Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals?

Nature Reviews Molecular Cell Biology volume 8, pages 722–728 (2007)Cite this article

Abstract

The reactive oxygen species that are generated by mitochondrial respiration, including hydrogen peroxide (H2O2), are potent inducers of oxidative damage and mediators of ageing. It is not clear, however, whether oxidative stress is the result of a genetic programme or the by-product of physiological processes. Recent findings demonstrate that a fraction of mitochondrial H2O2, produced by a specialized enzyme as a signalling molecule in the pathway of apoptosis, induces intracellular oxidative stress and accelerates ageing. We propose that genes that control H2O2 production are selected determinants of lifespan.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The central role of H2O2 inside the cell.
Figure 2: Shc generates pro-apoptotic H2O2 through alternative redox reactions.
Figure 3: A model for H2O2 as a determinant of lifespan.

Similar content being viewed by others

References

  1. Frisard, M. & Ravussin, E. Energy metabolism and oxidative stress: impact on the metabolic syndrome and the ageing process. Endocrine 29, 27–32 (2006).

    Article  CAS  Google Scholar 

  2. Harman, D. Ageing: phenomena and theories. Ann. NY Acad. Sci. 854, 1–7 (1998).

    Article  CAS  Google Scholar 

  3. Balaban, R. S., Nemoto, S., & Finkel, T. Mitochondria, oxidants, and ageing. Cell 120, 483–495 (2005).

    Article  CAS  Google Scholar 

  4. Chance, B., Sies, H. & Boveris, A. Hydroperoxide metabolism in mammalian organs. Physiol Rev. 59, 527–605 (1979).

    Article  CAS  Google Scholar 

  5. Bayne, A. C., Mockett, R. J., Orr, W. C. & Sohal, R. S. Enhanced catabolism of mitochondrial superoxide/hydrogen peroxide and ageing in transgenic Drosophila. Biochem. J. 391, 277–284 (2005).

    Article  CAS  Google Scholar 

  6. Valko, M. et al. Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol. 39, 44–84 (2007).

    Article  CAS  Google Scholar 

  7. Gius, D. & Spitz, D. R. Redox signaling in cancer biology. Antioxid. Redox Signal. 8, 1249–1252 (2006).

    Article  CAS  Google Scholar 

  8. Stone, J. R. & Yang, S. Hydrogen peroxide: a signaling messenger. Antioxid. Redox Signal. 8, 243–270 (2006).

    Article  CAS  Google Scholar 

  9. Choi, H. et al. Structural basis of the redox switch in the OxyR transcription factor. Cell 105, 103–113 (2001).

    Article  CAS  Google Scholar 

  10. Vivancos, A. P., Castillo, E. A., Jones, N., Ayte, J. & Hidalgo, E. Activation of the redox sensor Pap1 by hydrogen peroxide requires modulation of the intracellular oxidant concentration. Mol. Microbiol. 52, 1427–1435 (2004).

    Article  CAS  Google Scholar 

  11. Tavakoli, N., Kluge, C., Golldack, D., Mimura, T. & Dietz, K. J. Reversible redox control of plant vacuolar H+-ATPase activity is related to disulfide bridge formation in subunit E as well as subunit A. Plant. J. 28, 51–59 (2001).

    Article  CAS  Google Scholar 

  12. Davis, D. A. et al. HIV-2 protease is inactivated after oxidation at the dimer interface and activity can be partly restored with methionine sulphoxide reductase. Biochem. J. 346, 305–311 (2000).

    Article  CAS  Google Scholar 

  13. Atmane, N., Dairou, J., Paul, A., Dupret, J. M. & Rodrigues-Lima, F. Redox regulation of the human xenobiotic metabolizing enzyme arylamine N-acetyltransferase 1 (NAT1). Reversible inactivation by hydrogen peroxide. J. Biol. Chem. 278, 35086–35092 (2003).

    Article  CAS  Google Scholar 

  14. Poliak, A. et al. Inhibition of indoleamine 2,3 dioxygenase activity by H2O2 . Arch. Biochem. Biophys. 450, 9–19 (2006).

    Article  Google Scholar 

  15. Song, H., Bao, S., Ramanadham, S. & Turk, J. Effects of biological oxidants on the catalytic activity and structure of group VIA phospholipase A2. Biochemistry 45, 6392–6406 (2006).

    Article  CAS  Google Scholar 

  16. Bossis, G. & Melchior, F. Regulation of SUMOylation by reversible oxidation of SUMO conjugating enzymes. Mol. Cell 21, 349–357 (2006).

    Article  CAS  Google Scholar 

  17. Lee, S. R., Kwon, K. S., Kim, S. R. & Rhee, S. G. Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. J. Biol. Chem. 273, 15366–15372 (1998).

    Article  CAS  Google Scholar 

  18. Yu, C. K., Li, S. & Whorton, A. R. redox regulation of PTEN by S-nitrosothiols. Mol. Pharmacol. 68, 847–854 (2005).

    CAS  PubMed  Google Scholar 

  19. Rhee, S. G., Yang, K. S., Kang, S. W., Woo, H. A. & Chang, T. S. Controlled elimination of intracellular H2O2: regulation of peroxiredoxin, catalase, and glutathione peroxidase via post-translational modification. Antioxid. Redox Signal. 7, 619–626 (2005).

    Article  CAS  Google Scholar 

  20. Woo, H. A. et al. Reversible oxidation of the active site cysteine of peroxiredoxins to cysteine sulfinic acid. Immunoblot detection with antibodies specific for the hyperoxidized cysteine-containing sequence. J. Biol. Chem. 278, 47361–47364 (2003).

    Article  CAS  Google Scholar 

  21. Caplan, J. F., Filipenko, N. R., Fitzpatrick, S. L. & Waisman, D. M. Regulation of annexin A2 by reversible glutathionylation. J. Biol. Chem. 279, 7740–7750 (2004).

    Article  CAS  Google Scholar 

  22. Ahn, S. G. & Thiele, D. J. Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene activation and protection from stress. Genes Dev. 17, 516–528 (2003).

    Article  CAS  Google Scholar 

  23. Bulteau, A. L., Ikeda-Saito, M. & Szweda, L. I. Redox-dependent modulation of aconitase activity in intact mitochondria. Biochemistry 42, 14846–14855 (2003).

    Article  CAS  Google Scholar 

  24. Nulton-Persoson, A. C., Starke, D. W., Mieval, J. J. & Szweda, L. I. Reversible inactivation of α-ketoglutarate dehydrogenase in response to alterations in the mitochondrial glutathione status. Biochemistry 42, 4235–4242 (2003).

    Article  Google Scholar 

  25. Taylor, E. R. et al. Reversible glutathionylation of complex I increases mitochondrial superoxide formation. J. Biol. Chem. 278, 19603–19610 (2003).

    Article  CAS  Google Scholar 

  26. Mueller, S. Sensitive and nonenzymatic measurement of hydrogen peroxide in biological systems. Free Radic. Biol. Med. 29, 410–415 (2000).

    Article  CAS  Google Scholar 

  27. Seaver, L. C. & Imlay, J. A. Hydrogen peroxide fluxes and compartmentalization inside growing Escherichia coli. J. Bacteriol. 183, 7182–7189 (2001).

    Article  CAS  Google Scholar 

  28. Polle, A. Dissecting the superoxide dismutase-ascorbate-glutathione-pathway in chloroplasts by metabolic modeling. Computer simulation as a step towards flux analysis. Plant Physiol. 126, 445–462 (2001).

    Article  CAS  Google Scholar 

  29. Finkel, T. Redox-dependent signal transduction. FEBS Lett. 476, 52–54 (2000).

    Article  CAS  Google Scholar 

  30. Alexandrova, A. Y., Kopnin, P. B., Vasiliev, J. M. & Kopnin, B. P. ROS up-regulation mediates Ras-induced changes of cell morphology and motility. Exp. Cell Res. 312, 2066–2073 (2006).

