Overexpression of Mn Superoxide Dismutase Does Not Increase Life Span in Mice

Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78245-3207, USA.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences (Impact Factor: 5.42). 08/2009; 64(11):1114-25. DOI: 10.1093/gerona/glp100
Source: PubMed


Genetic manipulations of Mn superoxide dismutase (MnSOD), SOD2 expression have demonstrated that altering the level of MnSOD
activity is critical for cellular function and life span in invertebrates. In mammals, Sod2 homozygous knockout mice die shortly after birth, and alterations of MnSOD levels are correlated with changes in oxidative
damage and in the generation of mitochondrial reactive oxygen species. In this study, we directly tested the effects of overexpressing
MnSOD in young (4–6 months) and old (26–28 months) mice on mitochondrial function, levels of oxidative damage or stress, life
span, and end-of-life pathology. Our data show that an approximately twofold overexpression of MnSOD throughout life in mice
resulted in decreased lipid peroxidation, increased resistance against paraquat-induced oxidative stress, and decreased age-related
decline in mitochondrial ATP production. However, this change in MnSOD expression did not alter either life span or age-related

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Available from: Adam B Salmon
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    • "Unexpectedly, most interventional studies found a lack of effects in humans (Greenberg et al. 1994, Liu et al. 1999, Rautalahti et al. 1999, Virtamo et al. 2000, Various 2002, Sacco et al. 2003, Zureik et al. 2004, Czernichow et al. 2005, Czernichow et al. 2006, Cook et al. 2007, Kataja- Tuomola et al. 2008, Sesso et al. 2008, Katsiki and Manes 2009, Lin et al. 2009, Song et al. 2009), whereas others even suggested detrimental effects on human health, for instance promotion of cancer growth or induction of diseases with negative impact on human lifespan (Albanes et al. 1996, Omenn et al. 1996, Vivekananthan et al. 2003, Lonn et al. 2005, Bjelakovic et al. 2007, Ward et al. 2007, Lippman et al. 2009, Schipper 2004, DeNicola et al. 2011, Abner et al. 2011). Consistently, several studies overexpressing antioxidant enzymes in mice failed to exert positive effects on lifespan or associated parameters (Jang et al. 2009, Muller et al. 2007, Perez et al. 2011). Accordingly, several long-lived species were found to have a relatively lower expression of antioxidant genes than short-lived ones (Brown and Stuart 2007, Lopez-Torres et al. 1993, Page et al. 2010, Page and Stuart 2012, Salway et al. 2011). "
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    ABSTRACT: Increasing evidence indicates that reactive oxygen species (ROS), consisting of superoxide, hydrogen peroxide, and multiple others, do not only cause oxidative stress, but rather may function as signaling molecules that promote health by preventing or delaying a number of chronic diseases, and ultimately extend lifespan. While high levels of ROS are generally accepted to cause cellular damage and to promote aging, low levels of these may rather improve systemic defense mechanisms by inducing an adaptive response. This concept has been named mitochondrial hormesis or mitohormesis. We here evaluate and summarize more than 500 publications from current literature regarding such ROS-mediated low-dose signaling events, including calorie restriction, hypoxia, temperature stress, and physical activity, as well as signaling events downstream of insulin/IGF-1 receptors, AMP-dependent kinase (AMPK), target-of-rapamycin (TOR), and lastly sirtuins to culminate in control of proteostasis, unfolded protein response (UPR), stem cell maintenance and stress resistance. Additionally, consequences of interfering with such ROS signals by pharmacological or natural compounds are being discussed, concluding that particularly antioxidants are useless or even harmful.
    Full-text · Article · May 2014 · Dose-Response
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    • "Life span was reportedly unchanged in mice that overexpress Sod1 [39] [51] [52] or Gpx4 [39]. Overexpression of Sod2 has been reported to have no effect on life span in one study using B6 mice [53] and a small (4%) increase in life span in a second study using B6C3 mice [54], though no formal life-span analyses were reported in this study. In a situation similar to that presented for MsrA À / À mice above, a report from Mitsui et al. [55] suggested that overexpression of Trx1 extended life span $ 35%. "
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    ABSTRACT: Significant advances in maintaining health throughout life can be made through a clear understanding of the fundamental mechanisms that regulate aging. The Oxidative Stress Theory of Aging (OSTA) is likely the most well-studied mechanistic theory of aging and suggests that the rate of aging is controlled by accumulation of oxidative damage. To directly test the OSTA, aging has been measured in several lines of mice with genetic alteration of the expression of enzymatic antioxidants. Under its strictest interpretation, these studies do not support the OSTA, as modulation of antioxidant expression does not generally affect mouse lifespan. However, the incidence of many age-related diseases and pathologies is altered in these models suggesting that oxidative stress does significantly impact some aspects of the aging process. Further, oxidative stress may affect aging in disparate patterns among tissues or under different environmental conditions. In this review, we summarize the current literature regarding aging in antioxidant mutant mice and offer several interpretations on their support of the OSTA.
    Full-text · Article · Apr 2014 · Free Radical Biology and Medicine
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    • "The same results were found in PC-3 human prostate cancer cells, in which higher levels of hydrogen peroxide were correlated with MnSOD's overexpression and decreased cell growth [76]. In a study by Jang et al. [90], the effects of MnSOD overexpression on age-related biomarkers were investigated. When overexpressed, MnSOD protects mice from paraquat-induced oxidative stress and causes an increase in aconitase activity. "
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    ABSTRACT: Reactive oxygen species (ROS) are generated as a consequence of metabolic reactions in the mitochondria of eukaryotic cells. This work describes the role of the manganese superoxide dismutase (MnSOD) as a biomarker of different human diseases and proposes a new therapeutic application for the prevention of cancer and its treatment. The paper also describes how a new form of human MnSOD was discovered, its initial application, and its clinical potentials. The MnSOD isolated from a human liposarcoma cell line (LSA) was able to kill cancer cells expressing estrogen receptors, but it did not have cytotoxic effects on normal cells. Together with its oncotoxic activity, the recombinant MnSOD (rMnSOD) exerts a radioprotective effect on normal cells irradiated with X-rays. The rMnSOD is characterized by the presence of a leader peptide, which allows the protein to enter cells: this unique property can be used in the radiodiagnosis of cancer or chemotherapy, conjugating radioactive substances or chemotherapic drugs to the leader peptide of the MnSOD. Compared to traditional chemotherapic agents, the drugs conjugated with the leader peptide of MnSOD can selectively reach and enter cancer cells, thus reducing the side effects of traditional treatments.
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