Supplement Name: Resveratrol (polygonum cuspidatum)(root) (50%Trans-Resveratrol)

Background: Resveratrol, specifically sourced from the roots of Polygonum cuspidatum, has a distinct history and botanical profile separate from the general discovery of the compound. Resveratrol (RES), particularly the active trans-isomer found in Polygonum cuspidatum, has a strong scientific basis driven by its potent pleiotropic effects, primarily related to cellular protection and regulation of fundamental metabolic pathways. Resveratrol, often sourced from Polygonum cuspidatum, is the focus of immense research activity aimed at translating its potent cellular effects into clinically applicable therapies, particularly due to its capacity to activate pleiotropic pathways like Nrf2-Keap1 and SIRT1/AMPK.

Origin & Historical Context

The general substance, resveratrol (RES), is a stilbenoid natural polyphenol (a phytoalexin) produced by certain plants as a defense mechanism against stress, fungal infection, or pathogenic invasion.

The compound was first isolated and described in 1940 by Takaoka from the roots of Veratrum grandiflorum. However, it gained widespread international attention in the scientific community beginning around 1992 due to its association with the "French Paradox"—the observation that the French population has a comparatively low incidence of cardiovascular mortality despite a diet high in saturated fats, which was potentially attributed to moderate red wine consumption (a source of resveratrol). Scientific interest grew exponentially after an article published in Science in 1997 highlighted resveratrol's potential for cancer chemopreventive activity.

Botanical Overview

Resveratrol is a major component found in the roots of the medicinal plant, Reynoutria japonica Houtt, commonly known as Polygonum cuspidatum (or Japanese knotweed).

Resveratrol itself is classified as a stilbene (polyphenol), defined by a stilbenic structure featuring two phenolic rings connected by an ethylene bridge. It is considered a natural non-flavonoid polyphenolic compound.

Resveratrol exists in two geometric isomeric forms, cis and trans, due to the presence of a bis-styrene double bond. In nature, the trans -isomer (trans-3,4′,5-trihydroxystilbene) is the predominant form, possesses higher stability, and is considered the more biologically active variant compared to the cis isomer.

The commercial material specified in your query, containing 50% Trans-Resveratrol, utilizes this more biologically active form.

Geographic Origin

The source plant, Polygonum cuspidatum, is widely recognized as Japanese knotweed. It is a dietary and medicinal source of resveratrol.

Cultural Origins & Traditional Use Patterns

The roots of Polygonum cuspidatum, referred to as kojo-kon in Japanese, have a history of use in traditional oriental medicine.

Specifically, this medicinal plant has been documented in the Compendium of Materia Medica to possess various traditional therapeutic effects, including:

• Invigorating blood circulation.

• Removing blood stasis.

• Clearing heat.

• Draining pus.

Historically, the roots were valued in traditional Chinese and Japanese medicine for their potential antiplatelet and anti-inflammatory properties.

Pre-Clinical Biological Rationale

Resveratrol is studied primarily because it is a stilbenoid natural polyphenol (a phytoalexin) that demonstrates a wide range of beneficial biological and pharmacological properties relevant to chronic human diseases and aging.

The pre-clinical rationale focuses on its role as a master regulator for key biological processes:

1. Antioxidant and Anti-inflammatory Activity: RES possesses significant antioxidant and anti-inflammatory properties. These attributes help counteract oxidative stress, a crucial factor in the pathogenesis of numerous diseases.

2. Anti-aging and Metabolic Health: RES is linked to anti-aging effects and has been shown to mimic the beneficial effects of caloric restriction. It can protect against metabolic diseases, neurodegenerative disorders, and generally improves health and survival in metabolically-challenged animal models.

3. Cancer and Cardioprotection: RES demonstrates a broad spectrum of antitumor effects and provides multidimensional protection to the cardiovascular system, particularly the vasculature.

4. Intestinal Barrier Support: Crucially, RES is investigated for its potential role in strengthening the intestinal barrier, which is vital for preventing systemic inflammation and maintaining overall health.

