Constitutive Expression of Peroxisome Proliferator-Activated Receptor α-Regulated Genes in Dwarf Mice

Stauber, Anja J.; Brown‐Borg, Holly M.; Liu, Jie; Waalkes, Michael P.; Laughter, Ashley; Staben, Rebecca A.; Coley, Jaqueline C.; Swanson, Cynthia; Voss, Kenneth A.; Kopchick, John J.; Corton, J. Christopher

doi:10.1124/mol.104.007278

Cited by 40 publications

(33 citation statements)

References 40 publications

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“…Recent studies in Snell, GHRKO, and PAPPA‐KO mice have shown a common physiology that may control aging rate and multiple age‐related diseases (Murakami et al ., 2003; Boylston et al ., 2006; Brown‐Borg, 2006). These mice all exhibit high insulin sensitivity and an increased oxygen consumption with high levels of peroxisome proliferator‐associated receptor γ coactivator 1 (Pgc1α) from oxidative phosphorylation (Corton & Brown‐Borg, 2005; Stauber et al ., 2005). Similarly, CNOT3 heterozygous mice (Morita et al ., 2011) have been shown to have increased insulin sensitivity, oxidative phosphorylation (including higher Pgc1α expression), and oxygen consumption.…”

Section: Discussionmentioning

confidence: 99%

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

Dominick

Bowman

et al. 2016

Aging Cell

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SummaryStudies of the mTOR pathway have prompted speculation that diminished mTOR complex‐1 (mTORC1) function may be involved in controlling the aging process. Our previous studies have shown diminished mTORC1 activity in tissues of three long‐lived mutant mice: Snell dwarf mice, growth hormone receptor gene disrupted mice (GHRKO), and in this article, mice deficient in the pregnancy‐associated protein‐A (PAPPA‐KO). The ways in which lower mTOR signals slow aging and age‐related diseases are, however, not well characterized. Here, we show that Snell, GHKRO, and PAPPA‐KO mice express high levels of two proteins involved in DNA repair, O‐6‐methylguanine‐DNA methyltransferase (MGMT) and N‐myc downstream‐regulated gene 1 (NDRG1). Furthermore, we report that lowering mTOR enhances MGMT and NDRG1 protein expression via post‐transcriptional mechanisms. We show that the CCR4‐NOT complex, a post‐transcriptional regulator of gene expression, is downstream of the mTORC1 pathway and may be responsible for the upregulation of MGMT and NDRG1 in all three varieties of long‐lived mice. Our data thus suggest a novel link between DNA repair and mTOR signaling via post‐transcriptional regulation involving specific alteration in the CCR4‐NOT complex, whose modulation could control multiple aspects of the aging process.

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Section: Discussionmentioning

confidence: 99%

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

Dominick

Bowman

et al. 2016

Aging Cell

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“…It is not yet clear how the Snell dwarf mutation, and the drugs tested, lead to extended lifespan, and it is possible that the effects on proteasome biology reflect different cellular or physiological mechanisms. Elevated immunoproteasome expression in Snell dwarf mice is unlikely to be caused by increases in IFN-γ responses because IFN-γ receptor levels are downregulated in Snell dwarf mice (56). Elevation of TNF-α levels, seen in Snell dwarf mice (57), is a potent inducer of immunoproteasome expression (58).…”

Section: Discussionmentioning

confidence: 99%

Lifespan of mice and primates correlates with immunoproteasome expression

Pickering¹,

Lehr²,

Miller³

2015

J. Clin. Invest.

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“…Several peroxisome proliferator-activated receptor α-regulated genes and gene products including those involved in β-oxidation of fatty acids are elevated in dwarf mice (including Ames, Snell, and GHRKO mice; Stauber et al 2005).…”

Section: Discussionmentioning

confidence: 99%

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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Constitutive Expression of Peroxisome Proliferator-Activated Receptor α-Regulated Genes in Dwarf Mice

Abstract: Defects in growth hormone secretion or signaling in mice are associated with decreased body weights (dwarfism), increased longevity, increased resistance to stress, and decreases in factors that contribute to cardiovascular disease and cancer.

Cited by 40 publications

References 40 publications

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

Lifespan of mice and primates correlates with immunoproteasome expression

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

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