TNF-alpha and Inflammaging

TNF-alpha (tumor necrosis factor alpha) is a proinflammatory cytokine upregulated in aging. TNF-alpha acts as a signaling molecule in our immune system and is important in our innate immune response. But chronically elevated TNF-alpha is one cause of the diseases of aging. Inhibiting chronic inflammation is one tool available for longevity and healthspan.

This article will dig into the role of elevated TNF-alpha in the disease of aging as well as natural solutions for decreasing TNF-alpha and resolving inflammation.

Elevated TNF-alpha in aging:

TNF-alpha acts as a signaling molecule. Activated immune cells, such as macrophages, mast cells, B cells, and lymphocytes produce TNF-alpha. Its production also occurs in other cells, such as smooth muscle cells, in response to an injury.[ref]

TNF-alpha is a signal that calls in the troops to cause cell death. This is great when it involves tumor cells (get the name – tumor necrosis factor), but not great when we are talking about chronic inflammation.

Researchers have known for several decades that elevated TNF levels are a prognostic marker for mortality in the elderly.[ref][ref]

Genetics studies show that genetic variants associated with lower inflammatory cytokine production, including lower TNF-alpha levels, are linked to longevity.[ref]

One source of elevated TNF-alpha in aging is from B cells. A type of white blood cell, B cells are responsible for the body’s antibody response. In aging, a subset of B cells become inflammatory, secreting TNF-alpha among other cytokines.[ref]

Senescent cells, which are no longer able to function properly or reproduce, give off inflammatory cytokines, including TNF-alpha.[ref] Cellular senescence increases considerably with aging. Additionally, higher levels of inflammatory cytokines, such as TNF-alpha, can cycle back to increase cellular senescence.[ref]

Elevated TNF-alpha also plays a role in the pathogenesis of neurological diseases including Alzheimer’s, ALS, and Parkinson’s disease.[ref]

Production of TNF:

TNF-alpha is a cytokine that can either be on the membrane of a cell (in immune cells) or released from all types of cells in the soluble form.

TNF-alpha is a ‘pyrogen’, meaning it can cause fevers, signal cell death, and inhibit viral replication.

TNF-alpha receptors:

The signal from TNF-alpha received by several different receptors causes different actions to happen in a cell.

TNFR1, tumor necrosis factor receptor 1, is found on most types of cells throughout the body. When activated by TNF-alpha, it can signal to increase NF-κB, another important inflammatory cytokine in the important pathway for resisting infection. TNFR1 also signals for the initiation path for cellular death (such as for killing off tumor cells).

The TNFRSF1A gene codes for TNFR1, and variants in TNFRSF1A can cause periodic fever syndrome, a genetic auto-inflammatory disease.  Elevated TNFRSF1A levels are associated with schizophrenia, bipolar disorder, and dementia or cognitive impairment in aging.

TNFR2 (tumor necrosis factor receptor 2), on the other hand, interacts with T-cells in controlling the immune response. Dysregulation here is one factor in autoimmune diseases such as Crohn’s, MS, lupus, and type 1 diabetes.[ref]

The TNFRSF2A gene encodes the TNF receptor 2 protein found only on immune cells. It doesn’t initiate cell death. So to some extent, TNFR2 is playing more of a modulatory role in the immune response.

Why would you want to decrease TNF-alpha?

While TNF-alpha is essential for removing cells with DNA mutations that could cause cancer, chronically elevated TNF-alpha is not good and plays a causal role in many of the diseases of aging.

Quite a few studies show elevated TNF-alpha levels present in mild cognitive impairment (MCI) and Alzheimer’s disease. Animal studies show that once chronic brain inflammation is occurring, there is an upward spiral of TNF-alpha induced, which may stimulate amyloid-beta plaque formation.[ref] Note that chronically elevated TNF-alpha is just one of the players here — I don’t want it to seem like this is the only thing going on in the pathogenesis of Alzheimer’s disease.

