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Holly M. Brown-borg - One of the best experts on this subject based on the ideXlab platform.

  • The Ames Dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice
    Neurobiology of aging, 2016
    Co-Authors: Kendra L. Puig, Sharlene G. Rakoczy, Holly M. Brown-borg, Joshua A. Kulas, Whitney Franklin, Giulio Taglialatela, Colin K. Combs
    Abstract:

    APP/PS1 double transgenic mice expressing human mutant amyloid precursor protein (APP) and presenilin-1 (PS1) demonstrate robust brain amyloid beta (Aβ) peptide containing plaque deposition, increased markers of oxidative stress, behavioral dysfunction, and proinflammatory gliosis. On the other hand, lack of growth hormone, prolactin, and thyroid-stimulating hormone due to a recessive mutation in the Prop 1 gene (Prop1df) in Ames Dwarf mice results in a phenotype characterized by potentiated antioxidant mechanisms, improved learning and memory, and significantly increased longevity in homozygous mice. Based on this, we hypothesized that a similar hormone deficiency might attenuate disease changes in the brains of APP/PS1 mice. To test this idea, APP/PS1 mice were crossed to the Ames Dwarf Mouse line. APP/PS1, wild-type, df/+, df/df, df/+/APP/PS1, and df/df/APP/PS1 mice were compared at 6 months of age through behavioral testing and assessing amyloid burden, reactive gliosis, and brain cytokine levels. df/df mice demonstrated lower brain growth hormone and insulin-like growth factor 1 concentrations. This correlated with decreased astrogliosis and microgliosis in the df/df/APP/PS1 mice and, surprisingly, reduced Aβ plaque deposition and Aβ 1-40 and Aβ 1-42 concentrations. The df/df/APP/PS1 mice also demonstrated significantly elevated brain levels of multiple cytokines in spite of the attenuated gliosis. These data indicate that the df/df/APP/PS1 line is a unique resource in which to study aging and resistance to disease and suggest that the affected pituitary hormones may have a role in regulating disease progression.

  • Expression of DNA Methyltransferases Is Influenced by Growth Hormone in the Long-Living Ames Dwarf Mouse In Vivo and In Vitro
    The journals of gerontology. Series A Biological sciences and medical sciences, 2013
    Co-Authors: Vanessa Armstrong, Sharlene G. Rakoczy, Lalida Rojanathammanee, Holly M. Brown-borg
    Abstract:

    Methyltransferase expression and DNA methylation are linked to aging and age-related disease. We utilized 3-, 12-, and 24-month-old Ames Dwarf and their wild-type siblings to examine the genotype and age-related differences in the expression of methyltransferase enzymes related to DNA methylation in the liver, glycine-N-methyltransferase and DNA methyltransferase (DNMT). We found that DNMT proteins and transcripts are differentially expressed in Dwarf mice compared with wild-type siblings that can be attributed to age and/or genotype. However, DNMT1 protein expression is drastically reduced compared with wild-type controls at every age. DNMT3a protein levels coincide with differences observed in DNMT activity. Growth hormone appears to modulate expression of DNMT1 and 3a in Dwarf liver tissue and primary hepatocytes. Therefore, growth hormone may contribute to age-related processes, DNA methylation, and, ultimately, longevity.

  • NMDA and kainate receptor expression, long-term potentiation, and neurogenesis in the hippocampus of long-lived Ames Dwarf mice
    AGE, 2012
    Co-Authors: Sunita Sharma, Sharlene Rakoczy, Diane Darland, Saobo Lei, Holly M. Brown-borg
    Abstract:

    In the current study, we investigated changes in N -methyl d -aspartate (NMDA) and kainate receptor expression, long-term potentiation (LTP), and neurogenesis in response to neurotoxic stress in long-living Ames Dwarf mice. We hypothesized that Ames Dwarf mice have enhanced neurogenesis that enables retention of spatial learning and memory with age and promotes neurogenesis in response to injury. Levels of the NMDA receptors (NR)1, NR2A, NR2B, and the kainate receptor (KAR)2 were increased in Ames Dwarf mice, relative to wild-type littermates. Quantitative assessment of the excitatory postsynaptic potential in Schaffer collaterals in hippocampal slices from Ames Dwarf mice showed an increased response in high-frequency induced LTP over time compared with wild type. Kainic acid (KA) injection was used to promote neurotoxic stress-induced neurogenesis. KA mildly increased the number of doublecortin-positive neurons in wild-type mice, but the response was significantly enhanced in the Ames Dwarf mice. Collectively, these data support our hypothesis that the enhanced learning and memory associated with the Ames Dwarf Mouse may be due to elevated levels of NMDA and KA receptors in hippocampus and their ability to continue producing new neurons in response to neuronal damage.

