By Donnie Yance

“The noblest foundation for medicine is love.  It is love that teaches us the art of healing. Without love, true healing can never be born.” – Paracelsus

For thousands of years, medical herbalists in most cultures have utilized the power of whole herbs to promote health and support the body’s innate ability to improve the aging process and promote longevity. 

White willow bark (Salix alba) has been used for thousands of years as an anti-inflammatory, antipyretic, and analgesic. The willow tree stands as a powerful symbol in the history of medicine, linked to the discovery of one of the world’s most widely-used drugs: aspirin. This humble tree, with its graceful branches and soothing bark, has played a pivotal role in human health for millennia, offering a fascinating journey from ancient wisdom to modern pharmaceutical breakthroughs.

Ancient Roots: The Willow in Early Medicine

The medicinal properties of the willow tree have been recognized since antiquity:

• Assyrians (4000 BC) and Sumerians (3500 BC): These ancient civilizations were among the first to document the willow’s healing properties, laying the groundwork for its use in traditional medicine.
• Throughout history, various cultures utilized willow bark to alleviate pain, reduce fever, and treat inflammation.

The modern re-discovery of the therapeutic potential of willow tree in eighteenth-century England was achieved by an Oxfordshire clergyman, who accidentally chewed a twig of willow tree despite its extraordinarily bitter taste and later found himself relieved from his arthritic pain. 

In recent years, various in vitro and animal studies have demonstrated that the anti-inflammatory activity of willow bark extract is associated with down regulation of the inflammatory mediators including tumor necrosis factor-a (TNF-a), Interleukin-1, and 6,(IL1& 6) and nuclear factor-kappa B (NF-κB).  

The Active Compounds in Willow Bark

Willow bark extract is used to treat painful conditions like back pain and arthritis. Its effectiveness was long thought to come from salicin, which the body converts to salicylate compounds. However, recent clinical experience and research suggest that salicin alone doesn’t fully explain willow bark’s benefits. Unlike aspirin (ASA), salicin and its byproducts don’t acetylate, meaning they work differently in the body. Importantly, willow bark contains other phenolic compounds beyond salicin. These additional components contribute to the extract’s overall therapeutic effects, enhancing its medicinal value.

Taking white willow bark extract from a whole plant instead of aspirin does not irritate the stomach lining. This is because the salicin found naturally in white willow bark is only converted to the acid form after it has been absorbed by the stomach.  Researchers have also suggested that white willow bark is more effective than aspirin because of the other active compounds that are found in the bark but not the drug. Animal research compared a willow bark extract to Aspirin and found that willow bark extract (15% salicin) was as effective as aspirin in reducing inflammation, even though the salicin content was lower than the equivalent dose of Aspirin. While aspirin has been shown to have a lowering effect on some of the pro-inflammatory factors, it can also increase LTB4 (Leukotriene B4), which is a major inflammation-promoting mediator.

A detailed pharmacological screening of the aqueous willow bark extract STW 33-I, addressed the question of the identification of fractions contributing to the overall effect. All in vivo and in vitro models studied pointed to relevant contributions of the fractions of polyphenols and flavonoids, rather than the isolated compound, salicin, acting alone.

The main active compounds found in White Willow Bark Extract (WWBE) are:

• Salicin
• Chlorogenic acid
• Rutin
• Epicatechin

Willow extracts demonstrated significant antioxidant properties. They effectively neutralized two types of harmful molecules: DPPH (2,2-diphenyl-1-picrylhydrazyl) and Hydroxyl radicals (OH)

Scientists use DPPH in laboratories to study how well different compounds work as antioxidants. Computer simulations (molecular docking) showed that chlorogenic acid had the strongest interaction with two inflammation-related proteins: TNF-α and IL-6.

Willow bark contains a rich variety of compounds that act as antioxidants and reduce inflammation.

Could White Willow Bark Be One of the Keys To the Fountain of Youth?

A study conducted at Concordia University in Montreal measured the effects of thousands of molecules on the aging of yeast. Yeast was chosen because the aging mechanisms of yeast cells and human cells are very similar. “In total, we found six new groups of molecules that decelerate the chronological aging of yeast,” said biologist Vladimir Titorenko . A specific extract of White willow bark (WWBE) was found to be the most potent longevity-extending pharmacological intervention ever described in scientific literature so far. In testing, the willow bark extract increased the average chronological lifespan of yeast by 475 percent and the maximum chronological lifespan by 369 percent.”