Animal studies also elucidate the role of elevated TNF-alpha in the brain inflammation involved in Parkinson’s disease.[ref]

Higher levels of TNF-alpha due to genetic variants have links to gum disease, inflammatory bowel disease, asthma, COPD, heart disease, septic shock, and arthritis.[ref][ref][ref][ref][ref][ref][ref][ref][ref][ref] If you have your genetic data from 23andMe or AncestryDNA, check your TNF gene variants here.

Always keep in mind that it is a balancing act between not wanting chronic inflammation and the need for a good response to kill potentially cancerous cells.

Anti-TNF drugs:

TNF-alpha inhibitors approved by the FDA include:

  • infliximab (Remicade)
  • adalimumab (Humira)
  • certolizumab pegol (Cimzia)
  • golimumab (Simponi)
  • etanercept (Enbrel)

The inhibitors are used for autoimmune diseases such as rheumatoid arthritis, psoriasis, and IBD, which are all associated with increased TNF-alpha and too much cell death.[ref]

Note that one side effect of TNF-alpha inhibitors is an increased risk for certain cancers.

Natural TNF-alpha inhibitors:

Talk to your doctor or pharmacist if you are on any medications before beginning supplements.

Many of these natural TNF-alpha inhibitors have the added benefit of being anti-cancer molecules as well. This may be one advantage of using natural polyphenols for reducing elevated TNF-alpha over stronger pharmaceutical options.

Quercetin:

Quercetin is a flavonoid found in fruits and vegetables such as apples, onions, and blueberries. Many studies show that quercetin supplementation can decrease TNF-alpha levels.[ref][ref]

Quercetin has poor bioavailability, with only about 2% absorption for oral doses. Studies show absorption occurs in the upper section of the small intestines.[ref]

Quercetin can impact iron absorption — good if you are high in iron, but a problem if you are needing more iron. If you are low in iron, you may want to make sure to time your quercetin away from iron-rich meals or iron supplements.

Quercetin is better absorbed with fat. A study found a ~40% increase in bioavailability when taking a quercetin supplement along with a high-fat meal (15g of fat in their breakfast).[ref]

Curcumin:

Curcumin is a polyphenol found in turmeric (a spice). Many studies have shown both in humans and animals that curcumin is a natural inhibitor of TNF-alpha. It works to block the release of TNF from macrophages and it works to inhibit some of the downstream inflammatory effects when TNF-alpha binds to either TNF receptor.[ref]

Curcumin bioavailability improves 3-fold when taken with piperine, a component of black pepper. A clinical trial in people with NAFLD showed that 500 mg/day of curcumin + 5mg of piperine lowered TNF-alpha levels. Another clinical trial using 1,000 mg/day of curcumin + 10 mg piperine showed a significant reduction in TNF-alpha levels in people with diabetes. Final example – a clinical trial of 1,000 mg/day of curcumin in people with metabolic syndrome also showed a significant reduction in TNF-alpha levels.[ref][ref][ref]

Curcumin doesn’t absorb well in the intestines and quickly metabolizes once absorbed. The piperine allows it to stick around longer in the body, and nanoparticles and other complexes make it more bioavailable.[ref]

Cannabinoids:

Studies point to a role for cannabinoids in reducing TNF-alpha.[ref][ref]

Cannabidiol (CBD), a non-psychoactive component of cannabis and hemp, may also be an option for decreasing the release of TNF-alpha. [ref][ref][ref]

Luteolin:

Cell studies show that luteolin, a flavonoid, suppresses the release of TNF-alpha.[ref] Animal studies also show that luteolin can decrease the transcription of TNF-alpha.[ref] There are just a few human studies using luteolin as an anti-inflammatory. One study in children with autism showed that a supplement containing luteolin (100mg) and quercetin (70mg) reduced TNF-alpha levels.

Hesperidin:

One more anti-inflammatory flavonoid is hesperidin and it is found in citrus fruit. Animal and cell studies show that hesperidin decreases TNF-alpha levels.[ref][ref][ref]

Hesperidin doesn’t absorb well in the stomach or small intestines. Instead, the colon’s microbiome converts it to the more bioavailable aglycone hesperetin for easier absorption. It is possible the metabolites give the health benefits, rather than the original hesperidin molecule.[ref]