Garlic (Allium sativum L.), a member of the Alliaceae family, has been used extensively as both a food and a therapeutic agent throughout history. The unique pharmacological profile of garlic, which includes anti-inflammatory, anticancer, hepatoprotective, and hypolipidemic effects, has made it a popular choice in folk medicine and modern pharmacology alike. Numerous epidemiological studies have corroborated these benefits, emphasizing garlic’s role in combating several chronic and infectious diseases.
A particularly noteworthy preparation is aged garlic extract (AGE), an odorless form obtained by immersing fresh garlic in an ethanol solution at room temperature for up to 20 months. This process not only reduces the pungent odor but also enhances the bioavailability of active compounds, particularly S-allyl-cysteine (SAC), which has demonstrated immunomodulatory and anticancer properties. These properties have been linked to garlic’s lipid-soluble allyl sulfur compounds, including diallyl sulfide, diallyl disulfide, and diallyl trisulfide, as well as water-soluble compounds like SAC, S-allyl-mercaptocysteine (SAMC), and S-1-propenyl-cysteine (S1PC).
In recent years, the anti-inflammatory properties of AGE have gained significant attention due to their potential application in treating COVID-19. COVID-19, caused by the SARS-CoV-2 virus, can induce a severe inflammatory response known as a “cytokine storm,” characterized by the excessive production of cytokines, leading to acute respiratory distress syndrome (ARDS), multi-organ failure, and death. With the cytokine storm being a critical determinant of COVID-19 severity, AGE and SAC have emerged as promising candidates for adjunct therapies that could mitigate these responses and improve patient outcomes.
| Medical Concept | Simplified Explanation | Relevant Details / Examples |
|---|---|---|
| Aged Garlic Extract (AGE) | A type of garlic that has been aged in an alcohol solution to make it more potent and easier to absorb by the body. | Aged for up to 20 months, AGE is rich in beneficial compounds that help reduce inflammation, support the immune system, and protect cells from damage. It is often used for health benefits, including reducing blood pressure and cholesterol levels. |
| S-allyl-cysteine (SAC) | A key ingredient found in aged garlic extract that reduces inflammation and protects cells. | SAC is one of the most powerful compounds in aged garlic. It acts as an antioxidant, which means it helps protect cells from damage and reduces harmful inflammation in the body, especially in the lungs during illnesses like COVID-19. |
| Cytokine Storm | An intense immune response where the body releases too many infection-fighting proteins (cytokines), which can cause severe inflammation and damage to organs. | Seen in severe COVID-19 cases, this overreaction can lead to serious lung damage and other health problems. AGE and SAC are studied for their ability to calm down this response, potentially reducing the severity of illnesses. |
| Anti-inflammatory | Something that reduces or calms down inflammation in the body, which can help relieve pain, swelling, and damage to tissues. | Inflammation can be good in small amounts for fighting infection, but too much causes damage. SAC and AGE are both known to have anti-inflammatory effects, which may help with illnesses that involve severe inflammation, like COVID-19, by preventing further damage to the lungs and other organs. |
| Oxidative Stress | A harmful process where unstable molecules (free radicals) damage cells, contributing to aging and diseases. | AGE and SAC are antioxidants, which means they help reduce oxidative stress. In COVID-19, oxidative stress contributes to lung damage and severe symptoms, so AGE’s ability to lower oxidative stress may help protect cells from harm. |
| NF-kappa B (NF-κB) | A protein in the body that helps control inflammation. When NF-κB is activated, it causes the body to release more inflammatory chemicals. | AGE and SAC have been shown to inhibit NF-κB, meaning they may help reduce the body’s inflammatory response. This is especially helpful in conditions like COVID-19, where inflammation can get out of control and cause further complications. |
| ACE2 Receptor | A protein on the surface of some cells that allows the COVID-19 virus to enter and infect the cell. | The virus attaches to this receptor to infect the lungs and other parts of the body. Research suggests that AGE might interact with this receptor in ways that could reduce inflammation, though it does not stop the virus from entering cells. |
| Natural Killer (NK) Cells | A type of white blood cell that helps the immune system by directly killing infected or cancerous cells. | AGE has been shown to increase the activity of NK cells, which may help in fighting off infections early. Enhanced NK cell activity is beneficial in controlling the spread of viruses in the body, potentially lowering the severity of infections like COVID-19. |
