What is Tumor Necrosis Factor (TNF)?
The three most common inflammatory cytokines that are responsible for chronic inflammatory diseases are Tumor Necrosis Factor (TNF), Interleukin-1beta (IL-1b) and Interleukin-6 (IL-6). These are the most commonly talked about cytokines in the literature.
The transcription factor nuclear factor NF-kappaB is also heavily spoken about and these four proteins are what people most likely refer to when they talk about chronic inflammation (whether they are aware of this or not).
TNF can be increased in either Th1 dominance or Th2 dominance.
TNF increases CRP, which is a common blood measurement to gauge inflammation. However, CRP is not sensitive enough to detect lower, but chronic levels of TNF. See my discussion of this in my IL-6 post.
It’s important to realize that you can have TNF elevated locally in areas such as your hypothalamus or gut and it wouldn’t show on blood tests.
Many kinds of cells release TNF and then TNF goes on to stimulate other immune cells.
TNF is released by Macrophages, Dendritic cells, T cells, Fat cells, and Fibroblasts.
TNF then affects various cells. In particular, it will affect cells that line our blood vessels (endothelial cells), which causes vascular problems and this strongly causes cancer, as it causes angiogenesis and increased blood vessel formation (hypervascularization). It can also cause heart disease, kidney disease, and cognitive problems.
TNF stimulates macrophages and effector T cells, which leads to more inflammatory cytokine production and apoptosis resistance (which contributes to cancer).
Therefore, it’s good to have this elevated somewhat at night when we want to fall asleep. TNF is elevated naturally in healthy people at night time.
So high levels of TNF makes you thinner by causing you to eat less and by inhibiting glucose into fat cells.
If you decrease TNF, you will become more hungry and store more fat.
Hence, it’s not surprising that anti-TNF therapy results in weight gain -an average of 5.5kg or 11 pounds in only 12 weeks (R). It’s incredible that only one variable changed (TNF) and the study participants gained on average 11 pounds.
Even a relatively low level of TNF decreases aldosterone synthesis in response to ACTH (precursor of cortisol), which increases in response to stress and intense exercise (R). This can lower blood pressure.
Exercise increases ACTH, which normally tells our body to conserve salt by increasing aldosterone. However, if we have inflammation, then aldosterone production will be limited and if we sweat a lot it can cause low levels of salt in the body.
I have already spoken about how I think trying to increase your motivation or mood by hacks, tricks, or by changing your mindset will only increase your neuroticism.
If you have elevated TNF and you bring it down, this will positively affect your mood and motivation.
TNF plays a major role in many diseases and is a cytokine that is a performance killer.
TNF can cause lasting harm by damaging your mitochondria (R).
Orexin is an extremely important neurotransmitter for many bodily functions.
Orexin performs a number of key roles in memory acquisition and consolidation, as well as in long-term memory reinforcement (R). Hence, if you have elevated inflammation, it will harm your cognitive performance (also by decreasing BDNF, etc).
Diseases Associated With TNF-alpha
- Autoimmune disease: in general (R), Multiple Sclerosis (R), Behcet’s (R), SLE (R), Scleroderma (R), Sarcoidosis (R), Hidradenitis suppurativa (R), Ankylosing spondylitis (R), Erythema nodosum leprosum (R)
- Heart disease (R) – Heart failure (R), Atherosclerosis (R), Stroke (R)
- Cancer in general (R), Melanoma (R)
- Insulin Resistance (R), Diabetes II (R)
- Alzheimer’s (R), Parkinson’s (R), ALS (R)
- Major Depression (R) – Depressed people had TNF levels that were about 3.97 pg/ml higher than healthy people (R).
- IBS (R, R2), Crohn’s/Ulcerative Colitis (R)
- Rheumatoid Arthritis (R)
- Osteoporosis (R)
- Psoriasis (R), Eczema (R)
- Asthma (R), COPD (R). TNF stimulates various molecules which recruit eosinophils, neutrophils, and lymphocytes to the airway. TNF can induce corticosteroid resistance (R).
