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Resveratrol And The Human Immune System

By Max Cerquetti July 09, 2020

Many people are familiar with resveratrol (say “res-VER-ah-trahl”), a natural antioxidant compound found in many varieties of red grapes (including red wine), blueberries, rhubarb, dark chocolate and other foods. Resveratrol is also found in Japanese knotweed, a perennial plant native to East Asia, which has been used for centuries as an herbal remedy to boost circulation and restore heart health.


Resveratrol has been shown in animal models as well as human studies to have potent anti-inflammatory effects and has great promise as an agent that could slow or even halt the progression of many diseases that have inflammation as part of their clinical picture, including heart disease, diabetes, obesity, cancer and neurodegenerative disorders such as the dementias.

Resveratrol is what is known as an immune modulator, modifying the activity of the immune system by acting on several pathways and specific immune cells within the body, which in turn decreases the inflammatory response. Let’s look at the specifics of just some of the ways in which resveratrol influences the human immune system through the activation of sirtuins, its influence on macrophages, inhibition of T-cell activation, boosting the activity of NKs (Natural Killer Cells), and inactivation of regulatory B cells (Bregs).

Then we will examine what foods contain resveratrol, how diet alone cannot give you a therapeutic resveratrol dose and what to look for when you are considering resveratrol supplementation.

Resveratrol And SIRT1 (The Longevity Gene)

In a previous article, we took a close look at a family of proteins called the sirtuins (say “sir-TWO-ins”) also known as the longevity genes. Sirtuins are made by nearly every cell in your body and control aging by turning genes on and off. The most studied and well recognized sirtuin is known as SIRT1.

The sirtuins also have a wide variety of other roles, helping to repair DNA damage, assisting mitochondria (the “power plants” of your cells) to function more efficiently, inhibiting inflammation, regulating the release of insulin and playing a role in the mobilization of fats among other processes.

The loss of sirtuins has also been implicated in the development of various cancers as well as the development of various autoimmune diseases through the process of T-cell activation, a type of lymphocyte (white blood cell) which plays a central role in the immune response.

As explained in the previous article, sirtuins cannot function without the presence of NAD+ (nicotinamide adenine dinucleotide) which naturally declines as you age. You can think of NAD+ and NMN as the “food” the sirtuins need to have enough energy to do their work and resveratrol as the “accelerator” for that work through its role in increasing activation of the sirtuin genes.

When resveratrol binds to SIRT1 it not only activates this sirtuin, it increases SIRT1’s binding activity to its substrates. Many of these substrates are regulators of white blood cell activity and cytokine inflammatory signaling and these inflammatory functions are decreased or are completely inhibited as a result of SIRT1 binding.

 

 

Resveratrol And Its Influence On Macrophages

Macrophages are large white blood cells which play a very important role in the human immune system. The term “macrophage” literally means “big eater” from the Greek words “macro” meaning large or big and “phage” which means to eat. The major function of the macrophage is to locate, engulf and destroy foreign potentially harmful particles such as parasites, viruses, bacteria and fungi. These cells depend on a wide range of pattern recognition receptors, known as PRRs, to effectively identify the discrete molecular signatures found on bacteria, fungi, viruses and parasites.

Evidence suggests that the continuous activation or dysregulation of these pattern recognition receptors can ultimately give rise to a wide variety of pathological states which have been linked to this activation. Resveratrol has been shown to regulate the expression of these pattern recognition receptors and thus should be useful in the treatment of the diseases which have been linked to their activation. Among these are rheumatoid arthritis, heart disease, type 2 diabetes, obesity, fatty liver, Crohn's disease and some neurodegenerative disorders.

There are also multiple additional molecular pathways that are modulated effectively with resveratrol. For example, many human cancers, when examined microscopically, show they have been infiltrated with large numbers of macrophages.

This macrophage response is not too surprising, when you consider that cancer is perhaps the ultimate invader. But surprisingly, the presence of large numbers of macrophages in human cancers is not a good sign and is associated with a poor prognosis and relapse of the cancer.

