Antioxidants

Overview

The term “antioxidant” refers to the activity possessed by numerous vitamins, minerals and other phytochemicals to serve as protection against the damaging effects of highly reactive molecules known as free radicals. Free radicals have the ability to chemically react with, and damage, many structures in the body. Particularly susceptible to oxidative damage are the cellular membranes, mitochondrial membranes, and DNA of virtually all cells. Free radical reactions and oxidative damage have been linked to many of the “diseases of aging” such as heart disease and cancer. Antioxidant dietary supplements are routinely marketed with direct and implied claims for cellular protection, anti-aging effects, prevention of cancer and heart disease, reduction of wrinkles, enhancement of immune function, and prmotion of vision and eyesight.

The free radical theory of aging (and disease promotion) holds that through a gradual accumulation of microscopic damage to our cell membranes, DNA, tissue structures and enzyme systems, we begin to lose function and are predisposed to disease. In response to free radical exposure, the body increases its production of endogenous antioxidant enzymes (glutathione peroxidase, catalase, superoxide dismutase), but it has been theorized that supplemental levels of dietary antioxidants may be warranted in some situations to help prevent excessive oxidative damage to muscles, mitochondria and other tissues (such as during/following intense exercise and exposure to pollutants such as second hand smoke and oxidizing radiation such as sunlight).

Comments

The 4 key nutritional antioxidants, vitamins C and E, beta-carotene and selenium, are well studied, relatively inexpensive, and widely available as dietary supplements. There are also a multitude of fruit and vegetable phytonutrient extracts that also possess significant antioxidant activity. In most cases, phytonutrient extracts tend to be quite expensive, although their potent antioxidant activity may allow dosages to be fairly small. Some of the more popular antioxidant nutrients found in commercial dietary supplements also include Zinc, Copper, Ginkgo biloba extract, Grape seed extract , Pine bark extract, Lycopene, Lutein, Quercetin, and Alpha lipoic acid as well as dozens of others.

When it comes to antioxidant supplementation, it is the overall collection of several antioxidants that is important (rather than any single “super” antioxidant). This concept of balancing supplemental antioxidants is referred to as the “Antioxidant Network.” and is generally comprised of 5 major classes of antioxidants: Carotenoids, Tocopherols/Tocotrienols (Vitamin E), Vitamin C, Thiols (e.g. sulfur-containing compounds such as alpha-lipoic acid and cysteine), and Bioflavonoids. In theory, smaller doses of these antioxidant agents, when given in combination, will help to regenerate one another following free radical quenching – thus delivering a more effective and safer antioxidant regimen than with higher doses of isolated antioxidant nutrients. This combined approach to antioxidant supplementation is also logical because certain antioxidants will work primarily against certain free radicals and in specific parts of the body (e.g. vitamin E against hydroxyl radicals and within cell membranes or vitamin C against superoxide and within aqueous spaces).

Scientific Support

Thousands of studies have clearly documented the beneficial effects of dozens of antioxidant nutrients – and there are thousands of nutrients and phytochemicals that possess significant antioxidant activity in the test tube. Increased dietary intake of antioxidant nutrients, such as vitamins C and E, minerals such as selenium and various phytonutrients such as extracts from grape seed, pine bark and green tea have all been linked to reduced rates of oxidative damage and may help reduce the incidence of chronic diseases such as heart disease and cancer. Readers are referred to the specific sections dealing with each antioxidant nutrient for a full discussion of the pros and cons of supplementation with a given nutrient.

Safety / Dosage

At the typically recommended levels, the majority of antioxidants appear to be quite safe. For example, vitamin E, one of the most powerful membrane-bound antioxidants, also has one of the best safety profiles. Doses of 100-400 IU of vitamin E have been linked to significant cardiovascular benefits with no side effects. Vitamin C, another powerful antioxidant, can help to protect and restore the antioxidant activity of vitamin E, and is considered safe up to doses of 500-1,000mg. Higher doses of vitamin C are not recommended because of concerns that such levels may cause an “unbalancing” of the oxidative systems and actually promote oxidative damage instead of preventing it. Another popular antioxidant, beta-carotene, is somewhat controversial as a dietary supplement. Although diets high in fruits and vegetables deliver approximately 5-6 mg of carotenes daily, these would be a mixture of beta-carotene and other naturally occurring carotenoids. Concern was raised several years ago by studies in which high dose beta-carotene supplements appeared to promote lung cancer in heavy smokers. Those studies provided beta-carotene supplements of 20-60mg/day – about 5-10 times the levels that could reasonably be expected in the diet.