    Article  CAS  Google Scholar 

  31. Vafa, O. et al. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol. Cell 9, 1031–1044 (2002).

    Article  CAS  Google Scholar 

  32. Schimmel, M., Bauer, G. Proapoptotic and redox state-related signaling of reactive oxygen species generated by transformed fibroblasts. Oncogene 21, 5886–5896 (2002).

    Article  CAS  Google Scholar 

  33. Giles, G. I. The redox regulation of thiol dependent signaling pathways in cancer. Curr. Pharm. Des. 12, 4427–4443 (2006).

    Article  CAS  Google Scholar 

  34. North, S., Moenner, M. & Bikfalvi, A. Recent developments in the regulation of the angiogenic switch by cellular stress factors in tumors. Cancer Lett. 218, 1–14 (2005).

    Article  CAS  Google Scholar 

  35. Meng, T. C., Buckley D.A, Galic, S., Tiganis, T. & Tonks, N. K. Regulation of insulin signaling through reversible oxidation of the protein-tyrosine phosphatases TC45 and PTP1B. J. Biol. Chem. 279, 37716–37725 (2004).

    Article  CAS  Google Scholar 

  36. Cho, S.H. et al. Redox regulation of PTEN and protein tyrosine phosphatases in H2O2-mediated cell signaling. FEBS Lett. 560, 7–13 (2004).

    Article  CAS  Google Scholar 

  37. Caselli, A. et al. The inactivation mechanism of low molecular weight phosphotyrosine-protein phosphatase by H2O2 . J. Biol. Chem. 273, 32554–32560 (1998).

    Article  CAS  Google Scholar 

  38. Chiarugi, P. et al. Reactive oxygen species as essential mediators of cell adhesion: the oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion. J. Cell Biol. 161, 933–944 (2003).

    Article  CAS  Google Scholar 

  39. Meng, T. C., Fukada, T. & Tonks, N. K. Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol. Cell 9, 387–399 (2002).

    Article  CAS  Google Scholar 

  40. Sohn, J. & Rudolph, J. Catalytic and chemical competence of regulation of CDC25 phosphatase by oxidation/reduction. Biochemistry 42, 10060–10070 (2003).

    Article  CAS  Google Scholar 

  41. Nakashima, I. et al. Redox control of catalytic activities of membrane-associated protein tyrosine kinases. Arch. Biochem. Biophys. 434, 3–10 (2005).

    Article  CAS  Google Scholar 

  42. Paravicini, T. M. & Touyz, R. M. Redox signaling in hypertension. Cardiovasc. Res. 71, 247–258 (2006).

    Article  CAS  Google Scholar 

  43. Passos, J. F. & Von Zglinicki, T. Oxygen free radicals in cell senescence: are they signal transducers? Free Radic. Res. 40, 1277–1283 (2006).

    Article  CAS  Google Scholar 

  44. Kowaltowski, A. J., Castilho, R. F. & Vercesi, A. E. Mitochondrial permeability transition and oxidative stress. FEBS Lett. 495, 12–15 (2001).

    Article  CAS  Google Scholar 

  45. Trinei, M. et al. A p53–p66Shc signalling pathway controls intracellular redox status, levels of oxidation-damaged DNA and oxidative stress-induced apoptosis. Oncogene 21, 3872–3878 (2002).

    Article  CAS  Google Scholar 

  46. Pinton, P. et al. Protein kinase Cβ and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc. Science 315, 659–663 (2007).

    Article  CAS  Google Scholar 

  47. Migliaccio, E. et al. The p66Shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309–313 (1999).

    Article  CAS  Google Scholar 

  48. Giorgio, M. et al. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 122, 221–233 (2005).

    Article  CAS  Google Scholar 

  49. Bloch, C.A. & Ausubel, F.M. Paraquat-mediated selection for mutations in the manganese-superoxide dismutase gene sodA. J. Bacteriol. 168, 795–798 (1986).

