The Science on Ginseng in general, and Wild Ginseng in particular

Ginseng has been extensively studied scientifically. A Google Scholar search would indicate that there are over 400,000 scholarly articles on ginseng. According to the U.S. government, there are 20,754 research articles in English on ginseng in their database; that may be compared to acetaminophen, one of America’s most widely used drugs, which has 47,168 articles in English, (but a large proportion of which relate to adverse events). Chinese sources say there are more than double that, since more studies have been conducted by Asian researchers that were not translated into English.

An article published in the Journal of Ginseng Research, a high quality Korean government supported journal and an Elsevier Publication (a very prestigious Western publisher based in Amsterdam, with the tagline: Elsevier is a global information analytics business that helps institutions and professionals progress science, advance healthcare and improve performance) entitled “Ginseng, the ‘Immunity Boost’: The Effects of Panax ginseng on Immune System” by Soowon Kang and Hyeyoung Min started their review article with this introduction. These are eminent professors of pharmacology in Korea. [Note: The following quote has been slightly edited so as to remove terms that are potentially not acceptable to the FDA when discussing dietary supplements on a commercial platform. These redacted terms may be construed to constitute claims that we do not wish to make. This article broadly supports the regulating, adaptogenic nature of ginseng. We do not believe the edits in any way alter the intended message and opinions expressed by the authors.]

“Thousands of literatures have described the diverse role of ginseng in physiological processes . . . In particular, ginseng has been extensively reported to maintain homeostasis of the immune system and to enhance resistance through the regulation of immune system. The immune system is comprised of different types of cells fulfilling their own specialized functions, and each type of immune cell is differentially influenced and may be simultaneously controlled by ginseng [supplementation]. This review summarizes the current knowledge on the effects of ginseng on [the] immune system."
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“Thousands of literatures have described the diverse role of ginseng in physiological processes . . . In particular, ginseng has been extensively reported to maintain homeostasis of the immune system and to enhance resistance through the regulation of immune system. The immune system is comprised of different types of cells fulfilling their own specialized functions, and each type of immune cell is differentially influenced and may be simultaneously controlled by ginseng [supplementation]. This review summarizes the current knowledge on the effects of ginseng on [the] immune system. We discuss how ginseng regulates [the various] types of immune cells including macrophages, natural killer cells, dendritic cells, T cells, and B cells. We also describe how ginseng exhibits beneficial effects.

Keywords: Panax ginseng, Innate immunity, Acquired immunity, Immunomodulation, Cytokine

Ginseng has been well known as an immune modulator. Roots (mostly), stems, leaves of ginseng, and their extracts have been used for maintaining immune homeostasis and enhancing resistance to illness or microbial attacks* (our note: general and non-specific reference to “microbial attacks”) through effects on immune system. [The] immune system is composed of diverse types of cells with their own specialized functions, and each type of the immune cell differentially responds to ginseng.”

 

Clearly, even with the redactions, you can easily understand that the authors are emphasizing the “regulating”, “modulating,” “maintaining,” and “homeostasis maintaining” actions of ginseng. Ginseng is an adaptogen. Its primary function is to maintain homeostasis during stress, modulate complex bodily functions such as those of the immune system, while acknowledging its complexity, and enhancing the body’s own capacity to resist the stressors and dangers of the real world.

Hundreds of functions have been elucidated in all the studies on ginseng in the past 50 years. Science has been evolving rapidly and we now live in an era where powerful computers, very advanced research equipment and techniques, vast knowledge of the researchers, and unworldly capability to perform online literature research, is contributing to very deep understanding of ginseng, how it lives, and how it acts to support and promote healthy functioning within the human body.

The ginseng studies include biological, molecular, pharmacological, network pharmacological, genetic-epigenetic, proteomic, safety studies, and more. Many epidemiological and clinical studies have been conducted on small and large scales. Not all studies in the past have met every criterion set by some reviewers such as the strict Cochrane Review (and this is true for studies conducted throughout the world, including America, Europe, and Japan), but thousands of studies have been published in elite, medical, and scientific journals favored and respected in the west. The science is clear that ginseng is one of the most interesting, effective, beneficial, and promising ingestibles in the world. 

Ginseng Functions Verified by Modern Research

A Very Brief Summary

Ginseng has a wide range of bio-modulatory activities, including stress reduction, homeostasis, immunomodulation, and antifatigue, effects.  Ginseng has other effects that we cannot express or describe in a commercial website in the United States, and do not wish to emphasize because the emphasis on ginseng should always be on its powerful bioregulatory, adaptogenic, calming, strengthening, immunomodulating, and neuroprotective actions. In other words, the famed attributes of ginseng for promoting glowing health and resilience are being elucidated by modern research. There is far too much to discuss regarding these matters here, so the following will hopefully provide a sense of what the research is showing.

The biologically active components of ginseng mainly include ginsenosides (tetracyclic triterpenoid saponins), polysaccharides, polyphenolic compounds, polyacetylenes, fatty acids and amino acids. Recent studies have shown that the amino acids of ginseng are important tonic (regulatory) agents, with mood supporting, cardiovascular (blood pressure modulating), immune modulating and enhancing, hepato-protective, neurological and nootropic (cognition supporting) activities, among others.

Panax ginseng is effective in improving blood circulation and brain function, enhancing and modulating immune function, supporting insulin and blood sugar balance, improving sexual performance, and healthy aging. The active constituents responsible for these pharmacological effects are ginsenosides (saponins) and non-saponin components such as polysaccharides, peptides, polyacetylene.

Determining all the biochemical pathways and molecular interactions involved in the biological effects of ginseng is a daunting task that is far from completion. The range of compounds present in Panax ginseng extracts, the individual differences in the expression profiles of innate immune receptors in human subjects, and the intestinal bacterial flora would all influence the biological effects of Panax ginseng in humans. 

