The Benefits, Harms, and Confusion of Antioxidants

Antioxidants: Beneficial, Harmful, or Just Confusing

 
For millions of years, humans have been surrounded by stressful and unfavorable events and times, ranging from plagues and droughts, to periods of war and starvation. Most would consider these events as anything but good, and few would consider them to provide any health benefits whatsoever. But what if some so-called terrible, stressful events were actually good for us?
 
Actually, what if small amounts of dreadful events were really good for us? What if, while a massive plague may result in starvation and death, a short period of time without food helped to fight cancer and sickness?1–3
 
Intermittent periods of fasting, food restriction, and other insults to the body may actually provide more benefit than harm. The theory of hormesis states that toxins or other stressors lead to a small insult on the body, and the repair of this insult leaves the individual in a better condition than if the insult never occurred. Much like a muscle growing larger and stronger after the damage from weightlifting, the body prepares itself for future stresses. The insult does not tear us down, but rather causes us to become more robust.
 
The controversial phenomenon of hormesis was first described in 1888 when a German pharmacologist named Hugo Schulz found that a very small dose of potentially lethal poison caused yeast to grow instead of killing them. Not until the next century, in 1943, was the term hormesis officially used in a scientific document. More recently, the theory of hormesis has been awakened and advanced by Dr. Michael Ristow, whose research suggests that a small amount of insult to our mitochondria, the power houses of our cells, may provide a large benefit to our health. His lab in Germany continues to produce research that has been revealing these benefits.
 

Antioxidants to Fight Hormesis

 
Regardless of the current view on hormesis, fruits and vegetables have always been considered healthy for as long as I can remember. The reasons have varied, but the medical world has generally espoused their vitamin and nutrient content, pushed them as a healthy low fat food (right or wrong…), or often described them as a good source of fiber.
 
More recently, fruits and vegetables have received fame for their high content of antioxidants. We live in a toxic world where we are constantly bombarded with free radicals, and the antioxidants within fruits and vegetables were believed to help offset this damage.
 
The measure of food’s free radical-fighting and antioxidant potential occurs through various methods, including the amount of carotenoids in vegetables, content of ubiquinol or coenzyme Q (an antioxidant that is minimally absorbed when taken orally and naturally produced within our cells), or polyphenol content, among several others. Vitamin C (ascorbic acid) and vitamin E (tocopherol) are considered potent antioxidants, both in food and pill form. Foods that contain these vitamins are often recommended as healthy antioxidant foods. More recently, companies have been promoting supplementation with glutathione, a vital antioxidant produced within our cells.
 
Quantifying antioxidant levels has been a difficult task. Antioxidant content has been measured via oxygen radical absorbance capacity (OREC). The OREC was supposed to allow us to quantify the antioxidant “strength” of foods. This contrived system was hard for many to understand, until it was realized that the esoteric system was backed by no biologic evidence and it was eventually withdrawn by the USDA. The confusion of the OREC system merely parallels the confusion with antioxidants. You may notice that accompanying each attempt at descriptions of antioxidant levels are vague terms like “strength” that provide little in regards to scientific claims.
 
When it boils down to it, the antioxidant benefits of fruits, vegetables, and supplements generally lead to confusion and scientific ambiguity. The more I learned about the biologic and physiologic benefits of antioxidants, the more confused I found myself, and this is apparent in my earlier writings on this topic. Yet, apparently many other physicians and scientists found themselves in a similar position. The scientific literature is less than clear and recent papers thoroughly question any benefit of antioxidants within the diet.4
 

Antioxidant values often increase with more color in vegetabls like lettuce, but so do many other vitamins and nutrients.

Antioxidant values often increase with more color in vegetabls like lettuce, but so do many other vitamins and nutrients.


 
While the fiber in fruits and vegetables helps to feed our healthy bowel bacteria,5–8 and these plants certainly can provide a great amount of nutrition and vitamins,9–11 the theoretical benefits of the antioxidant aspects of fruits and vegetables remains, well, a theory – a theory that seems to be proven more incorrect on a daily basis.
 
Brighter colored fruits and vegetables apparently have more antioxidants than dull colored vegetables and grains, but they also have much more fiber per amount of carbohydrate. Which is more important?