The other five extracts studied come from Cimicifuga racemosa, Valeriana officinalis L., Passiflora incarnata L., Ginkgo biloba, and Apium graveolens L. Each of the six longevity-extending extracts increases lifespan more efficiently than any lifespan-prolonging chemical compound currently known, including outperforming the anti-aging effects of both rapamycin and metformin, two of the most popular drugs studied for anti-aging effects. In addition to slowing aging, the compounds may also have beneficial effects on cellular processes when it comes to preventing related diseases, such as cancer, the researchers say.

“Rather than focus on curing the individual disease, interventions on the molecular processes of aging can simultaneously delay the onset and progression of most age-related disorders,” said Idunn Technologies founder, Éric Simard. He continues, “This kind of intervention is predicted to have a much larger effect on healthy aging and life expectancy than can be attained by treating individual diseases.”

Some of the age-mitigating mechanisms of WWBE and other plant extracts include: 

1) amplified mitochondrial respiration and membrane potential; 

2) increased or decreased concentrations of Reactive Oxygen Species (ROS); 

3) reduced oxidative damage to cellular proteins, membrane lipids, and mitochondrial and nuclear genomes; 

4) enhanced cell resistance to oxidative and thermal stresses; and 

5) accelerated degradation of neutral lipids deposited in lipid droplets (LD)s. 

These findings provide important new insights into mechanisms through which some  plant compounds can slow biological aging. 

Nrf2- the Cellular Protectant That Supports Healthy Aging

WWBE increases antioxidant enzymes, preventing and reducing oxidative stress through activation of Nuclear factor erythroid 2-related factor 2 (Nrf2) independent of salicin. 

Nrf2 signaling has been linked to increased longevity in studies of C. elegans, Drosophila, and mice, and Nrf2 activation has attracted attention as a target molecule for various conditions, including many inflammatory diseases.

Nrf2 (Nuclear factor erythroid 2-related factor 2) is a ubiquitous transcription factor expressed in all tissues, with varying levels among different organs. The highest concentrations are found in key detoxification organs such as the kidneys and liver. 

Nrf2 expression can be further induced by cellular stressors, including:

1. Endogenous reactive oxygen species
2. Exogenous electrophiles from environmental pollutants

This fact that known harmful molecules can actually stimulate the body’s antioxidant defense system is a process known as hormesis, where small doses of a harmful substance can be beneficial, and larger doses can be more harmful.   

The Nrf2-signaling pathway is a crucial mediator of cytoprotection, activating the transcription of over 200 genes involved in:

• Drug and toxin metabolism
• Protection against oxidative stress and inflammation
• Protein stability maintenance
• Removal of damaged proteins via proteasomal degradation or autophagy

Nrf2 also interacts with other important cell regulators, including:

• Tumor suppressor protein 53 (p53)
• Nuclear factor-kappa beta (NF-κB)

Through these combined interactions, Nrf2 plays a vital role in protecting the health-span against various age-related diseases, such as cancer and neurodegeneration.

In summary, Nrf2 is a key player in cellular defense mechanisms, contributing to overall health and longevity through its wide-ranging cytoprotective functions.^,

A separate study investigated the mechanisms through which a specific WWBE (PE21), delays yeast chronological aging and extends yeast longevity. This study showed that PE21 causes a shift of lipid metabolism in chronological aging yeast, thereby creating changes in the concentrations of several lipid classes. 

Three mechanisms of aging delay and longevity from WWBE:

1. The WWBE slowed aging and prolonged longevity through its ability to decrease the intracellular concentration of free fatty acids. This postpones an age-related onset of liponecrotic cell death promoted by excessive concentrations of free fatty acids.

2. The WWBE demonstrated an ability to decrease the concentrations of triacylglycerols and increase the concentrations of glycerophospholipids within the endoplasmic reticulum membrane. This activates the unfolded protein response system in the endoplasmic reticulum, which then slows an age-related decline in protein and lipid homeostasis and decreases an aging-associated deterioration of cell resistance to stress. 
3. The WWBE also demonstrated an ability to change lipid concentrations in the mitochondrial membranes. This alters certain catabolic and anabolic processes in mitochondria, thus improving the pattern of age-associated changes in key aspects of mitochondrial function.

Based on several clinical studies, it is also believed that WWBE and salicin may have anti-aging capabilities when applied topically to human skin. Willow extract has been shown to help remove dead skin cells, reduce the appearance of fine lines, and support acne treatments.^,

White Willow Bark Extract (WWBE) for Inflammaging

Aging is an inevitable process in the human body that is associated with a multitude of systemic and localized changes. Inflammation contributes to premature aging through direct external damage to cells and tissue.  Inflammation is one of the seven evolutionarily conserved mechanistic pillars of aging that are shared by age-related conditions, including metabolic diseases. 

Inflammaging refers to all the processes that contribute to the occurrence of various diseases associated with aging such as: frailty, atherosclerosis, Alzheimer’s disease, sarcopenia, type 2 diabetes, or osteoarthritis. Inflammaging is systemic, chronic, and asymptomatic. All these conditions have a common pathogenic mechanism characterized by the presence of a low-grade pro-inflammatory status.

Osteoarthritis and many age-related degenerative joint diseases are correlated with aging mechanisms such as the presence of an inflammatory microenvironment and the impaired link between inflammasomes and autophagy. Maintaining a balance between pro- and anti-inflammatory status has been long linked with aging and longevity.

Mechanisms of Osteoarthritis

The Role of Chondrosenescence in Arthritis Development

Osteoarthritis (OA) is a degenerative joint disease that becomes more prevalent with age. However, it’s crucial to understand that aging itself is not the sole cause of OA. Rather, a complex interplay of factors contributes to the development of this condition. One key concept in understanding this relationship is “chondrosenescence.”

Chondrosenescence refers to the age-dependent deterioration of cartilage cells. This process is influenced by two main types of factors:

Intrinsic factors: These are related to the natural aging process.

Extrinsic factors: These include physical-mechanical stressors and various chemical stimuli.

The combination of these factors makes articular cartilage more susceptible to damage over time.

The Inflammatory Response

As chondrosenescence progresses, it triggers an inflammatory environment within the joint. This environment is characterized by: 

•  Increased levels of pro-inflammatory cytokines, including:
•  Tumor Necrosis Factor-alpha (TNFα)
•  Interleukin-6 (IL-6)
•  Interleukin-7 (IL-7)
•  Interleukin-1 beta (IL-1β)
•  Elevated chemokine production
•  Enhanced protease activity

The Cycle of Degeneration

This inflammatory setting further accelerates the aging process of chondrocytes, creating a self-perpetuating cycle. As this aging of cartilage advances, it promotes the development of degenerative joint changes, which are the hallmarks of osteoarthritis.

While the risk of osteoarthritis increases with age, it’s not an inevitable consequence of aging. Instead, it results from a complex interplay of factors that contribute to chondrosenescence, ultimately leading to the breakdown of joint cartilage and the onset of osteoarthritis symptoms.

Taking herbal formulas that feature WWBE is one way to manage inflammaging, an age-related inflammatory process that increases the chance of degenerative conditions.

Studies of Willow for Age-Related Arthritis 

In one study, the effectiveness of a willow bark extract providing 240 mg of salicin a day was compared to placebo in a 2-week randomized controlled trial in 78 people with osteoarthritis. After two weeks, the willow bark patients’ pain scores were reduced by 14% compared to the placebo group, which had a 2% increase in pain scores.

A randomized controlled trial examined the use of 120 mg or 240 mg salicin or placebo in 210 patients with low-back pain. In the fourth and final week of the study, 39% of the group taking 240 mg salicin, were pain free for at least 5 days, compared to 21% in the 120 mg group and only 6% in the placebo group.

A recent study conducted by European researchers examined the effectiveness of willow bark extract compared to rofecoxib, a non-steroidal anti-inflammatory drug (NSAID), in treating low back pain. The study involved 228 men and women randomly assigned to receive either willow bark extract or rofecoxib for a period of 4 weeks.

Key findings of the study include:

• Both groups reported significant reduction in back pain by the end of the study.
• After 4 weeks, 22 participants in the willow bark group and 20 in the NSAID group were completely pain-free.
• Few participants in either group required additional conventional medications for pain relief during the study.

While the study demonstrates comparable effectiveness between willow bark extract and rofecoxib in treating low-back pain, I believe willow extract is superior due to its lower side-effect profile when compared to rofecoxib, which was pulled from the market due to risks of cardiovascular damage.  

Inhibitory effects of botanical extracts on IL-1β-induced NF-κB activation in chondrocytes in vitro.

Mechanism of Botanical Extracts Shown To Block NF-KB in Cartilage

IL-1β stimulates the IL-1β receptor, initiating an intracellular signal transduction cascade, which activates the cytoplasmic IκB kinases (IκK)-α, IκK-β, and IκK-γ. These kinases phosphorylate inactive IκBα. Phosphorylated IκBα is then ubiquitinated and degraded by the proteasome, releasing active NF-κB. NF-κB translocates to the nucleus, where it activates pro-inflammatory and pro-apoptotic gene production.

In chondrocytes, botanical extracts have been shown to inhibit this NF-κB signal transduction pathway. Specifically, these extracts:

1. Inhibit the NF-κB signal transduction pathway
2. Block the ubiquitination of phosphorylated IκBα
3. Prevent the translocation of activated NF-κB to the nucleus

These effects suggest that certain botanical extracts, including white willow, may have potential therapeutic applications in managing inflammatory processes in chondrocytes, which are critical cells in cartilage tissue.

White Willow and Covid-19

Anti-Inflammatory Effects of White willow bark Extract (WWBE) and aspirin in COVID-19/SARS-CoV-2. Using SARS-CoV-2 peptide/IL-1β white willow extracts and aspirin concentration-dependently suppressed prostaglandin E2 (PGE₂), a principal mediator of inflammation. WWBE presented anti-inflammatory benefits in the context of SARS-CoV-2 beyond that of aspirin, and WWBE is safe and does not carry the side-effect risks that aspirin does.

White Willow and Cancer

White Willow bark extract (WWBE), rich in salicin, inhibits cell growth & promotes apoptosis in human colon & lung cancer through both selective and non-selective COX enzyme inhibition. 

Salicin, a natural compound, has demonstrated significant anti-angiogenic properties in both in vitro and in vivo studies. Its effects on endothelial cells, which play a crucial role in angiogenesis, are particularly noteworthy:

1. Suppression of angiogenic activity: Salicin inhibited key angiogenic processes in endothelial cells, including:

• Cell migration
• Tube formation
• Sprouting from aorta

2. Reduction of oxidative stress: Salicin decreased the production of reactive oxygen species (ROS) in endothelial cells

3. Inhibition of ERK pathway: Salicin suppressed the activation of the extracellular signal-regulated kinase (ERK) pathway, which is known to regulate various cellular functions such as:

• Cell growth
• Differentiation
• Migration
• Invasion

4. Downregulation of VEGF: The expression of vascular endothelial growth factor (VEGF), a potent pro-angiogenic factor, was reduced by salicin in endothelial cells.
5. In vivo anti-tumor and anti-angiogenic effects: When administered to mice, salicin demonstrated:

• Inhibition of tumor growth
• Suppression of angiogenesis in a mouse tumor model

These findings suggest that salicin may have potential as an anti-angiogenic agent in cancer treatment, warranting further investigation into its therapeutic applications.

Other synergistic anti-tumor compounds in WWBE include other salicyl-alcohol derivatives, flavonoids, and proanthocyanidins.^{, ,}

Taken together, salicin targets the signaling pathways mediated by ROS, ERK and VEGF, providing new perspectives into a potent therapeutic agent for hyper-vascularized tumors.

Gut Health and Inflammatory Bowel Diseases

Salicin administration also effectively and dose-dependently prevented pro-inflammatory cytokine expression in dextran sulfate sodium (DSS)-induced colitis in mice. Histological examination showed that salicin suppressed edema, mucosal damage, and the loss of crypts induced by DSS. Oral administration of salicin in DSS-treated mice prevented loss of gut microbiota during the short period of treatment. Salicin has an anti-inflammatory effect, and it may have therapeutic value in ameliorating inflammation during colitis.

Age-Related Eye Diseases

Retinal endothelial cells are involved in many ocular diseases such as age-related macular degeneration and diabetic retinopathy. The presence of salicin significantly reduces the IL-1β-induced release of lactate dehydrogenase, indicating that it mitigates cytokine-induced cell damage. Mechanistically, we show that salicin suppresses IL-1β-induced activation of the nuclear factor-kappa B (NF-κB) signaling as revealed by its suppression on nuclear p65 protein and transfected NF-κB promoters. This study demonstrated that salicin is a protective agent in retinal endothelial cells. These results imply its potential for therapeutic use in retinal disease.

Antiviral, Antibacterial, and Antioxidant Activities 

Salicinoids from willow bark can decompose into salicylic acid, which has been found to possess anti-inflammatory and antiviral properties. Highly-purified proanthocyanidin fractions of WWBE have also been reported to have antiviral and antibacterial activities. 

This study found that the antioxidant, antibacterial, and antiviral properties of white willow bark were highest in the polyphenol-rich bark extracts.

Willow Formulations for Aging and Inflammation

For chronic-age-related inflammation, I combine WWBE with marine/salmon collagen, along with Glucosamine and Chondroitin Sulfate.  Recently, an epidemiological study found that daily consumption of Glucosamine and Chondroitin Sulfate was linked to longevity. 

In its November/December 2020 issue, The Journal of the American Board of Family Medicine published the results of a study. That study matched 1999-2010 National Health and Nutrition Examination Survey data as researchers compared survey responses from nearly 16,686 adults over age 40 to mortality data from 2015. From the survey participants, 658 (or 3.98%) indicated that they’d been taking a glucosamine/chondroitin supplement for a year or longer. The mortality data showed that those 658 participants had an all-cause mortality rate that was 39% lower than that of other study participants. For cardiovascular-related deaths (including stroke, coronary artery disease and heart disease), the glucosamine/chondroitin group’s mortality rate was 65% lower.

Another White willow bark-based formula I developed, blends the following herbs for the maximum synergistic benefit: White willow (Salix alba) Bark 15% salicin, Corydalis (Corydalis yanhusuo) Rhizome 10:1 extract, Hops (Humulus lupulus) Cone extract Perluxan® 30% of alpha and iso-alpha acids, Wild Turmeric Rhizome (Curcuma aromatica) 12:1 extract , Frankincense (Boswellia serrata) Gum ext.75% boswellic acids, 30% AKBA , Myrrh gum (Commiphora myrrha) 4:1 extract, White Peony Root (Paeonia lactiflora) extract 10% Paeoniflorin, Notoginseng Root (Panax Notoginseng) extract 10% Notoginsenosides, and Licorice (Glycyrrhiza glabra) Root extract 25% glycyrrhizic acid.

Frankincense and myrrh, two of the three gifts brought to the baby Jesus, are widely used in clinics as a pair of herbs to obtain a synergistic effect for relieving pain.

Since antiquity, frankincense has been traded as a precious commodity, but it has also been used for the treatment of chronic disease, inflammation, oral health, and microbial infection.

Most of the published work focuses on the pharmacological activities of boswellic acids, specifically on their anti-inflammatory, analgesic, and anti-arthritic properties. As an example, there is growing evidence to support the clinical efficacy of Boswellia in osteoarthritis patients.

The Whole-Plant Synergy Approach 

Scientists are also discovering the advantage of using whole herbs, and specifically whole herbal extracts, which contain a complex symphony of biochemical compounds in a natural polypharmacy. In this way, medicine is slowly expanding from a single-target-based model to explore multi-targeted approaches. Numerous and chemically diverse secondary metabolites contribute to an array of global health-promoting effects within the various molecular, cellular, and organ-system networks.

Every herb can have a multitude of active compounds, each one able to communicate with several target proteins with a high number of protein-to-protein responsive interactions (high biological network connectivity) and these protein targets have higher network connectivity than do disease genes. Proteins play a pivotal role in many biological processes. 

Herbal medicine, in the form of harmonious formulations, naturally provides a synergistic and multi-targeted effect that supports the body’s return to health.

In the traditional understanding of Chinese medicine, Boswellia, Myrrh, Notoginseng, White Peony root, and Wild Turmeric are often used together in various combinations to move stagnation from the tissues, nourish the blood, relieve pain, and promote the healing response. A clinical trial with 201 patients suffering from degenerative osteoarthritis of the knees were given a combination of Curcumin and Boswellia extracts. The combination of the two compounds was found to be more effective than either agent alone or than placebo.

Conclusion

For thousands of years, people have used white willow bark for healing. White willow bark has anti-inflammatory, anti-viral, anti-aging, and pain-relieving properties and is the source of aspirin’s discovery. Ancient civilizations, including the Assyrians and Sumerians, used it to reduce pain, fever, and inflammation. Studies today show that willow bark’s benefits come from a mix of compounds, including salicin, flavonoids, and polyphenols, which help fight inflammation, pain, and aging without causing stomach irritation like aspirin. 

The bark may also help manage chronic diseases like arthritis, inflammatory bowel disease, and cancer; its antioxidant qualities could slow the effects of aging. Willow bark, in combination with other herbs and nutrients, provides a natural, multi-targeted approach to support overall health and longevity.

Next time you consider taking something to enhance your health, reduce inflammation, and aid in graceful aging, consider formulations that feature powerful white willow bark extract.

About the Author:

Donald R. Yance is the founder of the Mederi Center. A Clinical Master Herbalist and Certified Nutritionist, Donnie is renowned for his extraordinary knowledge and deep understanding of the healing properties of plants and nutrition, as well as of epigenetics, laboratory medicine, oncologic pathology, and molecular oncology. He is a professional member of the American Herbalists Guild, National Association of Nutrition Professionals, Academy of Integrative Health and Medicine, and the Society for Integrative Oncology.

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