It is very important to realize, and remember, that the ginsenosides present in a ginseng root or other parts are NOT, in most part, the final active molecules (metabolites) effecting activity and change inside the body. Ginsenosides are metabolized by the gut bacteria, and the active metabolites that result are what mediate their immune effects of ginseng. With the explosive expansion of knowledge of the functions of the microbiome, it appears that every herb and food that we consume is altered in the gut, and that a new field of biomolecules are the actual active principles once inside the blood stream and cells. 

Wild Ginseng

By definition, wild ginseng grows in the wild, unattended and unsupported by humans. Variants of ginseng grow in a fair number of places in the world, but only a couple are generally considered true “ginseng,” the “king of herbs.” These are Panax ginseng which grows in Asia, primarily in the northeast of China and up into Russia, and Panax quinquefolius, American Ginseng that grows in the northeast of the United States, the American Appalachians and Eastern Canada. Other varieties of “ginseng” are certainly used, and are quite useful and popular, but they are not the “ginseng” that most people are referring to with the term ginseng. Notoginseng, Prince Ginseng, Japanese Ginseng, Brazilian Ginseng (Suma), Indian Ginseng (Ashwagandha), Poor Man’s Ginseng (both Codonopsis and Gynostemma have used that name), and other herbs have remarkable properties, but these are not the herbs we are discussing today.

In fact, here we will focus most of our attention on Panax ginseng acquired from its authentic, original growing area on the pristine, rugged wild slopes of Changbai Mountain, in Manchuria, north of North Korea. Changbai Mountain is a vast biosphere centered by an enormous active volcano with a fearsome history, and still with very little impact from human civilization. As every ginseng expert and connoisseur knows, Changbai Mountain is the Di Tao (original and authentic) source of the highest quality, nutraceutically-richest ginseng in the world.

All parts of the ginseng plant are used. However, the root is by far the most precious and valuable part. Therefore, a ginseng plant is not renewable. When it is harvested, it is always root and all. Almost exclusively, in this report, we are discussing the ginseng root and its constituents. However, other parts are quite useful and are rich in active constituents that are worth exploring (at a different time).

Wild ginseng has maintained a reputation for thousands of years as the ultimate tonic herb. Ginseng root is the herb by which all other herbs are measured; and wild ginseng is the ultimate variety of this ginseng. As a result of its reputation and commercial value, wild ginseng is very rare and not enough can possibly be collected to serve all humans who desire it. It takes decades to mature, so there is no way to wildcraft it in sufficient quantities to service the world. As a result, people learned how to cultivate Panax ginseng on mountain plantations in Manchuria, starting in earnest about three hundred years ago.

Now, cultivated ginseng is ubiquitous throughout the world. One can buy it at fast food stores and find it in sports drinks. It is still not “cheap,” but it is within the wheelhouse of most people. Wild ginseng, on the other hand, is very rare, very expensive and worth every penny and more, precisely because it is wild. Perhaps “wild-natured” is the key concept. Grown in the wild and surviving drastic environmental shifts, ginseng is among the hardiest plants in the world, and it can convey that hardiness to those who consume it. That wild-natured power can be felt and experienced even beyond “feeling” – and that feeling and experience is what connoisseurs know about and want, and what most people don’t know even exists.

There are some significant similarities and some significant differences in the functions of wild and cultivated ginseng. This would involve physiological, neurological, cardiovascular, hepatic, renal, endocrine, muscular, hemopoietic (blood building), nootropic, sensorial, sexual, skeletal, genetic and other functions and multisystem networks.

In most cases, wild ginseng is considered to be significantly more active. In fairness, there are some cases when cultivated and probiotically-fermented-cultivated (red or black) ginseng can have specific phytochemical bioactivities that are of extreme value. No doubt about it. Red ginseng is produced by a traditional steaming process, where fresh ginseng is steamed over a pot, sometimes including other brewing herbs. The ginseng turns a reddish brown, and thus it is called red ginseng. Only cultivated ginseng is put through this process. The steaming breaks down some native ginsenosides and generates others, many of which have been found beneficial in certain situations. Fermentation with “intestinal probiotics” stimulates the “maturing” of red ginseng by producing many more ginsenosides that would only develop in a wild root after 30-40 years.

That said, older, fully mature, wild ginseng will have ginsenosides that no cultivated ginseng root can possess. To the knowledgeable ginseng connoisseur, wild ginseng is generally far superior to the cultivated product. One last point on this issue: there is no law that says a person must use wild or cultivated ginseng exclusively. A knowledgeable herb user understands that BOTH have benefits, and both can be used at the same time. Why not? They are not mutually exclusive. Virtually every member of Dragon Herbs staff uses both forms.

In wild ginseng, the contents of amino acids, such as sulfur-containing amino acids (S-adenosylmethionine, tryptophan, cysteine and others, and their derivatives) are higher when compared with those of cultivated ginseng. Of the 21 essential amino acids (required for life), 14 types of amino acids were higher in wild ginseng, compared with cultivated ginseng. Laboratory analysis indicates that the total amino acid contents of wild ginseng is 2.5 times higher than that of good quality, commercial-grade, cultivated ginseng. The essential amino acid content of wild ginseng is double that of cultivated ginseng. You might think that you will take only small amounts of ginseng compared to other protein sources, so who cares about the protein content. But the combination of amino acids in ginseng along with many other co-factors allows ginseng to have a very big impact in a very small dose. You are not taking ginseng to build muscle – you’re taking it to modulate critical cellular functions in remote regions of your body that most likely are literally starving without the ginseng amino acid supplementation.

