Antioxidants & Phytonutrients: Beyond the Basics

The Real Story of Oxidative Stress

Picture a campfire. Fire produces heat and light — useful, necessary, life-sustaining. But without a fireplace, that same fire burns the house down. Oxidative stress works the same way. Reactive oxygen species (ROS) are normal byproducts of mitochondrial energy production and immune defense. Your body uses them on purpose — to kill pathogens, signal between cells, and trigger adaptive responses. The problem isn’t free radicals themselves. The problem is when production overwhelms the containment system.

Antioxidants are the fireplace. They don’t eliminate fire — they manage it. And the most important insight from modern antioxidant science is that these molecules don’t work alone. They work as a network, recycling each other in an elegant relay race.

Vitamin C neutralizes a free radical, becomes oxidized itself, and is regenerated by glutathione. Glutathione is regenerated by alpha-lipoic acid. Alpha-lipoic acid is regenerated by NADH (from B3). Vitamin E protects cell membranes, gets oxidized, and is regenerated by vitamin C. Remove any player and the whole network degrades.

This is why mega-dosing a single antioxidant often fails in clinical trials — you’re overloading one position while starving the team.

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The Antioxidant Network: Core Players

Glutathione: The Master Antioxidant

Glutathione (GSH) is a tripeptide — glutamine, cysteine, glycine — produced in every cell. It is the body’s primary defense against oxidative stress, the central molecule of Phase 2 liver detoxification, and the immune system’s most important fuel. Without adequate glutathione, you cannot detoxify, cannot manage inflammation, and cannot mount an effective immune response.

Why it depletes: Chronic stress, toxin exposure (heavy metals, pesticides, mold, alcohol, acetaminophen), chronic infections, aging, poor protein intake (cysteine is the rate-limiting substrate), genetic variants (GSTM1 null, GSTP1).

Supplemental strategies:

• NAC (N-acetyl cysteine): 600-1800mg. Provides the rate-limiting cysteine. Most cost-effective approach. Extensive research base.
• Liposomal glutathione: 250-500mg. Direct oral glutathione was historically considered poorly absorbed, but liposomal delivery (phospholipid encapsulation) significantly improves bioavailability. The Setria Glutathione brand has published absorption studies (Richie 2015 — increased body stores by 30-35% over 6 months at 500mg).
• S-Acetyl glutathione: Acetylated form, more stable and better absorbed than reduced glutathione capsules.
• IV glutathione: 1,400-2,000mg push. Immediate systemic delivery, bypasses absorption entirely. Used in Parkinson’s (Hauser 2009 pilot study), acute toxic exposure, chronic fatigue.
• Whey protein (undenatured): Rich in cysteine and glutamylcysteine — provides the building blocks. Immunocal is a research-grade brand.

The glutathione recycling system: Glutathione peroxidase (requires selenium) uses GSH to neutralize peroxides. Glutathione reductase (requires B2/riboflavin) regenerates oxidized glutathione (GSSG) back to reduced form (GSH). Without selenium and B2, even adequate glutathione cannot function properly.

Alpha-Lipoic Acid (ALA): The Universal Antioxidant

Alpha-lipoic acid is unique — it’s both water-soluble and fat-soluble, allowing it to operate in every compartment of every cell. It regenerates vitamins C and E, raises intracellular glutathione, chelates heavy metals (mild affinity for mercury, arsenic, cadmium), and directly quenches multiple free radical species.

Clinical dosing: 300-600mg daily.

R-ALA vs racemic: Supplemental ALA comes as a 50/50 mixture of R-ALA (the biologically active form) and S-ALA. R-ALA supplements (stabilized as Na-R-ALA) are more potent per milligram. 150mg R-ALA approximately equals 300mg racemic.

Clinical applications:

• Diabetic neuropathy: The ALADIN trial (Ziegler 1995) and subsequent studies showed 600mg IV ALA significantly reduced neuropathic symptoms. Oral ALA at 600mg also shows benefit over longer treatment periods.
• Heavy metal chelation (mild): Not a replacement for DMSA or DMPS, but useful as adjunctive support.
• Insulin sensitivity: Improves glucose uptake independent of insulin.
• Liver protection: Supports both Phase 1 and Phase 2 detoxification.

CoQ10 / Ubiquinol: The Mitochondrial Spark Plug

Coenzyme Q10 sits in the inner mitochondrial membrane at Complex III of the electron transport chain — the final relay in ATP production. Without CoQ10, mitochondria cannot produce ATP efficiently. It’s also a potent lipid-soluble antioxidant protecting cell membranes from oxidation.

