Optimal DX Supplement Series: Antioxidant Support

Optimal Takeaways

Oxidative stress is simply defined as an excess production of reactive oxygen species (ROS) relative to antioxidant defenses. ROS, which include superoxide radicals, hydrogen peroxide, hydroxyl radicals, and singlet oxygen, are produced as a result of normal cellular metabolism (Pizzino 2017).

While often thought of in a purely negative way, ROS do serve necessary physiological functions. For instance, at low-to-moderate amounts, ROS play essential roles in the intracellular destruction of bacteria by phagocytes and some cellular signaling processes (i.e., redox signaling) (Sharifi-Rad 2020).

Problems arise when there is excessive production of ROS, creating oxidative stress. In this scenario, ROS cause cell and tissue damage. Excessive mitochondrion-generated ROS, a primary source of endogenous ROS, lead to lipid, protein, and DNA damage and are implicated in various human pathologies, including inflammation, cancer, mitochondrial and neurodegenerative diseases, diabetes, chronic diseases, and aging. In normal conditions, mitochondria are protected from ROS by multiple innate defense systems and antioxidants, including glutathione peroxidases, superoxide dismutases, glutathione (GSH), coenzyme Q, vitamins C and E, and carotene (Snezhkina 2019).

Exogenous factors also increase ROS in the body. Such factors include UV radiation, pollutants/toxins, heavy metals, certain medications, smoking, chronic disease, intense exercise, and severe life stress (de Almeida 2022). Modern exposures often tip the scales between ROS production and the body’s ability to detoxify ROS. Additional antioxidants are often necessary to create a better oxidant-antioxidant balance (redox balance).

Supportive Supplements

Coenzyme Q10 (CoQ10)

50 to 600 mg per day (Rabanal-Ruiz 2021, Sood 2024, Hargreaves 2020)

• Typical CoQ10 dosing is 100-300 mg/day or 5 mg/kg/day and toxicity is unlikely up to 1,200 mg/day (Sood 2024).

• 100 to 600 mg of CoQ10 per day decreases Statin-Associated Muscle Symptoms (SAMS).
• One double-blind, randomized controlled trial showed 300 mg daily to be safe and superior to placebo for migraine prevention, while another found that 100 mg of CoQ10 daily reduced the severity and number of migraines.
• A dose of 20 mg/kg/day provides a therapeutic benefit in those with nephrotic syndrome.
• 100 mg of CoQ10 per day can increase plasma CoQ10 to therapeutic levels of at least 2 ug/mL.
• 95% of serum CoQ10 is in the reduced ubiquinol form, the form produced in the intestine from ingested CoQ10.

• CoQ10 is efficacious in cardiovascular disease therapy and prevention (Rabanal-Ruiz 2021)
  • 90 mg/day can reduce heart failure severity.
  • 200 mg/day reduces fatigue, dyspnea, and interventricular septal thickness in severe hypertrophic cardiomyopathy.
  • 100-400 mg/day reduces CVD and all-cause mortality, improves brachial flow-mediated dilation, and significantly improves peripheral endothelial function in heart failure.
  • 150 mg/day decreases oxidative stress and increases antioxidant activity in coronary artery disease.
  • 100-300 mg/day given preoperatively significantly reduces complications from cardiac interventions and improves cardiac pumping, left ventricular ejection fraction, mitochondrial ATP, and blood levels of CoQ10. Higher blood levels are associated with more favorable LV remodeling and systolic function following primary angioplasty.
  • 200-300 mg/day of CoQ10 is recommended for 7-14 days before cardiac surgery to improve mitochondrial function and increase myocardial tolerance to oxidative stress.
  • CoQ10 regenerates other antioxidants, including beta-carotene and vitamin E, increasing their efficacy.
• CoQ10 can effectively increase blood levels and reduce biomarkers associated with dysfunction in cardiometabolic disorders (Hargreaves 2020)
  • Three months of supplementation with 100 mg of CoQ10 three times per day increased blood levels of CoQ10 to 3.4 ug/mL and significantly reduced major adverse cardiovascular events in heart failure patients taking part in the Q-SYMBIO study.
  • A dose of 150-200 mg/day significantly reduced HbA1C and fasting glucose in type 2 diabetics.
  • 100 mg three times per day significantly improved creatine level in chronic kidney disease patients.
  • 100 mg/day significantly reduced biomarkers of systemic inflammation and oxidative stress in NAFLD patients.

N-acetylcysteine/Glutathione

250 to 1,000 mg per day (Schmitt 2015, Paschalis 2018, Richie 2015)

• 150 mg of sublingual GSH (Sublinthion®) three times daily for 3 weeks, improved total and reduced GSH levels and significantly increased vitamin E levels over oral GSH or NAC (Schmitt 2015)
• 600 mg of NAC twice daily for 30 days restored both performance and redox homeostasis in individuals with low GSH status (Paschalis 2018)
• 250 and 1,000 mg/day of oral glutathione for 6 months effectively increased GSH body stores in a dose-dependent manner (Richie 2015)

Alpha Lipoic Acid (ALA)

600 mg per day (Zonooz 2021, Marangon 1999, Zembron-Lacny 2009)

• A systematic review and meta-analysis of 15 randomized, controlled trials, surmised that doses under 800 mg/d of ALA for >10 weeks provided the optimal effect on reducing malondialdehyde (MDA), a marker of oxidative stress and lipid oxidative damage (Zonooz 2021).
• 600 mg/day of ALA for 2 months decreased plasma- and low-density lipoprotein (LDL) oxidation and urinary isoprostanes (Marangon 1999)
• 600 mg/day of ALA for 8 days diminished oxidative damage in resistance-trained men (Zembron-Lacny 2009)

Vitamin C

400 to 1,000 mg per day (Popovic 2015, Goldfarb 2005, Carty 2000)

• 500 mg/day of vitamin for 14 days decreased serum MDA levels and suppressed lipid peroxidation in individuals tested by acute and regular exercise (Popovic 2015)
• 500 or 1,000 mg/day of vitamin C for 2 weeks attenuated exercise-induced protein oxidation in a dose-dependent manner (Goldfarb 2005)
• 10 and 15 weeks of 400 mg/day of vitamin C supplementation in healthy individuals demonstrated a reduction in certain types of oxidative protein damage in subjects with low basal vitamin C (Carty 2000)

Vitamin E (alpha-tocopherol)

General dosing 400-800 IU per day

• In a dose escalation study, 400 IU vitamin E was the minimum dose needed to decrease the susceptibility of LDL to oxidation (Jialal 1995)
• 800 IU vitamin E for 12 weeks decreased LDL susceptibility to oxidation in healthy male volunteers (Jialal 1992)

Condition-specific dosing (Kemnic 2023):

• Abetalipoproteinemia: 100-200 IU/kg/day
• Chronic cholestasis: 15-25 IU/kg/day
• Cystic fibrosis: 5-10 IU/kg/day
• Short-bowel syndrome: 200-3,600 IU/day
• Isolated vitamin E deficiency: 800-3,600 IU/day

Supplemental alpha-tocopherol (Ungurianu 2021):

• Vitamin E occurs naturally in food in eight different forms, i.e., alpha, beta, gamma, and delta-tocopherol, and alpha, beta, gamma, and delta-tocotrienol. These forms are found less commonly in supplement form.
• Alpha-tocopherol is the most common supplemental form of vitamin E and is quantified as milligrams or IUs.
• 1 IU = 0.67 mg natural or 0.45 mg synthetic alpha-tocopherol
• The tolerable upper limit (UL) for alpha-tocopherol is 1,000 mg/day equivalent to 1,500 IU/day for the natural form and 2200 IU/day for the synthetic form
• Individuals receiving higher doses must be monitored for adverse reactions

References

de Almeida, Arthur José Pontes Oliveira et al. “ROS: Basic Concepts, Sources, Cellular Signaling, and its Implications in Aging Pathways.” Oxidative medicine and cellular longevity vol. 2022 1225578. 19 Oct. 2022, doi:10.1155/2022/1225578

Carty, Julie L., et al. "The effects of vitamin C supplementation on protein oxidation in healthy volunteers." Biochemical and biophysical research communications 273.2 (2000): 729-735.