The Genetics of the Ginseng Plant Impacts How It Works for Us

The entire genomes of both Panax ginseng (Asian Ginseng) and Panax quinquefolius (American Ginseng) have been determined and, to the extent possible to date, characterized. First, it is interesting to note that wild ginseng plants have a surprisingly-high genetic diversity, and yet maintain great phenotypic stability (appearance and character) – partially explaining their remarkable endurance over the eons. Researchers did not expect high genetic diversity at all. Ginseng appears to be so stable. Yet despite the diversity, most wild ginseng looks alike to most people (experts can tell them apart), with just one color of fruit (red), one standard size and shape, one recognizable leaf shape, etc.

Panax ginseng (Asian Ginseng), as mentioned above, is a very, very old species of plant, going back tens of millions of years. Panax quinquefolius (American Ginseng) has its lineage in Panax ginseng, but it diverged off Panax ginseng in the far distant past.  Yet these two ginseng species that we see today are not very different from what they were millions of years ago. They have adapted genetically to changing environmental conditions, yet they have retained certain phenotypic characteristics for tens of millions of years.

Cutting edge proteomic (amino acid-based and protein-based) analyses of the amino acid and protein metabolism have been conducted on Panax ginseng from Changbai Mountain in Manchuria and from its adjacent mountain ranges in North and South Korea. Korean and Chinese mountain ginseng do in fact have a noticeable phenotypic distinction, which we’ll talk about in a future article. The studies show that Panax ginseng developed radical adaptive abilities long ago that would allow it to diversify genetically while maintaining appearance and character, a consistent role in its ecological niche, its highly sophisticated adaptability, as well as its Jing, Qi, Shen, and its “Ginseng soul.” All plants have many genes and genetic domains dedicated to adapting to stress and environmental change., but ginseng appears to be a super-adapter. It is clear that this enhanced adaptive capacity is conferred onto the humans, animals, and perhaps the forest, as a whole being, that consume it, when it has matured into a fully adaptive being that is as long lived as we can imagine a tiny ground plant to be.

Ginseng’s Super-Robust Stress Responses Account for Its Survival and Longevity – It’s All Rooted in Ginseng’s Genetics

This is first of a series of essays about Ginseng, not about us humans. I will discuss a few of the major reasons why Ginseng is so long-lived, why and how it has survived and thrived for tens-of-millions of years, and why it is such a powerful producer of nutraceutically active phytochemicals. We’ll discuss how ginseng recognizes potential or actual danger and assault, and how it acts to resist and overcome that danger.

A big part lies in its own remarkable genome, which features a whole array of genes that promote adaptability and highly adept self-regulation to preserve functional resilience over four very different seasons, over a lifetime, and over thousands of generations. In this series, we’ll explore the latest research on ginseng’s genetic and epigenetic development over the past 65 million years. This will provide insight into its awesome adaptogenic effects in the animals that consume it, including us humans.

Part 1 – How Ginseng Lives

Panax ginseng is well-known and is widely consumed worldwide as an adaptogenic tonic herb. It is primarily used to boost energy, libido, and both physical and mental endurance. However, its other actions are even more impressive. It is a major immune system modulator. Hundreds of labs have been studying ginseng in the last two decades to understand the vast array of actions of ginseng and its many constituents on immunological functions. It has powerful regulating effects on mood and cognition. It is being investigated for its effects on hundreds of human conditions. But most importantly, it is the standard of all herbs produced in nature as an adaptogen. Adaptogens are modulating substances that support the body and the mind’s capacity to deal with stresses of all kinds in a non-specific manner. The non-specificity is of great importance. That is how the body must respond to stress, since stress can have a multitude of sources, causes and deleterious attributes. The body and the mind cannot predict every stress it will ever face, so adaptogenic mechanisms become the measure of life for all living creatures on earth, especially for humans. Adaptability is innate, but it declines as one grows older. Scientists are coming to understand why our adaptability declines with age. Key molecules like NAD+, the sirtuins, klotho, and others that provide the power and functionality of adaptation, decline as we age. Now we are learning to re-establish health levels of these molecules, but that science is still in its infancy.

On the other hand, Chinese herbalism has understood this problem for a very long time, and solutions were discovered over the ages. These solutions are being validated right and left by modern science, especially now that computers make extremely complex actions simpler to identify and quantify. Chinese herbs (and primary herbs from other systems like Ayurveda as well) are still way ahead of the curve in the healthy lifespan promoting field. But scientists will not admit that. It’s the complexity of a plant that scares them. How does one study a plant with hundreds of constituents, most of which act cooperatively to affect the health of humans or other animals that consume them. Luckily, new technology has recognized the failure of the single-molecule approach to drug development, and a method of research called “network pharmacology” is rapidly developing. This cutting-edge form of research is only possible because of advanced computers, programming, and analysis. This is good. Many other advanced technologies are also being used and developed to understand herbal microbiotic environmental interactions that were difficult for scientists to grasp. However, Chinese health theory has seen much of this for centuries.

Panax ginseng (Chinese Ginseng) possesses numerous active constituents, including saponins known as ginsenosides. These powerful molecules are the subject of intense study around the world for their adaptogenic, remedial, anti-aging, fitness-inducing, and longevity-inducing actions. As a tonic herb, ginseng is extremely safe for most people when used moderately, even when used regularly over a lifetime.

Most people have heard of ginseng. And most people have very little understanding of what ginseng really is, or does, or what it can do. And for sure, most people do not know that ginseng plants themselves have an exceptionally long potential lifespan (we connoisseurs may know that, but not most lay people). And it wouldn’t matter to most people anyway, other than as a curiosity. However, ginseng’s capacity to live for decades and even centuries, can have a very powerful impact on those who understand it.