Metabolism & Mechanistic Pathways

The efficacy of RES largely depends on its interactions within the body, an area complicated by its physicochemical properties and rapid metabolic rate.

Metabolism and Bioavailability Challenges

Despite high absorption rates, RES suffers from very low systemic bioavailability in its free, unmetabolized form.

1. Absorption and Solubility: Oral absorption is relatively high (approximately 75%) and occurs quickly in the small intestine, primarily through passive diffusion. However, its use is limited by poor water solubility.

2. First-Pass Metabolism: RES undergoes rapid and extensive first-pass metabolism primarily in the intestine and liver. This process rapidly converts the parent compound.

3. Metabolite Forms: The major metabolites identified are glucuronide and sulfate conjugates. The highest concentration is generally observed for these conjugated metabolites, which can be 3- to 8-fold or up to 20-fold higher than that of free RES in plasma.

4. Biological Activity of Metabolites: It is theorized that these circulating conjugated metabolites also retain relevant biological activity, or may act as a systemic reserve pool that can be converted back into active, free RES within target tissues (recycling).

Mechanistic Pathways in Pre-clinical Models

Resveratrol exerts its cellular effects by influencing several key signaling hubs, including those governing oxidative defenses, energy metabolism, and cell survival.

1. Nrf2-Keap1 Antioxidant Pathway:

    ◦ Mechanism: RES functions as a major activator of the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) pathway. Nrf2 activation triggers the expression of numerous antioxidant and phase 2 detoxifying enzymes, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and heme oxygenase-1 (HO-1).

    ◦ Rationale: This pathway is critical for suppressing oxidative stress and maintaining cellular homeostasis, particularly helping to protect the integrity of the intestinal epithelial barrier against damage induced by reactive oxygen species (ROS).

2. SIRT1/AMPK Energy Regulation:

    ◦ Mechanism: RES is a recognized activator of Sirtuin 1 (SIRT1) and influences AMP-activated protein kinase (AMPK).

    ◦ Rationale: SIRT1 mediates anti-aging effects and promotes mitochondrial function. Activation of the SIRT1/AMPK axis enhances mitochondrial biogenesis and improves insulin-mediated glucose disposal, acting as an energy sensor to modulate metabolism and inhibit inflammation.

3. PI3K/AKT/mTOR Pathway:

    ◦ Mechanism: Resveratrol often suppresses signaling via the Phosphoinositide 3-kinase (PI3K)/AKT/mechanistic Target of Rapamycin (mTOR) axis.

    ◦ Rationale: In cancer, inhibiting this pathway contributes to cell cycle arrest and apoptosis. In cellular protection, the PI3K/Akt pathway acts upstream to promote Nrf2 activation, which is necessary for the cytoprotective effects observed against oxidative stress.

Analogy: Think of resveratrol as a vital, but fragile, message (the active compound) delivered by courier (oral ingestion). The courier (absorption) is usually successful, but immediately upon delivery, the message is intercepted by translators (metabolizing enzymes in the liver/intestine) who rapidly convert it into bulky, sealed packets (glucuronide and sulfate conjugates). Only a tiny bit of the original message gets through immediately. However, the sealed packets might be able to reach distant offices (tissues), where they can be unsealed and the original message regenerated, allowing the biological effects (the message’s instruction) to take place over a longer time, despite the poor initial delivery of the original form.

Areas of Active Research

Current research on resveratrol (RES) spans a wide spectrum, from fundamental mechanistic studies to clinical applications across numerous chronic conditions:

1. Oncology and Chemoprevention: RES exhibits a broad spectrum of antitumor effects and is actively studied for its potential in preventing and treating various cancers, including gynecological tumors (cervical, endometrial, ovarian), as well as colon, lung, prostate, liver, and pancreatic cancers. Mechanistically, RES promotes tumor cell apoptosis, inhibits proliferation, reduces metastasis, and enhances the sensitivity of tumor cells to conventional chemotherapy and targeted drugs.

