Oxidative Stress

In this page, I will first look at what produces oxidative stress (Section A) and thereafter, analyze a few methods to better mitigate this phenomenon (Section B)


A critical blow to the free radical theory of aging came from epidemiological studies showing that antioxidant supplementation did not lower the incidence of many age-associated diseases but, in some cases, increased the risk of death. Moreover, recent molecular evidence has shown that increasing generation of ROS, in some cases, increases longevity.


Gerontologists interested in free radical biology are at a crossroads and clearly new insights are required to clarify the role of ROS in the process of aging. The hurdles are, no doubt, very high, but the intellectual and practical promise of these studies is of such magnitude that we feel that all efforts will be generously rewarding.

J. Vina, C. Borras, K. M. Abdelaziz, R. Garcia-Valles, M. C. Gomez-Cabrera. The free radical theory of aging revisited: The cell signaling disruption theory of aging. Antioxid. Redox Signal. 2013 19(8):779 – 787.

Section A

Oxidative Stress’ Causes

Overproduction of reactive oxygen species (ROS) results in oxidative stress, shown to damage cellular structures, including membranes, lipids, proteins and DNA and thus, plays a central role in many human diseases and in aging. (1-3)

To manage oxidative stress, cells possess antioxidant protection mechanisms, which primarily consist of classical antioxidant enzymes such as superoxide dismutase (SOD), catalase, reduced glutathione (GSH) and phase II detoxifying enzymes, including glutamate-cysteine ligase (GCL), heme oxygenase-1 (HO-1) and glutathione S-transferase (GST) (4).

The most abundant natural cellular antioxidant is glutathion GSH, found in cells in milimolar concentrations (1–10 mM) and plays an essential role in maintaining the cellular redox state (5).

The protective effect of GSH is based on the generation of its oxidized form, glutathione disulphide (GSSG), which is reduced back to GSH by glutathione reductase to maintain a high cellular GSH/GSSG ratio, (6, 7).

The antioxidant cellular mechanism involving phase II detoxifying enzymes is regulated by the antioxidant response element (ARE), which is activated by the transcription factor nuclear factor erythroid 2 (NF-E2)-related factor-2 (Nrf2) (4-8). Upon oxidation of free sulfhydryl groups, known as the Nrf2 sensor for oxidative or electrophilic stress, Nrf2 is activated, translocated into the nucleus, where it interacts with ARE, resulting in expression of phase II antioxidants and detoxifying enzymes (8,9).

It has been known for many years that oxidative stress and/or a low level of cellular GSH, the major intracellular redox buffer, are associated with the development and/or progression of numerous pathological conditions, such as, diabetes (10) neurodegenerative diseases [1], chronic inflammation (2), atherosclerosis and cardiovascular disease (3).

Section B

New Strategies to lower Oxidative Stress and increase Detox Enzymes

GSH deficiency involvement in the indicated pathologies has prompted several researchers to investigate new strategies for maintaining or restoring the GSH level. Therefore, it is important to find ways to activate Nrf2 and increase antioxidants cellular level, mainly GSH, which will prevent and/or minimize ROS-induced cellular damage.

In this area of research, Conventional Medicine has invested in a Nrf2 activator called dimethyl fumarate (Tecfidera®), which appears to be still in clinical use for treating multiple sclerosis. It does not appear that this single agent drug will be without side or toxic effects. And it’s durable efficacy for MS remains to be proven.

On the hand hand, we have the Cruciferous family of veggies and itssulforaphane molecule, which is a natural dietary isothiocyanate found in broccoli and other cruciferous vegetables. These have been shown to induce phase II detoxification genes (11).

Other researchers are investing in other Nrf2 activators like allicin, anactive component in garlic. Thus, Powolny et al. (12) have shown that the garlic constituent diallyl trisulfide increases Caenorhabditis elegans (C. elegans) lifespan via SKN-1 (the worm ortholog of the Nrf2) activation. A recent study further showed that the natural thioallyl compounds S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC) increase C. elegans oxidative stress resistance and extend their lifespan by modulating SKN-1/Nrf2 (13).

Yet other studies have explored the protective effect of another allicin derivative, the allicin conjugate with N-acetylcysteine (NAC)–S-allylmercapto-N-acetylcysteine (ASSNAC) (15), not yet studied in C. elegans.