Commercial ginseng is typically harvested after just 4 to 6 years of growth. This is because, by that time, ginseng has produced a certain set of ginsenosides that have known or perceived health benefits that can be measured. Unfortunately, these 4 to 6-year-old roots are not actually mature. In China, ginseng plants are sometimes allowed to grow for up to 8, or even 10 years in rugged, alpine, volcanic, mountain plantations to achieve a higher, more refined range of active constituents (mostly ginsenosides). Thus, they are capable of more potent and refined effects when consumed by a human as a tonic herb for enhanced adaptability, superior fitness, improved endurance, enhanced cognition and so on. Because these roots must stay in the ground longer than the market generally requires, it is an added expense and risk to farmers. In America, you will not find 8-year-old cultivated Ginseng. In fact, 5 years is now the standard.

Ginseng is biologically “mature” at 13 years of age. At that time, and only at that time, the complete range of predictable ginsenosides has been developed. At that point, the ginsenosides are considered to be balanced: having both generally storing capacity and expressing capacity. Only wild ginseng, or semi-wild (wildcrafted) ginseng roots, reach this age. Yet these are still just younglings in the world of ginseng. 

Another and very profound reason that ginseng roots are considered mature only at thirteen is because at that time, the “death domain” of its genetic code suddenly turns off. This domain is still not clearly characterized, but it includes the whole sphere of genes that promote functional decline, and therefore drive a living being toward death. If a ginseng root has become thirteen, it is now likely able to live to be many decades old, or even a thousand years old. In reality, no one on earth knows how long ginseng can actually live. Unlike most other plants and animals, ginseng does not seem to have a defined lifespan. It lives until it is eaten or killed by an act of God (volcanic eruptions, come to mind). There are reliable and verifiable reports of ginseng roots that had lived for multiple centuries before being found and collected. Thousand-year-old ginseng roots have been reported, in recent years, in both China and Korea. We at Dragon Herbs have had the good fortune of coming into possession of over a hundred of these (only by luck or karma, we’re not sure which – or if there’s a difference – but that’s another article).

Chance (Luck) may be the most challenging factor for a ginseng plant’s survival and life expectancy. With luck (not being spotted and plucked for consumption by a human ginseng collector, or by a bear or deer, who also appreciate ginseng), a ginseng plant can thrive on the floor of a remote mountain forest for centuries.

A harsh environment is not apparently a disadvantage for ginseng. It is believed that harshness itself makes the ginseng stronger and promotes its resilience and longevity. There is a term for a living creature benefitting from harsh or even toxic conditions. It is called hormesis. In fact, hormesis is widely considered by scientists to be a primary means of attaining fitness and longevity. Many “healthy” substances are turning out to be healthy because they are hormetic, that is, they provide just enough irritation and harm to the body or mind to stimulate an adaptive response, which in turn makes the creature (or person) stronger and healthier. It has been established, in fact, that a significant part of ginseng’s benefits to human health are due to its hormetic effects in humans. The same has been demonstrated to be true of many foods and herbs that humans consume to support their health, including extra virgin olive oil, the phenolic acids derived from the polyphenols in colored fruits and vegetables, green tea, vitamin E, many phytochemicals including terpenoids (as in Reishi mushroom), crucifer-derived sulfur compounds, carotenoids, resveratrol (from grapes, peanuts and some Chinese herbs), many fruits, leafy green vegetables, legumes, onions, tomato (lycopene), garlic, olives, curcumin, ginger, spices such rosemary, brussels sprouts (sulforaphane), garlic (allicin), and many others.

Every year, due to variations in climate and infestation, ginseng will produce new ginsenosides. It has been shown that there are a possible 650 ginsenosides. It has also been proven that the older a ginseng plant, the more ginsenosides it will have in its root and other structures. Furthermore, the more stress and challenge a ginseng plant experiences, the more ginsenosides it will produce. These ginsenosides protect the ginseng plant, by making it arguably the world’s most adaptogenic plant, until it dies. Ginsenosides are the main active constituents in Panax ginseng that benefit human health when consumed. Again, the older a ginseng root is, the more ginsenosides it has and the more powerful it is as a tonic and protector. The extreme complexity of ginseng may scare some science obsessed people away from ginseng and its dozens or hundreds of ginsenosides, but they had better avoid leafy greens, ginger, garlic, olive oil, tomatoes, spices, resveratrol, curcumin, brussels sprouts, and all the other hormetic agents as well. They can try living on vitamin pills and other single-molecule supplements that are less complex or are at least less complex in their minds. Panax ginseng has been used by humans for thousands of years, and by millions of people every day. And still, after so much time, the FDA considers ginseng to be “generally recognized as safe” – because it is.

At the end of the day, the older a ginseng root is, the more valuable it is considered to be in every conceivable way.

Part 2 – Ginseng’s Capacity to Adapt and Thrive Over Decades – and Over Millions of Years – Is Controlled by a Set of Genes Called the WRKY Genes (pronounced “worky jeans”)

All higher plants and many primitive plants have, within their genomes, a set of genes that are specifically dedicated to adapting to stress (significant challenges), both biotic and abiotic. Biotic stressors include all harmful pathogens, worms, larvae, all forms of parasites, and so on. Abiotic stressors include heat, cold, dryness (draught), excessive moisture (flood), salt, metals, crushing and severing injuries and assaults, atmospheric anomalies, excessive radiation exposure, and so on.

Plant complexity-and-organization is only possible as a result of intricate inter-connections between genes and regulatory networks inside the individual cells, and between cells in different plant tissues and parts. In higher plants, inter-cellular biological circuits are governed at several levels. The most fundamental regulatory network, that which controls the adaptive interaction of the plant with its environment, is regulated by a specific group of DNA-binding proteins known as the WRKY (pronounced “worky”) genes.

Despite the enormous flexibility of genomes, the corresponding metabolic synthesis networks follow specific inherent rules that are responsible for their rigidity. Evolutionary strategies are suited to utilize this genomic flexibility to adapt desired phenotypes to balance the metabolic network adaptive measures required for optimal performance. Within this framework of opposing dynamics, ginseng shows remarkable adaptability and simultaneously a very stable phenotype over years, decades, generations and eons.

