Acupuncture & Chinese Medicine ● Longevity Nutrition

TNF alpha

 

IMG_1102

To review, inflammation is not the underlying root of any disease. It is a side effect of a deeper cause. In the previous article I outlined the four core causes of inflammation and discussed some potential problems and benefits of boosting the immune system by stimulating inflammation. Continuing with TNFα as an example, let’s look at the potential problems of taking anti-aging substances to reduce inflammation.

TNFα is an inflammation weapon produced by certain immune cells to protect us from viruses and cancer.

What happens when you take substances that reduce TNFα activty? Several strong pharmaceutical drugs like Humira® and Enbrel® were developed specifically for the purpose of suppressing excess activity of TNFα and relieving the inflammation of many autoimmune diseases. The immune-suppressing side effects of these strong drugs offer glimpse of what happens to the body when TNFα levels are too low. As we would expect, many of side effects revolve around the microbial kingdom gaining the upper hand. These include acute infections of the nose, throat or sinus, cellulitis, fungal infections, reactivated tuberculosis, shingles and bacterial sepsis.   For those suffering from autoimmune disorders, this is a calculated risk. By shutting down inflammation, these drugs disarm the immune system so it can no longer effectively fight invaders.

Several herbs and supplements also suppress TNFα. Touted as “anti-inflammatory” or “anti-aging” these include curcumin[i], black cumin seed[ii], Boswellia[iii] and Cat’s Claw[iv]. While nowhere as strong as some of the pharmaceuticals, what happens to the body’s immune defenses when TNFα is artificially lowered? Some pathogens suppress TNFα as a way manipulate and elude the immune system[v]. Over time can moderate suppression of TNFα compromise the body’s natural defenses against overgrowth of pathogens? Since we are turning off the chemicals that cause the symptoms, how would we even know? Our current medical technology has very limited tools for detecting the presence of an invading pathogen. Most of our tools look to the immune system to provide clues about invaders. A simple urinalysis or blood test cannot detect specific pathogens. Instead it looks for high levels of immune cells like neutrophils or lymphocytes to help the physician determine what is causing the infection. By the time these immune cells show up in lab work, there has already been a significant breach of the immune system.

We know that lectins, proteins found in beans and lentils, will raise levels of TNFα. This is not because these foods have mysterious powers. It’s because the immune system mistakes them for an invader and launches an attack against them. Lectins are not inherently dangerous. However, the immune response that they elicit could certainly influence the rate of aging of any tissues participating in the reaction. Perhaps this is why the Indian diet evolved to include so many herbs that suppress this type of inflammation from immune activity. But where is the line? If there are signs of inflammation, how do we know if it is coming from a legitimate invader or if it’s an artifact of our evolution? If someone is experiencing inflammatory symptoms, shouldn’t we identify what is triggering the immune system to act before we suppress it?

 

An Anti-Aging Regimen Gone Awry

I felt compelled to write this after seeing an extremely healthy patient with recurrent thrush (a yeast infection of the mouth). It was fairly mild but was enough for his doctor to perform an HIV test. It was negative. This gentleman was obsessed with life extension and he was seemingly doing everything right. He was doing intermittent fasting, interval exercise, alkaline water, Paleo Diet, lots of veggies, adequate protein, low sugar and carbs, blackout curtains at night. His labs showed everything as perfect. Even his neutrophils (the immune cells that fight yeast) were on target. As part of his life extension regimen, he was paying a small fortune every month for herbs and supplements. Of interest, these included curcumin, Pterostilbene, green tea extract, fish oil, Boswellia and, when it was still available, Anatobloc®. Unless he took antifungals all the time, the thrush would come back. For awhile, I thought it was microbiome issue. A microbial stool analysis showed only mild yeast overgrowth. This was notable but not remarkable because I see these mild levels in at least 70% of the patients tested. We tried various live-shipped probiotics and fermented foods with no improvement.   After a couple of months it finally occurred to me that he may have been going to far with suppressing inflammation. After some negotiating, he finally agreed to stop the Anatobloc, curcumin and Boswellia for a few weeks. Sure enough, within a week, no more thrush!

Perhaps one day we will have amazing assays to instantly identify any immune trigger that is causing inflammation. Until then how do we find that sweet spot where we suppress inflammation while still helping our immune system do what it already knows how to do?