Based on the available scientific evidence, daily supplementation with Vitamin E (100 to 400 IU), Vitamin C (250 to 1,000mg), Beta-carotene (5 to 6mg), and Selenium (70 to 200mcg) appears to be prudent.

References

1.Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001 Oct;119(10):1439-52.

2.Age-Related Eye Disease Study Research Group. The effect of five-year zinc supplementation on serum zinc, serum cholesterol and hematocrit in persons randomly assigned to treatment group in the age-related eye disease study: AREDS Report No. 7. J Nutr. 2002 Apr;132(4):697-702.

3.Balakrishnan SD, Anuradha CV. Exercise, depletion of antioxidants and antioxidant manipulation. Cell Biochem Funct. 1998 Dec;16(4):269-75.

4.Bartlett H, Eperjesi F. Age-related macular degeneration and nutritional supplementation: a review of randomised controlled trials. Ophthalmic Physiol Opt. 2003 Sep;23(5):383-99.

5.Dragan I, Dinu V, Mohora M, Cristea E, Ploesteanu E, Stroescu V. Studies regarding the antioxidant effects of selenium on top swimmers. Rev Roum Physiol. 1990 Jan-Mar;27(1):15-20.

6.Evans JR, Henshaw K. Antioxidant vitamin and mineral supplementation for preventing age-related macular degeneration. Cochrane Database Syst Rev. 2000;(2):CD000253.

7.Gale CR, Ashurst HE, Powers HJ, Martyn CN. Antioxidant vitamin status and carotid atherosclerosis in the elderly. Am J Clin Nutr. 2001 Sep;74(3):402-8.

8.Girodon F, Blache D, Monget AL, Lombart M, Brunet-Lecompte P, Arnaud J, Richard MJ, Galan P. Effect of a two-year supplementation with low doses of antioxidant vitamins and/or minerals in elderly subjects on levels of nutrients and antioxidant defense parameters. J Am Coll Nutr. 1997 Aug;16(4):357-65.

9.Grievink L, Smit HA, Veer P, Brunekreef B, Kromhout D. Plasma concentrations of the antioxidants beta-carotene and alpha-tocopherol in relation to lung function. Eur J Clin Nutr. 1999 Oct;53(10):813-7.

10.Grievink L, Zijlstra AG, Ke X, Brunekreef B. Double-blind intervention trial on modulation of ozone effects on pulmonary function by antioxidant supplements. Am J Epidemiol. 1999 Feb 15;149(4):306-14.

11.Hammond BR Jr, Johnson MA. The age-related eye disease study (AREDS). Nutr Rev. 2002 Sep;60(9):283-8.

12.Jacques PF, Halpner AD, Blumberg JB. Influence of combined antioxidant nutrient intakes on their plasma concentrations in an elderly population. Am J Clin Nutr. 1995 Dec;62(6):1228-33.

13.Ji LL. Oxidative stress during exercise: implication of antioxidant nutrients. Free Radic Biol Med. 1995 Jun;18(6):1079-86.

14.Kaikkonen J, Kosonen L, Nyyssonen K, Porkkala-Sarataho E, Salonen R, Korpela H, Salonen JT. Effect of combined coenzyme Q10 and d-alpha-tocopheryl acetate supplementation on exercise-induced lipid peroxidation and muscular damage: a placebo-controlled double-blind study in marathon runners. Free Radic Res. 1998 Jul;29(1):85-92.

15.Kanter M. Free radicals, exercise and antioxidant supplementation. Proc Nutr Soc. 1998 Feb;57(1):9-13.

16.Marangon K, Herbeth B, Lecomte E, Paul-Dauphin A, Grolier P, Chancerelle Y, Artur Y, Siest G. Diet, antioxidant status, and smoking habits in French men. Am J Clin Nutr. 1998 Feb;67(2):231-9.

17.McBee WL, Lindblad AS, Ferris FL 3rd. Who should receive oral supplement treatment for age-related macular degeneration? Curr Opin Ophthalmol. 2003 Jun;14(3):159-62.

18.McQuillan BM, Hung J, Beilby JP, Nidorf M, Thompson PL. Antioxidant vitamins and the risk of carotid atherosclerosis. The Perth Carotid Ultrasound Disease Assessment study (CUDAS). J Am Coll Cardiol. 2001 Dec;38(7):1788-94.

19.Mitchell P, Smith W, Cumming RG, Flood V, Rochtchina E, Wang JJ. Nutritional factors in the development of age-related eye disease. Asia Pac J Clin Nutr. 2003;12 Suppl:S5.

20.Rousseau AS, Hininger I, Palazzetti S, Faure H, Roussel AM, Margaritis I. Antioxidant vitamin status in high exposure to oxidative stress in competitive athletes. Br J Nutr. 2004 Sep;92(3):461-8.

21.Sackett CS, Schenning S. The age-related eye disease study: the results of the clinical trial. Insight. 2002 Jan-Mar;27(1):5-7.

22.Sanchez-Quesada JL, Jorba O, Payes A, Otal C, Serra-Grima R, Gonzalez-Sastre F, Ordonez-Llanos J. Ascorbic acid inhibits the increase in low-density lipoprotein (LDL) susceptibility to oxidation and the proportion of electronegative LDL induced by intense aerobic exercise. Coron Artery Dis. 1998;9(5):249-55.

23.Schunemann HJ, Grant BJ, Freudenheim JL, Muti P, Browne RW, Drake JA, Klocke RA, Trevisan M. The relation of serum levels of antioxidant vitamins C and E, retinol and carotenoids with pulmonary function in the general population. Am J Respir Crit Care Med. 2001 Apr;163(5):1246-55.

24.Singh RB, Ghosh S, Niaz MA, Singh R, Beegum R, Chibo H, Shoumin Z, Postiglione A. Dietary intake, plasma levels of antioxidant vitamins, and oxidative stress in relation to coronary artery disease in elderly subjects. Am J Cardiol. 1995 Dec 15;76(17):1233-8.

25.Singh RB, Niaz MA, Bishnoi I, Sharma JP, Gupta S, Rastogi SS, Singh R, Begum R, Chibo H, Shoumin Z. Diet, antioxidant vitamins, oxidative stress and risk of coronary artery disease: the Peerzada Prospective Study. Acta Cardiol. 1994;49(5):453-67.

26.Ward JA. Should antioxidant vitamins be routinely recommended for older people? Drugs Aging. 1998 Mar;12(3):169-75.

27.Wolters M, Hermann S, Hahn A. Effects of 6-month multivitamin supplementation on serum concentrations of alpha-tocopherol, beta-carotene, and vitamin C in healthy elderly women. Int J Vitam Nutr Res. 2004 Mar;74(2):161-8.

28.Wood LG, Fitzgerald DA, Lee AK, Garg ML. Improved antioxidant and fatty acid status of patients with cystic fibrosis after antioxidant supplementation is linked to improved lung function. Am J Clin Nutr. 2003 Jan;77(1):150-9.

29.Yu BP, Kang CM, Han JS, Kim DS. Can antioxidant supplementation slow the aging process? Biofactors. 1998;7(1-2):93-101.

EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.

Alpha-Lipoic Acid

Overview

Alpha lipoic acid is a sulfur-containing fatty acid compound found in the mitochondria – the energy producing structures found in our cells. As a dietary supplement, alpha-lipoic acid (also known as lipoic acid and thioctic acid) may act as a powerful antioxidant, where it may work in synergy with other nutritional antioxidants like vitamins C and E to help prevent cellular damage from free radicals. Alpha-lipoic acid has also been shown to help control blood sugar levels in patients with diabetes.

Although alpha lipoic acid is involved in cellular energy production, its chief role as a dietary supplement may be as a powerful antioxidant. The body appears to be able to manufacture enough alpha-lipoic acid for its metabolic functions (as a co-factor for a number of enzymes involved in converting fat and sugar to energy), but the excess levels provided by supplements allow alpha-lipoic acid to circulate in a “free” state (outside of the cells where it is usually found). In this state, alpha-lipoic acid has functions as both a water- and fat-soluble antioxidant. This unique ability of alpha-lipoic acid to be active in both water and lipid compartments of the body is important because most antioxidants, such as vitamins C and E, are effective in only one area or the other. For instance vitamin C is usually restricted to the interior compartment of cells and the aqueous (“watery”) portion of blood, while vitamin E embeds itself in the lipid (“fatty”) portion of cell membranes. Adding to the potential importance of alpha-lipoic acid is its role in the production of glutathione, one of the chief cellular antioxidants produced directly by the body.