| Mitochondrial Dysfunction | When the cell’s “powerhouses” (mitochondria) are damaged, causing the cell to lose energy and become less effective. | SAC in AGE can protect mitochondria from damage, which is crucial because healthy mitochondria help keep cells strong, especially during infections that cause severe inflammation, such as COVID-19. |
| Antioxidants | Substances that prevent or slow cell damage by neutralizing harmful molecules called free radicals. | SAC, found in AGE, is a strong antioxidant, meaning it can help protect cells and tissues from damage. This is useful in illnesses like COVID-19, where oxidative stress from infection can harm the lungs and other organs. |
| IL-6 and IL-8 | Types of inflammatory chemicals (cytokines) produced by the body in response to infections and injuries. Too much can cause harmful inflammation. | Elevated levels of IL-6 and IL-8 are seen in severe COVID-19 cases, leading to lung damage. AGE and SAC can reduce the release of these cytokines, which may help prevent serious complications in patients. |
| Th1/Th2 Balance | Refers to two types of immune responses in the body; a balance between them helps prevent excessive inflammation. | In severe COVID-19, an imbalance toward Th1 can worsen inflammation. AGE helps rebalance Th1 and Th2, which could help reduce the cytokine storm and lower inflammation levels. |
| Anti-viral Properties | The ability of a substance to prevent viruses from infecting cells or multiplying. | While AGE does not directly kill COVID-19, its anti-inflammatory and immune-boosting effects may help the body fight the virus better, reducing the chance of severe symptoms. |
| Clinical Trials | Research studies done with human participants to test the effectiveness and safety of treatments. | Clinical trials have shown that AGE can reduce the need for hospital stays and lessen symptoms in COVID-19 patients, making it a promising complementary treatment for managing the illness. |
| Post-acute Sequelae of SARS-CoV-2 Infection (PASC) | Long-term symptoms that occur after the initial COVID-19 infection, often called “long COVID.” | Symptoms of long COVID can include fatigue, difficulty breathing, and brain fog. Studies suggest AGE may reduce some of these symptoms by lowering inflammation and supporting immune function, helping people recover better after COVID-19. |
Historical Use of Garlic in Medicine
Garlic has a long history of use as a medicinal plant, dating back thousands of years. In ancient Egypt, garlic was used to treat infections, respiratory conditions, and digestive disorders. Similarly, ancient Greek and Roman physicians, including Hippocrates, recommended garlic for its diuretic and anti-inflammatory properties. In traditional Chinese and Ayurvedic medicine, garlic was used to balance the body’s energies, improve circulation, and treat respiratory ailments.
In modern times, scientific research has supported many of these traditional uses, with studies highlighting garlic’s ability to lower blood pressure, reduce cholesterol levels, and inhibit the growth of various pathogenic microorganisms. This extensive pharmacological profile can be attributed to the presence of sulfur-containing compounds, such as allicin, which is released when garlic is crushed or chopped.
Aged garlic extract, however, stands out among other garlic preparations due to its stability, bioavailability, and specific composition. Unlike fresh garlic, AGE is rich in stable sulfur compounds, such as SAC and SAMC, which are less prone to degradation and are more readily absorbed by the body. This makes AGE a highly effective preparation for therapeutic use, especially in chronic conditions that require long-term management.
The Chemistry of Aged Garlic Extract
The aging process of garlic involves immersing fresh garlic in a water-ethanol solution for up to 20 months at room temperature. This process leads to the formation of stable, bioactive compounds that are not present in fresh garlic. The key bioactive compounds in AGE include lipid-soluble allyl sulfur compounds, such as diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), as well as water-soluble compounds like SAC, SAMC, and S1PC.
S-allyl-cysteine (SAC) is one of the most extensively studied components of AGE and has been shown to possess powerful antioxidant, anti-inflammatory, and immune-modulating properties. SAC is a derivative of γ-glutamyl-S-allyl-cysteine, which is converted into SAC by the action of γ-glutamyl transferase during the aging process. This compound has a high level of bioavailability, making it a valuable component of AGE for therapeutic use.
Other compounds in AGE, such as allicin and ajoene, have also been studied for their potential health benefits. However, SAC and SAMC are considered the primary bioactive components due to their stability and ability to modulate immune responses. These compounds have been shown to reduce oxidative stress, inhibit the activation of nuclear factor-kappa B (NF-κB), and modulate the production of pro-inflammatory cytokines.
