Antioxidants – disenchanted

Antioxidants are considered an all-purpose weapon against aging and an effective means of preventing various diseases. Antioxidants protect the body from free radicals that cause oxidative stress. The industry offers a wide range of products in the form of pills, creams and dietary supplements for this purpose, using catchy and well-publicized phrases. Meanwhile, oxidative stress, free radicals and antioxidants have become firmly imprinted as terms in many people’s minds. You, too, have probably heard a lot about it. The following article will explain some facts and myths around these terms.

A pioneer of this antioxidant hype was Linus Carl Pauling (1901-1994), who convincingly declared that large amounts of vitamin C would help prevent colds, aging, and cancer. On this topic, there is an interesting television interview on YouTube with Linus Pauling about vitamin C from 1991. As a daily dose, he recommended 18 g of vitamin C, 800 units of vitamin E, and of the B vitamins, about 25 times the amount normally recommended [1].

Free radical theories

Free radicals are atoms or molecules with at least one unpaired electron. Radicals are therefore mostly reactive – thus often short-lived – and play an important role in oxidation processes, in chain polymerizations and substitution reactions. The unpaired electron is usually located at carbon, nitrogen or oxygen atoms. In 1916, Lewis described the organic free radical for the first time [2]. About 40 years later, it was found that the concentration of free radicals is particularly high in metabolically active tissues (e.g., liver, kidney) and that radicals are formed as intermediates of biochemical processes. Gerschman et al. described for the first time the damaging effect of reactive oxygen species (ROS) and Harman formulated the “free radical theory of aging” a little later [3,4].

The thesis is that free radicals damage functionally important molecules such as DNA, RNA, and a variety of proteins and lipids. This leads to an ever-growing accumulation of damaged cellular components that are thought to drive the complex aging process. This account was extended by the theory of mitochondrial aging. The mitochondria’s own genetic material (mtDNA) is damaged by nascent ROS from the respiratory chain. Mutations of mtDNA accumulate in the normal aging process and respiratory chain function decreases in inverse proportion, leading to a decrease in energy provision [5].

How does the body defend itself?

In the course of evolution, the organism has also developed defense mechanisms against free radicals. Thus, endogenously synthesized substances – often referred to as radical scavengers (antioxidants) – can neutralize free radicals. These include enzymes such as catalase, superoxide reductase, glutathione peroxidase, etc., as well as a number of endogenous, water- and lipid-soluble, low-molecular-weight molecules such as uric acid, oleic acid and unsaturated fatty acids. This endogenous protective system is supported by antioxidants supplied through dietary intake. Vitamins A, C and E, water-soluble polyphenols and lipid-soluble carotenoids are typical representatives.

Are the theories still valid today?

Based on the free radical theory of aging and based on the desire to support the body’s own system, many people today are trying to limit or even prevent oxidative stress in the body and skin. Means for this are especially vitamin-rich diet – fruits and vegetables -, systemically supplied dietary supplements and topically applied products with natural and synthetic antioxidants.

Today, however, the question arises whether the free radical theory of aging, developed almost 60 years ago, still has a validity that is also proven by more recent experiments.
Unfortunately, it has been shown that the Harman experiments cannot be fully replicated, and that depending on the experimental setup in worms and mice, an increased occurrence of ROS may even lead to an extension of lifespan. It is postulated that ROS even initiate a cellular repair network [6]. A large number of experiments from the last 20 years suggest that the importance of antioxidants in humans is not yet fully understood.

People with above-average intake of fruits and vegetables have a lower risk of lung cancer – or so the idea goes, based on research from the 1990s. Subsequently, attempts were made to add certain food components (e.g. β-carotene) as a supplement to the diet. Unexpectedly, however, two trials of high-dose β-carotene supplementation had to be terminated about 15 years ago because the risk of lung cancer in smokers increased after β-carotene administration. Further studies in vitro and in vivo have been interpreted in the sense that β-carotene antagonizes tumor formation, but its oxidation product is cancer-promoting, possibly due to the instability of the β-carotene molecule in a free radical-rich environment in the lungs of cigarette smokers [7,8]. Meanwhile, it has also been shown that there is no convincing evidence that fruits and vegetables play a role in cancer etiology [9].

In a large, multicenter, double-blind, placebo-controlled clinical prevention trial, 864 subjects who had had colon polyps removed received 25 mg of β-carotene or placebo daily, combined with 1000 mg of vitamin C and 400 mg of vitamin E or placebo. After four years, the following observations were made regarding β-carotene supplementation and the development of colon polyps: significant reduction in risk for nonsmokers and nondrinkers; slightly increased risk for smokers or alcohol consumers; doubling of risk for those who smoke cigarettes and consume more than one alcoholic beverage daily [10].

Clinical studies also showed that the administration of β-carotene did not change the number of new cases of non-melanoma skin cancer. In contrast, significant enhancement of UV-related carcinogenesis occurred following a β-carotene-supplemented diet. A photoprotective effect was not obtained [11].

Data situation remains unclear

The World Cancer Research Fund has conducted the largest study of lifestyle and cancer and published several recommendations. These include, among others, the recommendation not to use dietary supplements for cancer prevention because the risk-benefit ratio cannot be reliably predicted and unexpected and unusual opposite effects may occur [12].

The U.S. National Cancer Institute fact sheet includes as one of its main statements, “Laboratory and animal research have shown that antioxidants help prevent the free radical damage associated with cancer. However, current clinical studies in the general population do not agree with this. Antioxidants are provided by a healthy diet that includes a variety of fruits and vegetables.” [13]

Bjelakovic and colleagues conclude their 2012 Cochrane systematic review, which included 78 randomized trials with 296,707 participants, with the remarkable statement: “We found no evidence to support antioxidant supplements for primary or secondary prevention. Beta-carotene and vitamin E seem to increase mortality, and so may higher doses of vitamin A. Antioxidant supplements need to be considered as medicinal products and should undergo sufficient evaluation before marketing.” [14]

Recent work by Ristow and collaborators from Leipzig, Potsdam, and Harvard is also noteworthy. They found in athletes that taking antioxidants – in the form of vitamins C and E as a supplement to exercise – reversed the positive effects of exercise (including improving insulin sensitivity) (Fig. 1) [15–17].

Topical better than systemic?

The mentioned works are about the systemic application of antioxidants. But what is the data situation for topically applied antioxidants? There is also a very large number of papers in this area, but these are often in vitro studies or poorly controlled human studies with small numbers of cases. Little of the emerging skepticism presented in the literature on systemically ingested antioxidants seems to have penetrated to the authors of papers on topically applied antioxidants. A number of key questions are not even asked and supported with data in many papers. These include [18,19]:

1. Is the antioxidant at all stable in the topical dosage form? Is its antioxidant capacity (“radical scavenging activity”) not compromised by a potentially “stressed” product (e.g., unsuitable vehicle ingredients or storage conditions)?
2. Does the antioxidant penetrate/permeate into and through the skin in sufficient quantity with sufficient antioxidant capacity, and does it reach its target intra- and/or extracellularly?
3. What is the correct dosage strength and ideal dosing interval?
4. Is the chosen antioxidant or antioxidant mixture the right one? E.g. plant extracts or antioxidants for hydrophilic (e.g. vitamin C) resp. lipophilic (e.g. vitamin E) compartments.
5. Can findings from in vitro studies be transferred to the situation of “healthy” skin with an intact skin barrier? Furthermore, these experimental conditions are extremely difficult to control.
6. How well and after what application or treatment time can a relevant experimental/clinical endpoint be linked to an antioxidant effect?
7. What influence does the stereochemistry of antioxidants have on efficacy?

The work published to date on topically applied antioxidants suggests that many questions about efficacy and, at best, safety remain unresolved.

