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Is the Free Radical Theory of Aging Dead?
Why Consuming Excessive Pure Antioxidant Supplements Can be Dangerous Rather than Health Producing


By HEIDI TOY, NTP

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It has been widely believed for decades that aging and disease are both the result of the accumulation of damage to the tissue by external sources called free radicals. A longstanding belief that has accompanied this theory has been that antioxidants consumed in the form of vitamins or by dietary choices would mitigate damaging oxidizing agents, thus reducing the risk of certain pathological conditions, such as cancer, diabetes, atherosclerosis, aging, and neurodegeneration.

Free radicals, or better known as reactive oxygen species (ROS), leading to oxidative stress is a natural part of the cellular metabolism and is further perpetuated by external elements such as; pollution, cigarette smoke, drugs, illness and stress.[6] A ROS ion is a molecule with an unpaired electron. The molecule is reactive and therefore, seeking an electron from another source in order to pair. Essentially it steals the electron from a healthy cell's cytoplasm. This theft initiates an uncontrolled chain reaction within the cells and in the tissue as more unstable radicals are produced, leading to tissue damage and causing various diseases. [5]

There have been recent advancements made in the area of anti aging and divergent disease states that challenge the theory of equipping the body with external sources of supplemental antioxidants.[2] These advances are based on the feedback nature of the cell's oxidation-reduction status (redox) system. [1] It has been found that chronic ingestion of artificial antioxidants may actually diminish the cells capability of providing its own defensive antioxidants to ward off the damage of ROS.

In order to maintain homeostasis and reduce oxidative damage, our cells house a family of antioxidant and detoxification enzymes, that are part of the cell's intricate mechanism to defend against ROS toxicity. The three primary antioxidant enzymes Superoxide Dismutase (SOD), Catalase, and Glutathione Peroxidase are induced by a transcription factor called nuclear factor erythroid 2-related factor (Nrf2), pronounced NERF 2. Nrf2 is sometimes referred to as the master regulator of antioxidant cellular detoxification. Activation of Nrf2 is the key to fighting oxidative stress. [3]

Under normal conditions, Nrf2 is bound to the cytoplasm and Keap1 (Kelch-like ECH-associated protein 1) in the cell. When Keap1 binding is disrupted by inflammatory, environmental, or ROS stressors Nrf2 is allowed to build up and eventually translocate into the nucleus of the cell where it binds with the gene promoter ARE (antioxidant response elements) of the DNA of cytoprotective genes.[8] Hundreds if not thousands of genes contain ARE in their regulatory promoter regions.[21]

There are substances that block the activation of Nrf2, such as electrophilic xenobiotics, statins, and cancer chemopreventive agents.[10] Additionally, artificially supplying the body with antioxidants is considered a source of ROS creating oxidative stress that can harm the cells by inhibiting the activation of Nrf2. While supplementation of antioxidants in small doses may not be bad, it should be considered that with less oxidative stress as a threat to the cell, the degradation of Nrf2 is increased when external sources are available. [9]

A better solution to artificial antioxidant supplementation is Nrf2 activation via diet, exercise, and nutritional supplements containing phytochemical activators of Nrf2. It has been found that food items and spices such as curcumin, turmeric, garlic, tomatoes, grapes, green tea, coffee, berries and sulforaphane from cruciferous vegetables such as  broccoli and Brussels sprouts demonstrate some Nrf2 activating properties when taken individually.[11,12,13,14]

The activation of Nrf2 pathways has been shown to have a profound effect in significantly attenuating the deleterious effects of oxidative stress and the role it plays in disease states such as IBD; including Crohn's disease and ulcerative colitis, HIV/AIDS, Sepsis (systemic inflammatory response syndrome), Lupus, sheering of the endothelial lining from laminar blood flow in the arterial system, Multiple Sclerosis, and Cancer prevention just to name a few. [15, 16, 17, 18]

