Resveratrol | Supplementopedia

Overview

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a naturally occurring polyphenol most famously found in the skin of red grapes, berries, and peanuts. In humans, it is taken as a dietary supplement primarily for its antioxidant and anti-inflammatory actions, which have been linked to cardiovascular, metabolic, and neuro-protective effects in pre-clinical and early-clinical studies.

Benefits

Cardiovascular health: Randomized trials show modest reductions in systolic blood pressure and improvements in endothelial function, likely via nitric-oxide enhancement and reduced oxidative stress (e.g., Timmers et al., 2012).
Metabolic regulation: In overweight adults, 150 mg/day for 12 weeks improved insulin sensitivity and lowered fasting glucose; animal data also suggest enhanced mitochondrial function (Baur et al., 2006).
Cognitive support: Small crossover trials report better verbal memory and reduced neuro-inflammation markers after 6 weeks of 200 mg/day, supporting neuro-protective potential (Wang et al., 2020).
Anti-aging/longevity: Activation of SIRT1 and AMPK pathways yields modest improvements in cellular senescence markers in human peripheral blood cells.
Exercise recovery: Acute dosing (500 mg) reduces post-exercise oxidative damage and muscle soreness in trained athletes (Gluza-Markiewicz et al., 2021).

How It Works

SIRT1 Activation: Resveratrol acts as a pleiotropic modulator, with its most studied target being SIRT1, a NAD⁺-dependent deacetylase; binding increases SIRT1 activity, leading to deacetylation of PGC-1α, FOXO, and p53, thereby enhancing mitochondrial biogenesis and stress resistance.
AMPK Activation: Simultaneously, it activates AMP-activated protein kinase (AMPK), which improves glucose uptake and fatty-acid oxidation.
NF-κB Inhibition: Resveratrol also inhibits NF-κB signaling, lowering pro-inflammatory cytokines (IL-6, TNF-α).
Antioxidant Activity: Its antioxidant activity derives from direct scavenging of ROS and up-regulation of endogenous antioxidant enzymes (e.g., SOD, catalase) via Nrf2 activation.
Estrogen Receptor Modulation: Finally, it modulates estrogen receptors (particularly ERα) and interacts with COX-2 and eNOS pathways, contributing to vasodilatory and anti-platelet effects.
Pathway Convergence: The convergence of these pathways underlies its metabolic, cardiovascular, and neuroprotective outcomes.

Dosage

Typical Dosage: Human studies typically use 150–500 mg/day of trans-resveratrol, taken with a meal containing fat to enhance absorption (bioavailability ~2 %).
Cardiometabolic Support: For cardiometabolic support, 200 mg once daily is common.
Cognitive/Exercise Recovery: For cognitive or exercise recovery protocols, 300-500 mg taken 30 min before activity have been examined.
Split Dosing: Split dosing (e.g., 100 mg morning + 100 mg evening) may improve steady-state plasma levels.
Type-2 Diabetes: In clinical trials for type-2 diabetes, 500 mg twice daily has been safe.
Low-Dose Regimens: Individuals with low-dose (≤100 mg) regimens often report no side effects.
Special Considerations:
- Athletes may prefer acute high-dose (up to 1 g) prior to exercise.
- Patients on anticoagulants should avoid >500 mg/day without medical supervision.

Safety & Side Effects

General Tolerance: Resveratrol is generally well-tolerated; mild gastrointestinal upset (nausea, diarrhea) occurs in ~5 % of users at doses >500 mg/day.
Contraindications: Contraindications include pregnancy, lactation, and patients with a history of hormone-sensitive cancers (due to weak estrogenic activity).
Drug Interactions: Potent inhibition of CYP3A4 and CYP2C9 may increase plasma concentrations of statins, anticoagulants (warfarin, DOACs), and immunosuppressants; dose adjustments or monitoring are advised.
High-Dose Effects: High doses (>1 g/day) in animal models have shown hepatic enzyme elevation, but human data are limited.
Medical Consultation: Individuals with liver disease, hematologic disorders, or autoimmune conditions should consult a clinician before supplementation.

Chemistry

Compound Type: Resveratrol is a stilbene polyphenol.
Molecular Formula: C₁₄H₁₂O₃
Molecular Weight: 228.24 g/mol
IUPAC Name: 5-(4-hydroxyphenyl)-1-(2-hydroxyphenyl)-2-propene (or trans-3-(4-hydroxyphenyl)-2-propene-5-ol).
Structure: It consists of two phenolic rings linked by an ethylene bridge (C=C), existing mainly as the trans isomer (more biologically active than the cis form).
Key Features: Key structural features include three hydroxyl groups (positions 3, 4′, and 5) conferring antioxidant activity, and a planar, conjugated double-bond system that enables free-radical scavenging.
Solubility: Solubility is low in water (<0.05 mg/mL) but higher in ethanol and oily matrices; the compound is stable under acidic conditions but degrades with light and high pH.

Sources & Quality

Natural Sources: Natural resveratrol is extracted from Vitis vinifera (red grape skins, red wine), Polygonum cuspidatum (Japanese knotweed), Arachis hypogaea (peanuts), and Vaccinium species (blueberries).
Extraction Methods:
- Commercially, high-pressure liquid chromatography (HPLC) isolates the trans-isomer from plant extracts.
- Alternatively, synthetic chemical routes (Wittig or Heck coupling) produce >99 % pure trans-resveratrol for pharmaceutical-grade products.
Quality Considerations:
- % trans-isomer purity
- Absence of heavy-metal contamination
- Verification by LC-MS or HPLC-UV
Manufacturing Practices: Good Manufacturing Practice (GMP) facilities often use supercritical CO₂ extraction to minimize solvent residues.
Product Verification: Look for third-party testing (e.g., USP, NSF) and an NRF (non-reactive filler) matrix to ensure stability and bioavailability.