2. Cardiovascular and Vascular Health (CVD): Extensive investigation focuses on treating CVDs, such as hypertension, atherosclerosis, heart failure, and coronary artery disease. RES works by promoting endothelial function, improving blood pressure, regulating lipid metabolism, and acting as a potent antioxidant against oxidative stress and vascular inflammation.

3. Metabolic and Anti-aging Effects: RES is investigated for its role in mitigating metabolic disorders, including Type 2 Diabetes Mellitus (T2DM), obesity, and Non-Alcoholic Fatty Liver Disease (NAFLD), often by mimicking the beneficial effects of caloric restriction. It promotes improved insulin sensitivity, modulates blood glucose and circulating lipids, and activates energy metabolism regulators like SIRT1.

4. Gastrointestinal and Intestinal Barrier Function: A significant area of mechanistic research involves maintaining intestinal barrier integrity. Preclinical studies show RES protects the intestinal barrier against injury (such as that induced by oxidative stress or NSAIDs) by enhancing tight junction protein expression (claudin-1, occludin, and ZO-1), mitigating inflammation, and regulating the intestinal microbiome and metabolites.

5. Neuroprotection and Cognitive Function: RES is studied as a potential treatment for neurodegenerative disorders (like Alzheimer's disease or AD) and acute injuries like ischemic stroke. It is known to cross the blood–brain barrier and exert neuroprotective effects via its antioxidant and anti-inflammatory mechanisms.

6. Musculoskeletal and Bone Health: Research explores RES in osteoporosis (OP) and intervertebral disc degeneration (IVDD). It has shown promise in improving bone mineral density and acting against processes like disc cell apoptosis by scavenging reactive oxygen species (ROS).

7. Pharmaceutical Development: Due to its poor water solubility, instability, and low systemic bioavailability (often reported as less than 1% of the parent compound after oral administration), extensive work is dedicated to developing improved delivery systems. This includes testing various nanodelivery systems (e.g., liposomes, polymeric, and inorganic nanoparticles) and bioenhancers (like piperine) to increase absorption and therapeutic efficacy.

Evidence Tier Summary

The confirmation of RES benefits in humans through randomized clinical trials (RCTs) remains limited despite the vast output of preclinical data.

Analogy: Resveratrol research is like searching for gold using a map drawn from microscopic dust samples. The dust (cellular data) hints at rich veins (therapeutic potential), but when researchers try to mine it (human trials), they discover that the active ingredient (free RES) is washed away almost instantly by a strong river (metabolism) before it can reach the target, leaving only traces and metabolites whose true effect remains largely unproven in the clinic.

Resveratrol Patient Population 

The benefits and outcomes associated with resveratrol (RES) depend significantly on the patient population, the dose administered, and the specific health status being investigated.

Over the last 20 years, approximately 200 studies have evaluated RES across at least 24 indications, and the overall consensus is that RES consistently reduces inflammatory markers and improves aspects of a dysregulated metabolism. However, there is currently no conclusive clinical evidence to advocate for its recommendation in any healthcare setting, and large-scale, high-quality clinical trials are still needed.

The key benefits observed across specific populations, largely drawing from human clinical trials, include:

I. Metabolic and Endocrine Disorders

II. Cardiovascular and Vascular Health

III. Musculoskeletal and Inflammatory Conditions

IV. Oncology and Neurodegenerative Disease

Krafted Formulation Rationale 

Supplements Krafted Different

Krafted Supplements formulates botanical products using a clinical-first, regulatory-aware framework, applying principles drawn from pharmaceutical development rather than conventional supplement marketing. Each formulation is treated as a biologically active system where source, chemical form, dose, and delivery materially influence physiological outcomes.

Resveratrol is not approached as a generic antioxidant, but as a dose-sensitive, pleiotropic polyphenol with well-characterized metabolic limitations, non-linear response behavior, and safety considerations that demand conservative, evidence-guided formulation.