Brighter colored fruits and vegetables apparently have more antioxidants than dull colored vegetables and grains, but they also have much more fiber per amount of carbohydrate. Which is more important?


 

The Antioxidant Theory of Aging

 
Like most things in the diet, supplement, and nutrition world, it all started with a theory. That theory gave birth to pathways, which gave birth to more theories on how to affect those pathways. What we were left with were more theories to affect those pathways to affect that initial theory. Confusion ensued. Many, such as Nick Lane, have attempted to deconstruct these multifaceted issues, and you can turn to his book Power, Sex, Suicide: Mitochondria and the Meaning of Life for a thorough tour through our cellular past and how we got to this current theoretical position.
 
In this instance, the theory of antioxidants described why we age. The free radical theory of aging made perfect sense:
1. Our body is bombarded with free radicals.
2. Free radicals cause damage.
3. This damage causes wear and tear that includes cancer, diabetes, atherosclerosis, joint and mechanical damage, heart damage, and Alzheimer’s and damage to the brain.
4. If able, the body must use its resources to fix this damage.
5. Due to the damage and attempts to fix the damage, the body ages.
 
This theory was first introduced midway through the twentieth century by Denham Harman. Around the same time, research was accumulating regarding the function of the powerhouses of our cells, known as the mitochondria. Mitochondria have several important functions, but are most famous for their ability to create energy for our cells through the process of respiration.
 
Respiration within the lungs pulls oxygen from our environment and into our tissue and cells. This physiologic process differs from cellular respiration, where our cells derive energy from nutrients through several reactions with oxygen to form adenosine triphosphate (ATP).
 
In a series of reactions within the mitochondria, protons and electrons are passed around in an area called the electron transport chain. During this handoff of electrons, there are donors and acceptors as the ultimate goal of ATP generation is met. Oxygen is important as it serves as an electron acceptor during the energy generation. This is the key step for the free radical theory of aging, as it creates a damaging free radical or oxidant from this oxygen molecule. The oxygen we breathe is the double edged sword of life as it is required for existence yet ultimately leads to our demise.
 

The Rise of Antioxidants

 
If mitochondria produced free radicals and free radicals provide oxidative damage to our cells, it followed logically that taking supplements to offset free radicals may protect our cells from this damage and even increase longevity. If we decrease the damage to our car, it will last longer. The body has a similar fate.
 
As is often the case in the world of vitamins, supplements, and nutrition, science failed to follow our logical conclusions. Many trials have taken place to assess the impact of supplementation with antioxidants. A large analysis of trials including a review from the Cochrane database revealed no benefit with supplementation with vitamin C. Worse off, the analysis revealed an increase in mortality with supplementation with vitamin A, β-carotene, or vitamin E.12,13
 
As discussed in chapter 11 in Misguided Medicine, rarely do supplements or pills provide an abbreviated path to optimal health. The failure of the antioxidant theory further establishes this point – oftentimes a healthy benefit comes from the longer pathway taken. In Nassim Nicholas Taleb’s insightful book Antifragile: Things That Gain from Disorder, his title may provide a similar phenomenon occurring within our cells and mitochondria. Perhaps a little disorder is what our body needs.
 
And the data does point toward supporting this notion. While the benefits of antioxidants in food and supplement sources are unknown or perhaps nonexistent, our innate cellular mechanisms of providing antioxidant protection appear to be backed by more significant science. As our vital mitochondria also have produced some harmful exhaust during their normal engine-like activities, it only stands to reason that our cells have developed mechanisms to offset this potential harm.
 
Perhaps most interesting about antioxidants is how they are still frequently used as a reason to eat certain foods. Fruits and vegetables, for instance, provide fiber to feed our bowel bacteria, along with some vitamins and minerals. Vegetables like broccoli and Brussels sprouts even provide some substances like sulforaphane that actually do the exact opposite of supplemental antioxidants – they signal damage and upregulate our body’s own free radical fighting mechanisms.14,15 Paradoxically, the benefits of fruits and vegetables may be their pro-oxidant activity. Newer data is revealing that dietary and supplemental antioxidants do not replace or even approach mimicking our cellular production, potentially providing more harm than good.
 
