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

Jang, Youngmok C.; Pérez, Viviana; Song, Wook; Lustgarten, Michael S.; Salmon, Adam B.; Mele, James; Qi, Wenbo; Liu, Yuhong; Liang, Hanyu; Chaudhuri, Asish; Ikeno, Yuji; Epstein, Charles J.; Remmen, Holly Van; Richardson, Arlan

doi:10.1093/gerona/glp100

Cited by 176 publications

(155 citation statements)

References 64 publications

(47 reference statements)

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“…Our data indicate that lifespan extension in Irs1 −/− mice is not associated with enhanced CuZnSOD or MnSOD activity. These findings support recent studies showing that global overexpression of either CuZnSOD or MnSOD had no impact on longevity in mice (Jang et al 2009;Perez et al 2009). …”

Section: Nssupporting

confidence: 92%

Longevity of insulin receptor substrate1 null mice is not associated with increased basal antioxidant protection or reduced oxidative damage

Page

Withers

Selman

2012

AGE

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Insulin receptor substrate-1 null (Irs1 −/− ) mice are long lived and importantly they also demonstrate increased resistance to several age-related pathologies compared to wild type (WT) controls. Currently, the molecular mechanisms that underlie lifespan extension in long-lived mice are unclear although protection against oxidative damage may be important. Here, we determined both the activities of several intracellular antioxidants and levels of oxidative damage in brain, skeletal muscle, and liver of Irs1 −/− and WT mice at 80, 450, and 700 days of age, predicting that long-lived Irs1 −/− mice would be protected against oxidative damage. We measured activities of both intracellular superoxide dismutases (SOD); cytosolic (CuZnSOD) and mitochondrial (MnSOD), glutathione peroxide (GPx), glutathione reductase (GR), catalase (CAT), and reduced glutathione (GHS). Of these, only hepatic CAT was significantly altered (increased) in Irs1 −/− mice. In addition, the levels of protein oxidation (protein carbonyl content) and lipid peroxidation (4-hydroxynonenal) were unaltered in Irs1 −/− mice, although the hepatic GSH/ GSSG ratio, indicating an oxidized environment, was significantly lower in long-lived Irs1 −/− mice. Overall, our results do not support the premise that lifespan extension in Irs1 −/− mice is associated with greater tissue antioxidant protection or reduced oxidative damage.

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Section: Nssupporting

confidence: 92%

Longevity of insulin receptor substrate1 null mice is not associated with increased basal antioxidant protection or reduced oxidative damage

Page

Withers

Selman

2012

AGE

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“…Whilst MnSOD overexpression can extend life span in flies (Sun et al 2002;Curtis et al 2007), deletion of a mitochondrial SOD gene actually increases life span in C. elegans (Van Raamsdonk and Hekimi 2009). MnSOD +/− mice have normal life spans (Van Remmen et al 2003), as do some MnSOD overexpressors (Jang et al 2009; but see Hu et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Antioxidant enzyme activities are not broadly correlated with longevity in 14 vertebrate endotherm species

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Richardson

Wiens

et al. 2010

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The free radical theory of ageing posits that accrual of oxidative damage underlies the increased cellular, tissue and organ dysfunction and failure associated with advanced age. In support of this theory, cellular resistance to oxidative stress is highly correlated with life span, suggesting that prevention or repair of oxidative damage might indeed be essential for longevity. To test the hypothesis that the prevention of oxidative damage underlies longevity, we measured the activities of the five major intracellular antioxidant enzymes in brain, heart and liver tissue of 14 mammalian and avian species with maximum life spans (MLSPs) ranging from 3 years to over 100 years. Our data set included Snell dwarf mice in which life span is increased by ∼50% compared to their normal littermates. We found that CuZn superoxide dismutase, the major cytosolic superoxide dismutase, showed no correlation with MLSP in any of the three organs. Similarly, neither glutathione peroxidase nor glutathione reductase activities correlated with MLSP. MnSOD, the sole mitochondrial superoxide dismutase in mammals and birds, was positively correlated with MLSP only for brain tissue. This same trend was observed for catalase. For all correlational data, effects of body mass and phylogenetic relatedness were removed using residual analysis and Felsenstein's phylogenetically independent contrasts. Our results are not consistent with a causal role for intracellular antioxidant enzymes in longevity, similar to recent reports from studies utilising genetic modifications of mice (Pérez et al., Biochim Biophys Acta 1790:1005-1014). However, our results indicate a specific augmentation of reactive oxygen species neutralising activities in brain associated with longevity.

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“…Although there is currently much debate over the importance of increased cellular oxidative stress in regulation of life span (4,29), there is a consensus that increased ROS levels importantly contribute to the development of age-associated diseases (68). There is strong evidence that oxidative stress develops with age in the arterial system both in humans (19 -21, 25, 28) and laboratory animals (16,24,26,44,61).…”

mentioning

confidence: 99%

Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response

Ungvári

Bailey-Downs

Sоsnowska

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

226

156

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There is strong evidence showing that aging is associated with vascular oxidative stress, which has been causally linked to the development of cardiovascular diseases. NF-E2-related factor-2 (Nrf2) is a transcription factor, which is activated by reactive oxygen species in the vasculature of young animals leading to the upregulation of various antioxidant genes. The present study was designed to elucidate age-related changes in the homeostatic role of Nrf2-driven free radical detoxification mechanisms in the vasculature. We found that in the aorta of Fischer 344 ϫ Brown Norway rats, aging results in a progressive increase in O 2 ·Ϫ production, and downregulates protein and mRNA expression of Nrf2, which is associated with a decreased nuclear Nrf2 activity and a decrease in the Nrf2 target genes NAD(P)H:quinone oxidoreductase 1, ␥-glutamylcysteine synthetase, and heme oxygenase-1. There was an inverse relationship between vascular expression of Nrf2 target genes and agerelated increases in the expression of the NF-B target genes ICAM-1 and IL-6, which was significant by regression analysis. In cultured aorta segments of young (3 mo old) rats treatment with H 2O2 and high glucose significantly increases nuclear translocation of Nrf2 and upregulates the expression of Nrf2 target genes. In contrast, in cultured aorta segments of aged (24 mo old) rats, the induction of Nrf2-dependent responses by H 2O2 and high glucose are blunted. High glucose-induced vascular oxidative stress was more severe in aortas of aged rats, as shown by the significantly increased H 2O2 production in these vessels, compared with responses obtained in aortas from young rats. Moreover, we found that aging progressively increases vascular sensitivity to the proapoptotic effects of H 2O2 and high glucose treatments. Taken together, aging is associated with Nrf2 dysfunction in the vasculature, which likely exacerbates age-related cellular oxidative stress and increases sensitivity of aged vessels to oxidative stressinduced cellular damage.senescence; apoptosis; oxidative stress resistance; vascular injury THE OXIDATIVE STRESS THEORY of aging postulates that increased production of reactive oxygen species (ROS) with age induces a variety of macromolecular oxidative modifications and that accumulation of such oxidative damage is a major causal factor in organismic senescence. Although there is currently much debate over the importance of increased cellular oxidative stress in regulation of life span (4, 29), there is a consensus that increased ROS levels importantly contribute to the development of age-associated diseases (68). There is strong evidence that oxidative stress develops with age in the arterial system both in humans (19 -21, 25, 28) and laboratory animals (16,24,26,44,61). Increased production of ROS in the aged vasculature results in endothelial dysfunction and promotes the development of atherosclerotic vascular diseases (including myocardial infarction, stroke, vascular dementia), which are responsible for the majority of agerelate...

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

Cited by 176 publications

References 64 publications

Longevity of insulin receptor substrate1 null mice is not associated with increased basal antioxidant protection or reduced oxidative damage

Longevity of insulin receptor substrate1 null mice is not associated with increased basal antioxidant protection or reduced oxidative damage

Antioxidant enzyme activities are not broadly correlated with longevity in 14 vertebrate endotherm species

Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response

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