Sci. Aging Knowl. Environ., 23 June 2004
Vol. 2004, Issue 25, p. pe27
[DOI: 10.1126/sageke.2004.25.pe27]

PERSPECTIVES

S.W.A.T.--SOD Weapons and Tactics

James N. Sampayo, and Gordon J. Lithgow

The authors are at The Buck Institute for Age Research, Novato, CA 94945, USA. E-mail: jsampayo{at}buckinstitute.org (J.N.S.)

http://sageke.sciencemag.org/cgi/content/full/2004/25/pe27

Key Words: superoxide dismutase • SOD • posttranslational activation • reactive oxygen species • oxidative stress

Introduction

Like the rapid-response special weapons and tactics (SWAT) teams used by the police in times of serious danger, a team of antioxidant proteins is ever-present in the cell, ready to defend against and neutralize attacks by reactive oxygen species (ROS) in a matter of minutes, according to a recent paper by Brown et al. (1). The authors demonstrate that a pool of inactive superoxide dismutase 1 (apoSOD1) is armed to scavenge ROS by a second protein, a specific copper chaperone (CCS), in the presence of oxygen. This discovery highlights the importance of a rapid response to stress and reminds us that posttranslational regulation is the quickest way to respond to changing conditions in the cell.

Oxidative Damage and Aging

Damage to biological macromolecules caused by their interaction with ROS has been proposed as one of the driving forces behind processes associated with aging and the development of a number of diseases (2-5) (see "The Two Faces of Oxygen" and Ogawa Perspective). An age-related decline in the effectiveness of intracellular antioxidant defenses and an increase in the production of ROS with advancing age have been demonstrated in a number of organisms (4,6). These elevated concentrations of ROS are thought to eventually lead to an accumulation of ROS-mediated damage to proteins, lipids, and DNA, affecting their essential functions and perpetuating the gradual loss of vitality of the whole organism (4, 7-10).

The majority of ROS are produced as byproducts of normal respiration by the mitochondria of aerobic organisms (see Nicholls Perspective and Kristal Perspective). The inappropriate donation of electrons to molecular oxygen by coenzyme Q during electron transport results in the formation of the superoxide anion (O2). This reactive form of oxygen can be converted to less reactive hydrogen peroxide (H2O2) by specialized enzymes, the superoxide dismutases (SODs) (11). Although H2O2 is relatively innocuous, it is unstable and can give rise to the destructive hydroxyl radical (·OH). To avoid the formation of ·OH radicals, other antioxidant defenses, including catalase (CAT) and the glutathione system, have evolved to convert H2O2 to water and oxygen.

SOD Structure and Localization

Broadly speaking, two main forms of SOD are found in complex organisms, which differ in their metal content and their subcellular localization. One form contains copper and zinc (Cu/ZnSOD) and is represented by SOD1 and SOD3. SOD1 is found outside the mitochondrial matrix (primarily in the cytoplasm and to a lesser degree in the intermembrane space of the mitochondria), and SOD3 is localized to the extracellular space. The other main form contains manganese (MnSOD, also called SOD2) and is found inside the mitochondrial matrix, which is the main site of superoxide production.

Most forms of eukaryotic SOD1 that have been analyzed to date have been found to be homodimeric (Fig. 1); each monomer typically contains a single copper ion, a zinc ion and one disulphide bond (12,13). The zinc ion and the disulphide bonds are believed to be important for the stability of the enzyme, whereas the copper ion is essential for dismutase activity (14,13). As mentioned above, a small proportion of SOD1 resides in the intermembrane space of the mitochondria, but in order to pass through the outer membrane, SOD1 must be devoid of copper and must not have formed the disulphide bonds (15-17). The copper ion is directly inserted into the active site by CCS, which binds copper tightly and transfers the ion specifically to SOD1, a process that probably involves the formation of a heterodimeric complex of SOD1 and CCS in the intermembrane space (18-21). Because free copper exists at a very low concentration in the cell (less than one ion per cell) as a result of the efficiency of intracellular copper chelators, CCS not only acts as a delivery system but also protects the crucial copper ions from being chelated and hence unavailable to activate SOD1 (18).