Age-related degeneration diseases and aging are believed to be the result of oxidative stress (ROS activity). Exposure to ROS, created through normal cellular metabolism and environmental hazards and inflammation, results in damage to cellular structures, leading to loss of critical cell functions

However, more studies, especially human trials would be useful if we are to ascertain what combo of nutrients can increase the expression of phase II detoxifying enzymes and Nfr2.


References and Precision Notes

1. Schulz J, Lindenau J, Seyfried J, Dichgans J. Glutathione, oxidative stress and neurodegeneration. European Journal of Biochemistry. 2000;267: 4904–4911. [PubMed]

2. Fridovich I. Fundamental aspects of reactive oxygen species, or what’s the matter with oxygen? Oxidative/energy Metabolism in Neurodegenerative Disorders. 1999;893: 13–18. [PubMed]

3. Rosenblat M, Coleman R, Aviram M. Increased macrophage glutathione content reduces cell-mediated oxidation of LDL and atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis. 2002;163: 17–28. [PubMed]

4. Masella R, Di Benedetto R, Vari R, Filesi C, Giovannini C. Novel mechanisms of natural antioxidant compounds in biological systems: Involvement of glutathione and glutathione-related enzymes. J Nutr Biochem. 2005;16: 577–586. doi: 10.1016/j.jnutbio.2005.05.013 [PubMed]

5. Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39: 44–84. doi: 10.1016/j.biocel.2006.07.001 [PubMed]

6. Bergamini C, Gambetti S, Dondi A, Cervellati C. Oxygen, reactive oxygen species and tissue damage. Curr Pharm Des. 2004;10: 1611–1626. [PubMed]

7. Dickinson D, Forman H. Glutathione in defense and signaling—Lessons from a small thiol. Cell Signaling, Transcription, and Translation as Therapeutic Targets. 2002;973: 488–504. [PubMed]

8. Ishii T, Itoh K, Yamamoto M. Roles of Nrf2 in activation of antioxidant enzyme genes via antioxidant responsive elements. Protein Sensors and Reactive Oxygen Species, Pt B, Thiol Enzymes and Proteins. 2002;348: 182–190. [PubMed]

9. Wang Q, Chuikov S, Taitano S, Wu Q, Rastogi A, Tuck SJ, et al. Dimethyl Fumarate Protects Neural Stem/Progenitor Cells and Neurons from Oxidative Damage through Nrf2-ERK1/2 MAPK Pathway. International Journal of Molecular Sciences. 2015;16: 13885–13907. doi: 10.3390/ijms160613885 [PMC free article] [PubMed]

10. Shurtz-Swirski R, Sela S, Herskovits A, Shasha S, Shapiro G, Nasser L, et al. Involvement of peripheral polymorphonuclear leukocytes in oxidative stress and inflammation in type 2 diabetic patients. Diabetes Care. 2001;24: 104–110. [PubMed]

11. Enrique Guerrero-Beltran C, Calderon-Oliver M, Pedraza-Chaverri J, Irasema Chirino Y. Protective effect of sulforaphane against oxidative stress: Recent advances. Experimental and Toxicologic Pathology. 2012;64: 503–508. doi: 10.1016/j.etp.2010.11.005 [PubMed]

12. Powolny AA, Singh SV, Melov S, Hubbard A, Fisher AL. The garlic constituent diallyl trisulfide increases the lifespan of C. elegans via skn-1 activation. Exp Gerontol. 2011;46: 441–452. doi: 10.1016/j.exger.2011.01.005 [PMC free article] [PubMed]

13. Ogawa T, Kodera Y, Hirata D, Blackwell TK, Mizunuma M. Natural thioallyl compounds increase oxidative stress resistance and lifespan in Caenorhabditis elegans by modulating SKN-1/Nrf. Sci Rep. 2016;22;6: 21611. [PMC free article] [PubMed]

14. Kim J, Park S. SUPPLEMENTATION OF S-ALLYL CYSTEINE IMPROVES HEALTH SPAN IN Caenorhabditis elegans. Bioscience Journal. 2017;33: 411–421.

15. Izigov N, Farzam N, Savion N. S-allylmercapto-N-acetylcysteine up-regulates cellular glutathione and protects vascular endothelial cells from oxidative stress. Free Radical Biology and Medicine. 2011;50: 1131–1139. doi: 10.1016/j.freeradbiomed.2011.01.028 [PubMed]



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