Long-Lived Ames Dwarf Mice Are Resistant to Chemical Stressors

Bokov, Alex; Lindsey, Merry L.; Khodr, Christina E.; Sabia, Marian; Richardson, Arlan

doi:10.1093/gerona/glp052

Cited by 74 publications

(71 citation statements)

References 79 publications

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“…In turn, mitochondrial hydrogen peroxide production is significantly lower in liver tissue from dwarf mice (Brown-Borg et al 2001a,b). In support of this evidence, the enhanced protein and activity levels of endogenous antioxidant enzymes are functional as they provide resistance to both in vivo (Bartke 2000;Bokov et al 2009) and in vitro (Salmon et al 2005) oxidative challenge resulting in Ames dwarf mice and cells derived from these mice, out-surviving their wild-type counterparts.…”

Section: Introductionmentioning

confidence: 92%

Expression of oxidative phosphorylation components in mitochondria of long-living Ames dwarf mice

Brown‐Borg

Johnson

Rakoczy

2011

AGE

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Reduced signaling of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) pathway is associated with extended life span in several species. Ames dwarf mice are GH-deficient and live >50% longer than wild-type littermates. Previously, we have shown that tissues from Ames mice exhibit elevated levels of antioxidative enzymes, less H 2 O 2 production, and lower oxidative damage suggesting that mitochondrial function may differ between genotypes. To explore the relationship between hormone deficiency and mitochondria in mice with extended longevity, we evaluated activity, protein, and gene expression of oxidative phosphorylation components in dwarf and wild-type mice at varying ages. Liver complex I+III activity was higher in dwarf mice compared to wildtype mice. The activity of I+III decreased between 3 and 20 months of age in both genotypes with greater declines in wild-type mice in liver and skeletal muscle. Complex IV activities in the kidney were elevated in 3-and 20-month-old dwarf mice relative to wild-type mice. In Ames mice, protein levels of the 39 kDa complex I subunit were elevated at 20 months of age when compared to wild-type mouse mitochondria for every tissue examined. Kidney and liver mitochondria from 20-month-old dwarf mice had elevated levels of both mitochondrially-encoded and nuclear-encoded complex IV proteins compared to wild-type mice (p<0.05). Higher liver ANT1 and PGC-1α mRNA levels were also observed in dwarf mice. Overall, we found that several components of the oxidative phosphorylation (OXPHOS) system were elevated in Ames mice. Mitochondrial to nuclear DNA ratios were not different between genotypes despite the marked increase in PGC-1α levels in dwarf mice. The increased OXPHOS activities, along with lower ROS production in dwarf mice, predict enhanced mitochondrial function and efficiency, two factors likely contributing to long-life in Ames mice.

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Section: Introductionmentioning

confidence: 92%

Expression of oxidative phosphorylation components in mitochondria of long-living Ames dwarf mice

Brown‐Borg

Johnson

Rakoczy

2011

AGE

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“…These mechanisms include resistance to oxidative and cytotoxic stress Murakami et al, 2003;Bokov et al, 2007), increased activity of antioxidant enzymes (BrownBorg et al, 2001;Romanick et al, 2004), reduced body temperature (Hunter et al, 1999;Hauck et al, 2001) and reduced susceptibility to cancer (Yang et al, 1996;Bugni et al, 2001;Deitel et al, 2002;Ikeno et al, 2003). Recent elegant studies by AmadorNoguez et al (2004AmadorNoguez et al ( , 2007 have added to the list of likely mechanisms of extended longevity in GH-deficient mice.…”

Section: Other Mechanisms Linking Gh and Agingmentioning

confidence: 99%

“…Interactions between the suspected mechanisms of extended longevity are suggested by the observations that resistance to Paraquat is shared by hypopituitary Ames dwarf mice Bokov et al, 2007) and IGFIR +/-animals (Holzenberger et al, 2003) and by the evidence that farnesoid X receptors -in addition to their involvement in regulation of xenobiotic metabolism -can influence carbohydrate regulation by inhibiting gluconeogenesis (Stayrook et al, 2005).…”

Section: Other Mechanisms Linking Gh and Agingmentioning

confidence: 99%

Impact of reduced insulin‐like growth factor‐1/insulin signaling on aging in mammals: novel findings

2008

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“…Inter-species comparisons indicate that, with some exceptions, longer-lived species have increased cellular stress resistance (Kapahi et al 1999;Ogburn et al 2001;Miller et al 2010), and comparisons amongst mice harbouring single gene mutations that increase lifespan also reveal this trend (Holzenberger et al 2003;Salmon et al 2005;Maynard and Miller 2006;Bokov et al 2009). A key observation is that inter-and intraspecies differences in cellular stress resistance are present in young adults, suggesting that longevity is associated with enhanced stress resistance over the lifespan rather than becoming evident only with advanced age.…”

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confidence: 99%

Enhanced protein repair and recycling are not correlated with longevity in 15 vertebrate endotherm species

Salway

Page

Faure

et al. 2010

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Previous studies have shown that longevity is associated with enhanced cellular stress resistance. This observation supports the disposable soma theory of aging, which suggests that the investment made in cellular maintenance will be proportional to selective pressures to extend lifespan. Maintenance of protein homeostasis is a critical component of cellular maintenance and stress resistance. To test the hypothesis that enhanced protein repair and recycling activities underlie longevity, we measured the activities of the 20S/26S proteasome and two protein repair enzymes in liver, heart and brain tissues of 15 different mammalian and avian species with maximum lifespans (MLSP) ranging from 3 to 30 years. The data set included Snell dwarf mice, in which lifespan is increased by ∼50% compared to their normal littermates. None of these activities in any of the three tissues correlated positively with MLSP. In liver, 20S/26S proteasome and thioredoxin reductase (TrxR) activities correlated negatively with body mass. In brain tissue, TrxR was also negatively correlated with body mass. Glutaredoxin (Grx) activity in brain was negatively correlated with MLSP and this correlation remained after residual analysis to remove the effects of body mass, but was lost when the data were analysed using Felsenstein's independent contrasts. Snell dwarf mice had marginally lower 20S proteasome, TrxR and Grx activities than normal controls in brain, but not heart tissue. Thus, increased longevity is not associated with increased protein repair or proteasomal degradation capacities in vertebrate endotherms.

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Long-Lived Ames Dwarf Mice Are Resistant to Chemical Stressors

Cited by 74 publications

References 79 publications

Expression of oxidative phosphorylation components in mitochondria of long-living Ames dwarf mice

Expression of oxidative phosphorylation components in mitochondria of long-living Ames dwarf mice

Impact of reduced insulin‐like growth factor‐1/insulin signaling on aging in mammals: novel findings

Enhanced protein repair and recycling are not correlated with longevity in 15 vertebrate endotherm species

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