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The bright side of reactive oxygen species: lifespan extension without cellular demise

Kenneth Maiese

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E-mail : wntin75@yahoo.com

DOI: 10.15761/JTS.1000138.

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Abstract

Oxidative stress and the generation of reactive oxygen species (ROS) can lead to mitochondrial dysfunction, DNA damage, protein misfolding, programmed cell death with apoptosis and autophagy, and the promotion of aging –dependent processes.  Mitochondria control the processing of redox energy that yields adenosine triphosphate (ATP) through the oxidation of glucose, pyruvate, and nicotinamide adenine dinucleotide.  Ultimately, the generation of ROS occurs with the aerobic production of ATP.  Although reduced levels of ROS may lead to tolerance against metabolic, mechanical, and oxidative stressors and the generation of brief periods of ROS during ischemia-reperfusion models may limit cellular injury, under most circumstances ROS and mitochondrial dysfunction can lead to apoptotic caspase activation and autophagy induction that can result in cellular demise.  Yet, new work suggests that ROS generation may have a positive impact through respiratory complex I reverse electron transport that can extend lifespan.  Such mechanisms may bring new insight into clinically relevant disorders that are linked to cellular senescence and aging of the body’s system.  Further investigation of the potential “bright side” of ROS and mitochondrial respiration is necessary to target specific pathways, such as the mechanistic target of rapamycin, nicotinamidases, sirtuins, mRNA decoupling and protein expression, and Wnt signaling, that can impact oxidative stress-ROS mechanisms to extend lifespan and eliminate disease onset.

Key words

 apoptosis, autophagy, cell longevity, forkhead transcription factors, mechanistic target of rapamycin (mTOR), mitochondria, nicotinamidases, oxidative stress, programmed cell death, reactive oxygen species, sirtuins, Wnt signaling

Increased reactive oxygen species production through reverse electron transport may extend lifespan and prevent programmed cell death

Reactive oxygen species (ROS) are generated during oxidative stress that include nitrogen based free radical species, such as nitric oxide and peroxynitrite, and oxygen derivatives involving superoxide free radicals, hydrogen peroxide, and singlet oxygen [1-3].  Mitochondria lead to the generation of ROS.  Mitochondria yield adenosine triphosphate (ATP) through the oxidation of glucose, pyruvate, and nicotinamide adenine dinucleotide (NAD+) that exist in the cytosol.  In the tricarboxylic acid cycle, NAD+ and flavin adenine dinucleotide (FAD) are reduced to NADH and FADH2.  The redox energy from NADH and FADH2 is transferred to oxygen through the electron transport chain.  This process allows protons to be transferred from respiratory complexes I, III, and IV in the inner membrane to the intermembrane space with a subsequent proton gradient that is formed across the inner membrane.  Complex V (ATP synthase) subsequently accumulates the energy from this gradient to produce ATP from adenosine diphosphate (ADP) and inorganic phosphate (Pi).  With the aerobic production of ATP, the generation of ROS occurs [4].

A fine balance appears necessary for the generation of ROS to limit cell injury and extend lifespan.  For example, moderate levels of ROS may be required for the tolerance against metabolic, mechanical, and oxidative stressors [5] and the generation of brief periods of ROS during ischemia-reperfusion models may limit cellular injury [6,7] through several different pathways such as those that involve the mechanistic target of rapamycin (mTOR) [8] or Wnt signaling [9,10].  Yet, at increased levels, ROS through oxidative stress can result in mitochondrial and other organelle injury, DNA damage, protein misfolding, cell demise, and the promotion of aging [11].  The depletion of NAD+ has been associated with aging and the maintenance of adequate NAD+ stores has been linked to a reduction in the aging process and increased resistance to oxidative stress [12].  In addition, agents such as nicotinamide may reduce ROS and prevent cellular senescence [13,14].  At high levels of ROS generation, mitochondrial dysfunction and oxidative stress also can result in the induction of apoptotic pathways [11,15-18].  Mitochondrial dysfunction results in the opening of the mitochondrial membrane permeability transition pore, release of cytochrome c, and apoptotic caspase activation [19-21].  Other pathways of programmed cell death also may be involved during oxidative stress and mitochondrial dysfunction [22,23].  Autophagy can impair endothelial progenitor cells, and lead to mitochondrial oxidative and endoplasmic reticulum stress [15,24].  However, autophagy also may be necessary for the removal of misfolded proteins and to eliminate non-functioning mitochondria [25] that has been shown to maintain b-cell function and prevent the onset of diabetes mellitus [26]. 

