ROS PRODUCTION

Reactive oxygen species (ROS) are biological products of metabolism that exert both positive and negative effects on the body.  ROS include free radicals like the hydroxyl radical (OH·), superoxide anion radical (O2–), nitric oxide (NO·), etc.1 as well as other oxidants  (e.g. hydrogen peroxide (H2O2), peroxynitrite (ONOO-) singlet oxygen (1O2), etc.).2 The primary source of ROS formation occurs via the  membrane-bound NADPH oxidase enzyme complex and the electron transport chain (primarily complex 1 and 3) of the mitochondria3 during aerobic metabolism.

NEGATIVE EFFECTS OF ROS

Numerous articles discuss the negative consequences of ROS and their implications on virtually every disease: Immune disorders, such as diabetes mellitus,4 multiple sclerosis,5 asthma,6 rheumatoid arthritis,7 chronic inflammation,8 and other fatal diseases such as cardiovascular disease,9,10 cancer,11 neurodegenerative diseases such as Alzheimer’s disease12 and Parkinson’s disease13 as well as aging14,15 (perhaps due to telomere shortening16).

POSITIVE EFFECTS OF ROS

Matrix Metabolic Enzymes

A more recent understanding of ROS17-20 demonstrates that although they may have negative side effects at high levels, they are also important biological signaling molecules that exert therapeutic and protective effects against diseases, and play a pivotal role in mediating the benefits of exercise.21 The above figure illustrates ROS production in the mitochondria and its involvement in cell signal transduction.

PROTECTIVE MECHANISM OF THE BODY

Because high levels of ROS are strongly implicated in the progression and pathogenesis of disease, our bodies have  the ability to scavenge these ROS after they exert their beneficial signaling effects.  For example, the mitochondrial-produced superoxide is dismutated to hydrogen peroxide by superoxide dismutase, which is subsequently reduced to water via the glutathione peroxidase/reductases/NADPH system22. The body also uses catalase, glutathione, vitamins A, C, E, etc. to help protect against ROS-induced damage.

REDUCTIVE STRESS AND OXIDATIVE STRESS

There are two opposing forces in biological systems: oxidative stress and reductive stress. Reductive stress is achieved when the concentrations of reducing agents exceeds that of oxidizing agents. This is seen under the metabolism of ethanol (i.e. high ratios of NADH/NAD+ & NADPH/NADP+).23  Reductive stress may also partly explain why high doses of conventional antioxidants may increase cardiovascular disease24, cancer25 and absolute mortality26. Aging has recently been linked to a loss of oxidizing potential of the ER, which impairs protein folding; whereas, the cytosol becomes more oxidizing. Thus, it is possible to have reductive stress in one system, and oxidative stress in another.

Oxidative stress is defined as when the formation and concentration of ROS exceeds the clearance and scavenging activity of the body’s endogenous antioxidant self-defense system.27 Oxidative stress is correlated with aging and the standard American diet.  Interestingly, exercise drastically increases the levels of ROS and consequent oxidative stress.28 Therefore, one may conclude that exercise has negative side effects to health; however, it is well known that exercise exerts potent therapeutic and protective effects.29 Research has demonstrated that one of the reasons why regular exercise exerts these therapeutic effects is because it upregulates the body’s endogenous antioxidant activity, which reduces the absolute risk of cellular injury by oxidative stress.30

ANTIOXIDANTS MAY NEGATE EXERCISE BENEFITS

Furthermore, exercise-induced ROS formation enhances insulin sensitivity via ROS-dependent transcriptional coactivators PGC1-a, PGC1-b and the transcription factor PPAR, which are linked to diabetes31. However, the pathway is blocked by ingestion of high amounts of conventional antioxidants vitamin C and E32. The ROS-related induction of PPARa, PGC1a, and PGC1b lead to an increased expression of the ROS-detoxifying enzymes, including SOD1, SOD2, and GPx1 thus offering an increased protection against various diseases that arise from oxidative stress.

HOW MUCH EXERCISE IS NEEDED?

It is unclear the frequency, duration or intensity of exercise needed to up-regulate the expression of these endogenous antioxidant enzymes to such a degree that will offer protective effects against oxidative insult.  The literature, however, does shed some light into the effects of a single session of exercise versus regular exercise.