Comments

If alpha-lipoic acid were just another antioxidant, then its value would be far less. After all, there are dozens of ingredients on the market that have powerful antioxidant functions. The unique qualities possessed by alpha-lipoic acid, functioning as both a water- and fat-soluble antioxidant as well as its role in increasing the overall function of other dietary antioxidants, make it an intriguing supplement worthy of serious consideration – especially for people with diabetes because of its particular benefits in potentially preventing some forms of diabetic peripheral and autonomic neuropathy.

Scientific Support

In animal studies and human trials, alpha-lipoic acid supplementation has been shown to improve several indices of metabolic activity and lower the degree of oxidative stress (Androne et al. 2000, Arivazhagan et al. 2000). Alpha-lipoic acid supplementation may also help to reverse the decline in mitochondrial energy production that is commonly observed during the “normal” aging process (Ames 2003). Physical activity levels in animals can be increased by approximately 3-fold when supplemented with alpha-lipoic acid (Hagen et al. 1999), suggesting a beneficial effect on energy metabolism (Khanna et al. 1998). Levels of other antioxidants, such as glutathione and ascorbic acid, were also elevated in animals consuming alpha-lipoic acid, suggesting that the supplement may help protect and/or recycle these antioxidants and contribute to the overall capacity of the body to neutralize free radical damage (Packer et al. 1997, Packer et al. 1995).

In conjunction with other antioxidants, such as vitamin E, alpha-lipoic acid may be particularly helpful in patients with diabetes. By promoting the production of energy from fat and sugar in the mitochondria, glucose removal from the bloodstream may be enhanced and insulin function improved. Indeed, alpha-lipoic acid has been shown to decrease insulin resistance and is prescribed frequently in Europe as a treatment for peripheral neuropathy (nerve damage) associated with diabetes. In the U.S., the American Diabetes Association has suggested that alpha-lipoic acid plus vitamin E may be helpful in combating some of the health complications associated with diabetes, including heart disease, vision problems, nerve damage and kidney disease. Alpha-lipoic acid has also been implicated in helping to protect the brain from damage following a stroke.

There is a consistent body of evidence that intravenous infusions of alpha-lipoic acid are associated with a reduction in sensory symptoms of diabetic neuropathy (Ametov et al. 2003, Ziegler et al 2004) and that benefits are seen within 8-14 days of treatment on measures of pain, burning, numbness in patients receiving alpha-lipoic acid supplements. In human feeding studies (as opposed to studies of intravenous infusions of lipoic acid where most of the positive results exist for diabetic neuropathy), a handful of studies demonstrate that dietary supplementation with alpha-lipoic acid is able to help prevent hyperglycemia (Kinrad et al. 1999) and improve energetic substrates in muscle cells (Burke et al. 2003).

Safety / Dosage

Although there have been relatively few feeding studies conducted with alpha-lipoic acid in humans, it appears to be safe as a dietary supplement. Intakes of as much as 600mg per day have been used for treatment of diabetic neuropathy, with no serious side effects. General recommendations for antioxidant benefits typically call for 50 – 100mg per day as a general antioxidant, with higher levels of 300-600mg/day for preventing/treating complications of diabetes.

References

1.Ames BN. The metabolic tune-up: metabolic harmony and disease prevention. J Nutr. 2003 May;133(5 Suppl 1):1544S-8S.

2.Ametov AS, Barinov A, Dyck PJ, Hermann R, Kozlova N, Litchy WJ, Low PA, Nehrdich D, Novosadova M, O'Brien PC, Reljanovic M, Samigullin R, Schuette K, Strokov I, Tritschler HJ, Wessel K, Yakhno N, Ziegler D; SYDNEY Trial Study Group. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care. 2003 Mar;26(3):770-6.

3.Androne L, Gavan NA, Veresiu IA, Orasan R. In vivo effect of lipoic acid on lipid peroxidation in patients with diabetic neuropathy. In Vivo. 2000 Mar-Apr;14(2):327-30.

4.Arivazhagan P, Panneerselvam C. Effect of DL - alpha -lipoic acid on neural antioxidants in aged rats. Pharmacol Res. 2000 Sep;42(3):219-22.

5.Gualandri W, Gualandri L, Demartini G, Esposti R, Marthyn P, Volonte S, Stangoni L, Borgonovo M, Fraschini F. Redox balance in patients with Down's syndrome before and after dietary supplementation with alpha-lipoic acid and L-cysteine. Int J Clin Pharmacol Res. 2003;23(1):23-30.

6.Haak E, Usadel KH, Kusterer K, Amini P, Frommeyer R, Tritschler HJ, Haak T. Effects of alpha-lipoic acid on microcirculation in patients with peripheral diabetic neuropathy. Exp Clin Endocrinol Diabetes. 2000;108(3):168-74.

7.Hagen TM, Ingersoll RT, Lykkesfeldt J, Liu J, Wehr CM, Vinarsky V, Bartholomew JC, Ames AB. (R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB J. 1999 Feb;13(2):411-8.

8.Jacob S, Ruus P, Hermann R, Tritschler HJ, Maerker E, Renn W, Augustin HJ, Dietze GJ, Rett K. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Free Radic Biol Med. 1999 Aug;27(3-4):309-14.

9.Khanna S, Atalay M, Lodge JK, Laaksonen DE, Roy S, Hanninen O, Packer L, Sen CK. Skeletal muscle and liver lipoyllysine content in response to exercise, training and dietary alpha-lipoic acid supplementation. Biochem Mol Biol Int. 1998 Oct;46(2):297-306.

10.Konrad T, Vicini P, Kusterer K, Hoflich A, Assadkhani A, Bohles HJ, Sewell A, Tritschler HJ, Cobelli C, Usadel KH. alpha-Lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Diabetes Care. 1999 Feb;22(2):280-7.

11.Marriage B, Clandinin MT, Glerum DM. Nutritional cofactor treatment in mitochondrial disorders. J Am Diet Assoc. 2003 Aug;103(8):1029-38.

12.Miquel J. Can antioxidant diet supplementation protect against age-related mitochondrial damage? Ann N Y Acad Sci. 2002 Apr;959:508-16.

13.Morcos M, Borcea V, Isermann B, Gehrke S, Ehret T, Henkels M, Schiekofer S, Hofmann M, Amiral J, Tritschler H, Ziegler R, Wahl P, Nawroth PP. Effect of alpha-lipoic acid on the progression of endothelial cell damage and albuminuria in patients with diabetes mellitus: an exploratory study. Diabetes Res Clin Pract. 2001 Jun;52(3):175-83.

14.Nickander KK, McPhee BR, Low PA, Tritschler H. Alpha-lipoic acid: antioxidant potency against lipid peroxidation of neural tissues in vitro and implications for diabetic neuropathy. Free Radic Biol Med. 1996;21(5):631-9.

15.Packer L, Tritschler HJ, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med. 1997;22(1-2):359-78.

16.Packer L, Witt EH, Tritschler HJ. alpha-Lipoic acid as a biological antioxidant. Free Radic Biol Med. 1995 Aug;19(2):227-50.

17.Podda M, Tritschler HJ, Ulrich H, Packer L. Alpha-lipoic acid supplementation prevents symptoms of vitamin E deficiency. Biochem Biophys Res Commun. 1994 Oct 14;204(1):98-104.

18.Roy S, Sen CK, Tritschler HJ, Packer L. Modulation of cellular reducing equivalent homeostasis by alpha-lipoic acid. Mechanisms and implications for diabetes and ischemic injury. Biochem Pharmacol. 1997 Feb 7;53(3):393-9.

19.Ruhe RC, McDonald RB. Use of antioxidant nutrients in the prevention and treatment of type 2 diabetes. J Am Coll Nutr. 2001 Oct;20(5 Suppl):363S-369S.

20.Ziegler D, Gries FA. Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy. Diabetes. 1997 Sep;46 Suppl 2:S62-6.

21.Ziegler D, Hanefeld M, Ruhnau KJ, Hasche H, Lobisch M, Schutte K, Kerum G, Malessa R. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care. 1999 Aug;22(8):1296-301.

22.Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schutte K, Gries FA. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia. 1995 Dec;38(12):1425-33.

23.Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004 Feb;21(2):114-21.

24.Ziegler D, Reljanovic M, Mehnert H, Gries FA. Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials. Exp Clin Endocrinol Diabetes. 1999;107(7):421-30.

EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS