CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life

Elchuri, Sailaja; Oberley, Terry D.; Qi, Wenbo; Eisenstein, Richard S.; Roberts, L. Jackson; Remmen, Holly Van; Epstein, Charles J.; Huang, Ting

doi:10.1038/sj.onc.1208207

Cited by 581 publications

(501 citation statements)

References 73 publications

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“…The importance of the antioxidant defense system in the maintenance of genome stability was demonstrated by Busuttil et al, who demonstrated greatly accelerated mutation accumulation in liver of SOD1-null mice (Busuttil et al, 2005). This indicates that oxidative stress is a causal factor of the increased incidence of liver cancer in this mutant mouse model (Elchuri et al, 2005). Hence, the lower spontaneous somatic mutation accumulation observed for the GH/IGF1-deficient mice in our present study could be a result of a decreased susceptibility to oxidative damage-induced mutagenesis.…”

Section: Discussionmentioning

confidence: 76%

Effect of Ames dwarfism and caloric restriction on spontaneous DNA mutation frequency in different mouse tissues

Garcı́a

Busuttil

Calder

et al. 2008

Mechanisms of Ageing and Development

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Genetic instability has been implicated as a causal factor in cancer and aging. Caloric restriction (CR) and suppression of the somatotroph axis significantly increase life span in the mouse and reduces multiple symptoms of aging, including cancer. To test if in vivo spontaneous mutation frequency is reduced by such mechanisms, we crossed long-lived Ames dwarf mice with a C57BL/6J line harboring multiple copies of the lacZ mutation reporter gene as part of a plasmid that can be recovered from tissues and organs into E. coli to measure mutant frequencies. Four cohorts were studied: (1) ad lib wild-type; (2) CR wild-type; (3) ad lib dwarf; and (4) CR dwarf. While both CR wild-type and ad lib dwarf mice lived significantly longer than the ad lib wild-type mice, under CR conditions dwarf mice did not live any longer than ad lib wild-type mice. While this may be due to an as yet unknown adverse effect of the C57Bl/6 background, it did not prevent an effect on spontaneous mutation frequencies at the lacZ locus, which were assessed in liver, kidney and small intestine of 7-and 15-month old mice of all four cohorts. A lower mutant frequency in the ad lib dwarf background was observed in liver and kidney at 7 and 15 months of age and in small intestine at 15 months of age as compared to the ad lib wild-type. CR also significantly reduced spontaneous mutant frequency in kidney and small intestine, but not in liver. In a separate cohort of lacZ-C57BL/6J mice CR was also found to significantly reduce spontaneous mutant frequency in liver and small intestine, across three age levels. These results indicate that two major pro-longevity interventions in the mouse are associated with a reduced mutation frequency. This could be responsible, at least in part, for the enhanced longevity associated with Ames dwarfism and CR.

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Section: Discussionmentioning

confidence: 76%

Effect of Ames dwarfism and caloric restriction on spontaneous DNA mutation frequency in different mouse tissues

Garcı́a

Busuttil

Calder

et al. 2008

Mechanisms of Ageing and Development

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“…Reduced lifespan observed in SOD1 −/− ,27 PRX1 −/− ,250 PRX2 −/− 251 and TRX2 +/− 252 models is much more prominent in the SOD1 −/− rodent model,281 indicating that specific key RONS regulatory systems and redox signalling pathways are implicated in the processes of ageing. Moreover, although indistinguishable from WT mice at birth, by 5–8 months of age, SOD1 −/− mice show an accelerated neuromuscular ageing phenotype associated with myofibre atrophy (Figure 5), neurological impairments (Figure 6) and functional deficits 275.…”

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 97%

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

Sakellariou

Lightfoot

Earl

et al. 2017

J cachexia sarcopenia muscle

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Skeletal muscle is a major site of metabolic activity and is the most abundant tissue in the human body. Age‐related muscle atrophy (sarcopenia) and weakness, characterized by progressive loss of lean muscle mass and function, is a major contributor to morbidity and has a profound effect on the quality of life of older people. With a continuously growing older population (estimated 2 billion of people aged >60 by 2050), demand for medical and social care due to functional deficits, associated with neuromuscular ageing, will inevitably increase. Despite the importance of this ‘epidemic’ problem, the primary biochemical and molecular mechanisms underlying age‐related deficits in neuromuscular integrity and function have not been fully determined. Skeletal muscle generates reactive oxygen and nitrogen species (RONS) from a variety of subcellular sources, and age‐associated oxidative damage has been suggested to be a major factor contributing to the initiation and progression of muscle atrophy inherent with ageing. RONS can modulate a variety of intracellular signal transduction processes, and disruption of these events over time due to altered redox control has been proposed as an underlying mechanism of ageing. The role of oxidants in ageing has been extensively examined in different model organisms that have undergone genetic manipulations with inconsistent findings. Transgenic and knockout rodent studies have provided insight into the function of RONS regulatory systems in neuromuscular ageing. This review summarizes almost 30 years of research in the field of redox homeostasis and muscle ageing, providing a detailed discussion of the experimental approaches that have been undertaken in murine models to examine the role of redox regulation in age‐related muscle atrophy and weakness.

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“…Since then the core statement of the MFRTA has been reinforced by the discovery of superoxide dismutases, by the observation that mitochondria continuously produce ROS, and by the observation that oxidative damage increases with age [18]. Most recently, the lethal phenotype of mice that completely lack the mitochondrial superoxide dismutase SOD2, and the shortened lifespan of mice that completely lack the cytoplasmic SOD1 have also supported the MFRTA [19,20].…”

Section: The Logic Of the Mitochondrial Free Radical Theory Of Aging mentioning

confidence: 97%

Taking a “good” look at free radicals in the aging process

Hekimi

Lapointe

Yang

2011

Trends in Cell Biology

501

359

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The mitochondrial free radical theory of aging (MFRTA) proposes that aging is caused by damage to macromolecules from mitochondrial reactive oxygen species (ROS). This is based on the observed association of the rate of aging and the aged phenotype with the generation of ROS and with oxidative damage. The theory has led to the strong conviction in the general public that the consumption of antioxidants is crucial to health and beneficial to lifespan. However, a variety of recent findings convincingly demonstrate that ROS generation and oxidative damage cannot be the cause of aging. Here we propose that ROS play a role in mediating a stress response to agedependent damage, which could generate the observed correlation between aging and ROS without implying that ROS cause aging. Redefining our understanding of the relationship between ROS and agingMitochondria are a major source of reactive oxygen species (ROS), a type of molecule that includes free radicals such as superoxide. ROS spontaneously oxidize and damage macromolecules such as proteins, lipids and nucleic acids. Cells and organisms are said to be sustaining oxidative stress when an imbalance between ROS generation and detoxification or repair leads to an increase in the level of ROS-dependent damage. The mitochondrial free radical theory of aging (MFRTA) has provided an attractive framework that integrates numerous observations about the generation, the toxicity and the detoxification of ROS, as well as about how these parameters change with the physiological state of cells and organisms and with chronological age. The theory proposes that aging is actually caused by the toxicity of ROS through a vicious cycle in which ROS damage to the constituents of mitochondria leads to the generation of more ROS. The theory is based on numerous observations, including (1) that there is a strong correlation between chronological age and the level of ROS generation and oxidative damage, (2) that mitochondrial function is gradually lost during aging, (3) that inhibition of mitochondrial function can enhance ROS production, and (4) that several age-dependent diseases are associated with severe increases in oxidative stress.The strength of the MFRTA is that it provides a framework for many observations while also stating a plausible causal theory of aging. Furthermore, it provided a clear research program by proposing a theory to be tested as well as by suggesting that decreasing the generation of ROS will result in health benefits. In fact the MFRTA is often taught in textbooks and in *

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CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life

Cited by 581 publications

References 73 publications

Effect of Ames dwarfism and caloric restriction on spontaneous DNA mutation frequency in different mouse tissues

Effect of Ames dwarfism and caloric restriction on spontaneous DNA mutation frequency in different mouse tissues

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

Taking a “good” look at free radicals in the aging process

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