View larger version (42K):
[in this window]
[in a new window]
 
Fig. 1. Structure of the human Cu/Zn SOD dimer. Copper and zinc atoms are shown as a red ball and a blue ball, respectively. [Credit: M. DiDonato/The Scripps Research Institute and the Joint Center for Structural Genomics]

 
Posttranslational Activation of SOD1

SOD1 transcription and translation can be induced by various conditions, including exposure to high oxygen concentrations, copper ions, and oxidative stress (22-24). One of the key mediators in the transcriptional activation of yeast SOD1 is the transcription factor yAP-1, which acts as a sensor of the redox state of the cell (25). Under oxidative stress conditions, yAP-1 moves from the cytoplasm to the nucleus and induces expression of a number of target genes encoding protective enzymes, including SOD1 (26). However, rapid transcriptional regulation might not prevent damage during a particularly acute stress, and thus it might be better to have a pool of inactive enzyme already present in the cell, ready for activation. Brown et al. have now demonstrated the requirement for both CCS and the presence of oxygen (or superoxide) for the posttranslational activation of SOD1, both in vitro and in yeast cells (1).

The first series of experiments described by Brown et al., performed using purified forms of human SOD1 and human CCS, demonstrated that the characteristic electron paramagnetic resonance signal from Cu(II)-SOD1 is only generated from inactive apoSOD1 when the preparation contains CCS and is exposed to oxygen. When SOD1 activity was measured directly in an in vitro assay, CCS was shown to activate apoSOD1 in the presence of oxygen. The researchers found that SOD1 activation requires only a few minutes of oxygen exposure. If the assay was performed under completely anaerobic conditions, however, CCS was unable to activate SOD1. This in vitro method showed an absolute requirement for the presence of both CCS and an oxidant to bring about SOD1 activation.

Furthermore, the authors show that yeast cultures grown under anaerobic conditions exhibit undetectable SOD1 activity, but these levels quickly rise when the cultures are moved to an aerobic environment. By comparing wild-type yeast and a mutant strain lacking CCS (lys7{Delta}), Brown et al. illustrate that SOD1 protein concentrations rise (in both strains) if oxygen exposure is increased or prolonged, but SOD1 enzyme activity increases only in the wild-type strain, indicating that CCS is required for this effect. These observations and those from previous studies led the authors to conclude that the synthesis of new SOD1 contributes to an effective oxidative stress response, but from their earlier experiments that showed oxygen-dependent activation of purified SOD1, they had an inkling that something else was afoot. By blocking the production of new proteins and repeating their experiments, Brown et al. discovered that SOD1 activity can be induced without the need for new protein synthesis.

The model the authors propose is that not only can elevated superoxide levels induce transcription and translation of the SOD1 gene, but there is an additional point of control at the posttranslational level mediated by CCS in an oxygen-dependent manner, namely, to activate an existing pool of inactive enzyme in times of oxidative stress. Although the chemical mechanism of these interactions remains unknown, the evolution of such an extremely rapid response to superoxide highlights just how toxic these ROS must be to the cell.

The results from this study also emphasize the need to proceed with caution when interpreting changes evident in microarray and protein expression studies, especially if additional levels of control of a gene or protein product are not thoroughly characterized. As mentioned above, in a number of the experiments performed in different genetic backgrounds (for example, in the the lys7{Delta} mutant), elevated levels of gene expression were detected that were not commensurate with increases in enzyme activity (1). Conversely, in certain experiments the SOD1 concentration appeared not to change, but enzyme activity increased (1).

Why Is SOD1 Activity Regulated?

No one wants a SWAT team hanging out at their house just in case trouble breaks out, but why not just have active SOD1 floating around from the get-go? This might not work in part because of the need for translocation of the apo form of the enzyme to the intermembrane space of the mitochondria mentioned above. The authors also suggest that posttranslational activation of SOD1 not only allows a rapid response to ROS to be mounted, but helps limit the commitment of the cell's resources if the oxidative stress is minor and passes quickly (1).