Two forms:

• Ubiquinone: Oxidized form. Must be reduced to ubiquinol to function. Adequate for younger individuals with good redox capacity.
• Ubiquinol: Reduced (active) form. Better absorbed, especially for those over 40, chronically ill, or with high oxidative burden. Kaneka QH is the most researched brand.

Clinical dosing: 100-400mg daily with a fat-containing meal (fat-soluble).

Critical applications:

• Statin depletion: Statins block HMG-CoA reductase, the same pathway that produces CoQ10. Every statin patient should be on 100-200mg CoQ10. Statin-related myopathy, fatigue, and cognitive complaints often resolve with CoQ10 repletion.
• Heart failure: The Q-SYMBIO trial (Mortensen 2014) — 420 patients over 2 years — showed 300mg CoQ10 reduced cardiovascular mortality by 43% and all-cause mortality by 42%. This is one of the strongest supplement trials ever conducted for heart failure.
• Migraines: 100-300mg showed reduction in frequency (Sandor 2005).
• Fertility: Improves both egg quality (Bentov 2014) and sperm parameters.
• Mitochondrial disease/dysfunction: Foundational supplement.

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Polyphenols: The Plant Intelligence

Polyphenols are the secondary metabolites plants produce for defense — against UV radiation, pathogens, and herbivores. When we consume them, these same molecules activate our own defense pathways through xenohormesis — a low-dose stress signal that upregulates antioxidant enzymes, detoxification pathways, and cellular repair mechanisms. This is why isolated antioxidant vitamins in pills often disappoint in trials while diets rich in plant polyphenols consistently protect against chronic disease.

Curcumin: The NF-kB Master Switch

Curcumin, the active compound in turmeric, inhibits NF-kB — the master transcription factor for inflammatory gene expression. Over 12,000 published studies have examined curcumin for inflammation, pain, cancer, neurodegeneration, metabolic syndrome, and gut health.

The bioavailability problem: Native curcumin absorption is approximately 1%. The form matters enormously:

• Meriva (phytosome technology): Curcumin bound to phosphatidylcholine. 29x improved absorption. Well-studied for joint pain (Belcaro 2010).
• Longvida (SLCP technology): Designed for BBB penetration. Best for neurological applications.
• BCM-95 (CurcuGreen): Curcumin with essential oils of turmeric. 6.93x absorption.
• C3 Complex + BioPerine: Standard curcuminoids with piperine (black pepper extract). 20x absorption. Most affordable.

Clinical dosing: 500-2000mg depending on form (Meriva needs lower doses than standard curcuminoids).

Resveratrol: The Longevity Molecule

Resveratrol activates SIRT1, the longevity gene associated with caloric restriction benefits — improved mitochondrial biogenesis, DNA repair, and cellular stress resistance. Found in red grape skins, red wine, peanuts, and Japanese knotweed.

Clinical dosing: 200-500mg trans-resveratrol daily.

Pterostilbene (found in blueberries) is a methylated form of resveratrol with 4x greater bioavailability and longer half-life. May be the superior clinical choice.

Applications: Cardiovascular protection, anti-aging, neuroprotection, metabolic syndrome, inflammation.

Quercetin: The Mast Cell Stabilizer

Quercetin is a flavonoid found in onions, apples, berries, capers, and green tea. It stabilizes mast cells (preventing histamine release), acts as a zinc ionophore (carries zinc into cells — relevant for antiviral defense), has senolytic properties (clears senescent cells when combined with dasatinib — Kirkland 2017), and modulates NF-kB.

Clinical dosing: 500-1000mg daily. Take with bromelain or vitamin C for enhanced absorption.

Applications: Mast cell activation syndrome (MCAS), histamine intolerance, allergies, sinusitis, antiviral protocols, longevity (senolytic stacking), prostatitis.

EGCG (Epigallocatechin Gallate)

EGCG from green tea activates Nrf2 (Phase 2 detoxification), has thermogenic properties, inhibits angiogenesis (cancer research), and provides neuroprotection.

Clinical dosing: 400-800mg EGCG (equivalent to 4-8 cups of green tea).

Liver caution: Concentrated green tea extract at high doses (>800mg EGCG) has been associated with rare but serious hepatotoxicity. Drinking green tea itself is safe; isolated high-dose extracts require monitoring.

Berberine: The Natural Metformin

Berberine is an alkaloid from goldenseal, Oregon grape, and Chinese goldthread. It activates AMPK — the same metabolic switch that exercise and caloric restriction activate. AMPK is the cellular energy sensor that triggers glucose uptake, fatty acid oxidation, and mitochondrial biogenesis.