There has been a considerable amount of press regarding synthetic activation of Nrf2 by a pharmaceutical grade drug called Tecfidera/BG12 to be used in the treatment of psoriasis and MS. Unfortunately Tecfidera also mutes the immune system in ways that have been linked to immunosuppressive drugs carrying dangerous side effects.[19]

There are also natural supplements available that have been shown to activate the Nrf2 pathway that include the spices and the phytonutrients identified, that show no negative effects in regard to suppression of the immune system and therefore do not carry the same risk as synthetic activators. [22,23,24, 25]  Additionally synthetic pharmaceutical grade Nrf2 activators will only be made available for disease states that warrant their uses; however, researchers have discovered that Nrf2 activation plays a largely protective and beneficial role under normal conditions as a preventive measure in the management of oxidative stress.

Nrf2 activation and its discovery is not new; however, it is paving the way for new research for the role it plays in the way of anti aging therapies, sports recovery, and divergent diseases based on the nature of oxidative damage to cells and tissues. Great effort is being made on a global scale in regard to both pharmaceutical grade and nutrigenomics for their influence on Nrf2 activation that will contribute to a greater understanding of how our own cellular defense mechanism can be harnessed in the treatment and prevention of degenerative and immunologic disorders.


Cited

1. Redox systems of the cell: Possible links and implications Kumuda C. Das, Carl W. White Proc Natl Acad Sci U S A. 2002 July 23; 99(15): 9617–9618. Published online 2002 July 16. doi: 10.1073/pnas.162369199 PMCID: PMC124948

2. Controversy of free radical hypothesis: reactive oxygen species--cause or consequence of tissue injury Juránek I1Bezek S. Gen Physiol Biophys. 2005 Sep;24(3):263-78.

3. The cytoprotective Nrf2 transcription factor controls insulin receptor signaling in the regenerating liver Beyer TA1Werner S. Cell Cycle. 2008 Apr 1;7(7):874-8. Epub 2008 Jan 18

4. ROS signaling, oxidative stress and Nrf2 in pancreatic beta-cell function Jingbo Pi, Qiang Zhang, [...], and Melvin E. Andersen, Toxicology and applied pharmacolog

5. Review An introduction to free radical biochemistry. Cheeseman KH, Slater TF Br Med Bull. 1993 Jul; 49(3):481-93.

6. Bagchi K, Puri S. Free radicals and antioxidants in health and disease. East Mediterranean Health Jr.1998;4:350–60.

7. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu RM, Hagen TM. Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3381-6. Epub 2004 Feb 25.PMID:14985508[PubMed - indexed for MEDLINE] 

8. Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Yamamoto, T., Suzuki, T., Kobayashi, A., et al. Mol Cell Biol 28(8) 2758-2770 (2008).

9. Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2,Huang, H.C., Nguyen, T., Pickett, C.B. et al. (2000). Proc Natl Acad Sci U S A 97(23), 12475-80 

10. Small maf (MafG and MafK) proteins negatively regulate antioxidant response element-mediated expression and antioxidant induction of the NAD(P)H:Quinone oxidoreductase1 gene. Dhakshinamoorthy, S., Jaiswal, A.K. (2000) J. Biol. Chem. 275(51), 40134-41

11. Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression Lee, Khor ,Shu Su, Fuentes, Kong (2013)

12. Spices as Functional Foods M. Viuda-Martos, Y. Ruiz-Navajas, J. Fernández-López, J. A. Pérez-Álvarez Critical Reviews in Food Science and Nutrition Vol. 51, Iss. 1, 2010

13. Nitric oxide scavenging by curcuminoids, Sreejayan A, Rao MN (1997). J Pharm Pharmacol 49:105–107 

14. Scavenging effect of extracts of green tea and natural antioxidants on active oxygen radicals, Zhao BL et al (1989) Scavenging. Cell Biophys 14:175–185

15. Shear stress stabilizes NF-E2-related factor 2 and induces antioxidant genes in endothelial cells: Role of reactive oxygen/nitrogen species   Warabi, Takabe,  Minami,  Inoue,  Itoh, Masayuki Yamamoto,  Ishii,  Kodama,  Noguchi. Free Radical Biology and Medicine Vol 42, Is2, 15 Jan 2007, 260–269

