Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 18, 2026.

The overexpression of major antioxidant enzymes does not extend the lifespan of mice

Viviana I. Pérez, Holly Van Remmen, Alex Bokov and 3 more

Aging Cell · 2009

doi:10.1111/j.1474-9726.2008.00449.x

Abstract

Summary We evaluated the effect of overexpressing antioxidant enzymes on the lifespans of transgenic mice that overexpress copper zinc superoxide dismutase (CuZnSOD), catalase, or combinations of either CuZnSOD and catalase or CuZnSOD and manganese superoxide dismutase (MnSOD). Our results show that the overexpression of these major antioxidant enzymes, which are known to scavenge superoxide and hydrogen peroxide in the cytosolic and mitochondrial compartments, is insufficient to extend lifespan in mice.

Shown for reading. Its publisher allows quoting it, not republishing it.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 18, 2026. Paragraph numbers are ours, so an answer can point at one.

The oxidative stress theory of aging offers a credible explanation of a molecular mechanism underlying the aging process. One of the most direct tests of the oxidative stress theory of aging has been to alter oxidative stress/damage and then determine how this alteration affects lifespan (e.g. to genetically manipulate the expression of antioxidant enzymes and observe the effects on lifespan). Based on studies to date, the effect of oxidative stress as a lifespan determinant has been dependent upon the type of animal model tested. Transgenic Drosophila overexpressing either CuZnSOD or MnSOD have extended longevity.

Although several studies have shown that overexpression of antioxidant enzymes in mice has a protective effect against oxidative stress, with a diminished accumulation of oxidative damage in macromolecules, reported that transgenic mice overexpressing CuZnSOD (two- to five-fold increase) did not show any increase in lifespan. In contrast, targeted catalase to mitochondria and observed a 21% extension in the lifespan of transgenic mice.

We studied the effects of CuZnSOD and catalase overexpression on lifespan, as well as the effects of combinations of CuZnSOD and catalase or CuZnSOD and MnSOD overexpression. Transgenic CuZnSOD and catalase mice were generated using large genomic segments of the human genes containing the intact genes with their endogenous promoter. The MnSOD transgenic mice were generated by Dr Epstein's laboratory using the mouse Sod2 genomic fragment. These mice overexpress the expected enzymes, with increases of two- to four-fold in all tissues tested and no diminution of the expression of other major antioxidant enzymes. Fibroblast cell cultures derived from these mice were observed to be more resistant to oxidant stress.

Figure 1 shows the survival curves of each single or double transgenic mouse strain compared to the wild type (WT) controls. Analysis of the survival curves by the log-rank test showed no statistical differences in the survival curves between the WT mice and any of the transgenic mice. The survival data in Table 1 also show no significant differences in the mean, median, or 90% (when 90% of the mice have died) survivals of any of the transgenic strains compared to the WT mice. It should be noted that we studied cohorts of 44–54 animals, which allow us to detect a 10% change in mean survival. The mean and maximum survivals for the WT mice were more than 31 and 41 months (respectively), which is in the accepted range for well-maintained colonies of C57BL/6J mice and well-run longevity studies and is higher than published results for other vivaria (see ). Thus, the husbandry conditions used in this study minimize/eliminate deaths from infectious disease and other causes that can make survival data unreliable. Our data confirm the earlier study by showing that the overexpression of CuZnSOD has no effect on the lifespan of mice, but are strikingly different from what has been observed in Drosophila in which lifespan is increased when CuZnSOD is overexpressed. Our data might appear to conflict with the study by, which showed that the overexpression of catalase increased the lifespan of transgenic mice. However, whereas Schriner et al. overexpressed catalase in mitochondria, catalase overexpression in our transgenic mouse occurred in the peroxisomes, where catalase is normally expressed.

Our study is the first to determine whether simultaneously overexpressing two antioxidant enzymes has an effect on the lifespan of mice. initially reported that the overexpression of CuZnSOD and catalase together increased the lifespan of Drosophila. However, Tower's laboratory did not find a significant increase in the lifespan of Drosophila when either catalase or MnSOD was overexpressed with CuZnSOD. As shown in Fig. 1 and Table 1, overexpressing CuZnSOD and catalase or CuZnSOD and MnSOD had no effect on the lifespan of mice.

Based on the studies with Drosophila, we anticipated that we would see an increase in lifespan in one or more of the transgenic mouse models. However, our data demonstrate that overexpression of the major antioxidant enzymes that regulate oxygen metabolism in the cell, either by themselves or in combination, does not have an impact on the lifespan of mice. Therefore, these findings do not provide support for the role oxidative stress in the aging of mice.

References 18

  1. 1.