Even more worrisome is newer data revealing that antioxidant supplementation may enhance the aggressiveness of cancer cells and their ability to metastasize.16,17 The exact mechanisms remain as murky as the whole antioxidant theory, but may point towards inactivation of tumor suppressor genes.
 

The Exercise Paradox

 
While antioxidant supplements and food sources seemed to fail in their supposed benefits, it does appear that pro-oxidants may actually serve this purpose. Have you ever wondered how exercise actually works to increase health? This is not a straightforward answer, and I would wager that if ten health and exercise experts were asked this question, ten different answers would likely be given.
 
Yes, exercise increases blood flow to our organs and brain, improving cognition and vascular function, decreasing our risk of Parkinson’s Disease and dementia.18 Yes, exercise increases insulin sensitivity, lowering blood glucose levels and decreasing our risk of diabetes.19 Yes, exercise burns calories and improves our metabolic function.20 And yes, exercise upregulates metabolic pathways like AMPK to help decrease the risk of cancer.21
 
The benefits of exercise are endless. Yet, exercise by definition is a stress on the body, our muscles, our heart, and our mitochondria. This stress upregulates mitochondria and even increases mitochondrial biogenesis, or in other words, our cells create more of their powerhouses to help aid in exercise.22,23 As mitochondria are our prime sources of free radicals per the antioxidant aging theory, wouldn’t this work in opposition to antioxidants?
 
Our cells are smarter than we think. The stress on our body paradoxically lowers oxidative damage. In a sense, oxidative damage via external sources like exercise unexpectedly creates an antioxidant effect. When scientists disrupt mitochondrial function in mice, they experience an increases in oxidative damage.24 When they increase oxidative damage and mitochondrial function, they see a decrease in diseases caused by free radical damage, like cancer and heart disease.25
 
Confused yet?
 
This frustration is shared by many, but the benefits of exercise provide some insight. Dr. Ristow and his group set out to provide some clarity.26 Earlier research has shown that exercise increases mitochondrial function, therefore increasing free radical production. Muscle contraction during exercise has also been shown to increase free radical production. While the benefits of exercise are plenty, Ristow has theorized that this production of free radicals may actually provide health benefits in itself.
 
He took 40 study participants, separated them into four groups, and placed them on a four week exercise regimen. The free radical production in these individuals doubled from the exercise regimen. However, half of the participants were given antioxidants prior to exercise. This group had no increase in their free radical formation.
 
Increased insulin sensitivity, lower circulating insulin, and lower blood sugar levels leave the body in a physiologically healthier state, as described in previous chapters. A major health benefit of exercise is its ability to increase insulin sensitivity and lower blood sugar levels. Yet, Ristow found that those given antioxidants prior to exercise did not experience this benefit. He also found that the individuals given antioxidants did not experience an elevation in the body’s innate mechanism to offset free radicals, including the production of superoxide dismutase 2 and glutathione peroxidase 1. These cellular processes strongly detoxify free radicals and were only enhanced in those individuals that experienced the normal free radical increase from exercise. Once again, not only do oral antioxidants provide no benefit, but they may be harmful as they do not allow the body to naturally respond to oxidative threat.
 
Mitohormesis
 
Dr. Ristow has also shown that stress from hormesis and mitochondrial stimulation greatly increases our body’s natural free-radical defense mechanismism.27 From there, he took his research with hormesis the furthest when he showed that stimulation of the mitochondria (which happens during mitohormesis) gave mice the ability to fight colon cancer in experiments.25,28 Other activities that stimulate the mitochondria are intermittent fasting and carbohydrate restriction.29 The benefits of mitochondrial stimulation and hormesis may be far and wide.
 

What can we learn from the studies and antioxidants and hormesis?

 
While the theory of hormesis remains both controversial and compelling, it teaches us some lessons.
 
The human body was built to experience and even thrive from stress and mild physical insult, as it has for millions of years. This stress provides health naturally, and these effects can be channeled for benefit. The next time you are hungry and have not eaten for a prolonged period of time (intermittent fasting) and experience some hunger, or feel like skipping that walk or trip to the gym, keep in mind that your body is optimized to experience some healthy stress and to deny it this stress may be denying it health.
 