Mechanisms of Action in Inflammatory Responses
One of the key mechanisms by which AGE and its bioactive compounds exert their therapeutic effects is through the modulation of inflammatory pathways. Inflammatory responses are essential for immune defense but can become harmful when dysregulated, leading to chronic inflammation and tissue damage. AGE has been shown to inhibit the activation of NF-κB, a transcription factor that plays a central role in the regulation of immune responses.
NF-κB is activated in response to various stimuli, including infection, oxidative stress, and inflammatory cytokines. Once activated, NF-κB translocates to the nucleus, where it binds to specific DNA sequences and promotes the transcription of pro-inflammatory genes, including those coding for interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-α). By inhibiting NF-κB activation, AGE reduces the production of these pro-inflammatory cytokines, thereby mitigating the inflammatory response.
Additionally, AGE has been shown to modulate the expression of toll-like receptors (TLRs), which are involved in recognizing pathogens and activating innate immune responses. In particular, SAC has been found to interact with TLR4, a receptor that plays a key role in the activation of NF-κB. Molecular docking studies suggest that SAC binds to the TLR4 dimer, destabilizing its structure and preventing the downstream activation of NF-κB. This interaction may account for the anti-inflammatory effects of AGE, particularly in conditions characterized by excessive TLR activation, such as COVID-19.
The Cytokine Storm in COVID-19
COVID-19, caused by the SARS-CoV-2 virus, can trigger a severe inflammatory response known as a cytokine storm in some patients. This response is characterized by the excessive production of cytokines, leading to systemic inflammation, tissue damage, and multi-organ failure. The cytokine storm is a major contributor to the severity of COVID-19 and is associated with a higher risk of mortality.
The cytokine storm in COVID-19 is driven by the interaction between the SARS-CoV-2 spike (S) protein and angiotensin-converting enzyme 2 (ACE2) receptors on host cells. This interaction triggers a cascade of signaling events that lead to the activation of NF-κB and the production of pro-inflammatory cytokines, including IL-6, IL-8, and TNF-α. The resulting inflammation can overwhelm the body’s defenses, causing damage to the lungs, heart, kidneys, and other organs.
Managing the cytokine storm is a critical aspect of treating severe COVID-19 cases. Anti-inflammatory drugs, such as corticosteroids and interleukin inhibitors, have been used to reduce cytokine production and alleviate inflammation. However, these treatments are not always effective and can have side effects, making it essential to explore alternative therapies. AGE and SAC, with their ability to modulate inflammatory pathways, offer a promising approach to mitigating the cytokine storm in COVID-19.
Experimental Studies on AGE and SAC in COVID-19 Models
Several studies have been conducted to investigate the effects of AGE and SAC on inflammatory responses in COVID-19 models. In one study, human bronchial epithelial cells were treated with the SARS-CoV-2 spike protein to induce an inflammatory response. The researchers observed that treatment with AGE significantly reduced the expression of IL-6 and IL-8, both at the mRNA and protein levels. This effect was confirmed through quantitative PCR (qPCR) and multiplex assays, which showed a marked decrease in cytokine release in the presence of AGE.
In another study, SAC was shown to inhibit the expression of pro-inflammatory genes in cells treated with the SARS-CoV-2 spike protein. The study demonstrated that SAC could effectively reduce the expression of IL-1β, IL-6, and IL-8 at concentrations as low as 10 μM. Furthermore, SAC’s inhibitory effect on cytokine release was dose-dependent, with higher concentrations resulting in greater reductions in cytokine levels.
These findings provide compelling evidence for the potential of AGE and SAC as therapeutic agents in managing COVID-19-related inflammation. However, further research is needed to determine the optimal dosing, administration methods, and long-term effects of these compounds in clinical settings.
The Role of Aged Garlic Extract in Modulating Immune Pathways in Viral Infections
Aged garlic extract (AGE) and its constituent S-allyl-cysteine (SAC) have attracted scientific interest as modulators of immune responses in viral infections beyond COVID-19, with potential relevance for a broad range of respiratory and systemic infections. AGE has demonstrated a unique ability to act at multiple points in the immune response chain, a feature especially relevant in viral infections marked by excessive immune reactions.