16. Nrf2 is involved in inhibiting Tat-induced HIV-1 long terminal repeat transactivation, Hong-Sheng Zhang, Hong-Yan Li, Yue Zhou, Meng-Ran Wu, Hong-Sen Zhou Free Radical Biology and Medicine, Volume 47, Issue 3, 1 August 2009, Pages 261-268, ISSN 0891-5849, http://dx.doi.org/10.1016/j.freeradbiomed.2009.04.028

17. Oxidative stress and redox signaling mechanisms of inflammatory bowel disease: updated experimental and clinical evidence, Zhu, Li, Exp Biol Med (Maywood). 2012 May;237(5):474-80. doi: 10.1258/ebm.2011.011358. Epub 2012 Mar 22.

18. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis Rajesh K. Thimmulappa, Hannah Lee, Tirumalai Rangasamy, Sekhar P. Reddy, Masayuki Yamamoto, Thomas W. Kensler, Shyam Biswal Volume 116, Issue 4J Clin Invest. 2006; 116(4):984–995 doi:10.1172/JCI25790

19. BG12 and its potential for the prevention of relapse in multiple sclerosis, Ginannetti P, Niccolini F, Nicholas R, Oct 2012 Vol 2012:2 Pg 119-132

20.The role of Nrf2 in the attenuation of cardiovascular disease.Reuland DJ, McCord JM, Hamilton KL. Exerc Sport Sci Rev. 2013 Jul;41(3):162-8. doi: 10.1097/JES.0b013e3182948a1e. Review. PMID:23558695[Source: PubMed - indexed for MEDLINE]

21. Upregulation of phase II enzymes through phytochemical activation of Nrf2 protects cardiomyocytes against oxidant stress. Reuland DJ, Khademi S, Castle CJ, Irwin DC, McCord JM, Miller BF, Hamilton KL.Free Radic Biol Med. 2013 Mar;56:102-11. doi: 10.1016/j.freeradbiomed.2012.11.016. Epub 2012 Nov 30. PMID:23201694 [Source: PubMed - in process]

22. Phytochemical activation of Nrf2 protects human coronary artery endothelial cells against an oxidative challenge.Donovan EL, McCord JM, Reuland DJ, Miller BF, Hamilton KL.

Oxid Med Cell Longev. 2012;2012:132931. doi: 10.1155/2012/132931. Epub 2012 May 22. PMID:22685617 [Source: PubMed - indexed for MEDLINE]

23. Protandim attenuates intimal hyperplasia in human saphenous veins cultured ex vivo via a catalase-dependent pathway.Joddar B, Reen RK, Firstenberg MS, Varadharaj S, McCord JM, Zweier JL, Gooch KJ.Free Radic Biol Med. 2011 Mar 15;50(6):700-9. doi: 10.1016/j.freeradbiomed.2010.12.008. Epub 2010 Dec 15.PMID:21167278 [Source: PubMed - indexed for MEDLINE]

24. The Dietary Supplement Protandim Decreases Plasma Osteopontin and Improves Markers of Oxidative Stress in Muscular Dystrophy Mdx Mice.Qureshi MM, McClure WC, Arevalo NL, Rabon RE, Mohr B, Bose SK, McCord JM, Tseng BS.J Diet Suppl. 2010 Jun 1;7(2):159-178.PMID:20740052 [PubMed]

25. Protandim does not influence alveolar epithelial permeability or intrapulmonary oxidative stress in human subjects with alcohol use disorders. Burnham EL, McCord JM, Bose S, Brown LA, House R, Moss M, Gaydos J.Am J Physiol Lung Cell Mol Physiol. 2012 Apr 1;302(7):L688-99. doi: 10.1152/ajplung.00297.2011. Epub 2012 Jan 20. PMID:22268125 [Source: PubMed - indexed for MEDLINE]