The Experts below are selected from a list of 162 Experts worldwide ranked by ideXlab platform
John Papaconstantinou - One of the best experts on this subject based on the ideXlab platform.
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akt pkb and p38 mapk signaling translational initiation and longevity in snell Dwarf Mouse livers
Mechanisms of Ageing and Development, 2004Co-Authors: Ching-chyuan Hsieh, John PapaconstantinouAbstract:The insulin/IGF-1/GH and p38 MAPK signaling pathways play a key role in the regulation of protein synthesis. The regulation of GH and TSH secretion hormones, that affect the activity of these pathways, plays an important role in the decline of rates of protein synthesis in aged rodent tissues. Studies have indicated that longevity of the Snell Dwarf (Pit-1) Mouse mutant is associated with the reduction of function of the insulin/IGF-1/GH signaling pathway. We have previously shown that PI3K activity, a signaling protein that plays a key role in the regulation of translation, is also dramatically decreased in the Snell Dwarf liver suggesting that the protein synthesis-signaling pathway may be attenuated in this long-lived Mouse. Similarly, signaling via p38 MAPK also plays a role in the regulation of protein synthesis. In this study we examined the activities of these signaling pathways to determine if the translation-signaling pathway is altered in young versus aged Snell Dwarf Mouse livers. Our data indicate that the phosphorylation and kinase activities of Akt/PKB and p38 MAPK, and the levels of phosphorylation of downstream regulators of translation are decreased in Dwarf Mouse livers. Thus, the overall activities of major components of the translational initiation pathway are decreased in the long-lived Snell Dwarf Mouse livers. We propose that down-regulation of protein synthesis may be an important characteristic of the Pit-1 mutation and longevity of the Snell Dwarf Mouse.
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Altered oxidative stress response of the long-lived Snell Dwarf Mouse.
Biochemical and biophysical research communications, 2004Co-Authors: Mark A. Madsen, Ching-chyuan Hsieh, Kevin Flurkey, David E. Harrison, William H. Boylston, John PapaconstantinouAbstract:Abstract Several single gene mutations in mice that increase the murine life span have been identified, including the Pit-1 mutation which results in the Snell Dwarf (Pit1dw/dw), however, the biological mechanism of this life-span extension is still unclear. Based on studies that show oxidative stress plays an important role in the aging process, we hypothesized that the increased longevity seen in Snell Dwarf mice may result from a resistance to oxidative stress. We report that Snell Dwarf mice respond to oxidative stress induced by 3-NPA differently than their wild type littermates. This altered response results in diminished activation of the MEK–ERK kinase cascade and virtually no phosphorylation of c-Jun at Ser63 in Dwarf mice after 3-NPA treatment, despite a robust phosphorylation of Ser63 in wild type mice. We propose that this altered management of oxidative stress in Dwarf mice is partially responsible for the increased longevity in Snell Dwarf mice.
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Akt/PKB and p38 MAPK signaling, translational initiation and longevity in Snell Dwarf Mouse livers.
Mechanisms of ageing and development, 2004Co-Authors: Ching-chyuan Hsieh, John PapaconstantinouAbstract:The insulin/IGF-1/GH and p38 MAPK signaling pathways play a key role in the regulation of protein synthesis. The regulation of GH and TSH secretion hormones, that affect the activity of these pathways, plays an important role in the decline of rates of protein synthesis in aged rodent tissues. Studies have indicated that longevity of the Snell Dwarf (Pit-1) Mouse mutant is associated with the reduction of function of the insulin/IGF-1/GH signaling pathway. We have previously shown that PI3K activity, a signaling protein that plays a key role in the regulation of translation, is also dramatically decreased in the Snell Dwarf liver suggesting that the protein synthesis-signaling pathway may be attenuated in this long-lived Mouse. Similarly, signaling via p38 MAPK also plays a role in the regulation of protein synthesis. In this study we examined the activities of these signaling pathways to determine if the translation-signaling pathway is altered in young versus aged Snell Dwarf Mouse livers. Our data indicate that the phosphorylation and kinase activities of Akt/PKB and p38 MAPK, and the levels of phosphorylation of downstream regulators of translation are decreased in Dwarf Mouse livers. Thus, the overall activities of major components of the translational initiation pathway are decreased in the long-lived Snell Dwarf Mouse livers. We propose that down-regulation of protein synthesis may be an important characteristic of the Pit-1 mutation and longevity of the Snell Dwarf Mouse.
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effects of the pit1 mutation on the insulin signaling pathway implications on the longevity of the long lived snell Dwarf Mouse
Mechanisms of Ageing and Development, 2002Co-Authors: Ching-chyuan Hsieh, James H. Deford, Kevin Flurkey, David E. Harrison, John PapaconstantinouAbstract:Mutations in Caenorhabditis elegans and mice have identified candidate genes that increase their lifespan via hormonal signal transduction, i.e. the insulin/IGF-1-like pathway. In this study we propose that longevity of the Snell Dwarf (Pit1(dw)/Pit1(dw)) Mouse is associated with a decrease of the insulin/IGF-1 signaling pathway caused by the Pit1 mutation. We recently demonstrated that the growth hormone deficiency of the Dwarf Mouse alters circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway, which is a determining factor in the increased nematode lifespan. The decreased activity of the insulin/IGF-1 signaling pathway is indicated by decrease of (a) IRS-two pool levels; (b) docking of p85 alpha to IRS-2; (c) docking of p 85 alpha to p110 alpha or p110 beta, and (d) IRS-2-associated PI3K activity. In this study we present data suggesting that the InR beta-IRS-1-PI3K pathway is attenuated in the Snell Dwarf Mouse liver. Our data show that the PI3K activity associated with IRS-1, the docking of IRS-1 to InR beta and the docking of p85 alpha to IRS-1 are attenuated in the aged Snell Dwarf. Our studies suggest that the Pit1 mutation results in a decreased activity of the insulin/IGF-1 pathway; that this plays a key role in the longevity of the Snell Dwarf Mouse and conforms to the nematode longevity paradigm.
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Effects of the Pit1 mutation on the insulin signaling pathway: implications on the longevity of the long-lived Snell Dwarf Mouse.
Mechanisms of ageing and development, 2002Co-Authors: Ching-chyuan Hsieh, James H. Deford, Kevin Flurkey, David E. Harrison, John PapaconstantinouAbstract:Abstract Mutations in Caenorhabditis elegans and mice have identified candidate genes that increase their lifespan via hormonal signal transduction, i.e. the insulin/IGF-1-like pathway. In this study we propose that longevity of the Snell Dwarf (Pit1dw/Pit1dw) Mouse is associated with a decrease of the insulin/IGF-1 signaling pathway caused by the Pit1 mutation. We recently demonstrated that the growth hormone deficiency of the Dwarf Mouse alters circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway, which is a determining factor in the increased nematode lifespan. The decreased activity of the insulin/IGF-1 signaling pathway is indicated by decrease of (a) IRS-two pool levels; (b) docking of p85α to IRS-2; (c) docking of p85α to p110α or p110β, and (d) IRS-2-associated PI3K activity. In this study we present data suggesting that the InRβ-IRS-1-PI3K pathway is attenuated in the Snell Dwarf Mouse liver. Our data show that the PI3K activity associated with IRS-1, the docking of IRS-1 to InRβ and the docking of p85α to IRS-1 are attenuated in the aged Snell Dwarf. Our studies suggest that the Pit1 mutation results in a decreased activity of the insulin/IGF-1 pathway; that this plays a key role in the longevity of the Snell Dwarf Mouse and conforms to the nematode longevity paradigm.
Ching-chyuan Hsieh - One of the best experts on this subject based on the ideXlab platform.
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akt pkb and p38 mapk signaling translational initiation and longevity in snell Dwarf Mouse livers
Mechanisms of Ageing and Development, 2004Co-Authors: Ching-chyuan Hsieh, John PapaconstantinouAbstract:The insulin/IGF-1/GH and p38 MAPK signaling pathways play a key role in the regulation of protein synthesis. The regulation of GH and TSH secretion hormones, that affect the activity of these pathways, plays an important role in the decline of rates of protein synthesis in aged rodent tissues. Studies have indicated that longevity of the Snell Dwarf (Pit-1) Mouse mutant is associated with the reduction of function of the insulin/IGF-1/GH signaling pathway. We have previously shown that PI3K activity, a signaling protein that plays a key role in the regulation of translation, is also dramatically decreased in the Snell Dwarf liver suggesting that the protein synthesis-signaling pathway may be attenuated in this long-lived Mouse. Similarly, signaling via p38 MAPK also plays a role in the regulation of protein synthesis. In this study we examined the activities of these signaling pathways to determine if the translation-signaling pathway is altered in young versus aged Snell Dwarf Mouse livers. Our data indicate that the phosphorylation and kinase activities of Akt/PKB and p38 MAPK, and the levels of phosphorylation of downstream regulators of translation are decreased in Dwarf Mouse livers. Thus, the overall activities of major components of the translational initiation pathway are decreased in the long-lived Snell Dwarf Mouse livers. We propose that down-regulation of protein synthesis may be an important characteristic of the Pit-1 mutation and longevity of the Snell Dwarf Mouse.
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Altered oxidative stress response of the long-lived Snell Dwarf Mouse.
Biochemical and biophysical research communications, 2004Co-Authors: Mark A. Madsen, Ching-chyuan Hsieh, Kevin Flurkey, David E. Harrison, William H. Boylston, John PapaconstantinouAbstract:Abstract Several single gene mutations in mice that increase the murine life span have been identified, including the Pit-1 mutation which results in the Snell Dwarf (Pit1dw/dw), however, the biological mechanism of this life-span extension is still unclear. Based on studies that show oxidative stress plays an important role in the aging process, we hypothesized that the increased longevity seen in Snell Dwarf mice may result from a resistance to oxidative stress. We report that Snell Dwarf mice respond to oxidative stress induced by 3-NPA differently than their wild type littermates. This altered response results in diminished activation of the MEK–ERK kinase cascade and virtually no phosphorylation of c-Jun at Ser63 in Dwarf mice after 3-NPA treatment, despite a robust phosphorylation of Ser63 in wild type mice. We propose that this altered management of oxidative stress in Dwarf mice is partially responsible for the increased longevity in Snell Dwarf mice.
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Akt/PKB and p38 MAPK signaling, translational initiation and longevity in Snell Dwarf Mouse livers.
Mechanisms of ageing and development, 2004Co-Authors: Ching-chyuan Hsieh, John PapaconstantinouAbstract:The insulin/IGF-1/GH and p38 MAPK signaling pathways play a key role in the regulation of protein synthesis. The regulation of GH and TSH secretion hormones, that affect the activity of these pathways, plays an important role in the decline of rates of protein synthesis in aged rodent tissues. Studies have indicated that longevity of the Snell Dwarf (Pit-1) Mouse mutant is associated with the reduction of function of the insulin/IGF-1/GH signaling pathway. We have previously shown that PI3K activity, a signaling protein that plays a key role in the regulation of translation, is also dramatically decreased in the Snell Dwarf liver suggesting that the protein synthesis-signaling pathway may be attenuated in this long-lived Mouse. Similarly, signaling via p38 MAPK also plays a role in the regulation of protein synthesis. In this study we examined the activities of these signaling pathways to determine if the translation-signaling pathway is altered in young versus aged Snell Dwarf Mouse livers. Our data indicate that the phosphorylation and kinase activities of Akt/PKB and p38 MAPK, and the levels of phosphorylation of downstream regulators of translation are decreased in Dwarf Mouse livers. Thus, the overall activities of major components of the translational initiation pathway are decreased in the long-lived Snell Dwarf Mouse livers. We propose that down-regulation of protein synthesis may be an important characteristic of the Pit-1 mutation and longevity of the Snell Dwarf Mouse.
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effects of the pit1 mutation on the insulin signaling pathway implications on the longevity of the long lived snell Dwarf Mouse
Mechanisms of Ageing and Development, 2002Co-Authors: Ching-chyuan Hsieh, James H. Deford, Kevin Flurkey, David E. Harrison, John PapaconstantinouAbstract:Mutations in Caenorhabditis elegans and mice have identified candidate genes that increase their lifespan via hormonal signal transduction, i.e. the insulin/IGF-1-like pathway. In this study we propose that longevity of the Snell Dwarf (Pit1(dw)/Pit1(dw)) Mouse is associated with a decrease of the insulin/IGF-1 signaling pathway caused by the Pit1 mutation. We recently demonstrated that the growth hormone deficiency of the Dwarf Mouse alters circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway, which is a determining factor in the increased nematode lifespan. The decreased activity of the insulin/IGF-1 signaling pathway is indicated by decrease of (a) IRS-two pool levels; (b) docking of p85 alpha to IRS-2; (c) docking of p 85 alpha to p110 alpha or p110 beta, and (d) IRS-2-associated PI3K activity. In this study we present data suggesting that the InR beta-IRS-1-PI3K pathway is attenuated in the Snell Dwarf Mouse liver. Our data show that the PI3K activity associated with IRS-1, the docking of IRS-1 to InR beta and the docking of p85 alpha to IRS-1 are attenuated in the aged Snell Dwarf. Our studies suggest that the Pit1 mutation results in a decreased activity of the insulin/IGF-1 pathway; that this plays a key role in the longevity of the Snell Dwarf Mouse and conforms to the nematode longevity paradigm.