- OCD – only sometimes (R), Schizophrenia (R), Bipolar (R, R2), Anorexia (R)
- PCOS (R) – TNF shifts production of cortisol to testosterone, hence causing PCOS (R).
- Chronic Fatigue Syndrome (R), Fibromyalgia (R) – contradictory (R).
- Others: Tinnitus (R), Epilepsy (R), Cystic Fibrosis (R), Chemotherapy-induced neuropathy (R), Diabetic Neuropathy (R), Chronic liver disease (R), Fatty Liver (R)
The Most Significant Factors That Influence TNF
Recent research indicates that TNF is potently inhibited by exercise (specifically, myokines or proteins produced by the muscles such as IL-6) (R). However, excessive exercise or Marathons will elevate TNF (R).
An infection can also elevate TNF. Bacterial (rather than viral) infections are more likely if you have elevated TNF (R).
- Oxidative stress – TNF activity is dependent on the generation of ROS (R).
- Lectins – For people who are lectin sensitive (perhaps a quarter of the population)
- Sun – Both UVA and UVB, which are emitted by the sun, acutely increase TNF-alpha (R, R2, R3). I still support sun exposure.
- Excessive exercise/Marathons (R)
- Sleep deprivation (R)
- Chronic insomnia – in the day time (R).
- Obesity (R)
- High glucose levels (R) – usually because of high glycemic index foods (R).
- A lack of exercise (R)
- A lack of resistant starch (R)
- Circadian disruption (R)
- Excess alcohol (R)
- Smoking (R)
- A high-fat diet (especially palmitic acid (R) – this doesn’t mean to eat a low fat diet) (R).
- A lack of foods like fruits and vegetables, which contain phytochemicals that inhibit TNF and other kinds of inflammation (R, R2).
- Heavy metals (R)
- Some toxins (R)
- Magnesium deficiency (R)
- Zinc deficiency (R)
- Vitamin D deficiency (R, R2, R3)
- Chromium deficiency (R)
- Choline Deficiency (R) – People who consumed more than 360 mg per a day had a 12% lower concentrations of TNF than those who consumed less.
- Coffee – Coffee drinkers had an average of 28% higher TNF, but maybe people with high TNF are tired, so they’re more likely to drink coffee. I got inflammation from it.
- Goji Berries (R), Aloe – (in cancer cells) (R), Reishi (R) – decreases if high (R), Andrographis (R), Apismin – found in honey and royal jelly (R). (I once took 20X the dosage of royal jelly and got fever from it). Arabinogalactan – (R).
- Vasopressin (R), IGF-1 (R), Angiotensin II (R).
Joe’s Top ways to Inhibit TNF alpha
- Vagus nerve stimulation (R)
- Ketosis (R)
- Acute psychological stress (R) and Glucocorticoids/Cortisol (R) (not recommended)
- Calorie restriction (R)
- Yoga (R)
- Tai Chi (R)
- Wim Hof Breathing/Meditation (R)
- Cycling (R)
- Mediterranean diet (R)
- Elemental diet for lectin sensitive (R).
- Napping after sleep loss (R).
- Falling in love, having sex, nursing, and positive social encounters. All of these lead to increased oxytocin (R). L Reuteri also increases oxytocin (R).
- LLLT (R, R2, R3)
- Elemental diet (R)/ Lectin avoidance diet if lectin sensitive
- Fish Oil/DHA+EPA (R)
- Fasting (R)
- PQQ (R)
- Curcumin (R, R)
- EGCG (R)
- Cinnamon/Sodium Benzoate (R, R2)
- Black Cumin Seed Oil (R)
- Rooibos (R)
- Carob (R)
- Nicotinamide Riboside NAD+ (R)
- Kombucha/Lactic acid (R)
- Hops (xanthohumol) (R)
Since TNF is one factor that makes us tired at night, I recommend taking most supplements in the day time.