A single session of exercise increases the levels of ROS and reactive nitrogen species.33-35 This increase leads to acute oxidative damage33-37 and a lower resistance to oxidative stress.35 Physiological function also decreases;35 however, the activity of endogenous antioxidant enzymes increases, 34, 36, 37 with a possible increase in oxidative repair mechanisms.38-39

In contrast, regular exercise is associated with an absolute decrease in ROS and reactive nitrogen species,40 as well as lower oxidative damage.34,41,42,43 Moreover, physiological function44-49, resistance to oxidative stress42,43,50-52 , oxidative repair mechanisms43, 53,54 and activity of endogenous antioxidants 34, 41 all increase with regular exercise.

CONCLUSION AND RECOMMENDATION

In order to experience the positive therapeutic effects of exercise-induced upregulation of the endogenous antioxidant self-defense system, regular exercise is needed.

  • Exercise regularly
  • Be cautious about ingesting high amounts of conventional “pill” antioxidants
  • Consume molecular hydrogen(H2), as H2 only reduces “excessive” oxidative stress, and does not interfere with beneficial ROS55.
  1. Bayr, H. (2005). Reactive oxygen species. Critical care medicine, 33(12), S498-S501.
  2. Turrens, J. F. (2003). Mitochondrial formation of reactive oxygen species. The Journal of physiology, 552(2), 335-344.
  3. Muller, F. L., Lustgarten, M. S., Jang, Y., Richardson, A. and Van Remmen, H. (2007). “Trends in oxidative aging theories.”. Free Radic. Biol. Med. 43 (4): 477–503.
  4. Houstis, N., Rosen, E. D., & Lander, E. S. (2006). Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature, 440(7086), 944-948.
  5. LeVine, S. M. (1992). The role of reactive oxygen species in the pathogenesis of multiple sclerosis. Medical hypotheses, 39(3), 271-274.
  6. Henricks, P. A., & Nijkamp, F. P. (2001). Reactive oxygen species as mediators in asthma. Pulmonary pharmacology & therapeutics, 14(6), 409-420.
  7. Bauerova, K., & Bezek, S. (2000). Role of reactive oxygen and nitrogen species in etiopathogenesis of rheumatoid arthritis. General Physiology and Biophysics, 18, 15-20.
  8. Grisham, M. B., Jourd’Heuil, D., & Wink, D. A. (2008). Review article: chronic inflammation and reactive oxygen and nitrogen metabolism–implications in DNA damage and mutagenesis. Alimentary pharmacology & therapeutics, 14(s1), 3-9.
  9. Abe, J. I., & Berk, B. C. (1998). Reactive oxygen species as mediators of signal transduction in cardiovascular disease. Trends in cardiovascular medicine, 8(2), 59-64.
  10. Watson, T., Goon, P. K., & Lip, G. Y. (2008). Endothelial progenitor cells, endothelial dysfunction, inflammation, and oxidative stress in hypertension. Antioxidants & redox signaling, 10(6), 1079-1088.
  11. Cerutti, P. A., & Trump, B. F. (1991). Inflammation and oxidative stress in carcinogenesis. Cancer cells (Cold Spring Harbor, NY: 1989), 3(1), 1.
  12. Poh Loh, K., Hong Huang, S., De Silva, R., Tan, H., Benny, K., & Zhun Zhu, Y. (2006). Oxidative stress: apoptosis in neuronal injury. Current Alzheimer Research, 3(4), 327-337.
  13. Nunomura, A., Moreira, P. I., Takeda, A., Smith, M. A., & Perry, G. (2007). Oxidative RNA damage and neurodegeneration. Current medicinal chemistry, 14(28), 2968-2975.
  14. Harman, D. (1981). The aging process. Proceedings of the National Academy of Sciences, 78(11), 7124-7128.
  15. Finkel, T., & Holbrook, N. J. (2000). Oxidants, oxidative stress and the biology of ageing. NATURE-LONDON-, 239-247.
  16. Harman, D. (2003). The free radical theory of aging. Antioxidants and Redox Signaling, 5(5), 557-561.
  17. Forman, H. J., Maiorino, M., & Ursini, F. (2010). Signaling functions of reactive oxygen species. Biochemistry, 49(5), 835-842.
  18. Finkel, T. (2011). Signal transduction by reactive oxygen species. The Journal of cell biology, 194(1), 7-15.