These tumor associated macrophages (called TAMS) not only act directly within the cancer itself, but when found in the peripheral bloodstream are thought to play a role in the migration of tumor cells and the development of metastatic disease. In an exciting experiment in vitro (in the lab, not in a human or animal), a synthetic resveratrol was successful in increasing interferon y, an important cytokine which is a macrophage activator. The increase in interferon y, brought about by the resveratrol, successfully reprogrammed the tumor associated macrophages.

 

 

Resveratrol And The Inhibition of T-cell activation  

We have already mentioned the role of T cell activation as a part of the human immune response but abnormal T cell activation plays a role in the development of many autoimmune diseases including multiple sclerosis, rheumatoid arthritis, lupus and insulin dependent diabetes.

Resveratrol inhibits abnormal T cell activation, not by acting directly on the T cell population, but by regulating the function of SIRT1 as described above. Because this abnormal T cell activation is present in so many autoimmune diseases, it is reasonable to believe that resveratrol could perhaps prevent the progression of autoimmune disorders.

 

Resveratrol And The Activity of NKs (Natural Killer Cells)
Natural killer cells (NKs) are a type of lymphocyte (white blood cell) that circulates in the bloodstream. These cells serve as an early defense mechanism against viruses, bacteria, parasites and perhaps most importantly, against tumor cells.

Like the macrophages, natural killer cells respond to specific molecular patterns associated with each pathogen, which activates the NKs and prompts them to release toxic compounds directed toward a particular pathogenic target. Resveratrol not only directly positively influences the killing ability of NK cells but at the same time it affects other immune cells, enhancing their effects as well.


Resveratrol And Inactivation Of Regulatory B Cells (Bregs)
B cells have been called the “antibody factories” of the immune system. They are one of two types of lymphocytes, with the other type being the T cells. While T cells have multiple roles, including the activation of other immune cells, directly killing infected host cells, and a role in the regulation of the immune response, B cells have one main job: producing y shaped proteins called antibodies. These antibodies are specific for each invading bacteria or virus and latch onto the pathogen, marking it as a target for destruction by other cells in the immune system.

The regulatory B cells, also known as Bregs, are subsets of the B cell population that require a combination of different molecules in order to become activated and go on to produce an immunosuppressive effect. Bregs have been implicated in cancer metastasis, particularly in some forms of lung and breast cancers.

Studies show that low doses of resveratrol prevents progression of metastasis in some types of melanoma as well as certain breast and lung cancers.

 

Resveratrol’s Benefits And Why Supplementation Is Key
A wide variety of research shows resveratrol’s regulatory and immunomodulatory role in the human immune system and point to many potential uses of this compound in the prevention and treatment of many chronic diseases which include cardiovascular and neurological disease, various inflammatory and metabolic conditions and even some infectious diseases.

Plus, there is research showing resveratrol’s promise in sensitizing some cancers to the effects of chemotherapy. Resveratrol has also been shown to both increase cell survival and slow aging, first in yeast and later in mice, through the activation of SIRT1.

While resveratrol is present in relatively small amounts in many foods, its bioavailability is also poor, making it nearly impossible to get a therapeutic dose from food alone. Plus the amount of resveratrol found in red wine combined with low bioavailability, make getting a therapeutic dose from drinking wine impractical as well. These factors combine to produce negative results when researchers have examined the effects of a resveratrol rich diet on human health.

Therapeutic doses of resveratrol range from 100 milligrams to about 1 gram a day. A five ounce glass of red wine, which some people tout as being rich in resveratrol, contains a paltry 1.8 milligrams of resveratrol, making supplementation the only practical way to get enough of this health promoting compound.

Here are just a few of the studies showing resveratrol’s positive effect on human health:

In people who had been diagnosed with type 2 diabetes, supplementation with one gram a day of resveratrol reduced blood pressure, fasting insulin levels, and fasting blood glucose while also increasing the levels of HDL (good cholesterol).

