How to Bring Intelligence to Antioxidant Supplementation

It is a basic fact of physiology that the efficiency of any biochemical pathway is limited by the chemical substrate that is most essential and least available. This is known as Von Liebig's Law of Limiting Substances, and as clinicians we would do well to keep it in mind.

Justus von LiebigJustus von Liebig, an early pioneer in biochemistry and agriculture (and founder of the first company to make dehydrated beef bouillon cubes), postulated in 1840 that the health and growth of plants was determined not by the total amount of nutrients available but by the amount of the scarcest essential nutrients. This also holds true throughout the animal kingdom.

All human systems operate under the principle that "the least available required nutrient controls the system." It is certainly true of cellular repair, and the neutralization of oxidative stressors. Cellular health depends on the presence of sufficient levels of essential nutrients when and where they are needed.

Most people with chronic illnesses have functional deficits in protective antioxidants, from vitamins and minerals to cofactors and essential fats. When there is a deficiency of antioxidant intake or an over-stimulation of free radicals due to the exposure to environmental toxins, the scales tip and excessive free radicals lead to excessive oxidation. Free radicals damage proteins and DNA, increasing the risk of Alzheimer's, premature senility, Parkinson's disease, tumors, cardiovascular disease, and diabetes.

Simply put, electrons properly shuttled from membrane to mitochondria within cells energize ATP production. Electrons not properly chaperoned become free radicals. Examples are Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS). Healthy tissues can neutralize these radicals through antioxidant mediation---provided they have the antioxidants they need to do so.

In the absence of adequate antioxidant capacity, free radicals become damaging, and cell nuclei are especially vulnerable.

Tracking Free-Radical Risk

From a clinical practice perspective, the biomarkers that best predict cell nuclear functional distress are '8-OHdG,' also known as 8-hydroxy-2' -deoxyguanosine (8-OHdG), and 8-oxo-7, 8-dihydro-2' -deoxyguanosine (8-oxodG).

Easily measured in urine, the ratio between 8-OHdG and 8-oxodG can tell you a lot about the extent of oxidative damage, and can help you develop supplementation strategies that will ensure sufficient levels of rate-limiting antioxidant compounds at the cellular level.

The 8-OHdG / 8-oxodG ratio is pivotal for measuring the effect of endogenous oxidative damage to DNA that increases cancer risk. It has been used to estimate the DNA damage in humans after exposure to a wide variety of cancer-causing agents, such as tobacco smoke, asbestos fibers, heavy metals, and polycyclic aromatic hydrocarbons (PAHs).

The proposed "healthy" value for 8-OHdG is <5 ng/mg creatinine. This is the value indicating antioxidant sufficiency, and the least risk of oxidative distress. In contrast, elevated 8-OHdG is a sign that antioxidants with an affinity for the nucleus need to be increased. Environmental toxins, particularly hormone mimicking molecules, are linked with increased oxidative challenge that is reflected in an elevated 8-OHdG level.

Like the seven other tests that I've come to qualify as Predictive Biomarkers, the urinary 8-OHdG test has been independently validated on large populations and reflects a primary aspect of epigenetic control. It can be used to create personalized action plans that carry little risk but tremendous potential benefit for prevention of chronic disease states.

The 8-OHdG test, like the other predictive biomarkers, can also be used in comparative effectiveness outcomes studies

Solutions for Elevated 8-OHdG

Antioxidants accept and transfer electrons, enabling cells to store the energy as ATP. Healthy cells have 100 times more ATP than ADP. Below is a clinical protocol for reducing oxidative stress and bringing 8-OHdG levels down toward the desired goal value of <5 ng/mg creatinine.

Ascorbates: The "Mother" Antioxidants: The first and most important protective antioxidant is ascorbate, the buffered form of vitamin C. While named a vitamin, ascorbate is actually a substrate: it is used up and must be constantly replaced to avoid chronic or even acute scurvy. Ascorbate protects cell components from oxidative damage, restores cell energy production, rehabilitates mitochondria, and resets homeostatic repair mechanisms.

Ascorbate gets used up in proportion to total oxidative stress. In a sense, it sacrifices itself so other antioxidants like glutathione, tocopherol, lipoic acid, and taurine can be produced and recycled.

The "C Cleanse Protocol" is an individualized approach that allows us to find out how much ascorbate each person needs to manage oxidative stress and stimulate repair.

This process involves having the patient take repeating doses of buffered, l- ascorbate powder dissolved in water, in increments of 15 minutes, until there is a complete evacuation of the digestive tract (very watery stools). The buffered ascorbate mobilizes toxins and eliminates them from the body via the GI tract.

The amount of ascorbate needed to induce this flush will tell you a lot about someone's overall ascorbate status. To begin the C Cleanse, the starting dose should be 0.5 teaspoon per glass of water if someone is generally healthy; 1 teaspoon if someone is slightly unwell, and 2 teaspoons if someone is ill.

The total amount required to induce the flush can also be used to calculate how much supplemental ascorbate someone should take on an on going basis. I generally recommend 75% of the flush-inducing amount as a good daily dosing guideline, although it is fine to start anywhere between 5-50% of the cleanse dose with simultaneous digestive repair.