  19. Brosché, M., Overmyer, K., Wrzaczek, M., Kangasjärvi, J., & Kangasjärvi, S. (2010). Stress signaling III: Reactive oxygen species (ROS). Abiotic Stress Adaptation in Plants, 91-102.
  20. Mittler, R., Vanderauwera, S., Suzuki, N., Miller, G., Tognetti, V. B., Vandepoele, K., … & Van Breusegem, F. (2011). ROS signaling: the new wave?. Trends in plant science, 16(6), 300-309.
  21. Powers, S. K., Duarte, J., Kavazis, A. N., & Talbert, E. E. (2010). Reactive oxygen species are signalling molecules for skeletal muscle adaptation. Experimental physiology, 95(1), 1-9.
  22. Gutteridge, J. (1985). Superoxide dismutase inhibits the superoxide-driven Fenton reaction at two different levels: Implications for a wider protective role. FEBS letters, 185(1), 19-23.
  23. Cederbaum, A. I., Lu, Y., & Wu, D. (2009). Role of oxidative stress in alcohol-induced liver injury. Archives of toxicology, 83(6), 519-548.
  24. Lonn, E., Bosch, J., Yusuf, S., Sheridan, P., Pogue, J., Arnold, J. M., … & Dagenais, G. R. (2005). Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA: the journal of the American Medical Association, 293(11), 1338.
  25. Klein, E. A., Thompson Jr, I. M., Tangen, C. M., Crowley, J. J., Lucia, M. S., Goodman, P. J., … & Baker, L. H. (2011). Vitamin E and the risk of prostate cancer. JAMA: the journal of the American Medical Association, 306(14), 1549-1556.
  26. Miller 3rd, E. R., Pastor-Barriuso, R., Dalal, D., Riemersma, R. A., Appel, L. J., & Guallar, E. (2005). Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Annals of internal medicine, 142(1), 37.
  27. Chrissobolis, S., Miller, A. A., Drummond, G. R., Kemp-Harper, B. K., & Sobey, C. G. (2011). Oxidative stress and endothelial dysfunction in cerebrovascular disease. Frontiers in bioscience: a journal and virtual library, 16, 1733.
  28. Alessio, H. M., Hagerman, A. E., Fulkerson, B. K., Ambrose, J. E. S. S. I. C. A., Rice, R. E., & Wiley, R. L. (2000). Generation of reactive oxygen species after exhaustive aerobic and isometric exercise. Medicine and science in sports and exercise, 32(9), 1576.
  29. Elward, K., & Larson, E. B. (1992). Benefits of exercise for older adults. A review of existing evidence and current recommendations for the general population. Clinics in geriatric medicine, 8(1), 35.
  30. Powers, S. K., Ji, L. L., & Leeuwenburgh, C. H. R. I. S. T. I. A. A. N. (1999). Exercise training-induced alterations in skeletal muscle antioxidant capacity: a brief review. Medicine and science in sports and exercise, 31(7), 987.
  31. Patti ME, et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci USA. 2003;100:8466–8471.
  32. Ristow, M., Zarse, K., Oberbach, A., Klöting, N., Birringer, M., Kiehntopf, M., … & Blüher, M. (2009). Antioxidants prevent health-promoting effects of physical exercise in humans. Proceedings of the National Academy of Sciences, 106(21), 8665-8670.
  33. Davies, K. J.; Quintanilha, A. T.; Brooks, G. A.; Packer, L. Free radicals and tissue damage produced by exercise. Biochem. Biophys. Res. Commun. 107:1198–1205; 1982.
  34. Radak, Z.; Taylor, A. W.; Ohno, H.; Goto, S. Adaptation to exerciseinduced oxidative stress: from muscle to brain. Exerc. Immunol. Rev. 7:90–107; 2001.
  35. Radak, Z.; Pucsok, J.; Mecseki, S.; Csont, T.; Ferdinandy, P. Muscle soreness-induced reduction in force generation is accompanied by increased nitric oxide content and DNA damage in human skeletal muscle. Free Radic. Biol. Med. 26:1059–1063; 1999.
  36. Radak, Z.; Asano, K.; Inoue, M.; Kizaki, T.; Oh-Ishi, S.; Suzuki, K.; Taniguchi, N.; Ohno, H. Superoxide dismutase derivative reduces oxidative damage in skeletal muscle of rats during exhaustive exercise. J. Appl. Physiol. 79:129–135; 1995.