Probably the most compelling evidence to suggest that large pools of active enzyme might not be a good thing comes from the existence of certain disease states that involve elevated levels of active SOD1. For example, Down syndrome patients display increased expression of SOD1, and overexpression of SOD1 in mice and in cells in culture results in negative effects that might be related to symptoms in Down syndrome patients (27,28). For example, increased lipid peroxidation was observed in both Down syndrome patients and the model systems investigated, potentially caused by increases in hydrogen peroxide concentration (29,30), which suggests that a regulated balance between ROS and antioxidant defenses is essential.

SOD1 has also been under investigation in relation to the familial form of amyotrophic lateral sclerosis (ALS or Lou Gherig's disease), a neurodegenerative condition that affects the motor neurons of the brain and spinal cord. Although most ALS cases are sporadic, familial ALS (fALS) (a condition that is inherited as an autosomal dominant trait) is sometimes caused by mutations in the SOD1 gene (see "A Game of Cellular Clue"). Approximately 90 different mutations in SOD1 have been linked to fALS (13,31). Brown et al. hint that their discoveries might have important implications for at least one form of fALS (1). Current thinking about the connection between mutant SOD1 expression and the progression of fALS focuses on the propensity of certain mutant forms of SOD1 to form aggregates and fibrils, which could overload cellular "housekeeping" resources (for example, chaperone activity and proteasome function) or inhibit the machinery involved in neuronal transport (13). The different forms of SOD1 (immature, partially modified, and fully active) might possess varying degrees of stability and consequently be more or less prone to aggregate formation. As the transition from one form to another is controlled in part by oxygen tension, Brown et al. suggest that changes in oxygen concentration could have an effect on the pathological mechanisms involved in the progression of fALS (1).

ROS, SOD1, and Life Span

Unfortunately, cellular antioxidant defenses are not 100% efficient, and age-related accumulation of oxidative damage still occurs. Despite some studies showing negative effects from overexpression of antioxidant defenses, it is still a logical, reasonable (and tempting!) assumption that increasing the levels of cellular defenses would lead to an overall reduction in oxidative damage, a slowing of aging, and an extended life span.

This hypothesis has been investigated in a variety of ways in a number of organisms (4,32). In the nematode Caenorhabditis elegans, stress response proteins, particularly molecular chaperones, have been shown to be important in life span determination (33-39). A correlation exists between single gene mutations that extend life span (for example, in the age-1 gene) and their effect on stress response proteins. C. elegans strains harboring mutations in an insulin/IGF-1-like signalling pathway have been shown to be both resistant to a variety of stresses and long-lived (33, 40-46) (see Sonntag Perspective). Some of these strains also show elevated concentrations of SOD1 later in life, suggesting that the ability to deal effectively with cellular stress is crucial for longevity (42). The effects of administering SOD/catalase mimetic compounds also support a relation to aging. These compounds (for example, EUK-8 and EUK-134) help inherent antioxidant defenses to detoxify ROS, leading to an increase in the resistance of C. elegans to oxidative stress, and can also, under certain laboratory conditions, extend their life span (47-49) (see "Casting Doubt" and "Wrinkle Treatment for Worms").

Whilst evidence exists for the role of oxidative stress in life span determination, the importance of SOD1 is less clear. Genetic perturbations that decrease SOD1 abundance and activity have been shown to result in a decrease in life span in some organisms (for example, yeast) and an induction of senescence in cultured human fibroblasts (50-53). However, the effects on life span caused by increasing the abundance of SOD1 are somewhat mixed. An increase in life span has been achieved in both flies and yeast by the over-expression of SOD1, but there is evidence that these effects may depend on the genetic background of the organisms tested (54-57). It is suggested that overexpression of SOD1 is capable of extending life span only in short-lived laboratory strains and in some (but not all) natural genetic backgrounds, perhaps rescuing some inherent defect present in these animals (58-62) (see Spencer Perspective).