  • Hippocampus of Ames Dwarf mice is resistant to β-amyloid-induced tau hyperphosphorylation and changes in apoptosis-regulatory protein levels
    Hippocampus, 2008
    Co-Authors: Matthew Schrag, Holly M. Brown-borg, Sunita Sharma, Othman Ghribi
    Abstract:

    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.

  • Methionine flux to transsulfuration is enhanced in the long living Ames Dwarf Mouse.
    Mechanisms of ageing and development, 2006
    Co-Authors: Eric O. Uthus, Holly M. Brown-borg
    Abstract:

    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.

Andrzej Bartke - One of the best experts on this subject based on the ideXlab platform.

  • MicroRNA regulation in Ames Dwarf Mouse liver may contribute to delayed aging
    Aging cell, 2009
    Co-Authors: David J. Bates, Andrzej Bartke, Ruqiang Liang, Harshini Sarojini, Michal M. Masternak, Eugenia Wang
    Abstract:

    The Ames Dwarf Mouse is well known for its remarkable propensity to delay the onset of aging. Although significant advances have been made demonstrating that this aging phenotype results primarily from an endocrine imbalance, the posttranscriptional regulation of gene expression and its impact on longevity remains to be explored. Towards this end, we present the first comprehensive study by microRNA microarray screening to identify Dwarf-specific lead microRNAs, and investigate their roles as pivotal molecular regulators directing the long-lived phenotype. Mapping the signature microRNAs to the inversely expressed putative target genes, followed by in situ immunohistochemical staining and in vitro correlation assays, reveal that Dwarf mice posttranscriptionally regulate key proteins of intermediate metabolism, most importantly the biosynthetic pathway involving ornithine decarboxylase and spermidine synthase. Functional assays using 3′UTR reporter constructs in co-transfection experiments confirm that microRNA-27a indeed suppresses the expression of both of these proteins, marking them as probable targets of this microRNA in vivo. Moreover, the putative repressed action of this microRNA on ornithine decarboxylase is identified in Dwarf Mouse liver as early as two months of age. Taken together, our results show that among the altered aspects of intermediate metabolism detected in the Dwarf Mouse liver — glutathione metabolism, the urea cycle, and polyamine biosynthesis — microRNA-27a is a key posttranscriptional control. Furthermore, compared to its normal siblings, the Dwarf Mouse exhibits a head start in regulating these pathways to control their normality, which may ultimately contribute to its extended healthspan and longevity.

  • reduced levels of thyroid hormones insulin and glucose and lower body core temperature in the growth hormone receptor binding protein knockout Mouse
    Experimental Biology and Medicine, 2001
    Co-Authors: Steven J Hauck, William S Hunter, Natasha Danilovich, John J Kopchick, Andrzej Bartke
    Abstract:

    The mechanisms that are responsible for the extension of lifespan in the Mouse with targeted disruption (knockout [KO]) of the growth hormone (GH) receptor/binding protein (GHR-KO) are unknown. However, in the long-living Ames Dwarf Mouse, blood glucose and body core temperature (Tco) are consistently lower than in normal mice. In addition, insulin levels are reduced and corticosterone levels are elevated in male Dwarfs. These functional alterations, similar to those seen in animals under caloric restriction, have not been proven to be causally related to the extension of lifespan, but they do provide some insight into what traits may be necessary for long life. Therefore, to investigate which of these parameters are similarly affected in two genetically unrelated, yet similarly long-living Mouse models, we measured Tco, thyroid hormones (triiodothyronine [T3] and thyroxine [T4]), and insulin, in addition to morning and afternoon levels of glucose and corticosterone, in young adult male and/or female GHR-KO mice and their normal siblings. Tco in GHR-KO mice was numerically reduced throughout the 24-hr period; however, these differences were only significant 4 hr prior to lights-off (14:00 hr), immediately after lights-off (18:00 hr), and during the 3 hr preceding lights on (03:00 to 06:00 hr). GHR-KO mice had significantly reduced levels of T3 and T4, while the ratio of these hormones was similar to that in normal mice. Insulin levels in GHR-KO mice were lower than in normal mice; levels in male GHR-KO mice were below the detectable limits of the assay used. Glucose levels in GHR-KO mice (male and females) were lower than in normal mice in measurements taken in both morning and afternoon; however, these differences arose from consistent reductions in males, as morning glucose levels in GHR-KO females were similar to those of normal mice. Corticosterone levels measured in blood plasma collected under basal (nonstressed) conditions showed sex-related alterations. Basal corticosterone levels in female GHR-KO mice were similar to normal females, while those in male GHR-KO mice were higher than in normal males in the afternoon. Corticosterone levels in stressed GHR-KO females were similar to those measured in stressed normal females. These data show that the long-living GHR-KO Mouse shares a reduction in glucose, insulin, thyroid hormones, and Tco with the Ames Dwarf Mouse. Reductions in these parameters may be important to the underlying mechanisms of delayed aging in these animals.

  • Array-Based Expression Analysis of Mouse Liver Genes Effect of Age and of the Longevity Mutant Prop1df
    The journals of gerontology. Series A Biological sciences and medical sciences, 2001
    Co-Authors: Igor Dozmorov, Andrzej Bartke, Richard A. Miller
    Abstract:

    Ames Dwarf mice, homozygous for the df allele at the Prop1 locus, live 40% to 70% longer than nonmutant siblings and represent the first single-gene mutant that extends life span in a mammal. To gain insight into the basis for the longevity of the Ames Dwarf Mouse, we measured liver mRNA levels for 265 genes in a group of 11 df/df mice, (three to four mice per age group), at ages 5, 13, and 22 months, and in 13 age- and sex-matched control mice. The analysis showed seven genes where the effects of age reach p < .01 in normal mice and six others with possible age effects in Dwarf mice, but none of these met Bonferroni-adjusted significance thresholds. Thirteen genes showed possible effects of the df/df genotype at p < .01. One of these, insulin-like growth factor 1 (IGF-1), was statistically significant even after adjustment for multiple comparisons; and genes for two IGF-binding proteins, a cyclin, a heat shock protein, p38 mitogen-activated protein kinase, and an inducible cytochrome P450 were among those implicated by the survey. In young control mice, half of the expressed genes showed SDs that were more than 58% of the mean, and a simulation study showed that genes with this degree of interanimal variation would often produce false-positive findings when conclusions were based on ratio calculations alone (i.e., without formal significance testing). Many genes in our data set showed apparent young-to-old or normal-to-Dwarf ratios above 2, but the large majority of these proved to be genes where high interanimal variation could create high ratios by chance alone, and only a few of the genes with large ratios achieved p < .05. The proportion of genes showing relatively large changes between 5 and 13 months, or from 13 to 22 months of age, was not diminished by the df/df genotype, providing no support for the idea that the Dwarf mutation leads to global delay or deceleration of the pace of age-dependent changes in gene expression. These survey data provide the foundation for replication studies that should provide convincing proof for age- and genotype-specific effects on gene expression and thus reveal key similarities among the growing number of Mouse models of decelerated aging.

  • Evidence That Ames Dwarf Mice Age Differently From Their Normal Siblings in Behavioral and Learning and Memory Parameters
    Hormones and behavior, 2001
    Co-Authors: Beth Kinney, C.j. Meliska, Richard W. Steger, Andrzej Bartke
    Abstract:

    There is strong evidence supporting the deleterious effects of aging on learning and memory and behavioral parameters in normal mice. However, little is known about the Ames Dwarf Mouse, which has a Prop-1 gene mutation resulting in deficiencies in growth hormone, thyroid-stimulating hormone, and prolactin. These mice are much smaller and live significantly longer than their normal siblings. Using the elevated plus-maze, locomotor activity meters, and an inhibitory avoidance learning task, the present study compared Ames Dwarf mice to their normal siblings. Results showed that Ames Dwarf mice did not experience an age-related decline in locomotor activity when compared to their young counterparts. Furthermore, old Dwarf mice did not differ from the young groups in inhibitory avoidance retention, while old normal animals performed more poorly than both young groups on this test. Elevated plus-maze behavior did not differ in the old normal versus Dwarf groups, but the old groups did differ from the young. Results indicate that both old groups experienced a significant decline in anxiety with age. Taken together, these results indicate that multiple hormone deficiencies resulting from a lack of primary pituitary function have beneficial effects on cognitive function and locomotor behavior in advanced age. In fact, the Ames Dwarf Mouse may provide a model for studies of delayed mental as well as physical aging.