All of the products that are not drugs are in my toolkit unless there’s a star next to it.
There are drugs that target TNF (monoclonal antibodies). They are effective and should be taken if all else fails and if they are indicated for your condition (with the approval of your doctor). You’d also want to measure your blood levels of TNF before you take these drugs.
The biggest problem with inhibiting TNF too much is that you become more susceptible to infections – and when you do get sick it’s more dangerous.
When researchers tried to give drugs to inhibit TNF and IL-1b together, they had to stop the trials because people started to get sick very easily. The supplements are not as strong, so there’s not much concern here. Also, when herbs inhibit TNF, they are simultaneously acting as antimicrobials, which prevents you from getting infections to begin with (or activating latent infections).
If you take multiple supplements and combine them with diet and lifestyle, the effect should be significant, but I haven’t noticed an increase in infections on myself.
Diet And Lifestyle To Inhibit TNF
One study found no difference in IL-6 or TNF in people who ate whole grains vs refined grains for 12 weeks (R). However, I’ve come across many studies that do show a reduction in inflammation with legume consumption (R, R2) — but obviously not for lectin sensitive people.
Interestingly, in men, red meat was associated with lower TNF (but was correlated with CRP in women) (R).
Foods To Inhibit TNF
- Sardines (the protein in it) (R)
- Cinnamon/Sodium Benzoate
- Nutritional Yeast/B-glucans (R, R2) – found in mushrooms.
- Stevia (R, R2)
- Honey (R)
- Chocolate /Coffee – PDE inhibitors such as xanthines, caffeine, and theophylline
- Trehalose (R, R2)
- Garlic (R)
- Fish Oil (R)
- Dates (R, R2)
- Blueberries/Berries/Cyanidin-3-O-β-glucoside (C3G) – typical anthocyanin found in blackcurrant pomace, European elderberry, red raspberries, plum, peach, lychee, and açaí (R).
- Sulforaphane/Broccoli Sprouts/Cruciferous Veggies (R)
- Soy (R)
- Betalain/Beets (R)
- Kamut (R)
- Coriander (R)
- Tamarind (R)
- Slippery elm (R)
- Dandelion (R)
- Cortisol (R)
- MSH (R)
- ACTH (R)
- Oxytocin (R)
- Adiponectin (R)
- Melatonin (R)
- Vitamin D3 (R)
- Progesterone (Pregnenolone converts to it) (R)
- Estrogen (Pregnenolone converts to it) (R)
- DHEA (R)
- Ghrelin (R)
Top Supplements To Inhibit TNF
- Aspirin (R)
- Inositol (R, R2) – also see picture above
- Boswellia (R)
- Nicotinamide (R)
- EGCG (R)
- Hydroxytyrosol (R)
- Licorice (R), LicoA (R), Glycyrrhizin (R)
- Luteolin (R)
- Andrographolide (R)
- Fisetin (R)
- Resveratrol (R)
Other Supplements To Inhibit TNF
- Bile (R)
- Lactoferrin (R)
- Glycine (R)
- Chromium (R)
- Sialic Acid (R, R2)
- Arginine (R)
- Bromelain (R)
- Berberine (R, R2)
- Apple polyphenols (R)
- Silymarin (R)
- Honokiol (R)
- Chinese Skullcap (R)/Baicalin (R)
- Ginkgo (R)
- Hespderidin (R)
- Carnosine (R)
- Phytosterols (R)
- Tart Cherry (R)
- Astaxanthin (R)
- Astragalus (R)
- Probiotics/B. coagulans (R)
- Cat’s claw (R)
- Artemisinin (R)
- Carnitine (R)
- Genistein (R)
- Amla/Indian Gooseberry (R)
- CoQ10 (R)
- Magnolol (R)
- Echinacea (R)
- Chaga/Betulin (R)
- Bitter melon (R)
- Mastic gum (R)
- Oxymatrine (R)
- Red clover (R)
- Glucosamine (R)
- Quercetin (R)
- Rutin (R)
- Myricetin (R)
- Chrysin (R)
- Mannose? (R)
- Forskolin (R)
- Molecular Hydrogen (R)
- Histidine (R)
- Antler velvet (R)
- Emodin (R).