Interestingly, new work suggests that ROS may be necessary for the promotion of extended lifespan [27].  Although the work supports prior studies that increased ROS can lead to injury and reduce lifespan, the study also illustrates that ROS production with reduced ubiquinone and possibly through respiratory complex I reverse electron transport can extend lifespan in Drosophila.  The authors suggest that an intact respiratory complex I may be required in this model as compared to other studies that can reverse oxidative damage with blockade of respiratory complex I [28].

There are a number of cell signaling pathways that may be tied to these mitochondrial processes that extend lifespan and control the aging process.  For example, increased decoupling of mRNA and protein expression can affect mTOR signaling and aging –dependent changes [29].  Hormones such as melatonin can oversee pathways of insulin-like growth factor 1 to increase lifespan [30].  Modulation of of nicotinamidases and sirtuin pathways also are involved in lifespan extension [31-34].  Down-regulation of mTOR pathways [35-38] as well as modulating forkhead transcription factors [39-42] may be another avenue to control cell senescence, extend lifespan, and modulate the process of aging.  Each of these mechanisms are clinically relevant and impact the aging process throughout the body such as the musculoskeletal system [43] and the endocrine system [44].  Further investigation is certainly warranted to target the potentially beneficial aspects of ROS generation through mitochondrial respiration to modulate the aging process of organisms and, in turn, hopefully extend lifespan and reduce disease onset.

Acknowledgments

 This research was supported by the following grants to Kenneth Maiese:  American Diabetes Association, American Heart Association, NIH NIEHS, NIH NIA, NIH NINDS, and NIH ARRA.

