Critical Evaluation of the Free Radical Theory of Aging

Yu, Byung Pal; Yang, Ryung

doi:10.1111/j.1749-6632.1996.tb39047.x

Cited by 153 publications

(57 citation statements)

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“…as the major site of electron leakage (70,71). Accordingly, a decrease in Q in clk-1 mutants could decrease respiratory electron transfer and perhaps the generation of superoxide, hydrogen peroxide, and hydroxyl radicals that have been proposed to contribute to cellular aging (72,73). In this oxidative stress theory of aging, mitochondria are considered to be both the main source and the target of oxygenderived free radicals (72).…”

Section: Coq7p/cat5p: Localization and Specificity In Q Biosynthesismentioning

confidence: 99%

Yeast Clk-1 Homologue (Coq7/Cat5) Is a Mitochondrial Protein in Coenzyme Q Synthesis

Jonassen¹,

Proft²,

Rández-Gil³

et al. 1998

Journal of Biological Chemistry

125

106

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Mutations in the clk-1 gene result in slower development and increased life span in Caenorhabditis elegans. The Saccharomyces cerevisiae homologue COQ7/CAT5 is essential for several metabolic pathways including ubiquinone biosynthesis, respiration, and gluconeogenic gene activation. We show here that Coq7p/Cat5p is a mitochondrial inner membrane protein directly involved in ubiquinone biosynthesis, and that the defect in gluconeogenic gene activation in coq7/cat5 null mutants is a general consequence of a defect in respiration. These results obtained in the yeast model suggest that the effects on development and life span in C. elegans clk-1 mutants may relate to changes in the amount of ubiquinone, an essential electron transport component and a lipid soluble antioxidant.

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Section: Coq7p/cat5p: Localization and Specificity In Q Biosynthesismentioning

confidence: 99%

Yeast Clk-1 Homologue (Coq7/Cat5) Is a Mitochondrial Protein in Coenzyme Q Synthesis

Jonassen¹,

Proft²,

Rández-Gil³

et al. 1998

Journal of Biological Chemistry

125

106

View full text Add to dashboard Cite

show abstract

“…Oxidative stress is considered as a major factor contributing to the aging process and leads to aberrant signaling pathways (Yu and Yang 1996). Aged rats are in the condition of increased oxidative stress and weakened antioxidative defense systems Therefore, to restrain the aging process, we need to seek ways to attenuate oxidative stress and strengthen the antioxidant system or to modulate the altered signaling pathway molecules.…”

Section: Introductionmentioning

confidence: 99%

Attenuation of age-related changes in FOXO3a activity and the PI3K/Akt pathway by short-term feeding of ferulate

Choi

Kim

Lee

et al. 2011

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Ferulate (4-hydroxy-3-methoxycinnamic acid) is a well-known phenolic compound that scavenges free radicals and exerts anti-inflammatory effects. Forkhead box O3a (FOXO3a), a transcription factor that plays important roles in aging processes, decreases with age and is negatively regulated through phosphorylation by phosphatidylinositol 3-kinase (PI3K)/Akt signaling. The present study investigated the efficacy of short-term ferulate feeding on age-related changes in PI3K/Akt/FOXO3a and upstream insulin signaling pathways in aged rats. In addition, changes in manganese superoxide dismutase (MnSOD) and catalase expression were examined because of their dependence on PI3K/Akt/FOXO3a activity. Short-term feeding experiments were done with a diet containing ferulate that was given to aged rats at doses of 3 or 6 mg kg −1 day −1 for 10 days.Results showed that FOXO3a activity was increased in the ferulate-fed old group compared with the control old group. Also, ferulate suppressed the PI3K/Akt signaling pathway that is responsible for FOXO3a inhibition in aged rats. Plasma insulin levels and the upstream insulin signaling pathway were also modulated by ferulate correspondingly with PI3K/ Akt/FOXO3a activity. The age-related decrease in two major antioxidant enzymes, MnSOD and catalase, was blunted by ferulate, which was accompanied by FOXO3a transcriptional activity. The significance of the present study is the finding that short-term feeding of ferulate effectively modulates age-related renal FOXO3a, PI3K/Akt and insulin signaling pathways, and MnSOD and catalase expression, all of which may be beneficial for attenuating the aging process.

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“…In addition, lipid hydroperoxides can undergo iron-mediated, one-electron reduction and oxygenation to form epoxyallylic peroxyl radicals, which trigger a chain reaction of free radical-mediated lipid peroxidation (2). The end-products of lipid peroxidation are reactive aldehydes such as 4-hydroxyl nonenal and malondialdehyde, many of which are highly toxic to cells (3). In addition, reactive aldehydes generated by lipid peroxidation can attack other cellular targets, such as proteins and DNA, thereby propagating the initial damage in cellular membranes to other macromolecules.…”

mentioning

confidence: 99%

Transgenic Mice Overexpressing Glutathione Peroxidase 4 Are Protected against Oxidative Stress-induced Apoptosis

Ran

Liang

et al. 2004

Journal of Biological Chemistry

229

192

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Glutathione peroxidase 4 (Gpx4) is uniquely involved in the detoxification of oxidative damage to membrane lipids. Our previous studies showed that Gpx4 is essential for mouse survival and that Gpx4 deficiency makes cells vulnerable to oxidative injury. In the present study, we generated two lines of transgenic mice overexpressing Gpx4 (Tg(GPX4) mice) using a genomic clone containing the human GPX4 gene. Both lines of Tg-(GPX4) mice, Tg5 and Tg6, had elevated levels of Gpx4 (mRNA and protein) in all tissues investigated, and overexpression of Gpx4 did not cause alterations in activities of glutathione peroxidase 1, catalase, Cu/Zn superoxide dismutase, and manganese superoxide dismutase. The human GPX4 transgene rescued the lethal phenotype of null mutation of the mouse Gpx4 gene, indicating that the transgene can replace the essential role of mouse Gpx4 in mouse development. Cell death induced by t-butylhydroperoxide and diquat was significantly less in murine embryonic fibroblasts from Tg(GPX4) mice compared with wild type mice. Liver damage and lipid peroxidation induced by diquat were reduced significantly in Tg(GPX4) mice. In addition, diquat-induced apoptosis was decreased in Tg(GPX4) mice, as evidenced by attenuated caspase-3 activation and reduced cytochrome c release from mitochondria. These data demonstrate that Gpx4 plays a role in vivo in the mechanism of apoptosis induced by oxidative stress that most likely occurs through oxidative damage to mitochondrial phospholipids such as cardiolipin.Reactive oxygen species (ROS), 1 such as superoxide and hydrogen peroxide, are constantly generated in aerobic organisms during normal respiration. In addition, environmental factors (such as ionizing radiation) and pathological compounds (such as ␤-amyloid in Alzheimer's disease) can generate ROS. Although ROS at physiological concentrations may be required for normal cell function, excessive production of ROS can be detrimental to cells, because ROS can cause oxidative damage to lipids, protein, and DNA. Polyunsaturated fatty acids, which are found predominantly in cellular membranes, are especially vulnerable to attack by ROS because of the high concentration of allylic hydrogens in their structure (1). The resulting lipid hydroperoxides can affect membrane fluidity and the function of membrane proteins. In addition, lipid hydroperoxides can undergo iron-mediated, one-electron reduction and oxygenation to form epoxyallylic peroxyl radicals, which trigger a chain reaction of free radical-mediated lipid peroxidation (2). The end-products of lipid peroxidation are reactive aldehydes such as 4-hydroxyl nonenal and malondialdehyde, many of which are highly toxic to cells (3). In addition, reactive aldehydes generated by lipid peroxidation can attack other cellular targets, such as proteins and DNA, thereby propagating the initial damage in cellular membranes to other macromolecules. Because lipid hydroperoxides formed in membranes are an important component of ROS generation in vivo, their detoxification appears to ...

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Critical Evaluation of the Free Radical Theory of Aging

Cited by 153 publications

References 0 publications

Yeast Clk-1 Homologue (Coq7/Cat5) Is a Mitochondrial Protein in Coenzyme Q Synthesis

Yeast Clk-1 Homologue (Coq7/Cat5) Is a Mitochondrial Protein in Coenzyme Q Synthesis

Attenuation of age-related changes in FOXO3a activity and the PI3K/Akt pathway by short-term feeding of ferulate

Transgenic Mice Overexpressing Glutathione Peroxidase 4 Are Protected against Oxidative Stress-induced Apoptosis

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