    Article  CAS  Google Scholar 

  50. Orr, W. C. & Sohal, R. S. Effects of Cu-Zn superoxide dismutase overexpression of life span and resistance to oxidative stress in transgenic Drosophila melanogaster. Arch. Biochem. Biophys. 301, 34–40 (1993).

    Article  CAS  Google Scholar 

  51. Amstad, P., Moret, R. & Cerutti, P. Glutathione peroxidase compensates for the hypersensitivity of Cu,Zn-superoxide dismutase overproducers to oxidant stress. J. Biol. Chem. 269, 1606–1609 (1994).

    CAS  PubMed  Google Scholar 

  52. Wallace, D. C. Animal models for mitochondrial disease. Methods Mol. Biol. 197, 3–54 (2002).

    CAS  PubMed  Google Scholar 

  53. Keaney, M., Matthijssens, F., Sharpe, M., Vanfleteren, J. & Gems, D. Superoxide dismutase mimetics elevate superoxide dismutase activity in vivo but do not retard ageing in the nematode Caenorhabditis elegans. Free Radic. Biol. Med. 37, 239–250 (2004).

    Article  CAS  Google Scholar 

  54. Melov, S. Therapeutics against mitochondrial oxidative stress in animal models of ageing. Ann. NY Acad. Sci. 959, 330–340 (2002).

    Article  CAS  Google Scholar 

  55. Peng, J., Stevenson, F. F., Doctrow, S. R. & Andersen, J. K. Superoxide dismutase/catalase mimetics are neuroprotective against selective paraquat-mediated dopaminergic neuron death in the substantial nigra: implications for Parkinson disease. J. Biol. Chem. 280, 29194–29198 (2005).

    Article  CAS  Google Scholar 

  56. Landis, G. N. & Tower, J. Superoxide dismutase evolution and life span regulation. Mech. Ageing Dev. 126, 365–379 (2005).

    Article  CAS  Google Scholar 

  57. Schriner, S. E. et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308, 1909–1911 (2005).

    Article  CAS  Google Scholar 

  58. Francia, P. et al. Deletion of p66Shc gene protects against age-related endothelial dysfunction. Circulation 110, 2889–2895 (2004).

    Article  CAS  Google Scholar 

  59. Menini, S. et al. Deletion of p66Shc longevity gene protects against experimental diabetic glomerulopathy by preventing diabetes-induced oxidative stress. Diabetes 55, 1642–1650 (2006).

    Article  CAS  Google Scholar 

  60. Napoli, C. et al. Deletion of the p66Shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet. Proc. Natl Acad. Sci. USA 18, 2112–2116 (2003).

    Article  Google Scholar 

  61. Rota, M. et al. Diabetes promotes cardiac stem cell ageing and heart failure, which are prevented by deletion of the p66Shc gene. Circ. Res. 99, 42–52 (2006).

    Article  CAS  Google Scholar 

  62. Holzenberger M. The GH/IGF-I axis and longevity. Eur. J. Endocrinol. 151 (Suppl. 1), S23–S27 (2004).

    Article  CAS  Google Scholar 

  63. Sedensky, M. M. & Morgan, P. G. Mitochondrial respiration and reactive oxygen species in mitochondrial ageing mutants. Exp. Gerontol. 41, 237–245 (2006).

    Article  CAS  Google Scholar 

  64. Martin, G. M. Somatic mutagenesis and antimutagenesis in ageing research. Mutat. Res. 350, 35–41 (1996).

    Article  Google Scholar 

  65. Trifunovich, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004).

    Article  Google Scholar 

  66. Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian ageing. Science 309, 481–484 (2005).