References

  1. Maiese K (2015) New Insights for Oxidative Stress and Diabetes Mellitus. Oxid Med Cell Longev 2015: 875961. [Crossref]
  2. Stefano GB, Kream RM (2016) Dysregulated mitochondrial and chloroplast bioenergetics from a translational medical perspective (Review). Int J Mol Med 37: 547-555. [Crossref]
  3. Tafani M, Sansone L, Limana F, Arcangeli T, De Santis E, et al. (2016) The Interplay of Reactive Oxygen Species, Hypoxia, Inflammation, and Sirtuins in Cancer Initiation and Progression. Oxid Med Cell Longev 2016: 3907147. [Crossref]
  4. Maiese K (2016) Molecules to Medicine with mTOR: Translating Critical Pathways into Novel Therapeutic Strategies. Elsevier and Academic Press, USA
  5. Lawler JM, Rodriguez DA, Hord JM (2016) Mitochondria in the middle: Exercise preconditioning protection of striated muscle. J Physiol. [Crossref]
  6. You H, Li T, Zhang J, Lei Q, Tao X, et al. Reduction in Ischemic Cerebral Infarction is Mediated through Golgi Phosphoprotein 3 and Akt/mTOR Signaling following Salvianolate Administration. Curr Neurovasc Res 11: 107-113. [Crossref]
  7. Zhou Y, Fang H, Lin S, Shen S, Tao L, et al. (2015) Qiliqiangxin Protects Against Cardiac Ischemia-Reperfusion Injury via Activation of the mTOR Pathway. Cell Physiol Biochem 37: 454-464. [Crossref]
  8. Maiese K (2016) Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR. Neural Reg Res 11: 372-385.
  9. Liu JD, Deng Q, Tian HH, Pang YT, Deng GL (2015) Wnt/Glycogen Synthase Kinase 3beta/beta-catenin Signaling Activation Mediated Sevoflurane Preconditioning-induced Cardioprotection. Chin Med J (Engl) 128: 2346-2353. [Crossref]
  10. Maiese K (2015) Novel applications of trophic factors, Wnt and WISP for neuronal repair and regeneration in metabolic disease. Neural Regen Res 10: 518-528. [Crossref]
  11. Mikhed Y, Daiber A, Steven S (2015) Mitochondrial Oxidative Stress, Mitochondrial DNA Damage and Their Role in Age-Related Vascular Dysfunction. Int J Mol Sci 16: 15918-15953. [Crossref]
  12. Poljsak B, Milisav I (2016) NAD+ as the Link Between Oxidative Stress, Inflammation, Caloric Restriction, Exercise, DNA Repair, Longevity, and Health Span. Rejuvenation Res. [Crossref]
  13. Kwak JY, Ham HJ, Kim CM, Hwang ES (2015) Nicotinamide exerts antioxidative effects on senescent cells. Mol Cells 38: 229-235. [Crossref]
  14. Maiese K, Chong ZZ, Hou J, Shang YC (2009) The vitamin nicotinamide: translating nutrition into clinical care. Molecules 14: 3446-3485. [Crossref]
  15. Maiese K (2015) mTOR: Driving apoptosis and autophagy for neurocardiac complications of diabetes mellitus. World J Diabetes 6: 217-224. [Crossref]
  16. Parmar MS, Syed I, Gray JP, Ray SD (2015) Curcumin, Hesperidin, and Rutin Selectively Interfere with Apoptosis Signaling and Attenuate Streptozotocin-Induced Oxidative Stress-Mediated Hyperglycemia. Curr Neurovasc Res 12: 363-374. [Crossref]
  17. Pérez-Gallardo RV, Noriega-Cisneros R, Esquivel-Gutiérrez E, Calderón-Cortés E, Cortés-Rojo C, et al. (2014) Effects of diabetes on oxidative and nitrosative stress in kidney mitochondria from aged rats. J Bioenerg Biomembr 46: 511-518. [Crossref]
  18. Wang P, Xing Y, Chen C, Chen Z, et al. (2016) Advanced glycation end-product (AGE) induces apoptosis in human retinal ARPE-19 cells via promoting mitochondrial dysfunction and activating the Fas-FasL signaling. Biosci Biotechnol Biochem 80: 250-256.[Crossref]
  19. Finelli MJ, Liu KX, Wu Y, Oliver PL, Davies KE (2015) Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations. Hum Mol Genet 24: 3529-3544. [Crossref]
  20. Maiese K (2015) Programming apoptosis and autophagy with novel approaches for diabetes mellitus. Curr Neurovasc Res 12: 173-188. [Crossref]
  21. Millet A, Bouzat P, Trouve-Buisson T, Batandier C, Pernet-Gallay K, et al. (2016) Erythropoietin and Its Derivates Modulate Mitochondrial Dysfunction after Diffuse Traumatic Brain Injury. J Neurotrauma. [Crossref]
  22. Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, et al. (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12: 1-222. [Crossref]
  23. Marrif HI, Al-Sunousi SI (2016) Pancreatic β Cell Mass Death. Front Pharmacol 7: 83. [Crossref]
  24. Martino L, Masini M, Novelli M, Beffy P, Bugliani M, et al. (2012) Palmitate activates autophagy in INS-1E β-cells and in isolated rat and human pancreatic islets. PLoS One 7: e36188. [Crossref]
  25. Maiese K, Chong ZZ, Shang YC, Wang S (2012) Targeting disease through novel pathways of apoptosis and autophagy. Expert Opin Ther Targets 16: 1203-1214. [Crossref]
  26. Liu Z, Stanojevic V, Brindamour LJ, Habener JF (2012) GLP1-derived nonapeptide GLP1(28-36)amide protects pancreatic β-cells from glucolipotoxicity. J Endocrinol 213: 143-154. [Crossref]
  27. Scialò F, Sriram A, Fernández-Ayala D, Gubina N, Lõhmus M, et al. (2016) Mitochondrial ROS Produced via Reverse Electron Transport Extend Animal Lifespan. Cell Metab 23: 725-734. [Crossref]
  28. Parameshwaran K, Irwin MH, Steliou K, Suppiramaniam V, Pinkert CA (2015) Antioxidant-mediated reversal of oxidative damage in mouse modeling of complex I inhibition. Drug Dev Res 76: 72-81. [Crossref]
  29. Wei YN, Hu HY, Xie GC, Fu N, Ning ZB, et al. (2015) Transcript and protein expression decoupling reveals RNA binding proteins and miRNAs as potential modulators of human aging. Genome Biol 16: 41. [Crossref]
  30. Jenwitheesuk A, Nopparat C, Mukda S, Wongchitrat P, Govitrapong P (2014) Melatonin regulates aging and neurodegeneration through energy metabolism, epigenetics, autophagy and circadian rhythm pathways. Int J Mol Sci 15: 16848-16884. [Crossref]
  31. Balan V, Miller GS, Kaplun L, Balan K, Chong ZZ, et al. (2008) Life span extension and neuronal cell protection by Drosophila nicotinamidase. J Biol Chem 283: 27810-27819. [Crossref]
  32. Luo XY, Qu SL, Tang ZH, Zhang Y, Liu MH, et al. (2014) SIRT1 in cardiovascular aging. Clin Chim Acta 437: 106-114. [Crossref]
  33. Maiese K (2015) SIRT1 and stem cells: In the forefront with cardiovascular disease, neurodegeneration and cancer. World J Stem Cells 7: 235-242. [Crossref]
  34. Moroz N, Carmona JJ, Anderson E, Hart AC, Sinclair DA, et al. (2014) Dietary restriction involves NAD⁺-dependent -dependent mechanisms and a shift toward oxidative metabolism. Aging Cell 13: 1075-1085. [Crossref]
  35. Maiese K (2014) Driving neural regeneration through the mammalian target of rapamycin. Neural Regen Res 9: 1413-1417. [Crossref]
  36. Maiese K (2015) Targeting molecules to medicine with mTOR, autophagy, and neurodegenerative disorders. Br J Clin Pharmacol. [Crossref]
  37. Walters HE, Deneka-Hannemann S, Cox LS (2016) Reversal of phenotypes of cellular senescence by pan-mTOR inhibition. Aging (Albany NY) 8: 231-244. [Crossref]
  38. Zhang D, Yan B, Yu S, Zhang C, Wang B, et al. (2015) Coenzyme Q10 inhibits the aging of mesenchymal stem cells induced by D-galactose through Akt/mTOR signaling. Oxid Med Cell Longev: 867293. [Crossref]
  39. Maiese K (2015) FoxO Transcription Factors and Regenerative Pathways in Diabetes Mellitus. Curr Neurovasc Res 12: 404-413. [Crossref]
  40. Okada M, Kim HW, Matsu-Ura K, Wang YG, Xu M, et al. (2016) Abrogation of Age-Induced MicroRNA-195 Rejuvenates the Senescent Mesenchymal Stem Cells by Reactivating Telomerase. Stem Cells 34: 148-159. [Crossref]
  41. Xia W, Zhang F, Xie C, Jiang M, Hou M (2015) Macrophage migration inhibitory factor confers resistance to senescence through CD74-dependent AMPK-FOXO3a signaling in mesenchymal stem cells. Stem Cell Res Ther 6: 82. [Crossref]
  42. Zhang F, Cui J, Liu X, Lv B, Liu X, et al. (2015) Roles of microRNA-34a targeting SIRT1 in mesenchymal stem cells. Stem Cell Res Ther 6: 195. [Crossref]
  43. Li Y, Wei X, Zhou J, Wei L (2013) The age-related changes in cartilage and osteoarthritis. Biomed Res Int: 916530. [Crossref]
  44. Vitale G, Salvioli S, Franceschi C (2013) Oxidative stress and the ageing endocrine system. Nat Rev Endocrinol 9: 228-240. [Crossref]

Editorial Information

Editor-in-Chief

Kenneth Maiese

Article Type

Research Article

Publication history

Received date: April 02, 2016
Accepted date: April 25, 2016
Published date: April 28, 2016

Copyright

©2016 Maiese K . This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Maiese K (2016) The bright side of reactive oxygen species: lifespan extension without cellular demise. J Transl Sci 2: doi: 10.15761/JTS.1000138.

Corresponding author

Kenneth Maiese

Cellular and Molecular Signaling, USA.

E-mail : wntin75@yahoo.com

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