  37. Radak, Z.; Asano, K.; Inoue, M.; Kizaki, T.; Oh-Ishi, S.; Suzuki, K.; Taniguchi, N.; Ohno, H. Superoxide dismutase derivative prevents oxidative damage in liver and kidney of rats induced by exhausting exercise. Eur. J. Appl. Physiol. Occup. Physiol. 72:189–194; 1996.
  38. Radak, Z.; Apor, P.; Pucsok, J.; Berkes, I.; Ogonovszky, H.; Pavlik, G.; Nakamoto, H.; Goto, S. Marathon running alters the DNA base excision repair in human skeletal muscle. Life Sci. 72:1627–1633; 2003.
  39. Radak, Z.; Sasvari, M.; Nyakas, C.; Kaneko, T.; Tahara, S.; Nakamoto, H.; Goto, S. Single bout of exercise eliminates the immobilization-induced oxidative stress rat brain. Neurochem. Int. 39:33–38; 2001.
  40. Radak, Z.; Chung, H. Y.; Naito, H.; Takahashi, R.; Jung, K. J.; Kim, H. J.; Goto, S. Age-associated increase in oxidative stress and nuclear factor kappaB activation are attenuated in rat liver by regular exercise. FASEB J. 18:749–750; 2004.
  41. Alessio, H. M.; Goldfarb, A. H. Lipid peroxidation and scavenger enzymes during exercise: adaptive response to training. J. Appl. Physiol. 64:1333–1336; 1988.
  42. Radak, Z.; Kaneko, T.; Tahara, S.; Nakamoto, H.; Ohno, H.; Sasvari, M.; Nyakas, C.; Goto, S. The effect of exercise training on oxidative damage of lipids, proteins, and DNA in rat skeletal muscle: evidence for beneficial outcomes. Free Radic. Biol. Med. 27:69–74; 1999.
  43. Radak, Z.; Sasvari, M.; Nyakas, C.; Pucsok, J.; Nakamoto, H.; Goto, S. Exercise preconditioning against hydrogen peroxide induced oxidative damage in proteins of rat myocardium. Arch. Biochem. Biophys. 376: 248–251; 2000.
  44. Cotman, C. W.; Engesser-Cesar, C. Exercise enhances and protects brain function. Exerc. Sport Sci. Rev. 30:75–79; 2002.
  45. Berchtold, N. C.; Chinn, G.; Chou, M.; Kesslak, J. P.; Cotman, C. W. Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus. Neuroscience 133:853–861; 2005
  46. Radak, Z.; Kaneko, T.; Tahara, S.; Nakamoto, H.; Sasvari, M.; Nyakas, C.; Goto, S. Regular exercise improves cognitive function and decreases oxidative damage in rat brain. Neurochem. Int. 38:17–23; 2001.
  47. Vaynman, S.; Ying, Z.; Gomez-Pinilla, F. Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity. Neuroscience 122:647–657; 2003.
  48. Van Praag, H.; Kempermann, G.; Gage, F. H. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 2:266–270; 1999.
  49. Van Praag, H.; Christie, B. R.; Sejnowski, T. J.; Gage, F. H. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc. Natl. Acad. Sci. USA 96:13427–13431; 1999.
  50. Adlard, P. A.; Cotman, C. W. Voluntary exercise protects against stressinduced decreases in brain-derived neurotrophic factor protein expression. Neuroscience 124:985–992; 2004.
  51. Radak, Z.; Toldy, A.; Szabo, Z.; Siamilis, S.; Nyakas, C.; Silye, G.; Jakus, J.; Goto, S. The effects of training and detraining on memory, neurotrophins and oxidative stress markers in rat brain. Neurochem. Int. 49:387–392; 2006.
  52. Ushio-Fukai, M.; Alexander, R. W. Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase. Mol. Cell. Biochem. 264:85–97; 2004.
  53. Radak, Z.; Naito, H.; Kaneko, T.; Tahara, S.; Nakamoto, H.; Takahashi, R.; Cardozo-Pelaez, F.; Goto, S. Exercise training decreases DNA damage and increases DNA repair and resistance against oxidative stress of proteins in aged rat skeletal muscle. Pflugers Arch. 445:273–278; 2002.
  54. Nakamoto, H., Kaneko, T., Tahara, S., Hayashi, E., Naito, H., Radak, Z., & Goto, S. (2007). Regular exercise reduces 8-oxodG in the nuclear and mitochondrial DNA and modulates the DNA repair activity in the liver of old rats. Experimental gerontology, 42(4), 287-295.
  55. OHSAWA, I., ISHIKAWA, M., TAKAHASHI, K., WATANABE, M., NISHIMAKI, K., YAMAGATA, K., KATSURA, K., KATAYAMA, Y., ASOH, S. & OHTA, S. (2007). Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med 13, 688-694.