    Andersen PK, Borgan O, Gill RD, Keiding N. Statistical Models Based on Counting Processes. 1993.

    Not in our library

  2. 2.

    Chen X, Mele J, Giese H, Van Remmen H, Dolle ME, Steinhelper M, Richardson A, Vijg J. A strategy for the ubiquitous overexpression of human catalase and CuZn superoxide dismutase genes in transgenic mice. Mech. Ageing Dev. 2003;124:219-227.

    Not in our library10.1016/s0047-6374(02)00161-6

  3. 3.

    Holm S. A simple sequentially rejective multiple test procedure. Scand. J. Statist. 1979;6:65-70.

    Not in our library

  4. 4.

    Huang TT, Carlson EJ, Gillespie AM, Shi Y, Epstein CJ. Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice. J. Gerontol. A Biol. Sci. Med. Sci. 2000;55:B5-B9.

    Not in our library10.1093/gerona/55.1.b5

  5. 5.

    Liang H, Masoro EJ, Nelson JF, Strong R, McMahan CA, Richardson A. Genetic mouse models of extended lifespan. Exp. Gerontol. 2003;38:1353-1364.

    Not in our library10.1016/j.exger.2003.10.019

  6. 6.

    Mele J, Van Remmen H, Vijg J, Richardson A. Characterization of transgenic mice that overexpress both copper zinc superoxide dismutase and catalase. Antioxid. Redox. Signal. 2006;8:628-638.

    Not in our library10.1089/ars.2006.8.628

  7. 7.

    Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H. Trends in oxidative aging theories. Free Radic. Biol. Med. 2007;43:477-503.

    Not in our library10.1016/j.freeradbiomed.2007.03.034

  8. 8.

    Orr WC, Sohal RS. Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science. 1994;263:1128-1130.

    Not in our library10.1126/science.8108730

  9. 9.

    Phillips JP, Parkes TL, Hilliker AJ. Targeted neuronal gene expression and longevity in Drosophila. Exp. Gerontol. 2000;35:1157-1164.

    Not in our library10.1016/s0531-5565(00)00117-0

  10. 10.

    Raineri I, Carlson EJ, Gacayan R, Carra S, Oberley TD, Huang TT, Epstein CJ. Strain-dependent high-level expression of a transgene for manganese superoxide dismutase is associated with growth retardation and decreased fertility. Free Radic. Biol. Med. 2001;31:1018-1030.

    Not in our library10.1016/s0891-5849(01)00686-4

  11. 11.

    Ran Q, Liang H, Ikeno Y, Qi W, Prolla TA, Roberts LJ, Wolf N, Van Remmen H, Richardson A. Reduction in glutathione peroxidase 4 increases life span through increased sensitivity to apoptosis. J. Gerontol. A Biol. Sci. Med. Sci. 2007;62:932-942.

    Not in our library10.1093/gerona/62.9.932

  12. 12.

    Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science. 2005;308:1909-1911.

    Not in our library10.1126/science.1106653

  13. 13.

    Shan X, Chi L, Ke Y, Luo C, Qian S, Gozal D, Liu R. Manganese superoxide dismutase protects mouse cortical neurons from chronic intermittent hypoxia-mediated oxidative damage. Neurobiol. Dis. 2007;28:206-215.

    Not in our library10.1016/j.nbd.2007.07.013

  14. 14.

    Sun J, Folk D, Bradley TJ, Tower J. Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster. Genetics. 2002;161:661-672.

    Not in our library10.1093/genetics/161.2.661

  15. 15.

    Sun J, Molitor J, Tower J. Effects of simultaneous over-expression of Cu/ZnSOD and MnSOD on Drosophila melanogaster life span. Mech. Ageing Dev. 2004;125:341-349.

    Not in our library10.1016/j.mad.2004.01.009

  16. 16.

    Sun J, Tower J. FLP recombinase-mediated induction of Cu/Zn-superoxide dismutase transgene expression can extend the life span of adult Drosophila melanogaster flies. Mol. Cell. Biol. 1999;19:216-228.

    Not in our library10.1128/mcb.19.1.216

  17. 17.

    Wang C, Li Q, Redden DT, Weindruch R, Allison DB. Statistical methods for testing effects on ‘maximum lifespan’. Mech. Ageing Dev. 2004;125:629-632.

    Not in our library10.1016/j.mad.2004.07.003

  18. 18.

    Zamocky M, Koller F. Understanding the structure and function of catalases: clues from molecular evolution and in vitro mutagenesis. Prog. Biophys. Mol. Biol. 1999;72:19-66.

    Not in our library10.1016/s0079-6107(98)00058-3

Cited by papers we hold 18

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.