It is important to use 100% l-ascorbate, reduced and buffered with alkalinizing minerals like magnesium, zinc, potassium and calcium.

Polyphenolics for Antioxidant Synergy: Quercetin is a bioflavonoid found in most fruits and vegetables. Quercetin dihydrate plus soluble or low molecular weight orthoproanthocyandins, taken with or without freeze-dried pomegranate juice work synergistically yet separately from ascorbates.

Quercetin dihydrate is the safer and more effective supplemental form of quercetin. Anywhere from 0.5-20 grams of quercetin dihydrate coupled with soluble OPC and ellagic-rich pomegranate juice extract (if needed), provides superior oxidative stress reduction, protects the cellular machinery, and activates repair.

Fully buffered ascorbates and flavonoid / flavonol complexes described here work synergistically, are anti-histaminic and hormone-sparing as well. Quercetin dihydrate and reduced glutathione both enhance reduction of dehydroascorbic acid (oxidized ascorbate) back to fully reduced ascorbate.

Coenzyme Q10: Protecting the Cellular "Battery": Coenzyme Q10 (CoQ10), occupies a vital position in metabolism. It is an essential cofactor for electron transport and ATP protection. It is also a potent scavenger of reactive oxygen species (ROS), thus protecting cells against oxidative stress. Levels of CoQ10 often decline when digestion is impaired or someone is harboring an unhealthy gut microbiome. Providing 300-1,200 mg of CoQ10 per day micellized with pure rice bran oil and tocopherols allows for three-fold greater absorption and enhanced antioxidant activity.

Help for Healthy Methylation: The entire team of B vitamins, as well as the substrate betaine, are required for healthy methylation. Impaired methylation is reflected in elevations in homocysteine above the healthy value of 6 µmol/L. Impaired methylation translates into problems with cellular communication, detoxification, and electron transport.

Betaine or trimethylglycine (TMG) are important as substrates for methyl group transfers and contribute to healthy stomach acid production. Betaine intake from 50-500 mg per day is usually sufficient. Antioxidant-deficient patients will also benefit from increasing foods in what I like to call the "GGOBE category:" namely, Ginger, Garlic, Onions, Broccoli sprouts and Eggs. All of these will help in increasing methylation.

Carotenoids: Specialized Antioxidants: Mixed natural carotenoids such as alpha & beta carotene, zeaxanthin, cryptoxanthin, lutein and lycopene are better than synthetic beta carotene. Each carotenoid has a different and specific function in the body. All are needed. I generally discourage large intake of synthetic beta-carotene. Mixed natural carotenoids such as those present in bright colorful fruits & vegetables are a much better option.

Mixed Natural Tocopherols & Selenomethionine: Vitamin E is not a single vitamin but a combination of 8 forms (alpha-, beta-, gamma-, and delta-tocopherol, and alpha-, beta-, gamma-, and delta-tocotrienol). Mixed natural tocopherols, at least 800-3,200 IU per day, are recommended for decreasing oxidized LDL and cholesterol, platelet aggregation and increasing vasodilation.

Selenium has gotten some bad press in recent years, but it should not be overlooked. The key is really to choose the right form. Selenomethionine is safe at intake ranges from 0.25 mg to 2 mg per day, depending on how much membrane oxidative stress is present. It can be very helpful. I advise against using other forms of selenium including selenite and selenate. These 'work-
alikes' are less helpful and more toxic than selenomethionine.

Vitamin D3: Proliferation Control & Calcium Balance: Vitamin D3 deficiency can lead to elevated levels of inflammatory markers like hsCRP, IL-2, IL-6 and insulin resistance. In turn, this raises 25-hydroxycholecalciferol (25-OH-D3) levels. Sufficient amounts of cholecalciferol in medium-chain triglyceride (MCT) oil are indicated to maintain goal values of 50-80ng/ml.


Uttara B, et al. Oxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options. Curr Neuropharmacol. Mar 2009; 7(1): 65–74.

Valavanidis A, et al. 8-hydroxy-2' -deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2009 Apr;27(2):120-39.

Wu LL, et al. Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. Clin Chim Acta. 2004 Jan;339(1-2):1-9.

Goodarzi MT, et al. Oxidative damage to DNA and lipids: correlation with protein glycation in patients with type 1 diabetes. J Clin Lab Anal. 2010;24(2):72-6. Relation of Urinary 8-OHdG, A Marker of Oxidative Stress to DNA, and Clinical Outcomes for Ischemic Stroke. Open Neurol J. 2012; 6: 51–57

Middleton, E. et al. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease and cancer. Pharmacol Rev, 2000; 52 : 673-751.

Chew BP, Park JS. Carotenoid action on the immune response. J Nutr. 2004 Jan;134(1):257S-261S.

Heaney RP. Vitamin D in health and disease. Clin J Am Soc Nephrol. 2008 Sep;3(5):1535-41.

Shute, EV. Proposed study of vitamin E therapy. Can Med Assoc J. 1972 May 20;106(10):1057