Protein oxidation during aging of the nematode Caenorhabditis elegans

Ishii, Naoaki; Goto, Sataro; Hartman, Paul A.

doi:10.1016/s0891-5849(02)00857-2

Cited by 55 publications

(29 citation statements)

References 41 publications

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“…Relative to other biological markers of aging that have identified changes at the midpoint of lifespan of C. elegans, at days 8-14 of adulthood, the loss of proteostasis occurs at a much earlier stage in multiple cell types, including neurons and muscles (11)(12)(13)(14)(15)(16)(17). How does an early event in adulthood affect cellular pathology and loss of physiological function during aging?…”

Section: Discussionmentioning

confidence: 99%

“…Many agedependent changes have been detected at mid-to-late lifespan of C. elegans, including the accumulation of damaged macromolecules, cell and organellar degeneration, and physiological decline (11)(12)(13)(14)(15)(16)(17). Likewise, aggregation and toxicity of diseaseassociated aggregation-prone proteins, such as huntingtin and A␤ peptide, is enhanced during aging in C. elegans and other model systems (18)(19)(20)(21).…”

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confidence: 99%

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Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging

Ben‐Zvi

Miller

Morimoto

2009

Proc. Natl. Acad. Sci. U.S.A.

610

604

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Protein damage contributes prominently to cellular aging. To address whether this occurs at a specific period during aging or accumulates gradually, we monitored the biochemical, cellular, and physiological properties of folding sensors expressed in different tissues of C. elegans. We observed the age-dependent misfolding and loss of function of diverse proteins harboring temperature-sensitive missense mutations in all somatic tissues at the permissive condition. This widespread failure in proteostasis occurs rapidly at an early stage of adulthood, and coincides with a severely reduced activation of the cytoprotective heat shock response and the unfolded protein response. Enhancing stress responsive factors HSF-1 or DAF-16 suppresses misfolding of these metastable folding sensors and restores the ability of the cell to maintain a functional proteome. This suggests that a compromise in the regulation of proteostatic stress responses occurs early in adulthood and tips the balance between the load of damaged proteins and the proteostasis machinery. We propose that the collapse of proteostasis represents an early molecular event of aging that amplifies protein damage in age-associated diseases of protein conformation.daf-16 ͉ folding sensors ͉ hsf-1 ͉ protein misfolding ͉ stress response T he stability of the proteome is challenged by conditions that cause proteotoxic stress including errors during protein synthesis, oxidant-induced covalent modifications, inherited polymorphisms, and misfolding (1-3). Consequently, all cells have highly conserved stress-inducible pathways that detect, prevent, and resolve such damage (4, 5). Accumulation of misfolded proteins titrate the negative regulation of chaperones from HSF-1 (4, 6, 7). Likewise, an E3 ubiquitin ligase was shown to regulate the levels of DAF-16, also indicating a link between stress response activation to the balance between proteostasis capacity and the load of damaged proteins (8). The activation of cellular stress responses limits the accumulation of damaged proteins by suppression of misfolding and enhancing chaperonemediated folding, promoting the enzymatic removal of covalent modifications, and stimulating clearance by ubiquitin-mediated, proteosomal, and autophagic processes (1, 4, 5, 9, 10). The dynamics of these processes during aging, however, are poorly understood.Aging can be characterized by the loss of cellular function and increased vulnerability to environmental and physiological stress that results in enhanced susceptibility to disease. Many agedependent changes have been detected at mid-to-late lifespan of C. elegans, including the accumulation of damaged macromolecules, cell and organellar degeneration, and physiological decline (11-17). Likewise, aggregation and toxicity of diseaseassociated aggregation-prone proteins, such as huntingtin and A␤ peptide, is enhanced during aging in C. elegans and other model systems (18-21).The regulation of aging and the maintenance of proteostasis has been recently established in C. elegans. Downregulatio...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging

Ben‐Zvi

Miller

Morimoto

2009

Proc. Natl. Acad. Sci. U.S.A.

610

604

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“…On the other hand, there are at least two relevant potentially distinct genetic influences, those that influence acute control of gene expression by glucose and those that influence the development of hysteretic effects. We suggest that genetic effects on both of these mechanisms must play a role in determining life span, since even at a young age species differ in their rate of production of reactive oxygen species [119] (possibly reflecting at least in part the acute effects of glucose on complex I activity), but on the other hand, the age-related increase in oxidative damage, reflecting hysteresis, scales with life span [123][124][125]. Thus we suggest that the rate of hysteresis may also be higher in short-lived than in long-lived species [119].…”

Section: Implications: Oxidative Stress and Tumor Burdenmentioning

confidence: 93%

Secrets of the lac Operon

Mobbs¹,

Mastaitis²,

Zhang³

et al. 2006

Interdisciplinary Topics in Gerontology

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Elevated blood glucose associated with diabetes produces progressive and apparently irreversible damage to many cell types. Conversely, reduction of glucose extends life span in yeast, and dietary restriction reduces blood glucose. Therefore it has been hypothesized that cumulative toxic effects of glucose drive at least some aspects of the aging process and, conversely, that protective effects of dietary restriction are mediated by a reduction in exposure to glucose. The mechanisms mediating cumulative toxic effects of glucose are suggested by two general principles of metabolic processes, illustrated by the lac operon but also observed with glucose-induced gene expression. First, metabolites induce the machinery of their own metabolism. Second, induction of gene expression by metabolites can entail a form of molecular memory called hysteresis. When applied to glucose-regulated gene expression, these two principles suggest a mechanism whereby repetitive exposure to postprandial excursions of glucose leads to an age-related increase in glycolytic capacity (and reduction in ␤-oxidation of free fatty acids), which in turn leads to an increased generation of oxidative damage and a decreased capacity to respond to oxidative damage, independent of metabolic rate. According to this mechanism, dietary restriction increases life span and reduces pathology by reducing exposure to glucose and therefore delaying the development of glucose-induced glycolytic capacity.

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“…While there is currently considerable debate on the exact role of ROS-induced oxidative stress in ageing (Gems and Doonan 2009;Perez et al 2009;Speakman and Selman 2011), evidence from long-lived invertebrate IIS mutants suggests that increased antioxidant protection and/or reduced oxidative stress can be associated with longevity. For example, some long-lived IIS mutant C. elegans have been shown to have higher basal levels of antioxidant enzymes (Vanfleteren 1993;Honda and Honda 1999;Brys et al 2007;Spanier et al 2010) and reduced oxidative damage (Ishii et al 2002;Brys et al 2007) compared to WT controls. Similarly, protein and activity levels of superoxide dismutase (SOD) were elevated in long-lived Drosophila IIS mutants (Clancy et al 2001;Tatar et al 2001;Kabil et al 2007).…”

Section: Introductionmentioning

confidence: 99%

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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Protein oxidation during aging of the nematode Caenorhabditis elegans

Cited by 55 publications

References 41 publications

Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging

Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging

Secrets of the lac Operon

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

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