Sourcing Standard

Krafted Resveratrol is sourced exclusively from Polygonum cuspidatum (Japanese knotweed) root, the most extensively studied botanical source of trans-resveratrol.

Sourcing requirements include:

• Verified botanical identity (Polygonum cuspidatum, root)

• Documentation of geographic origin and cultivation conditions

• Use of mature root material (not aerial parts)

• Controlled post-harvest processing to preserve trans-isomer integrity

• Supplier qualification with auditable records

Krafted avoids grape skin–derived or fermentation-based resveratrol sources due to variability in isomer ratio, inconsistent yield, and reduced traceability at scale.

Standardization Targets

Rather than total polyphenol content, Krafted standardizes specifically to:

• ≥50% trans-resveratrol, the biologically dominant and more stable isomer

• Confirmed cis/trans ratio stability

• Absence of synthetic resveratrol adulteration

This target reflects the compound most consistently studied across SIRT1, AMPK, Nrf2, and mitochondrial signaling pathways, while avoiding supraphysiologic purity levels associated with tolerability concerns at higher doses.

Purity Thresholds + Third-Party Testing Plan

Each production lot is supported by ISO-accredited third-party laboratory testing, including:

• Identity confirmation (HPTLC / FTIR)

• Assay verification for trans-resveratrol content

• Heavy metals (Pb, Cd, As, Hg) — USP <233> limits

• Pesticides — USP <561>

• Microbial screening (TAMC, TYMC, pathogens)

• Residual solvent analysis

• Adulterant screening (synthetic stilbenes)

Certificates of Analysis (COAs) are reviewed internally prior to batch release and retained for full lot traceability.

Formulation Logic 

(Phenotype Ratios + Excipient Rationale)

Resveratrol is formulated as a single-ingredient active to preserve interpretability, dose control, and regulatory clarity.

Excipients are intentionally minimal and function-driven:

• Microcrystalline cellulose for flow consistency and dose uniformity

• Hypromellose (vegetable capsule) for inert encapsulation and stability

No bioenhancers (e.g., piperine), lipid carriers, or nano-delivery systems are included in this formulation. This avoids:

• Unpredictable CYP enzyme interference

• Altered pharmacokinetics that complicate safety interpretation

• Barriers to future clinical or regulatory translation

Delivery Form Justification (Capsule vs. Powder/Liquid)

A capsule delivery system was selected based on:

• Precise, reproducible dosing

• Improved stability of trans-resveratrol vs. powders

• Reduced oxidation and photodegradation risk

• Improved compliance relative to bulk powders

• Compatibility with clinical trial dosing frameworks

Liquid formats were excluded due to resveratrol’s poor solubility, instability, and limited shelf-life without aggressive formulation modification.

Clinical Mindset + Future FDA Pathway Readiness

Krafted formulates with regulatory foresight, not retrospective claim justification.

This Resveratrol formulation is designed to be:

• Fully traceable from raw material to finished capsule

• Dose-aligned with ranges studied in human trials

• Excipient-minimal to support future IND compatibility

• Structurally suitable for observational studies or controlled trials

While currently positioned as a dietary supplement, the formulation architecture supports:

• Structure/function claim substantiation

• Mechanism-driven education without disease claims

• Potential advancement toward FDA-reviewed botanical drug pathways should evidence warrant further development

Krafted’s approach is not to blur the boundary between supplement and drug—but to respect it, building evidence forward rather than retrofitting claims later.

Safety, Interactions & Quality Considerations

Krafted approaches safety as a systems property, influenced by dose, chemical form, excipients, manufacturing quality, and user context—not as a binary “safe/unsafe” label. All safety framing reflects current human data, known mechanistic pathways, and conservative interpretation where evidence is limited.

Bioavailability & Dose Considerations (Non-Prescriptive)

Resveratrol exhibits low absolute oral bioavailability due to rapid first-pass metabolism; however, biological activity has been demonstrated at modest oral doses through metabolite-mediated signaling and indirect pathway activation.

Krafted formulations are designed to:

• Align with dose ranges evaluated in human studies

• Avoid aggressive bioenhancement strategies that alter pharmacokinetics

• Preserve predictable exposure rather than maximize peak plasma levels

No dosing guidance is intended to diagnose, treat, or prevent disease.

Known Safety Profile & Common Side Effects

Human studies generally characterize resveratrol as well tolerated at commonly studied supplemental doses.

Reported effects, when present, are typically mild and may include:

• Gastrointestinal discomfort

• Headache

• Transient changes in bowel habits

Adverse effects are more frequently observed at pharmacologic doses well above typical dietary supplement use.

Contraindications / Medication Interactions

(Limited evidence; caution populations)

Due to resveratrol’s involvement in:

• CYP enzyme modulation

• Platelet aggregation pathways

• Estrogen-receptor–adjacent signaling (in vitro)

Caution is advised for individuals:

• Taking anticoagulants or antiplatelet medications

• Using hormone-modulating therapies

• With active liver disease

• Who are pregnant or breastfeeding

These considerations reflect mechanistic plausibility, not confirmed clinical contraindications.

Quality Risks

Botanical polyphenols such as resveratrol are susceptible to:

• Isomer degradation (cis/trans instability)

• Synthetic adulteration

• Heavy metal and solvent contamination

• Variable microbial loads in poorly controlled supply chains

Lack of identity verification and over-standardization claims represent common industry failure points.

Quality Control Solutions

Krafted mitigates these risks through:

• Lot-specific identity and assay verification

• USP-aligned contaminant thresholds

• Supplier audits and documentation review

• Conservative standardization targets that preserve tolerability

• Internal review of all third-party COAs prior to release

Where applicable, USP monograph guidance and pharmacopoeial principles inform acceptance criteria and testing strategy.

Regulatory Status & Transparency

Krafted maintains strict separation between dietary supplement positioning and investigational drug development, ensuring regulatory clarity at every stage of product lifecycle.

Dietary Supplement Positioning + Structure/Function Language

All Krafted products are marketed as dietary supplements and described using structure/function language consistent with FDA and FTC guidance.

No disease claims are made or implied.

Labeling Guardrails

Product labeling and educational materials:

• Avoid references to disease states or therapeutic outcomes

• Emphasize biological mechanisms and physiological support

• Are reviewed for compliance prior to publication

Claims are substantiated by evidence without exceeding regulatory boundaries.

Manufacturing Standards

All Krafted products are manufactured in facilities operating under 21 CFR Part 111 (cGMP) standards, including:

• Batch-level Certificates of Analysis

• Finished product testing

• Full lot traceability from raw material to final product

Documentation Discipline (Internal QC/QA)

Krafted maintains internal documentation systems that exceed minimum compliance expectations, including:

• Supplier qualification records

• Batch production records

• COA review logs

• Deviation tracking and corrective action protocols

This documentation framework supports:

• Regulatory inspection readiness

• Future clinical or investigational pathways

• Long-term reproducibility and accountability

References

Core Reviews & High-Value Overviews

• Ramírez-Garza SL et al. Health Effects of Resveratrol: Results from Human Intervention Trials. Nutrients (2018)

• Patel KR et al. Clinical trials of resveratrol. Ann NY Acad Sci (2011)

• Meng X et al. Health Benefits and Molecular Mechanisms of Resveratrol. Foods (2020)

• Salehi B et al. Resveratrol: A Double-Edged Sword in Health Benefits. Biomedicines (2018)

• Ren ZQ et al. Resveratrol: Molecular Mechanisms, Health Benefits, and Potential Adverse Effects. MedComm(2025)

• Zhou DD et al. Effects and Mechanisms of Resveratrol on Aging and Age-Related Diseases. Oxid Med Cell Longev (2021)

• Bohara RA et al. Overview of Resveratrol’s Effects and Nano-Delivery Systems. Molecules (2022)

Human Clinical Trials & Human Intervention Data

• Ramírez-Garza SL et al., Nutrients (2018)

• Patel KR et al., Ann NY Acad Sci (2011)

• Sergides C et al. Bioavailability and safety study of resveratrol 500 mg. Exp Ther Med (2016)

• Szymkowiak I et al. Meta-analysis of oral resveratrol bioavailability. Phytother Res (2025)

Bioavailability, Pharmacokinetics & Dose Considerations

• Walle T. Bioavailability of resveratrol. Ann NY Acad Sci (2011)

• Cottart CH et al. Resveratrol bioavailability and toxicity in humans. Mol Nutr Food Res (2010)

• Sergides C et al., Exp Ther Med (2016)

• Szymkowiak I et al., Phytother Res (2025)

Safety Signals, Adverse Effects & Risk Framing

• Cottart CH et al., Mol Nutr Food Res (2010)

• Salehi B et al., Biomedicines (2018)

• Ren ZQ et al., MedComm (2025)

Mechanistic & Molecular Pathways

(Preclinical, cellular, animal, signaling-focused)

Core Signaling (SIRT1, AMPK, Nrf2, PI3K/Akt, FoxO)

• Dasgupta A et al. SIRT1-NOX4 signaling. J Exp Med (2020)

• Cao MM et al. SIRT1-mediated mitochondrial biogenesis. Exp Ther Med (2018)

• Jiang Y et al. Osteogenesis via SIRT1/FoxO1. Life Sci (2020)

• Li Z et al. Adipocyte browning via SIRT1. FASEB J (2020)

Oxidative Stress, Inflammation & Barrier Integrity

• Zhuang Y et al. Nrf2 signaling & intestinal barrier. Oxid Med Cell Longev (2019)

• Yu X et al. Ulcerative colitis & Nrf2/HO-1. Mol Med Rep (2024)

• Lee IT et al. EGFR / oxidative stress pathways. Antioxidants (2022)

Neuroprotection & Neuroinflammation

• Gaballah HH et al. Parkinson’s disease model. Chem Biol Interact (2016)

Oncology-Adjacent Mechanistic Data

(not therapeutic claims)

• Li X et al. COX-2 inhibition in A549 cells. Onco Targets Ther (2018)

Musculoskeletal, Bone, Cartilage & Disc Biology

(Preclinical + translational relevance)

Bone & Osteogenesis

• Jiang Y et al., Life Sci (2020)

• Chen H et al. SIRT1/FOXO3a & bone loss. Int J Biol Sci (2020)

• Loundagin L & Cooper D., Eur Cells Mater (2022)

Cartilage & Osteoarthritis

• Wei Y et al., Mol Med Rep (2018)

• Buhrmann C et al., PLoS ONE (2017)

• Liu FC et al., Arthritis Res Ther (2010)

Intervertebral Disc Biology

• Zehra U et al., Nat Rev Rheumatol (2022)

• Vergroesen PPA et al., Osteoarthritis Cartilage (2015)

• Jiang W et al., Sci Rep (2014)

• Li K et al., Int J Mol Med (2018)

Skeletal Muscle & Inflammation

• Sirago G et al., Int J Food Sci Nutr (2022)

Metabolic, Hepatic & Endocrine-Relevant Research

• Cao MM et al., Exp Ther Med (2018)

• Li Z et al., FASEB J (2020)

• de Moraes ACN et al. Liver regeneration. Food Res Int (2021)

Cardiovascular & Historical Context

• Renaud S & de Lorgeril M. French paradox. The Lancet (1992)

Pulmonary & Fibrosis-Related Mechanistic Context

• Ramli I et al. Pulmonary fibrosis targets. Front Biosci (2023)

Supporting Context (Foundational, Non-Claim-Generating)

• Renaud & de Lorgeril (1992) — epidemiologic context

• Loundagin & Cooper (2022) — bone remodeling frameworks

• Disc degeneration reviews (Zehra; Vergroesen)