases (including the ones listed above) are characterized by aberrant inflammatory cytokine activation.[ref]

Often, though, fatigue due to chronic illness is exacerbated by additional causes…

Not always a single source!

If you don’t have a ‘chronic disease’ such as those listed above, other environmental factors may play a role in constantly feeling fatigued.  While any one of these sources of inflammation (e.g., air pollution) is unlikely to cause constant fatigue, the combination of several could be.

Sleep and Circadian rhythm: We all know that sleep is essential to overall health. But the timing of sleep also comes into play with chronic inflammation. The body’s 24-hour circadian rhythm controls when inflammatory cytokines are high and when they are low. When your circadian system is out of balance (staying up late, traveling across time zones, eating at odd hours), this can alter the rhythm and amplitude of cytokine production.[ref]

Stress and Inflammation: We are built to respond to stressful situations periodically – running from a tiger, dealing with the death of a loved one. But repeated stresses cause an increase in pro-inflammatory cytokines, including inflammatory cytokine elevation in the areas of the brain related to fatigue and anxiety.[ref]

Air pollution: Increased air pollution exposure, especially to fine particulates, is linked to increased inflammation and increased oxidative stress.[ref] Specifically, higher levels of fine particulates correlate to higher levels of IL-1, IL-6, and TNF-alpha in healthy young adults.[ref]

Toxicants: Environmental exposure to toxicants is a vast topic. Some chemicals that we are exposed to daily are likely increasing oxidative stress and increasing inflammatory cytokines.[ref] But to some extent, there is an individualized response to detoxification (metabolism, elimination) of toxicants based on genetic variants in detoxification genes.

Toxicants that may cause increased oxidative stress and increased inflammatory cytokines include pesticides (organophosphates, paraquat, pyrethroids), flame retardants, metals (lead, mercury, aluminum, arsenic, manganese, cadmium, copper), plasticizers (BPA, phthalates), and PFOAs.[ref]

 Evidence showing inflammation causes fatigue:

Correlation vs. causation: Research is clear that elevated cytokine levels are found in people with fatigue, but that doesn’t necessarily prove that it is causal. The mechanism of action seems more than plausible, but let’s see what other evidence there is.

Animal studies clearly show that increasing certain cytokine levels consistently provokes fatigue-like behaviors.

Animal studies of the brain show changes that cause fatigue-like behavior:[ref]

  • Increasing TNF-alpha interferes with noradrenaline secretion in certain parts of the brain.
  • Elevated IL-1β along with IL-6 suppressed noradrenaline release.
  •  IL-2 can inhibit dopamine release from the striatum and noradrenaline release from the hypothalamus (regions of the brain).

Ok, so researchers can induce fatigue-like behavior in animals by increasing inflammation. But what about in humans?

Studies show that interferon-alpha, when used as a drug to fight chronic hepatitis C, causes fatigue symptoms. Clinical trials using interferon-alpha show that a common side effect of interferon-alpha is persistent fatigue lasting more than 6-months.[ref][ref]

Endotoxin (lipopolysaccharide, LPS) exposure causes fatigue in people. A study exposed participants to low levels of endotoxin, which is a molecule found on the out membrane of some bacteria, or to placebo. The endotoxin exposure (without any bacteria) caused an immediate rise in IL-6. While this is expected in response to a bacterial infection, there was no actual infection involved. The researchers went further and did neurological tests, with the results showing a quick depression in mood along with the rise in IL-6. Additionally, in women, the neurological tests also showed “increases in social pain-related neural activity” in certain brain regions.[ref]

Research shows that inflammation also decreases neurotransmitter formation via reducing BH4 (tetrahydrobiopterin), which is needed for dopamine and serotonin production.[ref]

The other side of the equation also works: reducing inflammation causes a reduction in fatigue.

For people with rheumatoid arthritis, drugs that target inflammatory cytokines, such as anti-TNF agents, lead to a moderate improvement in fatigue scores.[ref] As one research study points out, “Fatigue in RA is prevalent, intrusive and disabling.”[ref] Thus, the reduction in an inflammatory cytokine causing a reduction in fatigue points directly to the inflammation as the cause of fatigue.


Genetic variants linked to fatigue:

Not seeing your data below? Select your data file on the member’s dashboard. Not a member? Join now.

IL1B gene: encodes interleukin-1 beta, a pro-inflammatory cytokine

Check your genetic data for rs4848306 (23andMe v5; AncestryDNA):

  • A/A: typical fatigue
  • A/G: most common genotype
  • G/G: more likely to experience fatigue with inflammation[ref]

Members: Your genotype for rs4848306 is .

Check your genetic data for rs1143643 (23andMe v4; AncestryDNA):

  • C/C: typical
  • C/T: fatigue more likely in chronic illness
  • T/T: fatigue more likely in chronic illness[ref]

Members: Your genotype for rs1143643 is .

 

TNF gene: encodes the TNF-alpha cytokine

Check your genetic data for rs1800629 -308A/G (23andMe v4, v5; AncestryDNA):

  • A/A: Higher TNF-alpha levels.[ref][ref][ref][ref], greater fatigue levels[ref]
  • A/G: higher TNF-alpha levels, greater fatigue levels
  • G/G: typical

Members: Your genotype for rs1800629 is .

Check your genetic data for rs3093662  (23andMe v4, v5; AncestryDNA):

  • G/G: Higher TNF-alpha levels, greater fatigue levels[ref][ref]
  • A/G: higher TNF-alpha levels, greater fatigue levels
  • A/A: typical

Members: Your genotype for rs3093662 is .

 

IL6 gene: encodes interleukin-6, a pro-inflammatory cytokine

Check your genetic data for rs1800795 (23andMe v4, v5; AncestryDNA):

  • G/G: increased fatigue, higher IL6[ref]
  • C/G: increased fatigue
  • C/C: typical (less IL-6 produced)

Members: Your genotype for rs1800795 is .

 

INFG gene: interferon-gamma is part of the innate defense against viral pathogens

Check your genetic data for rs2430561 +874T>A (23andMe v5; AncestryDNA):

  • T/T: more common genotype;
  • A/T: higher interferon-gamma producers; increased fatigue and sickness behavior
  • A/A: higher interferon-gamma producers[ref] increase inflammatory[ref] increased risk of fatigue or sickness behavior[ref]

Members: Your genotype for rs2430561 is .

 

NLRP3 gene (CIAS1): encodes the NLRP3 protein

Check your genetic data for rs35829419 Q705K (23andMe v4; AncestryDNA):

  • A/A: Increased NLRP3 activation[ref][ref]; significantly increased risk of severe fatigue (13-fold) with inflammation[ref]
  • A/C: significantly increased risk of severe fatigue with inflammation
  • C/C: typical

Members: Your genotype for rs35829419 is . (If you don’t see your 23andMe v4 data for this one, check it on 23andMe. It doesn’t show up in some downloaded data sets.)


Lifehacks:

Fatigue can be a non-specific sign that something is wrong, and you should talk with your doctor about fatigue along with any other symptoms. For example, fatigue can be an initial symptom of cancer or autoimmune disease.[ref] Push for answers as to whether there are any indications of underlying diseases.

Dietary changes:

Anti-inflammatory diet:  Studies show that targeted dietary changes to reduce inflammation help fatigue in people with chronic diseases. A review sums it up: “clinical studies demonstrate that a balanced diet with whole grains high in fibers, polyphenol-rich vegetables, and omega-3 fatty acid-rich foods might be able to improve disease-related fatigue symptoms.” [ref]

While online diet gurus may argue the details of what constitutes an anti-inflammatory diet, the overarching theme is a diet that contains whole foods and not a lot of packaged, processed food.

High folate vegetable intake decreased TNF-alpha levels in women with the MTHFR C677T TT genotype.[ref]

Supplements to target inflammation:

Curcumin inhibits TNF-alpha production.[ref]

Apigenin and narigenin also inhibit TNF-alpha.[ref]

Korean Red Ginseng: A recent animal study shows that Korean red ginseng reduces fatigue by impacting the corticosteroid system, influencing inflammation.[ref] Other research shows that it may also inhibit inflammation through decreasing NLRP3 activation.[ref]

Dihydromyricetin is derived from natural flavonoids and has been shown to decrease IL-1B in animal studies.[ref] It may also decrease IL-6.[ref]

Quercetin, another natural flavonoid, significantly inhibits IL-1B production.[ref]

Panax ginseng has been shown in animal studies to reduce fatigue through reducing IL-6 and TNF-alpha. Human trials don’t show as much of an impact, though, as seen in animal studies.[ref]

NLRP3 specific supplements:

Methylene blue’s neuroprotective effects are, at least in part, via inhibition of NLRP3 activation in the microglia.[ref][refHead’s up: Don’t take methylene blue if you have G6PD deficiency. Read more about methylene blue as a nootropic.

CBD oil decreases inflammation, in part, through inhibition of the NLRP3 inflammasome.[ref] Read more on how your genetics can affect how it works for you.

EGCG, found in green tea, may help to suppress the activation of NLRP3. Research on EGCG in animals shows it suppresses the activation of NLRP3.[ref]

Lifestyle change:

Avoiding toxicants, air pollution, and cigarette smoke should reduce inflammation…but how do you do that?

If you live in an area with high air pollution or higher indoor VOC levels, look into air filtration systems with a HEPA filter.  One study (in China) found that indoor air purifiers reduced inflammatory biomarkers, including IL-1B.[ref]

Certain pesticides, such as rotenone and chlorpyrifos, activate the NLRP3 inflammasome.[ref] Avoiding pesticides as much as possible is a good idea. This could mean eating organic when possible, but it also, perhaps, more importantly, includes looking at what you spray in and around your house.

Moderate exercise exerts part of its anti-inflammatory effects via reducing TNF-alpha.[ref]


Extras for Members:

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Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.