Additional evidence that SOD1 is not a major life span determinant is provided by comparisons between species that live for varying amounts of time (9,63). These studies showed that SOD1 abundance is not correlated with life span. Furthermore, a recent study on the differences in life span in different castes of the same ant species (in which the life span of the queen is 28 years, of the worker is 1 to 2 years, and of the male is less than 1 month) determined that the queen displays reduced SOD1 expression and activity as compared to the other castes, indicating that increased SOD1 abundance may not be required for a long life (64).

It appears that SOD1 abundance influences life span in some organisms under certain conditions. What is emerging as more important for extended life span, however, is a reduction in the level of ROS production from the electron transport chain, and detoxification within the mitochondrial matrix, primarily by MnSOD (SOD2) (10, 65,66). However, this line of investigation is not without its own controversy.

Overexpression of SOD2 has been shown to extend life span in a number of organisms (for example, flies and yeast), both alone and in conjunction with SOD1 overexpression. SOD2 knockout mice, on the other hand, are very sick and extremely short-lived (67). They exhibit signs of premature aging and a number of other pathologies, many of which can be rescued by treatment with Mn-containing superoxide dismutase/catalase mimetics (68,69) (see "Drugs Protect Mice From Pernicious Forms of Oxygen"). It seems pretty clear-cut that SOD2 is good, more SOD2 is better, and less SOD2 is very bad! But, at the end of last year, a study describing the life-long reduction of SOD2 activity in mice showed no effect on aging or life span (70). These mice, heterozygous for the SOD2 gene, had reduced activity of the enzyme (approximately 50% of the activity in the wild type) and suffered increases in oxidative DNA damage and tumor incidence, but certain biomarkers of aging, as well as mean and maximum life span, were no different from those of wild-type controls.

Conclusion

This finding underlines the fact that the involvement of ROS and the levels of antioxidant defenses in aging and life span determination are not necessarily as clear as was once thought. The study by Brown et al. highlights an important potential confounding factor of many of the studies on ROS and aging. It is probably best to have active SOD1 only when and where it is required. Simply increasing or decreasing gene dosage or expression levels might have beneficial and detrimental effects at different times and in different tissues. This possibility might account for some of the negative effects caused by SOD1 overexpression, and points to the need for a much more detailed picture of the consequences of ROS production for normal aging.


June 28, 2004
  1. N. M. Brown, A. S. Torres, P. E. Doan, T. V. O'Halloran, Oxygen and the copper chaperone CCS regulate posttranslational activation of Cu,Zn superoxide dismutase. Proc. Natl. Acad. Sci. U.S.A. 101, 5518-5523 (2004).[Abstract/Free Full Text]
  2. D. Harman, Aging: a theory based on free radical and radiation chemistry. J. Gerontol. Biol. Sci. 11, 298-300 (1956).
  3. D. Harman, Free radical theory of aging. Mutation Res. 275, 257-266 (1992).
  4. K. B. Beckman, B. N. Ames, The free radical theory of aging matures. Physiol. Rev. 78, 547-581 (1998).[Abstract/Free Full Text]
  5. B. Halliwell, J. M. C. Gutteridge, Free Radicals in Biology and Medicine (Oxford University Press, Oxford, ed. 3, 2000).
  6. R. Sohal, Oxidative stress hypothesis of aging. Free Radic. Biol. Med. 33, 573 (2002).[CrossRef][Medline]
  7. R. L. Levine, E. R. Stadtman, Oxidative modification of proteins during aging. Exp. Gerontol. 36, 1495-1502 (2001).[CrossRef][Medline]
  8. R. S. Sohal, Role of oxidative stress and protein oxidation in the aging process. Free Radic. Biol. Med. 33, 37-44 (2002).[CrossRef][Medline]
  9. G. Barja, Rate of generation of oxidative stress-related damage and animal longevity. Free Radic. Biol. Med. 33, 1167-1172 (2002).[CrossRef][Medline]
  10. G. Barja, Endogenous oxidative stress: relationship to aging, longevity and caloric restriction. Ageing Res. Rev. 1, 397-411 (2002).[CrossRef][Medline]
  11. I. Fridovich, Superoxide radical and superoxide dismutases. Annu. Rev. Biochem. 64, 97-112 (1995). [CrossRef][Medline]
  12. J. S. Valentine, M. W. Pantoliano, in Copper Proteins, T. G. Spiro, Ed. (Wiley, New York, 1981), pp. 292-358.
  13. A. F. Miller, Superoxide dismutases: active sites that save, but a protein that kills. Curr. Opin. Chem. Biol. 8, 162-168 (2004).[CrossRef][Medline]
  14. L. Banci, I. Bertini, F. Cramaro, R. Del Conte, M. S. Viezzoli, Solution structure of Apo Cu,Zn superoxide dismutase: role of metal ions in protein folding. Biochemistry 42, 9543-9553 (2003).[CrossRef][Medline]
  15. R. A. Weisiger, I. Fridovich, Superoxide dismutase. Organelle specificity. J. Biol. Chem. 248, 3582-3592 (1973).[Abstract/Free Full Text]
  16. R. A. Weisiger, I. Fridovich, Mitochondrial superoxide dismutase. Site of synthesis and intramitochondrial localization. J. Biol. Chem. 248, 4793-4796 (1973).[Abstract/Free Full Text]
  17. L. A. Sturtz, K. Diekert, L. T. Jensen, R. Lill, V. C. Culotta, A fraction of yeast Cu,Zn-superoxide dismutase and its metallochaperone, CCS, localize to the intermembrane space of mitochondria. A physiological role for SOD1 in guarding against mitochondrial oxidative damage. J. Biol. Chem. 276, 38084-38089 (2001).[Abstract/Free Full Text]
  18. T. D. Rae, P. J. Schmidt, R. A. Pufahl, V. C. Culotta, T. V. O'Halloran, Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science 284, 805-808 (1999).[Abstract/Free Full Text]
  19. T. D. Rae, A. S. Torres, R. A. Pufahl, T. V. O'Halloran, Mechanism of Cu,Zn-superoxide dismutase activation by the human metallochaperone hCCS. J. Biol. Chem. 276, 5166-5176 (2001).[Abstract/Free Full Text]
  20. A. L. Lamb, A. S. Torres, T. V. O'Halloran, A. C. Rosenzweig, Heterodimeric structure of superoxide dismutase in complex with its metallochaperone. Nat. Struct. Biol. 8, 751-755 (2001).[CrossRef][Medline]
  21. A. S. Torres, V. Petri, T. D. Rae, T. V. O'Halloran, Copper stabilizes a heterodimer of the yCCS metallochaperone and its target superoxide dismutase. J. Biol. Chem. 276, 38410-38416 (2001).[Abstract/Free Full Text]
  22. E. B. Gralla, D. J. Kosman, Molecular genetics of superoxide dismutases in yeasts and related fungi. Adv. Genet. 30, 251-319 (1992).[CrossRef][Medline]
  23. F. Galiazzo, M. R. Ciriolo, M. T. Carri, P. Civitareale, L. Marcocci, F. Marmocchi, G. Rotilio, Activation and induction by copper of Cu/Zn superoxide dismutase in Saccharomyces cerevisiae. Presence of an inactive proenzyme in anaerobic yeast. Eur. J. Biochem. 196, 545-549 (1991).[Medline]
  24. F. Galiazzo, R. Labbe-Bois, Regulation of Cu,Zn- and Mn-superoxide dismutase transcription in Saccharomyces cerevisiae. FEBS Lett. 315, 197-200 (1993).[CrossRef][Medline]
  25. W. M. Toone, B. A. Morgan, N. Jones, Redox control of AP-1-like factors in yeast and beyond. Oncogene 20, 2336-2346 (2001).[CrossRef][Medline]
  26. S. Kuge, N. Jones, A. Nomoto, Regulation of yAP-1 nuclear localization in response to oxidative stress. EMBO J. 16, 1710-1720 (1997).[Abstract]
  27. J. M. McCord, in Superoxide Dismutase, L. Packer, Ed. (Academic Press, San Diego, CA, 2002), pp. 331-341.
  28. T. T. Huang, E. J. Carlson, A. M. Gillespie, Y. Shi, C. J. Epstein, Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice. J. Gerontol. A Biol. Sci. Med. Sci. 55, B5-B9 (2000).[Abstract/Free Full Text]
  29. H. J. Fullerton, J. S. Ditelberg, S. F. Chen, D. P. Sarco, P. H. Chan, C. J. Epstein, D. M. Ferriero, Copper/zinc superoxide dismutase transgenic brain accumulates hydrogen peroxide after perinatal hypoxia ischemia. Ann. Neurol. 44, 357-364 (1998).[CrossRef][Medline]
  30. M. Lee, D. Hyun, P. Jenner, B. Halliwell, Effect of overexpression of wild-type and mutant Cu/Zn-superoxide dismutases on oxidative damage and antioxidant defences: Relevance to Down's syndrome and familial amyotrophic lateral sclerosis. J. Neurochem. 76, 957-965 (2001).[CrossRef][Medline]
  31. D. W. Cleveland, J. D. Rothstein, From Charcot to Lou Gehrig: Deciphering selective motor neuron death in ALS. Nat. Rev. Neurosci. 2, 806-819 (2001).[CrossRef][Medline]
  32. K. B. Beckman, B. N. Ames, Oxidants, antioxidants and aging. In: Oxidative Stress and the Molecular Biology of Antioxidant Defenses, J. Scandalios, Ed. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1997), pp. 201-246.
  33. G. J. Lithgow, T. M. White, D. A. Hinerfeld, T. E. Johnson, Thermotolerance of a long-lived mutant of Caenorhabditis elegans. J. Gerontol. 49, B270-B276 (1994).[Abstract/Free Full Text]
  34. G. J. Lithgow, T. M. White, S. Melov, T. E. Johnson, Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc. Natl. Acad. Sci. U.S.A. 92, 7540-7544 (1995).[Abstract/Free Full Text]
  35. G. A. Walker, T. M. White, G. McColl, N. L. Jenkins, S. Babich, E. P. Candido, T. E. Johnson, G. J. Lithgow, Heat shock protein accumulation is upregulated in a long-lived mutant of Caenorhabditis elegans. J. Gerontol. A Biol. Sci. Med. Sci. 56, B281-B287 (2001).[Abstract/Free Full Text]
  36. G. J. Lithgow, G. A. Walker, Stress resistance as a determinate of C. elegans lifespan. Mech. Ageing Dev. 123, 765-771 (2002).[CrossRef][Medline]
  37. G. A. Walker, G. J. Lithgow, Lifespan extension in C. elegans by a molecular chaperone dependent upon insulin-like signals. Aging Cell 2, 131-139 (2003).[CrossRef][Medline]
  38. A. L. Hsu, C. T. Murphy, C. Kenyon, Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300, 1142-1145 (2003).[Abstract/Free Full Text]
  39. J. F. Morley, R. I. Morimoto, Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol. Biol. Cell 15, 657-664 (2004).[Abstract/Free Full Text]
  40. D. B. Friedman, T. E. Johnson, Three mutants that extend both mean and maximum life span of the nematode, Caenorhabditis elegans, define the age-1 gene. J. Gerontol. Biol. Sci. 43, B102-B109 (1988).
  41. P. L. Larsen, Aging and resistance to oxidative damage in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A. 90, 8905-8909 (1993).[Abstract/Free Full Text]
  42. J. R. Vanfleteren, Oxidative stress and ageing in Caenorhabditis elegans. Biochem. J. 292, 605-608 (1993).
  43. S. Murakami, T. E. Johnson, A genetic pathway conferring life extension and resistance to UV stress in Caenorhabditis elegans. Genetics 143, 1207-1218 (1996).[Abstract/Free Full Text]
  44. D. Barsyte, D. A. Lovejoy, G. J. Lithgow, Longevity and heavy metal resistance in daf-2 and age-1 long-lived mutants of Caenorhabditis elegans. FASEB J. 15, 627-634 (2001).[Abstract/Free Full Text]
  45. J. R. Cypser, T. E. Johnson, Multiple stressors in Caenorhabditis elegans induce stress hormesis and extended longevity. J. Gerontol. A Biol. Sci. Med. Sci. 57, B109-B114 (2002).[Abstract/Free Full Text]
  46. T. E. Johnson, S. Henderson, S. Murakami, E. de Castro, S. H. de Castro, J. Cypser, B. Rikke, P. Tedesco, C. Link, Longevity genes in the nematode Caenorhabditis elegans also mediate increased resistance to stress and prevent disease. J. Inherit. Metab. Dis. 25, 197-206 (2002).[CrossRef][Medline]
  47. S. Melov, J. Ravenscroft, S. Malik, M. S. Gill, D. W. Walker, P. E. Clayton, D. C. Wallace, B. Malfroy, S. R. Doctrow, G. J. Lithgow, Extension of life-span with superoxide dismutase/catalase mimetics. Science 289, 1567-1569 (2000).[Abstract/Free Full Text]
  48. J. N. Sampayo, A. Olsen, G. J. Lithgow, Oxidative stress in Caenorhabditis elegans: Protective effects of superoxide dismutase/catalase mimetics. Aging Cell 2, 319-326 (2003).[CrossRef][Medline]
  49. M. Keaney, D. Gems, No increase in lifespan in Caenorhabditis elegans upon treatment with the superoxide dismutase mimetic Euk-8. Free Radic. Biol. Med. 34, 277-282 (2003).[CrossRef][Medline]
  50. V. D. Longo, E. B. Gralla, J. S. Valentine, Superoxide dismutase activity is essential for stationary phase survival in Saccharomyces cerevisiae. Mitochondrial production of toxic oxygen species in vivo. J. Biol. Chem. 271, 12275-12280 (1996).[Abstract/Free Full Text]
  51. V. D. Longo, L. M. Ellerby, D. E. Bredesen, J. S. Valentine, E. B. Gralla, Human Bcl-2 reverses survival defects in yeast lacking superoxide dismutase and delays death of wild-type yeast. J. Cell Biol. 137, 1581-1588 (1997).[Abstract/Free Full Text]
  52. J. Wawryn, A. Swiecilo, G. Bartosz, T. Bilinski, Effect of superoxide dismutase deficiency on the life span of the yeast Saccharomyces cerevisiae. An oxygen-independent role of Cu,Zn-superoxide dismutase. Biochim Biophys. Acta 1570, 199-202 (2002).[Medline]
  53. G. Blander, R. M. de Oliveira, C. M. Conboy, M. Haigis, L. Guarente, Superoxide dismutase 1 knock-down induces senescence in human fibroblasts. J. Biol. Chem. 278, 38966-38969 (2003).[Abstract/Free Full Text]
  54. W. C. Orr, R. S. Sohal, Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science 263, 1128-1130 (1994).[Abstract/Free Full Text]
  55. R. S. Sohal, A. Agarwal, S. Agarwal, W. C. Orr, Simultaneous overexpression of copper- and zinc-containing superoxide dismutase and catalase retards age-related oxidative damage and increases metabolic potential in Drosophila melanogaster. J. Biol. Chem. 270, 15671-15674 (1995).[Abstract/Free Full Text]
  56. T. L. Parkes, A. J. Elia, D. Dickinson, A. J. Hilliker, J. P. Phillips, G. L. Boulianne, Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nat. Genet. 19, 171-174 (1998).[CrossRef][Medline]
  57. J. Sun, J. Tower, FLP recombinase-mediated induction of Cu/Zn-superoxide dismutase transgene expression can extend the life span of adult Drosophila melanogaster flies. Mol. Cell Biol. 19, 216-228 (1999).[Abstract/Free Full Text]
  58. R. S. Sohal, R. J. Mockett, W. C. Orr, Mechanisms of aging: an appraisal of the oxidative stress hypothesis. Free Radic. Biol. Med. 33, 575-586 (2002).[CrossRef][Medline]
  59. R. A. Miller, J. M. Harper, R. C. Dysko, S. J. Durkee, S. N. Austad, Longer life spans and delayed maturation in wild-derived mice. Exp. Biol. Med. (Maywood) 227, 500-508 (2002).[Abstract/Free Full Text]
  60. C. C. Spencer, C. E. Howell, A. R. Wright, D. E. Promislow, Testing an 'aging gene' in long-lived Drosophila strains: Increased longevity depends on sex and genetic background. Aging Cell 2, 123-130 (2003).[CrossRef][Medline]
  61. W. C. Orr, R. J. Mockett, J. J. Benes, R. S. Sohal, Effects of overexpression of copper-zinc and manganese superoxide dismutases, catalase, and thioredoxin reductase genes on longevity in Drosophila melanogaster. J. Biol. Chem. 278, 26418-26422 (2003).[Abstract/Free Full Text]
  62. W. C. Orr, R. S. Sohal, Does overexpression of Cu,Zn-SOD extend life span in Drosophila melanogaster? Exp.Gerontol. 38, 227-230 (2003).
  63. R. Perez-Campo, M. Lopez-Torres, S. Cadenas, C. Rojas, G. Barja, The rate of free radical production as a determinant of the rate of aging: Evidence from the comparative approach. J. Comp. Physiol. B 168, 149-158 (1998).[CrossRef][Medline]
  64. J. D. Parker, K. M. Parker, B. H. Sohal, R. S. Sohal, L. Keller, Decreased expression of Cu-Zn superoxide dismutase 1 in ants with extreme lifespan. Proc. Natl. Acad. Sci. U.S.A. 101, 3486-3489 (2004).[Abstract/Free Full Text]
  65. S. Melov, P. E. Coskun, D. C. Wallace, Mouse models of mitochondrial disease, oxidative stress, and senescence. Mutat. Res. 434, 233-242 (1999).[Medline]
  66. S. Melov, Animal models of oxidative stress, aging, and therapeutic antioxidant interventions. Int. J. Biochem. Cell Biol. 34, 1395-1400 (2002).[CrossRef][Medline]
  67. D. Hinerfeld, M. D. Traini, R. P. Weinberger, B. Cochran, S. R. Doctrow, J. Harry, S. Melov, Endogenous mitochondrial oxidative stress: neurodegeneration, proteomic analysis, specific respiratory chain defects, and efficacious antioxidant therapy in superoxide dismutase 2 null mice. J. Neurochem. 88, 657-667 (2004).[CrossRef][Medline]
  68. S. Melov, S. R. Doctrow, J. A. Schneider, J. Haberson, M. Patel, P. E. Coskun, K. Huffman, D. C. Wallace, B. Malfroy, Lifespan extension and rescue of spongiform encephalopathy in superoxide dismutase 2 nullizygous mice treated with superoxide dismutase-catalase mimetics. J. Neurosci. 21, 8348-8353 (2001).[Abstract/Free Full Text]
  69. E. Samper, D. G. Nicholls, S. Melov, Mitochondrial oxidative stress causes chromosomal instability of mouse embryonic fibroblasts. Aging Cell 2, 277-285 (2003).[CrossRef][Medline]
  70. H. Van Remmen, Y. Ikeno, M. Hamilton, M. Pahlavani, N. Wolf, S. R. Thorpe, N. L. Alderson, J. W. Baynes, C. J. Epstein, T. T. Huang, J. Nelson, R. Strong, A. Richardson, Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol. Genom. 16, 29-37 (2003).[Abstract/Free Full Text]
Citation: J. N. Sampayo, G. J. Lithgow, S.W.A.T.--SOD Weapons and Tactics. Sci. Aging Knowl. Environ. 2004 (25), pe27 (2004).








Science of Aging Knowledge Environment. ISSN 1539-6150