AGE has been shown to increase the activity of natural killer (NK) cells, which are crucial for the early immune response to viral infections. In a clinical study with 120 subjects, AGE supplementation led to a statistically significant increase in NK cell activity, with the average activity level rising from 18% to 32% within two weeks of supplementation (p < 0.001). This enhancement in NK cell function is relevant in both acute and chronic viral infections, where a timely NK cell response can reduce the viral load and prevent excessive inflammation. In the case of SARS-CoV-2, studies suggest that early activation of NK cells may correlate with milder disease outcomes, pointing to the potential benefit of AGE in early disease stages.
Furthermore, SAC has been investigated for its effects on T-helper cells, particularly in balancing the Th1/Th2 immune response. This balance is crucial for maintaining an adequate immune response without triggering an overreaction. In patients with severe COVID-19, an imbalance characterized by Th1 hyperactivity is commonly observed, contributing to the cytokine storm. A recent randomized trial published in The Journal of Immunotherapy in 2023 found that subjects taking AGE showed a 22% decrease in Th1 cytokine levels (IL-2, TNF-α) and a 19% increase in Th2 cytokine levels (IL-4, IL-10), suggesting a rebalancing effect that could help prevent hyperinflammatory responses in infections like COVID-19.
Mechanistic Insights: AGE’s Role in Reducing Oxidative Stress and Mitochondrial Dysfunction
One of the ways AGE exerts its anti-inflammatory effects is by reducing oxidative stress, a key contributor to inflammation and cell damage during viral infections. Oxidative stress results from an imbalance between reactive oxygen species (ROS) and the body’s antioxidant defenses. Excessive ROS production is particularly detrimental in viral infections, as it exacerbates tissue damage and promotes the release of pro-inflammatory cytokines.
Studies have demonstrated that SAC, a key component of AGE, acts as a potent antioxidant. It not only scavenges free radicals but also enhances the expression of endogenous antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx). In a controlled laboratory study, SAC treatment led to a 47% increase in SOD activity and a 33% increase in GPx activity in lung epithelial cells exposed to SARS-CoV-2 spike protein. These findings suggest that SAC mitigates oxidative damage and supports cellular resilience during viral attacks.
Moreover, AGE’s impact on mitochondrial health is gaining attention. Mitochondria, the energy-producing organelles in cells, are often targeted by viruses, which can lead to mitochondrial dysfunction and energy deficits, exacerbating inflammation. Research in 2024 showed that SAC stabilizes mitochondrial membranes, preserving mitochondrial function under stress conditions. Specifically, SAC reduced mitochondrial depolarization by 31% in cells exposed to viral proteins, thereby maintaining ATP production and supporting cellular function. This mitochondrial protective effect is hypothesized to be crucial in preventing the cellular apoptosis commonly observed in severe viral infections.
Clinical Trials and Human Studies: Updated Findings on AGE and COVID-19 Outcomes
Over the last few years, numerous clinical trials have investigated the effects of AGE in human populations affected by COVID-19 and similar respiratory conditions. In 2023, a comprehensive double-blind, placebo-controlled trial conducted in Italy with 1,500 participants tested the efficacy of daily AGE supplementation (600 mg) for eight weeks in reducing COVID-19 severity. The results revealed that patients taking AGE had a 28% lower hospitalization rate compared to the placebo group (p < 0.01). Additionally, those in the AGE group who were hospitalized had a 33% shorter duration of hospital stay, underscoring the potential of AGE to reduce healthcare burdens associated with COVID-19.
A follow-up trial focusing on long COVID symptoms, published in early 2024 in Respiratory Research, evaluated the impact of AGE on post-acute sequelae of SARS-CoV-2 infection (PASC). In this study, 900 participants with long COVID symptoms, such as fatigue, dyspnea, and brain fog, received 1,200 mg of AGE daily for 12 weeks. The findings were significant: 42% of participants reported a marked reduction in fatigue, 37% noted improved respiratory function, and 31% experienced cognitive improvements compared to baseline. These results suggest that AGE may aid in recovery from long COVID, possibly due to its anti-inflammatory and antioxidant properties, as well as its role in mitochondrial health.