Ginseng’s Genome Contains Regions of Genes that Specifically Promote Adaptation to Stress

Because of Panax ginseng’s huge economic and health-promoting value, it has recently been the subject of cutting-edge genome-wide analyses of its genome and network pharmacology. The entire Ginseng genome has been elucidated and characterized – though there is more to learn and characterize. There is much to discuss, but this report will focus on a special sector of the genome that has just been studied and characterized concerning ability of Ginseng to protect itself very successfully, both in the here-and-now, and over the eons. 

Ginseng has 2900 Mb of genes. This is a high number of genes for a plant. For example: a carrot has 421 Mb of genes; Chinese Red Salvia, a potent Chinese herb with a rich nutraceutical and pharmaceutical content, has 547 Mb of genes; and grapes have 427 Mb of genes. Ginseng is a giant. But why would that be advantageous to the plant itself, and to humans who consume it?

Panax ginseng has a very large number of WRKY adaptive genes. In ginseng, these genes are known as PgWRKY (“Pg” is for Panax ginseng). Panax ginseng has 137 WRKY genes, which is double that of most plants. These genes are modulated by PgWRKY activators and produce PgWRKY proteins.

These WRKY proteins are DNA-binding proteins. They recognize the specific elements found in the promoters of a large number of plant defense-related genes. These WRKY proteins are known as transcription factors, which in plants are transcriptional regulators. They perform integral and crucial roles in signaling webs that modulate many plant processes. 

PgWRKY genes exhibit extensive autoregulation and cross-regulation that facilitates transcriptional reprogramming in a dynamic web with built-in redundancy. WRKY transcription factors play crucial roles in plant resistance responses to pathogens.

WRKY proteins play regulatory roles in many aspects of biological processes in plants, such as plant development, adaptation to environmental challenges, and responses to biotic (living) or abiotic (environment) stress.  WRKY genes are the root of an essential system, and Ginseng has developed a super-system. 

PgWRKY genes express differently in different tissues, such as the main root cortex, the fiber root, leg roots, arm roots, the rhizome, the main root epidermis, the stem, leaf peduncles, leaflet pedicels, leaf blades, fruit peduncles, fruit pedicels, fruit flesh, and seeds. In all cases, PgWRKY is modulating, regulating and protective.

During a long period of evolution, plants have to face complex environmental factors, such as drought, salt, heat or cold, and other uncertain ecological changes. Numerous studies have demonstrated the important roles of WRKY transcription factors in the response to abiotic stress in plants.

Certain co-expression relationships reflect the modulation of ginsenoside biosynthesis by PgWRKYs. 

Co-expression analysis revealed the potential regulatory relationship of PgWRKYs to ginsenoside biosynthesis pathway genes. Our findings suggest a foundation for further functional study of the regulatory mechanism of PgWRKYs in the Panax ginseng plant stress responses. 

WRKYs are involved in an extensive range of plant physiological development processes and affect the biosynthesis of secondary metabolites such as saponins – ginsenosides in Panax ginseng. 13 PgWRKYs are positively correlated with ginsenoside biosynthesis pathway genes.

The story of ginseng’s WRKY genes goes on. It is a fascinating area of study because it reveals a mechanism that is actually found in plants throughout nature by which they can adapt, survive, and thrive. We humans think, “these poor plants are stuck in the ground, they can’t move, and being so primitive, they are so vulnerable. This egotistic human viewpoint is dissolving away as we discover the remarkable processes that plants employ in order to enjoy their lives, flourish, reproduce, and bask in the sun on our beautiful planet for years and even centuries. Remember, many of the ginseng roots in Spirit of the Mountain TaiJi Wild Ginseng Drops were older than you are, and may be older than a human can even live. It is largely because of this remarkable WRKY adaptogenic system that this longevity can be achieved. It is certain that the WRKY proteins will ultimately be discovered to have adaptive benefits to those of us who consume these wonderful plants of the Panax genus.

Ginseng Can Provide Some Protection from Radiation and Protect DNA from Mutations

A polysaccharide present in the root of Panax ginseng, ginsan, is present in full root extracts. This ginseng polysaccharide has been reported to have an immunostimulatory effect. Perhaps more importantly, ginsan appears to be capable of protecting DNA from radiation-induced mutations if taken prior to the radiation exposure. Of course, that is exactly how ginseng is used. It is a tonic herb taken to boost bodily and cerebral functioning, to enhance adaptogenic capacity to handle stress, and to provide protection. It is assumed that it is consumed prior to stressful events. Medicine is taken after; a tonic is taken before.

Some of the Effects of Ginseng on the Immune System

I will only summarize a few of the known effects of ginseng on the human immune system here. It is too broad a subject and too complex to describe briefly. I will provide full details of this activity in a new upcoming blog site.

Ginseng has a profound modulating effect on the human immune system. For example, functionally, ginseng has been shown to have the following antimicrobial activities:

• Bactericidal activity
• Antiviral activity
• Immunomodulatory effect
• Inhibition of DNA mutagenesis
• Anti-quorum sensing
• Anti-adhesive activity
• Inhibition of pathogen induced hemagglutination

This does not mean that ginseng should be taken to prevent, treat, cure or mitigate any disease. These are factors that improve a person’s resilience and immunological competence, when high quality a ginseng extract is consumed as a tonic herb on a regular basis, especially when the ginseng is from an authentic Di Tao source, is fully mature at the time of collection, and is properly extracted and presented.

Studies suggest that consuming ginseng can protect humans against pathogen infection in a broad non-specific manner because of the body’s enhanced immune functioning. This is not even “preventive medicine” (because that would require a specific, targeted pathogen), it is tonic herbalism, the use of tonic and adaptogenic herbs that support innate and adaptive immunity. Ginseng has effects that not only directly kill bacteria and viruses, but also work against bacterial adhesion, inflammation, cytotoxicity and hemagglutination. Ginseng may be consumed by relatively healthy individuals to optimize immunological readiness and immunocompetence.