 

[i] Cho, J., Lee, K., & Kim, C. (2007). Curcumin attenuates the expression of IL-1β, IL-6, and TNF-α as well as cyclin E in TNF-α-treated HaCaT cells; NF-κB and MAPKs as potential upstream targets. International Journal of Molecular Medicine, 19, 469-474. http://dx.doi.org/10.3892/ijmm.19.3.469

[ii] Aftab Ahmad, Asif Husain, Mohd Mujeeb, Shah Alam Khan, Abul Kalam Najmi, Nasir Ali Siddique, Zoheir A. Damanhouri, and Firoz Anwar A review on therapeutic potential of Nigella sativa: A miracle herb Asian Pac J Trop Biomed. 2013 May; 3(5): 337–352. doi:  10.1016/S2221-1691(13)60075-1 PMCID: PMC3642442

[iii] B. Gayathria, N. Manjulaa, K.S. Vinaykumara, B.S. Lakshmia, , , A. Balakrishnanb Pure compound from Boswellia serrata extract exhibits anti-inflammatory property in human PBMCs and mouse macrophages through inhibition of TNFα, IL-1β, NO and MAP kinases. International Immunopharmacology Volume 7, Issue 4, April 2007, Pages 473–482

[iv] Sandoval M1, Charbonnet RM, Okuhama NN, Roberts J, Krenova Z, Trentacosti AM, Miller MJ Cat’s claw inhibits TNFalpha production and scavenges free radicals: role in cytoprotection.

Free Radic Biol Med. 2000 Jul 1;29(1):71-8.

[v] Bosio CM. The Subversion of the Immune System by Francisella Tularensis. Frontiers in Microbiology. 2011;2:9. doi:10.3389/fmicb.2011.00009.

Facebooktwittergoogle_pluspinterestlinkedinby feather

Inflammation is not the underlying root of any disease. It is a side effect of a deeper cause. Tinkering with inflammation is tinkering with the immune system. Buzzwords like “anti-cancer”, “anti-viral”, “anti-inflammation” and “immune-boosting” are misleading and offer no information about how various herbs, supplements and pharmaceuticals actually work. Desperate for relief, ill consumers are constantly duped by the supplement industry as they seek easy answers for complex diseases. When the mechanism of a supplement doesn’t match the underlying cause of the immune imbalance, short-term side effects commonly occur. An understanding the mechanisms of aging offers us a glimpse of the potential short-term and long-term side effects that can result from tinkering with the immune system.

When I began studying functional medicine 18 years ago, I was awakened to the then controversial hypothesis that inflammation was the primary driver of many of the diseases of aging. There were hundreds of studies demonstrating the correlation between inflammation and conditions like heart disease, obesity, diabetes, cancer and even aging. As I developed my practice, it was like having magical powers believing that the cause of heart disease was not cholesterol but, in fact, inflammation. Armed with supplements like fish oil, curcumin and boswellia, I felt like Wonder Woman, striking down interleukin 6, NF-kappa B, TNFα and other inflammatory signals that could lead to disease. It wasn’t until I began treating autoimmune and skin disorders that I came to realize that inflammation is not the underlying root of any of these diseases. It’s a side effect of a deeper cause. In fact, suppressing inflammation without understanding its cause is as insane as turning off the fire alarm and going back to bed while the house fills with smoke.

There are four core mechanisms that drive inflammation.  This article will explore the most common; when the immune system recognizes something as an invader and launches an attack using inflammatory chemicals as weapons. In science we call this immune system activation by antigen recognition.

The other three (listed below) will be discussed in future posts.

  • Over activation of NFKappaB through dietary signaling. Activity of NFKappa B is highly influenced by the presence or absence of insulin[1]. In general, diet doesn’t cause inflammation; it simply acts like a volume control.  It isn’t until grossly pathological changes develop through excessive insulin signaling and ROS production that we begin to see the out-of-control inflammation associated with diseases like obesity and diabetes.
  • Deranged methylation and acetylation of DNA[2],[3]. Basically methyl groups (from SAMe) and acetyl groups are stuck to DNA to turn it on and off.
  • The healing response – the redness, pain and swelling that results from an injury is ultimately an immune response that drives healing. However, repeated injuries, like when high blood pressure repeatedly damages the arteries, will lead to thickening and scarring.