Clinical dosing: 500mg two to three times daily with meals (GI absorption improves with food, and dosing with meals targets postprandial glucose).

Applications:

• Blood sugar: Head-to-head with metformin (Yin 2008 — comparable HbA1c and fasting glucose reduction).
• Lipids: Reduces LDL, triglycerides, and total cholesterol through unique mechanisms (upregulates LDL receptor expression).
• Antimicrobial: Effective against SIBO, Candida, H. pylori, and various GI pathogens.
• Gut microbiome modulation: Increases Akkermansia muciniphila and other beneficial strains.

Caution: May interact with CYP3A4 and CYP2D6 metabolized medications. Monitor blood sugar closely in diabetic patients on medication (additive hypoglycemia risk).

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Carotenoids: The Color Code

Plants communicate their phytonutrient content through color. Carotenoids — the red, orange, and yellow pigments — are among the most clinically valuable.

Lycopene (red): Prostate protection (Chen 2015 meta-analysis — 10-30mg reduced prostate cancer risk), cardiovascular protection, skin UV protection. Found in cooked tomatoes (heat increases bioavailability — cooking with olive oil is ideal), watermelon, pink grapefruit.

Lutein + Zeaxanthin (yellow-orange): Concentrate in the macula of the eye, forming the macular pigment that filters blue light and protects photoreceptors. The AREDS2 trial (2013) established 10mg lutein + 2mg zeaxanthin as the standard for macular degeneration prevention and progression reduction. Sources: kale, spinach, egg yolks, corn.

Astaxanthin (red-pink): Produced by the microalgae Haematococcus pluvialis (what makes salmon and flamingos pink). The most potent singlet oxygen quencher known — 6,000x more powerful than vitamin C, 550x more than vitamin E, 800x more than CoQ10 (Naguib 2000). Clinical dose: 4-12mg. Applications: skin protection, eye health, exercise recovery, cardiovascular, anti-inflammatory.

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Sulforaphane: The Nrf2 Activator

Sulforaphane from cruciferous vegetables — particularly concentrated in broccoli sprouts — activates the Nrf2 pathway, the master switch for Phase 2 detoxification enzymes (glutathione S-transferase, NQO1, UGT). It is one of the most potent natural inducers of the body’s own antioxidant defense system.

The chemistry: Glucoraphanin (precursor, stored in plant cells) + myrosinase enzyme (released when cells are crushed/chewed) → sulforaphane. Mature broccoli contains moderate glucoraphanin. Three-day-old broccoli sprouts contain 10-100x more (Fahey 1997).

Clinical dosing: 30-60mg sulforaphane (or equivalent glucoraphanin + myrosinase from broccoli sprout extract). Home-grown broccoli sprouts: 1-2 ounces daily.

Clinical applications:

• Cancer prevention: Hecht 2000 — sulforaphane upregulates Phase 2 enzymes that neutralize carcinogens. NCI interest in chemoprevention.
• Autism: Singh 2014 randomized trial — sulforaphane significantly improved behavioral measures in young men with ASD. Mechanism: reducing oxidative stress and neuroinflammation.
• Detoxification: Accelerates clearance of environmental toxins (benzene, acrolein — Kensler 2012 China trial).
• H. pylori: Direct bactericidal activity against H. pylori, including antibiotic-resistant strains (Fahey 2002).

Cooking destroys myrosinase: Steaming broccoli for more than 3-4 minutes, or boiling, inactivates myrosinase. To rescue: add raw mustard seed powder (contains its own myrosinase) to cooked cruciferous vegetables. This trick restores sulforaphane production.

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The Phytonutrient Spectrum

The IFM teaches the “phytonutrient spectrum” — eating a diversity of plant colors to ensure broad phytonutrient intake:

• Red: Lycopene, anthocyanins, ellagic acid (tomatoes, watermelon, strawberries, pomegranate)
• Orange: Beta-carotene, beta-cryptoxanthin (carrots, sweet potato, oranges)
• Yellow: Lutein, zeaxanthin, curcumin (corn, egg yolks, turmeric)
• Green: Sulforaphane, chlorophyll, isothiocyanates (broccoli, kale, matcha)
• Blue-purple: Anthocyanins, resveratrol, pterostilbene (blueberries, grapes, eggplant)
• White-tan: Allicin, quercetin, EGCG (garlic, onions, mushrooms, green tea)

Each color family activates different defense pathways. No single supplement can replicate the synergy of a diverse, colorful, whole-food diet. Supplements fill specific therapeutic gaps. The diet lays the foundation.

This is the difference between antioxidant supplementation and antioxidant nutrition. The pills target specific pathways. The plate activates the whole network.

What color is missing from your plate today?