As stated by the good professors Kang and Min mentioned at the top of this article:

“Ginseng has been well known as an immune modulator. Roots (mostly), stems, leaves of ginseng, and their extracts have been used for maintaining immune homeostasis and enhancing resistance to illness or microbial attacks through effects on the immune system. The immune system is composed of diverse types of cells with their own specialized functions, and each type of immune cell differentially responds to ginseng.”

The human immune system, like the immune “systems” of all living beings, is a primarily adaptive system composed of various sub-systems that work in an integrated fashion to assure survival, health, the capacity to eat, breathe, reproduce, and attain a certain degree of longevity. The human immune system has been designed from bottom to top through evolutionary forces to be prepared to respond to detrimental entities, mainly foreign life forms that the body determines as potentially pathogenic. It can also deal with toxicity, but the human body has a dedicated anti-oxidant system that deals with that, headed by a master molecule known as NRF2. Interestingly (to me at least), ginseng has recently been discovered to have a profound influence on NRF2 and therefore into the whole realm of detoxification that the body must engage in at virtually every moment of our lives. Yes, ginseng is quite a busybody. Ginseng will also respond to detrimental cells that come from within our own body, some of which are quite formidable.

The immune system requires massive amounts of resources, including: nutrients (amino acids, carbohydrates, fats, phenolic compounds, etc.), minerals (compounds of iron, zinc, magnesium, sodium, calcium, manganese, molybdenum, selenium, germanium, and dozens more) , gases (oxygen, nitrogen, and hydrogen, plants aerosols), fluids (mostly water), and electrons (ions from the ocean and atmosphere, and many chemical sources), to remain in high alert, fully charged, and ready for high performance at a moment’s notice.

The human immune system can be weak, pretty okay, strong or even remarkably robust, depending the genetics and epigenetic state of the individual, upon the resources it has at its disposal in the short and long term, and the virility of the attacks it faces. This is not about medicine – this is about life force and a profound capacity to adapt and regulate responses in order to maintain the level of homeostasis required for a human to thrive in the short and long term. The immune system can, and does, become fatigued and can even be “used up.” Nourishing and maintaining the immune system is a prime goal of proper diet, breathing, drinking, sun exposure, tonic herb consumption (including ginseng consumption) and so on.

A remarkably robust immune system is possible, but some aspects of its cultivation must be initiated as early in life as possible and is maintained throughout life. Nevertheless, the immune system is quite plastic (sensitive, flexible, adaptive) and can quickly be re-balanced, tonified, activated, and even directed by those who know how to do it. Ginseng is among the most potent immune modulating foods in the world. It works at a very deep level to establish and maintain a balanced, robust immune system and immune responses. In many ways, it has bi-directional activity on the immune system. Mature ginseng is not dangerous to the immune system. This is largely due to the balanced functions of the ginsenosides, where Yin ginsenoside and Yang ginsenosides are balanced. Importantly, immature ginseng has not yet developed this balance, so it can have an imbalanced result in those who consume it.

Innate Immunity

Innate immunity is the first line of defense against various infections by foreign organisms or substances (antigens) and is composed of four principal components.

1. Physical and chemical barriers, examples of which are: your skin, mucous membranes, head and body hair, the chemicals excreted from these tissues, the acidity of the stomach, and the microbiome living in all of these tissues
2. Cellular components including phagocytes and natural killer cells
3. Blood proteins such as complements and inflammatory mediators, and
4. Cytokines and many related chemicals that regulate the cells of the innate immune system.

These components of innate immunity recognize foreign microbes, initiate rapid primary immune responses, and prevent or eliminate infection. In addition to its defensive function, the innate immune system also generates a wide range of chemical and bioelectronic signals that can result in pain and discomfort. These are first-response signs and symptoms that serve as an alarm system to the rest of the body, as well as to your subconscious and your conscious mind, alerting your entire being of the presence of pathogens, and of potential or active infection. These signals stimulate the subsequent adaptive immune response. 

Ginseng has been shown to become involved in virtually every one of the sub-systems of the innate immune system, supporting the body’s innate response. That is very important. The innate response CAN be all the body needs to respond to and repel an invading pathogen.

Mononuclear Phagocytes and Ginseng

The mononuclear phagocytes are composed of monocytes circulating in the blood and macrophages in the tissues. Macrophages exhibit different conformations (morphologic forms) in different tissues. They include the microglia of the central nervous system, Kupffer cells in the liver, alveolar macrophages in the lung, and osteoclasts in bone. Macrophages are principal components of innate defense, and they also play important roles in adaptive immune responses. When activated by various stimuli, macrophages enhance phagocytic activity, increase the ability to kill invading microbes, and produce many cytokines and inflammatory mediators such as nitric oxide and H₂O₂. They also express high levels of MHC molecules to present antigens to helper T cells, and thereby connect the innate and adaptive immune systems.

Many research studies have demonstrated and confirmed that ginseng enhances phagocytic activity of macrophages. One shouldn’t wait until they are infected to tonify their phagocytic activity. In a clinical trial with healthy adults, oral administration of ginseng extract improved phagocytic activity. 

In addition to the effects on phagocytosis, ginseng can stimulate the generation of inflammatory mediators as part of an innate immune response, such as nitric oxide, a reactive nitrogen intermediate, through up-regulation of iNOS. Macrophages produce nitric oxide to destroy phagocytized microbes, and ginseng aqueous extract has shown to up-regulate nitric oxide production in activated macrophages.

Upon activation by microbial residues markers, macrophages secrete IL-1β and TNF-α which induce inflammatory responses, and IL-12 to stimulate NK cells and T cells to produce an active form of interferon (IFN-γ).