Cellular methods to fight free radicals and our body’s innate antioxidant function are the ultimate connection of the benefits of a healthy diet and lifestyle. The human body has interacted with certain foods and environments for millions and years and channeling these responses via an overall active lifestyle, periods of more intense exercise, a diet that limits sugars and grains, optimal sleep, and periodic fasting provides us with the tools to live a long and healthy life.
 
What are your thoughts? This is a controversial and challenging topic. If you have any comments or insight, please let me know and comment below.

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References:

1. Simone BA, Champ CE, Rosenberg AL, et al. Selectively starving cancer cells through dietary manipulation: methods and clinical implications. Futur Oncol. 2013;9(7):959-976. doi:10.2217/fon.13.31.
2. Champ CE, Baserga R, Mishra M V, et al. Nutrient Restriction and Radiation Therapy for Cancer Treatment: When Less Is More. Oncologist. 2013;18(1):97-103. doi:10.1634/theoncologist.2012-0164.
3. Mattson MP, Wan R. Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. J Nutr Biochem. 2005;16(3):129-137. doi:10.1016/j.jnutbio.2004.12.007.
4. Pérez VI, Bokov A, Van Remmen H, et al. Is the oxidative stress theory of aging dead? Biochim Biophys Acta. 2009;1790(10):1005-1014. doi:10.1016/j.bbagen.2009.06.003.
5. Ott SJ. Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease. Gut. 2004;53(5):685-693. doi:10.1136/gut.2003.025403.
6. Li F, Hullar MAJ, Schwarz Y, Lampe JW. Human gut bacterial communities are altered by addition of cruciferous vegetables to a controlled fruit- and vegetable-free diet. J Nutr. 2009;139(9):1685-1691. doi:10.3945/jn.109.108191.
7. Johnson IT. Glucosinolates: bioavailability and importance to health. Int J Vitam Nutr Res. 2002;72(1):26-31. http://www.ncbi.nlm.nih.gov/pubmed/11887749. Accessed May 5, 2015.
8. Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the gut microbiota on human health: an integrative view. Cell. 2012;148(6):1258-1270. doi:10.1016/j.cell.2012.01.035.
9. Kamao M, Suhara Y, Tsugawa N, et al. Vitamin K content of foods and dietary vitamin K intake in Japanese young women. J Nutr Sci Vitaminol (Tokyo). 2007;53(6):464-470. http://www.ncbi.nlm.nih.gov/pubmed/18202532.
10. Eaton SB. The ancestral human diet: what was it and should it be a paradigm for contemporary nutrition? Proc Nutr Soc. 2006;65(1):1-6. http://www.ncbi.nlm.nih.gov/pubmed/16441938.
11. Misra S, Maikhuri RK, Kala CP, Rao KS, Saxena KG. Wild leafy vegetables: a study of their subsistence dietetic support to the inhabitants of Nanda Devi Biosphere Reserve, India. J Ethnobiol Ethnomed. 2008;4(1):15. doi:10.1186/1746-4269-4-15.
12. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane database Syst Rev. 2012;3:CD007176. doi:10.1002/14651858.CD007176.pub2.
13. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. 2007;297(8):842-857. doi:10.1001/jama.297.8.842.
14. Zhang Y, Kensler TW, Cho CG, Posner GH, Talalay P. Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates. Proc Natl Acad Sci. 1994;91(8):3147-3150. doi:10.1073/pnas.91.8.3147.
15. Cornblatt BS, Ye L, Dinkova-Kostova AT, et al. Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast. Carcinogenesis. 2007;28(7):1485-1490. doi:10.1093/carcin/bgm049.
16. Le Gal K, Ibrahim MX, Wiel C, et al. Antioxidants can increase melanoma metastasis in mice. Sci Transl Med. 2015;7(308):308re8-re308re8. doi:10.1126/scitranslmed.aad3740.
17. Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P, Bergo MO. Antioxidants accelerate lung cancer progression in mice. Sci Transl Med. 2014;6(221):221ra15. doi:10.1126/scitranslmed.3007653.
18. Elward K, Larson EB. Benefits of exercise for older adults. A review of existing evidence and current recommendations for the general population. Clin Geriatr Med. 1992;8(1):35-50. http://europepmc.org/abstract/MED/1576579. Accessed July 7, 2014.
19. Borghouts LB, Keizer HA. Exercise and insulin sensitivity: a review. Int J Sports Med. 2000;21(1):1-12. doi:10.1055/s-2000-8847.
20. Talanian JL, Galloway SDR, Heigenhauser GJF, Bonen A, Spriet LL. Two weeks of high-intensity aerobic interval training increases the capacity for fat oxidation during exercise in women. J Appl Physiol. 2007;102(4):1439-1447. doi:10.1152/japplphysiol.01098.2006.
21. Steinberg GR, Kemp BE. AMPK in Health and Disease. Physiol Rev. 2009;89(3):1025-1078. doi:89/3/1025 [pii] 10.1152/physrev.00011.2008.
22. Little JP, Safdar A, Wilkin GP, Tarnopolsky MA, Gibala MJ. A practical model of low-volume high-intensity interval training induces mitochondrial biogenesis in human skeletal muscle: potential mechanisms. J Physiol. 2010;588(6):1011-1022. doi:10.1113/jphysiol.2009.181743.
23. Zong H, Ren JM, Young LH, et al. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A. 2002;99(25):15983-15987. doi:10.1073/pnas.252625599.
24. Esposito LA, Melov S, Panov A, Cottrell BA, Wallace DC. Mitochondrial disease in mouse results in increased oxidative stress. Proc Natl Acad Sci U S A. 1999;96(9):4820-4825. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10220377.
25. Schulz TJ, Thierbach R, Voigt A, et al. Induction of Oxidative Metabolism by Mitochondrial Frataxin Inhibits Cancer Growth: OTTO WARBURG REVISITED. J Biol Chem. 2006;281(2):977-981. doi:10.1074/jbc.M511064200.
26. Ristow M, Zarse K, Oberbach A, et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A. 2009;106(21):8665-8670. doi:10.1073/pnas.0903485106.
27. Shoichet SA, Bäumer AT, Stamenkovic D, et al. Frataxin promotes antioxidant defense in a thiol-dependent manner resulting in diminished malignant transformation in vitro. Hum Mol Genet. 2002;11(7):815-821. doi:10.1093/hmg/11.7.815.
28. Ristow M, Pfister MF, Yee AJ, et al. Frataxin activates mitochondrial energy conversion and oxidative phosphorylation. Proc Natl Acad Sci. 2000;97(22):12239-12243. doi:10.1073/pnas.220403797.
29. Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 2007;6(4):280-293. doi:10.1016/j.cmet.2007.08.011.