Against the backdrop of the position paper by renowned US scientists published as early as 2002, which points out that aging can hardly be slowed down, stopped or reversed [20], and in view of the numerous studies on antioxidants and other anti-aging substances that have been published in the meantime, it is noteworthy how cosmetic
and food industry still preach the “Fountain of Youth” with these substances in semantically well-formulated sentences. The willingness of consumers to invest considerable amounts of money is also impressive.

Prof. Dr. phil. nat. Christian Surber

Literature:

1. www.youtube.com/watch?v=A0A6W9WSWC0.
2. Lewis GN: Steric Hindrance and the Existence of Odd Molecules (Free Radicals). Proc Natl Acad Sci USA 1916; 2: 586-592.
3. Gerschman R, et al: Oxygen Poisoning and X-irradiation: A Mechanism in Common. Science 1954; 119(3097): 623-626.
4. Harman D: Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956; 11: 298-300.
5. Beckman KB, et al: Mitochondrial aging: open questions. Ann N Y Acad Sci 1998; 854: 118-127.
6. Moyer MW: The myth of antioxidants, Sci Am 2013; 308(2): 62-67.
7. Wang XD, et al: Procarcinogenic and anticarcinogenic effects of beta-carotene. Nutr Rev 1999; 57: 263-272.
8. Meffert H: Antioxidants – friend or foe? GMS Ger Med Sci 2008; 6: Doc09.
9. Norat T, et al: Fruits and vegetables: updating the epidemiologic evidence for the WCRF/AICR lifestyle recommendations for cancer prevention. Cancer Treat Res 2014; 159: 35-50.
10. Baron JA, et al: Neoplastic and antineoplastic effects of betacarotene on colorectal adenoma recurrence: results of arandomized trial. J Natl Cancer Inst 2003; 95(10): 717-722.
11. Black HS: Pro-carcinogenic activity of beta-carotene, a putative systemic photoprotectant. Photochem Photobiol Sci 2004; 3(8): 753-758.
12. World Cancer Research Fund, American Institute for Cancer Research: Food, nutrition, physical activity, and the prevention of cnancer: a global perspective. Washington DC: AICR; 2007. ISBN: 978-0-9722522-2-5 or www.dietandcancerreport.org/cancer_resource_center/downloads/Second_Expert_Report_full.pdf.
13. National Cancer Institute, U.S. National Institutes of Health: Antioxidants and Cancer Prevention: Fact Sheet. www.cancer.gov/cancertopics/factsheet/antioxidantsprevention.
14. Bjelakovic G, et al: Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No.: CD007176. DOI: 10.1002/14651858.CD007176.pub2.
15. Ristow M, et al: Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS). Dose Response 2014; 12(2): 288-341.
16. Ristow M, et al: Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A 2009; 106(21): 8665-8670.
17. Gomez-Cabrera MC, et al: Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. Am J Clin Nutr 2008; 87(1): 142-149.
18. Berger RG, et al: Antioxidants in food: mere myth or magic medicine? Crit Rev Food Sci Nutr 2012; 52(2): 162-171.
19. Oresajo C, et al: Antioxidants and the skin: understanding formulation and efficacy. Dermatol Ther 2012 May-Jun; 25(3): 252-259.
20. Olshansky S, et al: No truth to the fountain of youth. Sci Am 2002; 286(6): 92-95.
21. Schulz TJ, et al: Glucose restriction extends caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metabolism 2007; 6: 280-293.

CONCLUSION FOR PRACTICE

• Free radicals are usually carbon, nitrogen or oxygen atoms or molecules with at least one unpaired electron. They cause the oxidative stress.  
• The body endogenously synthesizes substances (= radical scavengers/antioxidants) that neutralize the free radicals. Antioxidants supplied from the outside are vitamins A, C and E, water-soluble polyphenols and lipid-soluble carotenoids.
• Harman’s “free radical theory of aging” states that free radicals damage functionally important molecules. The accumulation of damaged cellular components is thought to drive the aging process. Unfortunately, the experimental results cannot be completely replicated.
• The unclear data situation suggests that the importance of antioxidants (delivered systemically or topically) in the human organism is not yet fully understood.

DERMATOLOGIE PRAXIS 2014; 24(6): 24-27