Resveratrol supplementation of 150 mg daily in obese people mimicked the therapeutic effects of calorie restriction, including decrease in blood pressure, blood glucose and triglyceride levels.

People who had been diagnosed with nonalcoholic fatty liver disease supplemented with either 300 or 500 milligrams of resveratrol a day for three months, saw a decrease in their LDL levels (bad cholesterol), liver fat concentration and blood markers for inflammation. At the same time, their sensitivity to insulin increased.

In patients who had suffered a prior heart attack, supplementing with 10 milligrams a day of resveratrol for three months reduced their LDL and also improved the function of the left ventricle of the heart, (the main pumping chamber) as well as the condition of the interior of their blood vessels.

With supplementation, you should be aware that resveratrol comes in two different molecular forms, cis and trans. The trans-resveratrol is found in most supplements as it is more bioavailable and is also more stable than the cis form. Studies also show that the cis form does not activate the longevity genes like the trans form of resveratrol. Also pay attention to the purity of the resveratrol you are purchasing and look for a product that is a trans-resveratrol and that is at least 98%+ pure.

Be aware also that the trans from, if exposed to light, can convert to the less active cis form and should be stored in a sealed light proof container in the refrigerator. A trans-resveratrol supplement is more bioavailable if taken with food (in particular some form of fat) and also when it is taken in the morning.

You can find more information on our high potency resveratrol supplement here. Taken daily, resveratrol supplementation will help you to harness this powerful compound’s anti-aging, anti-inflammatory, antioxidant and neuroprotective effects.


     

    References:

     

    -Malaguarnera L. Influence of Resveratrol on the Immune Response. Nutrients. 2019;11(5):946. Published 2019 Apr 26. doi:10.3390/nu11050946
    Borra MT, Smith BC, Denu JM. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem. 2005 Apr 29; 280(17):17187-95.

    -Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol. 2014;5:491. Published 2014 Oct 7. doi:10.3389/fimmu.2014.00491

    -Jeong SK, Yang K, Park YS, et al. Interferon gamma induced by resveratrol analog, HS-1793, reverses the properties of tumor associated macrophages. Int Immunopharmacol. 2014;22(2):303-310. doi:10.1016/j.intimp.2014.07.004

    -Zou T., Yang Y., Xia F., Huang A., Gao X., Fang D., Xiong S., Zhang J. Resveratrol Inhibits CD4+ T cell activation by enhancing the expression and activity of Sirt1. PLoS ONE. 2013;8:e75139. doi: 10.1371/journal.pone.0075139.

    -Falchetti R, Fuggetta MP, Lanzilli G, Tricarico M, Ravagnan G. Effects of resveratrol on human immune cell function. Life Sci. 2001;70(1):81-96. doi:10.1016/s0024-3205(01)01367-4

    -Lee-Chang C, Bodogai M, Martin-Montalvo A, et al. Inhibition of breast cancer metastasis by resveratrol-mediated inactivation of tumor-evoked regulatory B cells. J Immunol. 2013;191(8):4141-4151. doi:10.4049/jimmunol.1300606

    -Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444(7117):337-342. doi:10.1038/nature05354

    -Brasnyó P, Molnár GA, Mohás M, et al. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br J Nutr. 2011;106(3):383-389. doi:10.1017/S0007114511000316

    -Timmers S, Konings E, Bilet L, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011;14(5):612-622. doi:10.1016/j.cmet.2011.10.002

    -Chen S, Zhao X, Ran L, et al. Resveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: a randomized controlled trial. Dig Liver Dis. 2015;47(3):226-232. doi:10.1016/j.dld.2014.11.015

    -Magyar K, Halmosi R, Palfi A, et al. Cardioprotection by resveratrol: A human clinical trial in patients with stable coronary artery disease. Clin Hemorheol Microcirc. 2012;50(3):179-187. doi:10.3233/CH-2011-1424

     

     

     


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