Goldfarb, Allan H., et al. "Vitamin C supplementation affects oxidative-stress blood markers in response to a 30-minute run at 75% VO2max." International journal of sport nutrition and exercise metabolism 15.3 (2005): 279-290.

Jialal, Ishwarlal, Cindy J. Fuller, and Beverley A. Huet. "The effect of α-tocopherol supplementation on LDL oxidation: a dose-response study." Arteriosclerosis, thrombosis, and vascular biology 15.2 (1995): 190-198.

Jialal, Ishwarlal, and Scott M. Grundy. "Effect of dietary supplementation with alpha-tocopherol on the oxidative modification of low density lipoprotein." Journal of Lipid Research 33.6 (1992): 899-906.

Kemnic, Tyler R. and Meghan Coleman. “Vitamin E Deficiency.” StatPearls, StatPearls Publishing, 4 July 2023.

Marangon, Karine, et al. "Comparison of the effect of α-lipoic acid and α-tocopherol supplementation on measures of oxidative stress." Free Radical Biology and Medicine 27.9-10 (1999): 1114-1121.

Paschalis, Vassilis, et al. "N-acetylcysteine supplementation increases exercise performance and reduces oxidative stress only in individuals with low levels of glutathione." Free Radical Biology and Medicine 115 (2018): 288-297.

Pizzino, Gabriele et al. “Oxidative Stress: Harms and Benefits for Human Health.” Oxidative medicine and cellular longevity vol. 2017 (2017): 8416763. doi:10.1155/2017/8416763

Popovic, Ljiljana M., et al. "Influence of vitamin C supplementation on oxidative stress and neutrophil inflammatory response in acute and regular exercise." Oxidative medicine and cellular longevity 2015.1 (2015): 295497.

Rabanal-Ruiz, Yoana et al. “The Use of Coenzyme Q10 in Cardiovascular Diseases.” Antioxidants (Basel, Switzerland) vol. 10,5 755. 10 May. 2021, doi:10.3390/antiox10050755

Richie, John P., et al. "Randomized controlled trial of oral glutathione supplementation on body stores of glutathione." European journal of nutrition 54.2 (2015): 251-263.

Schmitt, Bernard, et al. "Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study." Redox Biology 6 (2015): 198-205.

Sharifi-Rad, Mehdi et al. “Lifestyle, Oxidative Stress, and Antioxidants: Back and Forth in the Pathophysiology of Chronic Diseases.” Frontiers in physiology vol. 11 694. 2 Jul. 2020, doi:10.3389/fphys.2020.00694

Snezhkina, Anastasiya V et al. “ROS Generation and Antioxidant Defense Systems in Normal and Malignant Cells.” Oxidative medicine and cellular longevity vol. 2019 6175804. 5 Aug. 2019, doi:10.1155/2019/6175804

Sood, Brittany, et al. “Coenzyme Q10.” StatPearls, StatPearls Publishing, 30 January 2024.

Ungurianu, Anca et al. “Vitamin E beyond Its Antioxidant Label.” Antioxidants (Basel, Switzerland) vol. 10,5 634. 21 Apr. 2021, doi:10.3390/antiox10050634

Zembron-Lacny, A., et al. "Assessment of the antioxidant effectiveness of alpha-lipoic acid in healthy men exposed to muscle-damaging exercise." J Physiol Pharmacol 60.2 (2009): 139-43.

Zonooz, Sanaz Rezaei, et al. "Effect of alpha-lipoic acid on oxidative stress parameters: A systematic review and meta-analysis." Journal of Functional Foods 87 (2021): 104774.