    Article  CAS  Google Scholar 

  67. Forster, M. J., Morris, P. & Sohal, R. S. Genotype and age influence the effect of caloric intake on mortality. FASEB J. 17, 690–692 (2003).

    Article  Google Scholar 

  68. Bonkowski, M. S., Rocha, J. S., Masternak, M. M., Al Regaiey, K. A. & Bartke, A. Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. Proc. Natl Acad. Sci. USA 103, 7901–7905 (2006).

    Article  CAS  Google Scholar 

  69. Magwere, T. et al. The effect of dietary restriction on mitochondrial protein density and flight muscle mitochondrial morphology in Drosophila. J. Gerontol. A. Biol. Sci. Med. Sci. 61, 36–47 (2004).

    Article  Google Scholar 

  70. Lopez-Lluch, G. et al. Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc. Natl Acad. Sci. USA 103, 1768–1773 (2006).

    Article  CAS  Google Scholar 

  71. Nisoli, E. et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310, 314–317 (2005).

    Article  CAS  Google Scholar 

  72. Weindruch, R. & Walford R. L. The Retardation of Ageing and Disease by Dietary Restriction (Charles C. Thomas, Springfield, Illinois, 1988).

    Google Scholar 

  73. Masaro, E. J., Yu, B. P. & Bertrand, H. A. Action of food restriction in delaying the ageing process. Proc. Natl Acad. Sci. USA 79, 4239–4241 (1982).

    Article  Google Scholar 

  74. McCarter, R. J. & Palmer, J. Energy metabolism and ageing: a lifelong study of Fischer 344 rats. Am. J. Physiol. 263, E448–E452 (1992).

    CAS  PubMed  Google Scholar 

  75. Gredilla, R., Lopez-Torres, M. & Barja, G. Effect of time of restriction on the decrease in mitochondrial H2O2 production and oxidative DNA damage in the heart of food-restricted rats. Microsc. Res. Tech. 59, 273–277 (2002).

    Article  CAS  Google Scholar 

  76. Hagopian, K. et al. Long-term calorie restriction reduces proton leak and hydrogen peroxide production in liver mitochondria. Am. J. Physiol. Endocrinol. Metab. 288, E674–E684 (2005).

    Article  CAS  Google Scholar 

  77. Agarwal, S., Sharma, S., Agrawal, V. & Roy, N. Caloric restriction augments ROS defence in S. cerevisiae, by a Sir2p independent mechanism. Free Radic. Res. 39, 55–62 (2005).

    Article  CAS  Google Scholar 

  78. Lin, S. J. et al. Calorie restriction extends Saccharomyces cerevisiae life span by increasing respiration. Nature 418, 344–348 (2002).

    Article  CAS  Google Scholar 

  79. Halliwell, B. & Gutteridge, J. M. C. Free Radicals in Biology and Medicine (Oxford University Press, 1998).

    Google Scholar 

  80. Sohal, R. S. & Allen, R. G. Oxidative stress as a causal factor in differentiation and ageing: a unifying hypothesis. Exp. Gerontol. 25, 499–522 (1990).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Enrica Migliaccio and Pier Giuseppe Pelicci are at the Department of Experimental Oncology, Marco Giorgio, IEO–European Institute of Oncology, and IFOM–FIRC Institute of Molecular Oncology, 20139 Milan, Italy.,

    Marco Giorgio, Enrica Migliaccio & Pier Giuseppe Pelicci

  2. Mirella Trinei is at Congenia Srl, 20139 Milan, Italy.,

    Mirella Trinei

Authors
  1. Marco Giorgio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mirella Trinei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Enrica Migliaccio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pier Giuseppe Pelicci
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pier Giuseppe Pelicci.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

Chromosome 21 trisomy

FURTHER INFORMATION

Pier Giuseppe Pelicci's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Giorgio, M., Trinei, M., Migliaccio, E. et al. Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals?. Nat Rev Mol Cell Biol 8, 722–728 (2007). https://doi.org/10.1038/nrm2240

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm2240

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing