Growth hormone administration to long-living dwarf mice alters multiple components of the antioxidative defense system

Brown‐Borg, Holly M.; Rakoczy, Sharlene

doi:10.1016/j.mad.2003.07.001

Cited by 82 publications

(66 citation statements)

References 30 publications

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“…Previous studies have focused on antioxidative defense, oxidative damage, and pathways leading to and including glutathione metabolism. We believe that the reduced GH signaling in the Ames mouse contributes to the enhanced antioxidative capacity, lower damage to proteins and DNA, and an increase in functioning of the methionine and glutathione metabolic pathways (Brown-Borg and Rakoczy 2003;Uthus and Brown-Borg 2003). An integral player in each of these observations is the mitochondria, organelles that drive energy metabolism, and possibly cellular aging according to several hypotheses of aging.…”

Section: Discussionmentioning

confidence: 96%

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: Discussionmentioning

confidence: 96%

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

Brown‐Borg

Johnson

Rakoczy

2011

AGE

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“…GH Administration-25 g of recombinant human GH (Reprokine) dissolved in water was injected subcutaneously twice daily (23). The site of injection was rotated daily to minimize discomfort, and weight measurements were taken in the morning prior to injection.…”

Section: Methodsmentioning

confidence: 99%

SOCS2 Balances Metabolic and Restorative Requirements during Liver Regeneration

Masuzaki

Zhao

Valerius

et al. 2016

Journal of Biological Chemistry

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After significant injury, the liver must maintain homeostasis during the regenerative process. We hypothesized the existence of mechanisms to limit hepatocyte proliferation after injury to maintain metabolic and synthetic function. A screen for candidates revealed suppressor of cytokine signaling 2 (SOCS2), an inhibitor of growth hormone (GH) signaling, was strongly induced after partial hepatectomy. Using genetic deletion and administration of various factors we investigated the role of SOCS2 during liver regeneration. SOCS2 preserves liver function by restraining the first round of hepatocyte proliferation after partial hepatectomy by preventing increases in growth hormone receptor (GHR) via ubiquitination, suppressing GH pathway activity. At later times, SOCS2 enhances hepatocyte proliferation by modulating a decrease in serum insulin-like growth factor 1 (IGF-1) that allows GH release from the pituitary. SOCS2, therefore, plays a dual role in modulating the rate of hepatocyte proliferation. In particular, this is the first demonstration of an endogenous mechanism to limit hepatocyte proliferation after injury.Control of liver regeneration requires both stimulatory and inhibitory factors (1-11). Although it might be expected that stimulatory factors are induced and inhibitory factors repressed after partial hepatectomy, in fact, for certain genes, the reverse occurs. For example, suppressor of cytokine signaling 3 (SOCS3), 2 an inhibitor of liver regeneration, is induced after partial hepatectomy (2). This observation raises the possibility that mechanisms exist to limit the rate of liver regeneration after injury. What is the reason for this? One possible explanation considers that metabolic activity may be impaired in proliferating compared with non-proliferating hepatocytes. If true, after severe injury liver regeneration might need to be limited to a rate that balances the acute need to maintain the diverse functions of the liver and prevent the death of the organism with the long-term need for hepatocytes to proliferate to restore mass and maximum functional capacity.Growth hormone (GH) signaling plays a central role in liver regeneration and may provide clues to how the rate of hepatocyte proliferation after injury is precisely regulated. Mice lacking GH activity display a diminished response to hepatectomy and do not restore liver mass even 7 days after partial hepatectomy (12). Loss of growth hormone receptor (GHR) impairs liver regeneration, and mice lacking Stat5, a transducer of GH signaling, demonstrate impaired hepatocyte proliferation after partial hepatectomy (13,14).GH is produced in the pituitary, stored in granules, and released into the circulation in response to growth hormone releasing hormone. This process is inhibited by a number of factors, including insulin-like growth factor 1 (IGF-1), which is produced primarily in the liver, and somatostatin (15).In target tissues, GH binds to the GHR and modulates phosphorylation of important intracellular messengers including JAK2, signal transdu...

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“…References; 1, Brown-Borg et al 2001;2, Brooks et al 2007;3, Hauck et al 2002 IIS insulin/IGF-1 signalling pathway mutant Irs1 −/− ; insulin receptor substrate-1 knockout GH growth hormone GHRKO growth hormone receptor/binding protein knockout M male and F female a Significant difference at young (3 months) but no difference at old age (24 months) b Significant difference at old age (24 month) but no difference at young age (3 months) c MDA+4-HNE; significant differences at middle-age (12 months) and old age (24 months) but no differences at young age (3 months) levels have previously been shown to be increased in brain, liver, and muscle tissue of Ames dwarf mice (Brown-Borg and Rakoczy 2003), as well as in dermal fibroblasts of Snell dwarf mice (Leiser and Miller 2010). Perhaps surprisingly, we observed no difference in protein (carbonyls) or lipid (4-HNE) oxidative damage in brain, skeletal muscle, or liver between Irs1 −/− and WT mice.…”

Section: Nsmentioning

confidence: 97%

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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Growth hormone administration to long-living dwarf mice alters multiple components of the antioxidative defense system

Cited by 82 publications

References 30 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

SOCS2 Balances Metabolic and Restorative Requirements during Liver Regeneration

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

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