Panax ginseng polysaccharides have been shown to augment the secretion of IL-1β and TNF-α from some types of macrophages. Ginseng polysaccharides-boosted macrophages can significantly increase the production of IL-1β and TNF-α as well as nitric oxide. IL- 12 release is also upregulated in macrophage cells by ginseng extract and its components.

Dendritic Cells and Ginseng

Dendritic cells (DCs) play important roles in innate immune responses and in linking innate and adaptive immune responses. DCs recognize antigens at the first sites of defense, migrate into lymphoid organs, and present antigenic molecules to lymphocytes to initiate lymphocytes activation. In addition, activated DCs release cytokines such as IL-12, IL-4, IFN-γ, and TNF-α to stimulate innate and adaptive immune responses.

So how does ginseng effect DCs? In general, ginseng exhibits immunostimulatory effects on DCs. When metabolized in the digestive tract, end products of certain ginseng saponins (ginsenosides) are able to drive the maturation of human DCs from monocytes. These surface molecules are associated with antigen-presenting capabilities of DCs and the increased expression of MHC molecules mentioned earlier, and co-stimulatory molecules can enhance the differentiation and proliferation of lymphocytes.

It is important to note that ginseng appears to have a bi-directional influence on DCs. Even though some ginsenosides activate DC expression, some do quite the opposite, having an inhibitory effect on the maturation of DCs. These inhibitory actions, still to be elucidated, diminish the secretion of cytokines such as IL-12 and TNF-α, and the expression of certain maturation co-factors. Although it remains a topic of research as to why ginseng shows such opposite effects, researchers suspect that ginseng may cause pro-maturation or anti-maturation of DCs and stimulate different signaling pathways. The bi-directional influence is therefore part of ginsengs adaptogenic sphere of influence, supporting a balanced immunological response.

Natural Killer Cells and Ginseng

NK cells are cytotoxic lymphocytes of innate immune system that are involved in the first line of defense against newly arising invasive cells. Distinguished from cytotoxic T lymphocytes, they can recognize target cells in the absence of antibodies and MHC, and do not require activation to kill target cells thereby enabling a fast immune response. In addition to killing target cells non-specifically, NK cells release pro-inflammatory cytokines such as IFN-γ, which activate macrophages to destroy phagocytized microbes.

A number of scientific papers have reported that ginseng extract enhances NK cell functions. Oral administration of aqueous extract of Panax ginseng increases natural killing activity. Placebo controlled human studies have demonstrated that NK cell function is promoted in individuals taking ginseng compared to placebo group. Interestingly, the activating effects of ginseng on NK cells were observed regardless of health condition of the host. The functions of NK cells stimulated by ginseng were comparable between immunosuppressed mice and immunocompetent mice. A trial using blood samples of people who had AIDS showed functional enhancement of NK cells isolated from peripheral blood mononuclear cells after consuming ginseng (this reflects a change in immune status, not a treatment or cure). The same has been shown for people with chronic fatigue syndrome (again, this does not imply any kind of treatment, mitigation, or prevention of this conditions). Collectively, these results suggest that ginseng may improve NK cell activity irrespective of host immune conditions. Oral administration of Panax ginseng extract to mice for just 2 days augmented the cytotoxicity (antigen killing capacity) of liver and spleen mononuclear immune cells against a pathogen. It is now known that Panax ginseng extract activates NK cells by activating IFN-γ (interferon).

Adaptive Immunity

Adaptive (or acquired) immunity is an antigen-specific immune response which occurs in response to the stimulation by specific antigens. The major players of acquired immunity are lymphocytes such as T cells and B cells and their secreted antibodies. B lymphocytes play a role in the humoral immune response, whereas T lymphocytes are primarily involved in cell-mediated immune response. The key feature of the adaptive immune response is its specificity and the ability to generate and maintain immunological memory. Upon antigenic stimulation, antigen-specific lymphocytes proliferate and differentiate into effector cells whose function is to eliminate the antigen, and into memory cells which possess an enhanced response to subsequent encounters with the same antigen.

Again, we are not suggesting that ginseng should be used to treat, cure, mitigate or prevent any specific disease or condition. The idea is to boost immunological competence versus all pathogens by tonifying the immune system by a human being.

Humoral Immune Response

The humoral immune response is an immunity mediated by antibodies, a system we’ve all heard a lot about lately. In this response, the immune system triggers specific B cells (mostly plasma cells) to proliferate and secrete large amounts of specific antibodies which then fight invading antigens (microorganisms, toxins, or other pathogenic organisms). Antibodies can bind to the antigens such as toxins and viruses and keep them from contacting and harming normal cells of the body. In addition, antigens coated with antibodies can be easily recognized and destroyed by phagocytes or macrophages. Antibodies are also able to stimulate the complement system to form a membrane attack complex on the membrane of invading microbes and kill them.

Although numerous studies describe the role of ginseng on antibody production, most of them evaluate its adjuvant potential on the secretion of specific antibodies. In general, ginseng extract successfully induced antigen-specific IgM, IgG, and IgA antibody responses when administered orally. Ginseng extract or its purified components appear to elicit improved humoral responses against microbial invasion irrespective of administration methods or types of microbes, suggesting the critical roles of ginseng as a dietary supplement, and more specifically as a tonic herb and adaptogen.

Cell Mediated Immune Response

Cellular immune response is principally mediated by T cells and NK cells and is effective at destroying virus-infected cells and cells with intracellular bacteria. It can also stimulate cells to release various cytokines in response to antigenic challenge and influence the function of numerous cells in the immune system. Many reports have described that ginseng extract significantly enhances antibody-dependent cellular cytotoxicity and NK cell activity.