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9 Comments

  1. Peter Trayhurn`

    Dear Brother Caveman,
    We are all caveman, its that simple!
    Great article as always.
    Enjoy germany!
    Keytones 1.2, still alive and 5 days of hbot this week

    Reply
    1. cavemandoctor (Post author)

      Yes we are! Take care Peter and good luck!

      Reply
  2. Larry

    Thanks for the thoughtful analysis of antioxidants. This post will help more people to realize the true significance of it and make use of them in a appropriate and beneficial way. Some drug discovery and development (http://www.bocsci.com/Drug-design.html) put too much emphasis on the benefits of them, making the public to some degree neglecting the drawbacks they hold.

    Reply
  3. Lisa

    A great scientific review of the pros and cons of different pro-oxidants at the cellular level appears in Int J Biochem Cell Biol. 2007;39(7-8):1297-304. Epub 2007 Apr 21. “Superoxide anion: oncogenic reactive oxygen species?” The theory outlined in this article, about the balance between superoxide and hydrogen peroxide, has gradually gained a lot of acceptance among biologists, because it explains a lot of confusing phenomena.

    Reply
    1. cavemandoctor (Post author)

      Great article Lisa! Thanks for the link

      Reply
  4. Herby Bell

    Dr. Champ,

    Another breath of fresh air as you, “Wait just a second here” regarding this unfurling knowledge. I am particularly impressed with the way that you return to trusting the wisdom of the body with an holistic eye, instead of suggesting we can find a way to trick our pristine, innate genetic intelligence.

    Great article and thanks for taking the time to write and share it, Colin.

    Herby Bell, D.C.

    Reply
    1. cavemandoctor (Post author)

      Thanks Dr. Bell!!

      Reply
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