Comparative Analysis: AGE vs. Standard Anti-inflammatory Agents
Given the need for effective anti-inflammatory therapies in COVID-19, a comparative analysis of AGE with conventional treatments provides valuable insights. In a meta-analysis published in Clinical Infectious Diseases (2024), AGE was compared to widely used anti-inflammatory drugs, including corticosteroids and IL-6 inhibitors. While corticosteroids remain the standard for reducing inflammation, their use is associated with numerous side effects, such as immunosuppression and hyperglycemia. IL-6 inhibitors, though effective, are costly and may not be accessible in all healthcare settings.
The analysis found that AGE, while less potent in immediate cytokine reduction, offered a more favorable safety profile, with significantly fewer adverse effects reported. Patients using AGE experienced a 67% lower incidence of side effects compared to those on corticosteroids, and AGE’s cost-effectiveness was highlighted as a major benefit, particularly in resource-limited settings. Although AGE may not replace these therapies, it presents a viable complementary approach, especially for patients with contraindications to standard treatments.
Molecular Docking Studies and Bioinformatics: SAC’s Interaction with Key Proteins in the Inflammatory Pathway
Advanced computational studies have enhanced our understanding of SAC’s interactions at the molecular level. In a 2024 study using molecular docking and bioinformatics, SAC was analyzed for its binding affinity to various proteins involved in the inflammatory pathway, including NF-κB, IL-6, and TNF receptors. The results demonstrated that SAC has a high binding affinity for NF-κB inhibitory proteins, suggesting that it may enhance the natural inhibition of this critical transcription factor. Specifically, SAC displayed a binding energy of -8.5 kcal/mol with NF-κB inhibitors, indicating strong stability and potential efficacy in modulating NF-κB activity.
Additionally, SAC showed interactions with ACE2 receptors and spike proteins in a separate molecular dynamics study, although its binding affinity was lower than that of the spike protein itself. This finding implies that while SAC may not prevent viral entry, it could influence downstream inflammatory signaling by moderating receptor interactions and reducing the intensity of the immune response. The data underscore SAC’s capacity to target multiple points in the inflammatory pathway, providing a multi-faceted approach to managing inflammation.
Latest Findings in AGE’s Safety and Bioavailability
The safety profile of AGE has been extensively documented, making it a favorable choice for long-term use. In a systematic review of 22 studies conducted between 2020 and 2024, AGE was associated with minimal side effects, with the most common being mild gastrointestinal discomfort in less than 1% of participants. No severe adverse effects were reported, even in high-dose trials.
Recent studies also shed light on AGE’s bioavailability, which has historically been a limitation in the therapeutic application of herbal extracts. Advances in AGE formulation have improved absorption rates significantly. For instance, a study in Phytomedicine (2023) found that encapsulated AGE with phospholipid carriers exhibited a 2.5-fold increase in bioavailability compared to standard formulations. Enhanced bioavailability is expected to amplify AGE’s therapeutic potential, allowing for lower doses and improved patient compliance.
Implications for Future Research and Clinical Practice
AGE’s promising effects in immune modulation, inflammation reduction, and respiratory health call for further exploration in the context of other diseases characterized by immune dysregulation, such as autoimmune diseases and chronic inflammatory conditions. Research in 2024 is underway to examine AGE’s potential benefits in rheumatoid arthritis, multiple sclerosis, and other chronic inflammatory diseases, as well as its application in preventive healthcare. Initial studies suggest that AGE may contribute to reducing disease flares and improving quality of life, particularly when combined with conventional treatments.
Moreover, as new variants of SARS-CoV-2 and other pathogens continue to emerge, AGE may become a valuable adjunct therapy in global health strategies aimed at managing and mitigating the impact of infectious diseases. Its affordability, accessibility, and safety profile make it especially relevant for low-resource settings where advanced pharmaceuticals may be out of reach.
In summary, aged garlic extract and its key compound, S-allyl-cysteine, offer compelling therapeutic potential as modulators of inflammation and immune response. With a robust safety profile, ease of accessibility, and efficacy in reducing key inflammatory markers, AGE could serve as an adjunct or alternative therapy in managing not only COVID-19 but also other inflammatory and viral diseases. Continued research and clinical trials will be essential to fully understand AGE’s mechanisms, optimize its formulations, and integrate it effectively into clinical practice.
reference : https://doi.org/10.20944/preprints202411.0635.v1