Much of inflammation is nothing more than a side effect of immune activity. A fundamental flaw in our current medical approach to inflammation is the false belief that the immune system is creating inflammation for no reason.   As a result, we have an entire industry of herbs, supplements and pharmaceuticals built upon the idea that suppressing inflammation is somehow healing the body. All this despite several large studies demonstrating that conditions associated with inflammation like heart disease[4], diabetes[5] and cancer[6] are mostly driven by external factors. To be clear, unless a true[7] autoimmune condition has developed, the immune system will not act unless there is something triggering it to act. Sometimes we don’t like the results. However, this ancient system that protects us from cancer and invaders is highly intelligent and tightly regulated. The immune system will launch an attack against any critters or substance that it identifies as an invader. These include bacteria, viruses, air pollutants, some metals, environmental contaminants and oxidized LDL cholesterol[8]. It will also attack undigested food proteins like gluten from wheat and lectins from beans. Food sensitivity tests like the ALCAT and Mediator Release Test (MRT) regularly reveal that the immune system will attack virtually any intact food protein or microbe that escapes past the protective gut mucosa (gut lining).

As one example in an ocean of inflammatory immune signals, look at what happens if we tinker with TNFα.

T= “tumor” like cancer

N=“necrosis” like death

Fα=“factor alpha” as a signal category

TNFα is an inflammation weapon produced by certain immune cells to protect us from viruses and cancer. It helps transmit signals from outside a cell to inside a cell’s nucleus where more signals tell the cell to kill itself. In science we call this apoptosis. It is helpful for ensuring that cells that have become cancerous do not survive to divide and grow into a tumor. TNFα also “serve[s] as a first-line defense against influenza virus[9]” and has “strong antiviral activity against many viruses including avian flu and swine flu2”. Upon first glance, it sounds like anything that will increase activity of TNFα can keep you from getting cancer and viruses. Woohoo! In fact, several medicinal mushrooms are promoted as having these anti-cancer and anti-viral properties. Cordyceps[10],[11], Maitake[12], Coriolus[13] and Ganoderma[14], all contain chemicals that increase activity of TNFα*. While this approach can be transformative for someone with a weak immune response, what effects does artificially increasing TNFα have in a healthy person?   We know that in high amounts, TNFα causes considerable collateral damage to tissues. It is one of the main participants in diseases like psoriasis[15], ulcerative colitis[16] and rheumatoid arthritis[17]. Moderately high levels are associated with Alzheimer’s disease[18] and even cancer10.

*I suspect that these mushrooms cause an increase in TNFα, not because they have magical properties, but because the immune system sees them as invaders and launches an attack.

Over the long term, does artificially raising TNFα activity accelerate the same degenerative problems that we see with any chronic inflammation? Wouldn’t mildly elevated levels still increase cell turnover, damage tissues, accelerate shortening of telomeres, speed aging and ultimately lead to early senescence*?

(*Senescence is a term used in aging research to describe the end stage of the aging process of a cell, tissue or system. When a cell reaches senescence it can no longer function properly or divide to form new cells. As more cells reach senescence in a given tissue, the more that tissue shrinks and becomes dysfunctional.)

Unless there is a specific reason to artificially stimulate TNF-alpha, it is important to weigh the potential effects of taking any herbs or mushrooms that raise it. Other herbs that stimulate inflammation by raising TNFα include Cistanches, Dipsacus, Echinacea and Psoralea. I have personally seen several patients whose autoimmune conditions were severely exacerbated from taking medicinal mushrooms. They were duped by claims and promises that somehow their condition was a result of a “weak” immune system and that these mushrooms were their salvation. On the other hand, with proper diagnosis, these types of mushrooms can be used as an effective tool when the immune response is too weak. Poor wound healing and recurrent viral infections (like shingles and Epstein Barr) are often caused by a weak immune response. Another scenario where these mushrooms may have benefit is with cancer. I have worked with scores of patients who were doing well months after their doctor prescribed Maitake-D as part of a larger protocol to help the immune system kill cancer cells. (Notice I said “part of a protocol”).

In the ocean of herbs and supplements that are supposed to help us live longer and healthier, how do we know which ones are actually helping? With illness, when the mechanism of a supplement doesn’t match the underlying cause of an immune imbalance short-term side effects commonly occur. What are the less detectable the long-term consequences? Is it possible to accelerate the aging process by inappropriately stimulating the immune system?

 

[1] Kurtak, K. Dietary and Nutritional Manipulation of the Nuclear Transcription Factors, PPAR’s and SREBP’s,as a Tool for Reversing the Primary Diseases of Premature Death and Aging. Rejuvenation Research 17-2. April 2014. P 140-44.