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Effects of the Pit1 mutation on the insulin signaling pathway: implications on the longevity of the long-lived Snell Dwarf Mouse.
Mechanisms of ageing and development, 2002Co-Authors: Ching-chyuan Hsieh, James H. Deford, Kevin Flurkey, David E. Harrison, John PapaconstantinouAbstract:Abstract Mutations in Caenorhabditis elegans and mice have identified candidate genes that increase their lifespan via hormonal signal transduction, i.e. the insulin/IGF-1-like pathway. In this study we propose that longevity of the Snell Dwarf (Pit1dw/Pit1dw) Mouse is associated with a decrease of the insulin/IGF-1 signaling pathway caused by the Pit1 mutation. We recently demonstrated that the growth hormone deficiency of the Dwarf Mouse alters circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway, which is a determining factor in the increased nematode lifespan. The decreased activity of the insulin/IGF-1 signaling pathway is indicated by decrease of (a) IRS-two pool levels; (b) docking of p85α to IRS-2; (c) docking of p85α to p110α or p110β, and (d) IRS-2-associated PI3K activity. In this study we present data suggesting that the InRβ-IRS-1-PI3K pathway is attenuated in the Snell Dwarf Mouse liver. Our data show that the PI3K activity associated with IRS-1, the docking of IRS-1 to InRβ and the docking of p85α to IRS-1 are attenuated in the aged Snell Dwarf. Our studies suggest that the Pit1 mutation results in a decreased activity of the insulin/IGF-1 pathway; that this plays a key role in the longevity of the Snell Dwarf Mouse and conforms to the nematode longevity paradigm.
Holly M. Brown-borg - One of the best experts on this subject based on the ideXlab platform.
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Hippocampus of Ames Dwarf mice is resistant to β-amyloid-induced tau hyperphosphorylation and changes in apoptosis-regulatory protein levels
Hippocampus, 2008Co-Authors: Matthew Schrag, Holly M. Brown-borg, Sunita Sharma, Othman GhribiAbstract:The Ames Dwarf Mouse has a long lifespan and is characterized by a marked resistance to cellular stress, an event that is implicated in the pathogenesis of many neurodegenerative disorders that are associated with aging, including Alzheimer's disease. However, very little is known on the extent to which the Ames Dwarf Mouse is protected against Alzheimer's disease. We have developed an organotypic slice system cultured from hippocampi of adult Dwarf mice and examined deleterious effects of beta-amyloid (Abeta) peptide, a key pathogenic event in the course of Alzheimer's disease. We present the first evidence that long living Ames mice resist beta-amyloid toxicity. We demonstrate that organotypic slices from adult Dwarf mice, but not their normal phenotype counterparts (wild type), are resistant to Abeta25-35-induced hyperphosphorylation of tau protein, reduction in levels of the antiapoptotic protein Bcl-2, increase in levels of the pro-apoptotic protein Bax, and activation of caspase 3. Moreover, incubation of organotypic sections with the GSK-3beta inhibitor SB216763 prevented tau phosphorylation but not alterations in levels of Bcl-2, Bax, and caspase-3. Because the hippocampus is a brain area that is severely affected in Alzheimer's disease, our study proposes that organotypic slices from hippocampi of adult Ames Dwarf mice may constitute a model system for understanding endogenous factors that may confer protection against Abeta.
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Methionine flux to transsulfuration is enhanced in the long living Ames Dwarf Mouse.
Mechanisms of ageing and development, 2006Co-Authors: Eric O. Uthus, Holly M. Brown-borgAbstract:Long-lived Ames Dwarf mice lack growth hormone, prolactin, and thyroid stimulating hormone. Additionally the Dwarf mice have enzyme activities and levels that combat oxidative stress more efficiently than those of normal mice. We have shown that methionine metabolism in Ames mice is markedly different than in their wild type littermates. In our previous work we hypothesized that the flux of methionine to the transsulfuration pathway is enhanced in the Dwarf mice. The current study was designed to determine whether the flux of methionine to the transsulfuration pathway is increased. We did this by injecting either l-[methyl-3H]-methionine or l-[35S]-methionine into Dwarf or normal mice and then determined retained label (in form of S-adenosylmethionine) 45 min later. The amount of retained hepatic 3H and 35S label was significantly reduced in the Dwarf mice; at 45 min the specific radioactivity of SAM (pCi/nmol SAM) was 56% lower (p < 0.05) for 3H-label and 64% lower (p < 0.005) for 35S-label in Dwarf than wild type mice. Retention of 35S was significantly lower in the brain (37%, p < 0.04) and kidney (47%, p < 0.02) of the Dwarf compared to wild type mice; there was no statistical difference in retained 3H-label in either brain or kidney. This suggests that both the methyl-moiety and the carbon chain of methionine are lost much faster in the Dwarf compared to the wild type Mouse, implying that both transmethylation in the liver and transsulfuration in the liver, brain, and kidney are increased in the Dwarf mice. As further support, we determined by real-time RT PCR the expression of methionine metabolism genes in livers of mice. Compared to wild type, the Ames Dwarf had increased expression of methionine adenosyltransferase 1a (2.3-fold, p = 0.013), glycine N-methyltransferase (3.8-fold, p = 0.023), betaine homocysteine methyltransferase (5.5-fold, p = 0.0006), S-adenosylhomocysteine hydrolase (3.8-fold, p = 0.0005), and cystathionase (2.6-fold; tended to be increased, p = 0.055). Methionine synthase expression was significantly decreased in Dwarf compared to wild type (0.48-fold, p = 0.023). These results confirm that the flux of methionine to transsulfuration is enhanced in the Ames Dwarf. This, along with data from previous studies support the hypothesis that altered methionine metabolism plays a significant role in the oxidative defense of the Dwarf Mouse and that the mechanism for the enhanced oxidative defense may be through altered GSH metabolism as a result of the distinctive methionine metabolism.
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Long-lived Ames Dwarf Mouse exhibits increased antioxidant defense in skeletal muscle.
Mechanisms of ageing and development, 2004Co-Authors: Mark Romanick, Sharlene G. Rakoczy, Holly M. Brown-borgAbstract:Resting and exercised (both acute and chronic) hindlimb skeletal muscle from long-lived Ames Dwarf and wild type mice at 3, 12, 18, and 24 months of age was tested for antioxidant enzyme activity and protein, non-enzymatic antioxidant ratios, mitochondrial hydrogen peroxide concentration, and plasma lactate levels. Differences were observed in GPX enzyme activity between Mouse genotypes at all physical activity levels, with Dwarf mice exhibiting depressed levels at younger ages (3 months: P = 0.09 [non-swim], P = 0.03 [acute swim], P = 0.04 [chronic swim]) and comparatively higher levels than wild type mice at older ages (18-24 months: P = 0.05 [acute swim], P = 0.07 [chronic swim]). Catalase enzyme activity and the GSH system rarely demonstrated significant differences between genotypes, regardless of age or activity. However, the chronic exercise group displayed a difference in GSH:GSSG ratios between Mouse genotypes (P = 0.005). Plasma lactate concentrations were elevated in the wild type mice compared to the Dwarf mice at all ages in all activity groups. These results suggest there are biological differences with regard to antioxidant defense that favor the Ames Dwarf Mouse in active and resting skeletal muscle when compared to wild type mice.
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Life extension in the Dwarf Mouse.
Current topics in developmental biology, 2004Co-Authors: Andrzej Bartke, Holly M. Brown-borgAbstract:Abstract Ames Dwarf mice and Snell Dwarf mice lack growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH), live much longer than their normal siblings, and exhibit many symptoms of delayed aging. “Laron Dwarf mice,” produced by targeted disruption of the GH receptor⧸GH-binding protein gene (GHR-KO mice), are GH resistant and also live much longer than normal animals from the same line. Isolated GH deficiency in “little” mice is similarly associated with increased life span, provided that obesity is prevented by reducing fat content in the diet. Long-lived Dwarf mice share many phenotypic characteristics with genetically normal (wild-type) animals subjected to prolonged caloric restriction (CR) but are not CR mimetics. We propose that mechanisms linking GH deficiency and GH resistance with delayed aging include reduced hepatic synthesis of insulin-like growth factor 1 (IGF-1), reduced secretion of insulin, increased hepatic sensitivity to insulin actions, reduced plasma glucose, reduced generation of reactive oxygen species, improved antioxidant defenses, increased resistance to oxidative stress, and reduced oxidative damage. The possible role of hypothyroidism, reduced body temperature, reduced adult body size, delayed puberty, and reduced fecundity in producing the long-lived phenotype of Dwarf mice remains to be evaluated. An important role of IGF-1 and insulin in the control of mammalian longevity is consistent with the well-documented actions of homologous signaling pathways in invertebrates.
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Long-living Ames Dwarf Mouse hepatocytes readily undergo apoptosis.
Experimental gerontology, 2003Co-Authors: Melissa A. Kennedy, Sharlene G. Rakoczy, Holly M. Brown-borgAbstract:Ames Dwarf mice live 50–64% longer and exhibit upregulated antioxidative defenses and lower cellular damage when compared to age-matched wild-type littermates. Due to the relationship between aging and apoptosis, the purpose of this study was to compare basal levels of apoptosis-related proteins in Dwarf and wild-type tissues and to compare the response of Dwarf and wild-type primary hepatocytes to oxidative stress. Hepatocytes from Dwarf and wild-type mice (6 month-old) were isolated using collagenase perfusion and treated with hydrogen peroxide. Viability, activity, protein levels, and morphological changes were evaluated. Procaspase-3 protein levels were increased in Dwarf kidney and liver (p
David E. Harrison - One of the best experts on this subject based on the ideXlab platform.
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Altered oxidative stress response of the long-lived Snell Dwarf Mouse.
Biochemical and biophysical research communications, 2004Co-Authors: Mark A. Madsen, Ching-chyuan Hsieh, Kevin Flurkey, David E. Harrison, William H. Boylston, John PapaconstantinouAbstract:Abstract Several single gene mutations in mice that increase the murine life span have been identified, including the Pit-1 mutation which results in the Snell Dwarf (Pit1dw/dw), however, the biological mechanism of this life-span extension is still unclear. Based on studies that show oxidative stress plays an important role in the aging process, we hypothesized that the increased longevity seen in Snell Dwarf mice may result from a resistance to oxidative stress. We report that Snell Dwarf mice respond to oxidative stress induced by 3-NPA differently than their wild type littermates. This altered response results in diminished activation of the MEK–ERK kinase cascade and virtually no phosphorylation of c-Jun at Ser63 in Dwarf mice after 3-NPA treatment, despite a robust phosphorylation of Ser63 in wild type mice. We propose that this altered management of oxidative stress in Dwarf mice is partially responsible for the increased longevity in Snell Dwarf mice.
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effects of the pit1 mutation on the insulin signaling pathway implications on the longevity of the long lived snell Dwarf Mouse
Mechanisms of Ageing and Development, 2002Co-Authors: Ching-chyuan Hsieh, James H. Deford, Kevin Flurkey, David E. Harrison, John PapaconstantinouAbstract:Mutations in Caenorhabditis elegans and mice have identified candidate genes that increase their lifespan via hormonal signal transduction, i.e. the insulin/IGF-1-like pathway. In this study we propose that longevity of the Snell Dwarf (Pit1(dw)/Pit1(dw)) Mouse is associated with a decrease of the insulin/IGF-1 signaling pathway caused by the Pit1 mutation. We recently demonstrated that the growth hormone deficiency of the Dwarf Mouse alters circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway, which is a determining factor in the increased nematode lifespan. The decreased activity of the insulin/IGF-1 signaling pathway is indicated by decrease of (a) IRS-two pool levels; (b) docking of p85 alpha to IRS-2; (c) docking of p 85 alpha to p110 alpha or p110 beta, and (d) IRS-2-associated PI3K activity. In this study we present data suggesting that the InR beta-IRS-1-PI3K pathway is attenuated in the Snell Dwarf Mouse liver. Our data show that the PI3K activity associated with IRS-1, the docking of IRS-1 to InR beta and the docking of p85 alpha to IRS-1 are attenuated in the aged Snell Dwarf. Our studies suggest that the Pit1 mutation results in a decreased activity of the insulin/IGF-1 pathway; that this plays a key role in the longevity of the Snell Dwarf Mouse and conforms to the nematode longevity paradigm.
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Effects of the Pit1 mutation on the insulin signaling pathway: implications on the longevity of the long-lived Snell Dwarf Mouse.
Mechanisms of ageing and development, 2002Co-Authors: Ching-chyuan Hsieh, James H. Deford, Kevin Flurkey, David E. Harrison, John PapaconstantinouAbstract:Abstract Mutations in Caenorhabditis elegans and mice have identified candidate genes that increase their lifespan via hormonal signal transduction, i.e. the insulin/IGF-1-like pathway. In this study we propose that longevity of the Snell Dwarf (Pit1dw/Pit1dw) Mouse is associated with a decrease of the insulin/IGF-1 signaling pathway caused by the Pit1 mutation. We recently demonstrated that the growth hormone deficiency of the Dwarf Mouse alters circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway, which is a determining factor in the increased nematode lifespan. The decreased activity of the insulin/IGF-1 signaling pathway is indicated by decrease of (a) IRS-two pool levels; (b) docking of p85α to IRS-2; (c) docking of p85α to p110α or p110β, and (d) IRS-2-associated PI3K activity. In this study we present data suggesting that the InRβ-IRS-1-PI3K pathway is attenuated in the Snell Dwarf Mouse liver. Our data show that the PI3K activity associated with IRS-1, the docking of IRS-1 to InRβ and the docking of p85α to IRS-1 are attenuated in the aged Snell Dwarf. Our studies suggest that the Pit1 mutation results in a decreased activity of the insulin/IGF-1 pathway; that this plays a key role in the longevity of the Snell Dwarf Mouse and conforms to the nematode longevity paradigm.
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Implications for the insulin signaling pathway in Snell Dwarf Mouse longevity: a similarity with the C. elegans longevity paradigm
Mechanisms of ageing and development, 2002Co-Authors: Ching-chyuan Hsieh, James H. Deford, Kevin Flurkey, David E. Harrison, John PapaconstantinouAbstract:Abstract Mutation analyses in the nematode, Caenorhabditis elegans , and mice have identified genes that increase their life-span via hormonal signal transduction, i.e. the insulin/insulin-like growth factor-1 (IGF-1) pathway in nematodes, and the growth hormone (GH)–thyriod stimulating hormone (TSH)–prolactin system in Snell Dwarf Mouse mutants. We have shown that the GH deficiency due to Pit1 mutation in the long-lived Snell Dwarf mice may decrease circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway. The data presented are consistent with our hypothesis that the decreased circulating insulin levels resulting from the Pit1 mutation mimics a physiological state similar to that proposed to occur in the long-lived C. elegans , daf-2 mutant. Our studies demonstrate a series of changes in components of the insulin/IGF-1-signaling pathway that suggest a reduction-of-function of this pathway in the aged Dwarf. These include a decreased IRS-2 pool level, a decrease in PI3K activity and its association with IRS-2 and decreased docking of p85α to IRS-2. Our data also suggest a preferential docking of IRS-2-p85α-p110α in the aged Dwarf liver and IRS-2-p85α-p110β in the aged control. We speculate that the preference for the p110α-containing complex may be a specific characteristic of a downstream segment of the longevity-signaling cascade. We conclude that the Pit1 mutation may result in physiological homeostasis that favors longevity, and that the Snell Dwarf mutant conforms to the nematode longevity paradigm.
Kevin Flurkey - One of the best experts on this subject based on the ideXlab platform.
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Altered oxidative stress response of the long-lived Snell Dwarf Mouse.
Biochemical and biophysical research communications, 2004Co-Authors: Mark A. Madsen, Ching-chyuan Hsieh, Kevin Flurkey, David E. Harrison, William H. Boylston, John PapaconstantinouAbstract:Abstract Several single gene mutations in mice that increase the murine life span have been identified, including the Pit-1 mutation which results in the Snell Dwarf (Pit1dw/dw), however, the biological mechanism of this life-span extension is still unclear. Based on studies that show oxidative stress plays an important role in the aging process, we hypothesized that the increased longevity seen in Snell Dwarf mice may result from a resistance to oxidative stress. We report that Snell Dwarf mice respond to oxidative stress induced by 3-NPA differently than their wild type littermates. This altered response results in diminished activation of the MEK–ERK kinase cascade and virtually no phosphorylation of c-Jun at Ser63 in Dwarf mice after 3-NPA treatment, despite a robust phosphorylation of Ser63 in wild type mice. We propose that this altered management of oxidative stress in Dwarf mice is partially responsible for the increased longevity in Snell Dwarf mice.
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effects of the pit1 mutation on the insulin signaling pathway implications on the longevity of the long lived snell Dwarf Mouse
Mechanisms of Ageing and Development, 2002Co-Authors: Ching-chyuan Hsieh, James H. Deford, Kevin Flurkey, David E. Harrison, John PapaconstantinouAbstract:Mutations in Caenorhabditis elegans and mice have identified candidate genes that increase their lifespan via hormonal signal transduction, i.e. the insulin/IGF-1-like pathway. In this study we propose that longevity of the Snell Dwarf (Pit1(dw)/Pit1(dw)) Mouse is associated with a decrease of the insulin/IGF-1 signaling pathway caused by the Pit1 mutation. We recently demonstrated that the growth hormone deficiency of the Dwarf Mouse alters circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway, which is a determining factor in the increased nematode lifespan. The decreased activity of the insulin/IGF-1 signaling pathway is indicated by decrease of (a) IRS-two pool levels; (b) docking of p85 alpha to IRS-2; (c) docking of p 85 alpha to p110 alpha or p110 beta, and (d) IRS-2-associated PI3K activity. In this study we present data suggesting that the InR beta-IRS-1-PI3K pathway is attenuated in the Snell Dwarf Mouse liver. Our data show that the PI3K activity associated with IRS-1, the docking of IRS-1 to InR beta and the docking of p85 alpha to IRS-1 are attenuated in the aged Snell Dwarf. Our studies suggest that the Pit1 mutation results in a decreased activity of the insulin/IGF-1 pathway; that this plays a key role in the longevity of the Snell Dwarf Mouse and conforms to the nematode longevity paradigm.
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Effects of the Pit1 mutation on the insulin signaling pathway: implications on the longevity of the long-lived Snell Dwarf Mouse.
Mechanisms of ageing and development, 2002Co-Authors: Ching-chyuan Hsieh, James H. Deford, Kevin Flurkey, David E. Harrison, John PapaconstantinouAbstract:Abstract Mutations in Caenorhabditis elegans and mice have identified candidate genes that increase their lifespan via hormonal signal transduction, i.e. the insulin/IGF-1-like pathway. In this study we propose that longevity of the Snell Dwarf (Pit1dw/Pit1dw) Mouse is associated with a decrease of the insulin/IGF-1 signaling pathway caused by the Pit1 mutation. We recently demonstrated that the growth hormone deficiency of the Dwarf Mouse alters circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway, which is a determining factor in the increased nematode lifespan. The decreased activity of the insulin/IGF-1 signaling pathway is indicated by decrease of (a) IRS-two pool levels; (b) docking of p85α to IRS-2; (c) docking of p85α to p110α or p110β, and (d) IRS-2-associated PI3K activity. In this study we present data suggesting that the InRβ-IRS-1-PI3K pathway is attenuated in the Snell Dwarf Mouse liver. Our data show that the PI3K activity associated with IRS-1, the docking of IRS-1 to InRβ and the docking of p85α to IRS-1 are attenuated in the aged Snell Dwarf. Our studies suggest that the Pit1 mutation results in a decreased activity of the insulin/IGF-1 pathway; that this plays a key role in the longevity of the Snell Dwarf Mouse and conforms to the nematode longevity paradigm.
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Implications for the insulin signaling pathway in Snell Dwarf Mouse longevity: a similarity with the C. elegans longevity paradigm
Mechanisms of ageing and development, 2002Co-Authors: Ching-chyuan Hsieh, James H. Deford, Kevin Flurkey, David E. Harrison, John PapaconstantinouAbstract:Abstract Mutation analyses in the nematode, Caenorhabditis elegans , and mice have identified genes that increase their life-span via hormonal signal transduction, i.e. the insulin/insulin-like growth factor-1 (IGF-1) pathway in nematodes, and the growth hormone (GH)–thyriod stimulating hormone (TSH)–prolactin system in Snell Dwarf Mouse mutants. We have shown that the GH deficiency due to Pit1 mutation in the long-lived Snell Dwarf mice may decrease circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway. The data presented are consistent with our hypothesis that the decreased circulating insulin levels resulting from the Pit1 mutation mimics a physiological state similar to that proposed to occur in the long-lived C. elegans , daf-2 mutant. Our studies demonstrate a series of changes in components of the insulin/IGF-1-signaling pathway that suggest a reduction-of-function of this pathway in the aged Dwarf. These include a decreased IRS-2 pool level, a decrease in PI3K activity and its association with IRS-2 and decreased docking of p85α to IRS-2. Our data also suggest a preferential docking of IRS-2-p85α-p110α in the aged Dwarf liver and IRS-2-p85α-p110β in the aged control. We speculate that the preference for the p110α-containing complex may be a specific characteristic of a downstream segment of the longevity-signaling cascade. We conclude that the Pit1 mutation may result in physiological homeostasis that favors longevity, and that the Snell Dwarf mutant conforms to the nematode longevity paradigm.