In addition, a number of ginsenosides are known to stimulate T cell proliferation as well as NK cell activity, revealing a critical immunomodulatory effect of ginseng on cellular immune responses. This, once again, goes to the modulatory regulatory nature of ginseng and its bioactive constituents. That is, ginseng can affect regulatory adjustments of the immune system. An immunomodulator, by definition, can modulate the immune response, encouraging it to operate at the correct level of response of the many moving parts that we call the immune response.

Hundreds of studies have been conducted on ginseng’s regulating impact on the immune system and have broadly focused considerable attention on ginseng’s capacity to modulate autoimmune responses. It is known that ginseng can help the body maintain its immunological balance, which includes protecting it from developing autoimmune conditions, by promoting the generation of immunosuppressive regulatory T cells (Tregs).

Ginseng Helps Regulate Cytokines

Cytokines are small proteins produced by both immune cells and non-immune cells and which have critical regulatory effects upon immune response. Cytokines are cell signaling molecules. Some cytokines stimulate the immune response, and others slow it down. Some cytokines that are rather well known to the public include the interleukins: IL-1β, IL-4, IL-6, IL-10, IL-12, and the interferons such as IFN-γ. There are others of vast importance found throughout the body such as TNF-α. The interplay of these cytokines ultimately regulates the immune response.

Many cytokines play critical roles in innate immunity against microbial invasion, and these mediators of innate immunity include TNFs, IL-1, IL-6, IL-12, type I interferons, and others. They are mainly secreted by macrophages and NK cells while some are produced by T cells, DCs, and endothelial cells. When this author gets his blood work done on a yearly basis, he never fails to have his IL-6 evaluated, as this is a reliable and dramatic indicator of one’s non-specific, subclinical, inflammatory status, and it is an excellent marker of chronological age. IL-6 is one of the favorite topics discussed by researchers and physicians working with seniors, geriatrics, and centenarians, and can even indicate how much longer one may live. IL-6 is a ubiquitous pro-inflammatory cytokine. Consider having it measured and evaluated the next time you receive your annual physical exam. If it is above the safe range, you need to reduce your chronic inflammation. Some ginseng products have been shown to have a significant downregulating effect on IL-6. Another important cytokine worth testing and watching over the years is TNF-α (tumor necrosis factor-alpha). This cytokine is a powerful activator of inflammatory response. In its healthy state, it protects bones and joints, among other tissues, but when it becomes chronically activated, bone and joint conditions inevitably occur.

Ginseng is a powerful modulator of TNF-alpha. This alone is a great reason to consume a mature variety of ginseng even when young, because degenerative conditions start in the young due to stress on joints and injuries to the musculoskeletal system. Ginseng can help maintain superb cytokine balance and help maintain healthy bones and joints. Ginseng supports collagen functions in the body.

The Yin and the Yang of Cytokines

Cytokines are the hormonal messengers responsible for most of the biological effects in the immune system, such as cell mediated immunity as well as allergic responses. There are a great many cytokines.

Cytokines have been in the news a lot lately (during the Covid-19 pandemic because of the “cytokine storms” associated with severe Covid). Now, a lot of people know a little about cytokines, but just in the context of Covid. Cytokines are now widely perceived as fearsome biomolecules that are overall “bad” for us. That is really not the case at all – cytokine storms are an example of a great thing gone to an extreme. In other words, with a cytokine storm, the body loses the ability to modulate the cytokine response, to regulate it in such a manner as to remain within safe limits. This is really a regulatory issue.

T cells, which are lymphocytes, are major generators of cytokines. These cells have antigen-specific receptors on their cell surfaces to allow them to recognize specific pathogens. T cells can also recognize normal cells. There are 2 main sets of T cells, distinguished by the presence of molecules located on the cell surface. These are known as CD4 and CD8. T cells expressing the CD4 motif are also called T helper cells, and they are the most prolific cytokine producers.

T helper cells are further subdivided into Th1 and Th2 cell types, and the cytokines they produce are known as Th1-type cytokines and Th2-type cytokines. It is a beautiful example of Yin-Yang functioning in our lives.

Th1-type cytokines tend to produce the proinflammatory responses responsible for killing intracellular parasites and for perpetuating autoimmune responses. Interferon gamma (IFN-γ) is the main Th1 cytokine. Excessive proinflammatory responses can lead to uncontrolled tissue damage, so there is a mechanism to counteract this. The Th2-type cytokines include interleukins 4, 5, and 13, which are associated with the promotion of IgE and eosinophilic responses, and also interleukin-10, which has more of an anti-inflammatory response. In excess, Th2 responses will counteract the Th1 mediated microbicidal action.

The optimal scenario for humans is to produce a well-balanced Th1 and Th2 response, that accurately and dynamically adapts to the immune challenge.

Ginseng – the Great Th1/Th2 (Yang/Yin) Modulator

Ginseng has a bi-directional regulating effect on the Th1 and Th2 cell balance. As mentioned earlier, Dendritic cells (DCs) play a pivotal role in the initiation of T-cell-mediated immune responses. The interaction of DC with T cells is crucial for directing T cell differentiation towards the Th1 or Th2 type response. IL-12 plays a central role in the immune system. This cytokine, an interleukin, augmenting the cytotoxic activity of T cells and NK cells and regulating IFN-γ production. IL-12 promotes the development of Th1 cells.

Ginseng has been shown to affect the differentiation, maturation, and function of DCs. Ginsenoside end products created during ginseng metabolism in the gut significantly induce DC maturation, which results in strong TH1 immune responses.

On the other hand, certain other ginsenosides elicit a balanced Th1 and Th2 immune response.

Moreover, ginsenoside-Ro increases the production and expression of Th2 cytokine IL-4 and decreases the production and expression of Th1 cytokine IFN-γ in induced murine splenocytes thus showing immunomodulatory effects by regulating the production and expression of Th1/Th2 cytokines in splenocytes.