- Danshen (R)/TanshioneII (R)
- Agmatine + Zymosan (R)
- Mercury – Low levels (R)
- Mud therapy (R)
Drugs That Inhibit TNF
- Cannabis/THC/Marijuana/Pot (R, R2)
- Low Dose Naltrexone – LDN (R)
- Metformin (R)
- Red Yeast Rice/Statins (R)
- MDMA (R)
- Psychedelics/Hallucinogens, via 5-HT2A agonism (extremely potent) (R). These include: Magic mushrooms (psilocybin, the psychedelic) (R), LSD(R), DOI (R), DMT (R), Ayahuasca (R) and Mescaline (R)
- Cocaine (R)
- Allegra/Fexofenadine (R)
- Mizolastine (antihistamine) (R)
- Bupropion (drug, Wellbutrin) (R)
- Rapamycin (R) longevity drug.
- Thalidomide and analogs (R) (Drug)
- Monoclonal antibodies are obviously the strongest: infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi), etanercept (Enbrel).
Pathways To Inhibit TNF
- Delta-opioid receptor activation (R)
- ACE inhibitors (drugs and most herbs are) (R)
- PPARy (R)
- HDAC inhibitors (Butyrate) (R)
Elevated TNF and Chronic Infection
Antibiotics like doxycycline should be explored as a last resort. While Doxycycline might not work and may have some side effects, at least it has some potential benefits. Doxycycline is a nootropic, where it increases neurogenesis and reduces microglia in the hippocampus (memory center) (R) and has been found to extend worm lifespans (R). Minocycline also increases neurogenesis in adults (R) and lifespan in flies (R).
Why Some People Produce More TNF Than Others
The reason why some people produce TNF more than others is at least partially as a result of genetic predisposition.
- RS1041981 (TNF)
- RS1799724 (TNF)
- RS1799724 (TNF)
- RS1799964 (TNF)
- RS1800629 (TNF)
- RS1800630 (TNF)
- RS1800750 (TNF)
- RS2229094 (TNF)
- RS2844484 (TNF)
- RS3093662 (TNF)
- RS3093665 (TNF)
- RS3093726 (TNF)
- RS361525 (TNF)
- RS673 (TNF)
- RS909253 (TNF)
Evolutionary Reason For Different TNF-alpha Levels
In different environments, different genes are better for survival. For example, higher levels of TNF help prevent a tuberculosis (TB) infection (R) and other infections. The microbe that caused the plague was able to decrease TNF (R), contributing to its deadliness. We might not think of this as significant, but in our history it mattered quite a bit.
With better hygiene and antibiotics and the desire for longer life, people with genes that cause elevated TNF are at a disadvantage in the modern era, even though it would’ve been useful in the past.
Skeletal remains show prehistoric humans from 4000 BC had TB, and researchers have found tuberculosis in the spines of Egyptian mummies dating from 3000–2400 BC. In Europe, rates of tuberculosis began to rise in the early 1600s to a peak level in the 1800s, when it caused nearly 25% of all deaths. By 1918, one in six deaths in France was still caused by TB (R).
In the year 588 AD, the Plague of Justinian (caused by the bacteria, Yersinia) killed as many as 100 million people across the world. It caused Europe’s population to drop by around 50% between 541 and 700 (R).
From 1347 to 1351, the Black Death (also caused by Yersinia) swept through Asia, Europe and Africa. It may have reduced the world’s population from 450 million to between 350 and 375 million. China lost around half of its population, from around 123 million to around 65 million; Europe around 1/3 of its population, from about 75 million to about 50 million; and Africa approximately 1/8 of its population, from around 80 million to 70 million. The plague kept killing huge swaths of Europe’s population until the late 1700’s and also affected China and the Islamic world, but seemingly less so (R).