[2] D. Bayarsaihan Epigenetic Mechanisms in Inflammation J Dent Res. 2011 Jan; 90(1): 9–17. doi:  10.1177/0022034510378683 PMCID: PMC3144097

[3] Stephen B Baylin DNA methylation and gene silencing in cancer. Nature Clinical Practice Oncology (2005) 2, S4-S11 doi:10.1038/ncponc0354. Received 16 August 2005 | Accepted 30 August 2005

[4] Prof Salim Yusuf DPhil,Steven Hawken MSc,Stephanie Ôunpuu PhD,Tony Dans MD,Alvaro Avezum MD,Fernando Lanas MD,Matthew McQueen FRCP,Andrzej Budaj MD,Prem Pais MD,John Varigos BSc,Liu Lisheng MD,on behalf of the INTERHEART Study Investigators Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study

The Lancet – 11 September 2004 ( Vol. 364, Issue 9438, Pages 937-952 )

DOI: 10.1016/S0140-6736(04)17018-9

[5] Dariush Mozaffarian, MD, DrPH; Aruna Kamineni, MPH; Mercedes Carnethon, PhD; Luc Djoussé, MD, ScD; Kenneth J. Mukamal, MD; David Siscovick, MD, MPH. Lifestyle Risk Factors and new Onset Diabetes Mellitus in Older Adults. Arch Intern Med. 2009;169(8):798-807. doi:10.1001/archinternmed.2009.21.

[6] Song Wu, Scott Powers, Wei Zhu & Yusuf A. Hannun. Substantial contribution of extrinsic risk factors to cancer development. Nature (2015) doi:10.1038/nature16166

Received 15 April 2015 Accepted 23 October 2015 Published online 16 December 2015

[7] From experience I have no doubt that many conditions that are diagnosed as “autoimmune” are nothing more than an appropriate immune reaction to an unidentified trigger that has grown out of control.   This is commonly seen with leaky gut syndrome, SIBO and dental infections.

[8] Although there are hundreds of studies showing that oxidized LDL elicits inflammation from macrophages, it has never been shown whether this is an immune reaction or a healing response.

[9] Seo SH, Webster RG. Tumor necrosis factor alpha exerts powerful anti-influenza virus effects in lung epithelial cells. J Virol. 2002 Feb;76(3):1071-6.

[10] Test on mononuclear cells Lymphoproliferative, inhibited NK cell activity, phytohemagglutinin response raises IL2, raises TNF-alpha, IL-2   Kuo YC1, Tsai WJ, Shiao MS, Chen CF, Lin CY. Cordyceps sinensis as an immunomodulatory agent. Am J Chin Med. 1996;24(2):111-25.

[11] Jong Seok Lee, Eock Kee Hong. Immunostimulating Activity of the Polysaccharides Isonated from Cordyceps militaris. International Immunopharmacology. Vol 11, Isue 9, September 2011 Pp 1226-1233 doi:10.1016/j.intimp.2011.04.001

[12] Matsui K1, Kodama N, Nanba H. Effects of maitake (Grifola frondosa) D-Fraction on the carcinoma angiogenesis. Cancer Lett. 2001 Oct 30;172(2):193-8.

[13] Cheuk-Lun Lee, Xiaotong Yang, Jennifer Man-Fan Wan. The culture duration affects the immunomodulatory and anticancer effect of polysaccharopeptide derived from Coriolus versicolor. Enzyme and Microbial Technology. Volume 38, Issues 1–2, 3 January 2006, Pages 14–21

[14] Hung-Sen Chena, Yow-Fu Tsaia, Steven Lina, Chia-Ching Lina, Kay-Hooi Khoo, Chun-Hung Lin , , Chi-Huey Won. “Studies on the immuno-modulating and anti-tumor activities of Ganoderma lucidum (Reishi) polysaccharides”. Bioorganic & Medicinal Chemistry Volume 12, Issue 21, 1 November 2004, Pages 5595–5601

[15] Victor FC, Gottlieb AB (2002). “TNF-alpha and apoptosis: implications for the pathogenesis and treatment of psoriasis”. J Drugs Dermatol 1 (3): 264–75. PMID 12851985.

[16] Sands BE1, Kaplan GG The role of in ulcerative colitis.. J Clin Pharmacol. 2007 Aug;47(8):930-41. Epub 2007 Jun 13.

[17] VASANTHI, P., NALINI, G. and RAJASEKHAR, G. (2007), Role of tumor necrosis factor-alpha in rheumatoid arthritis: a review. APLAR Journal of Rheumatology, 10: 270–274. doi: 10.1111/j.1479-8077.2007.00305.x

[18] Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N (2010). “A meta-analysis of cytokines in Alzheimer’s disease”. Biol Psychiatry 68 (10): 930–941. doi:10.1016/j.biopsych.2010.06.012. PMID 20692646.

Facebooktwittergoogle_pluspinterestlinkedinby feather