  • Array-based expression analysis of Mouse liver genes: effect of age and of the longevity mutant Prop1df. J Gerontol A Biol Sci Med Sci 56: B72–B80
    2001
    Co-Authors: Igor Dozmorov, Andrzej Bartke, Richard A. Miller
    Abstract:

    Ames Dwarf mice, homozygous for the df allele at the Prop1 locus, live 40 % to 70 % longer than nonmutant sib-lings and represent the first single-gene mutant that extends life span in a mammal. To gain insight into the basis for the longevity of the Ames Dwarf Mouse, we measured liver mRNA levels for 265 genes in a group of 11 df/df mice, (three to four mice per age group), at ages 5, 13, and 22 months, and in 13 age- and sex-matched control mice. The analysis showed seven genes where the effects of age reach p.01 in normal mice and six others with possible age effects in Dwarf mice, but none of these met Bonferroni-adjusted significance thresholds. Thirteen genes showed possible effects of the df/df genotype at

Holly M Brownborg - One of the best experts on this subject based on the ideXlab platform.

  • long living Ames Dwarf Mouse hepatocytes readily undergo apoptosis
    Experimental Gerontology, 2003
    Co-Authors: Melissa A. Kennedy, Sharlene Rakoczy, Holly M Brownborg
    Abstract:

    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<0.05) while Bcl-2 protein levels were significantly higher in Dwarf liver at 24 months of age. Bax protein levels were markedly elevated in several tissues at different ages and Bcl-2/Bax ratios were lower in many Dwarf tissues. In culture, peroxide-treated Dwarf hepatocytes showed lower viability (p<0.03) and higher caspase-3 activity induction when compared to peroxide-treated wild-type cells. Peroxide-treated Dwarf hepatocytes frequently showed morphological characteristics reminiscent of apoptosis, which were not observed in peroxide-treated wild-type hepatocytes. This suggests that when experiencing an oxidative challenge, Ames Dwarf hepatocytes more readily undergo apoptosis than wild-type cells, providing an advantage to Dwarf mice, whereby they more efficiently eliminate damaged cells, thus contributing to their longer lives.

  • age related effects of ectopic pituitary transplants on the activation of Ames Dwarf Mouse lymphocytes in vitro
    Experimental Biology and Medicine, 1996
    Co-Authors: Ana I. Esquifino, Holly M Brownborg, A. Szary, Andrzej Bartke
    Abstract:

    Prolactin (PRL), one of the anterior pituitary hormones, has been implicated in the development and maintenance of immune system function. The following experiments were conducted to evaluate age-related effects of PRL on immune system activity in a PRL-deficient Mouse model, the Ames Dwarf. Two- and ten-month-old Dwarf and phenotypically normal male mice were used. Six Dwarf mice from each age group received a surgically implanted pituitary (under the kidney capsule) from a normal donor female Mouse. Six different Dwarfs were similarly operated but had no pituitary graft inserted and will be referred to as sham-operated Dwarfs. Three weeks following surgery, spleens were removed from the Dwarfs and age-matched normal mice and splenocytes isolated. The two age groups will subsequently be referred to as "3-month-old" and "11-month-old", respectively, The splenocytes were used in mitogen-induced (concanavalin A (Con A); phytohemagglutinin (PHA); lipopolysaccharide (LPS)) proliferation assays, and histopaque isolated lymphocytes were used for T cell surface marker determination. Pituitary grafting increased body weights of Dwarf mice although the weights were less than control mice independent of age. A similar pattern was observed for total number of splenocytes per spleen. In young animals, the relative number of splenocytes per gram of body weight increased in pituitary grafted Dwarfs reaching values of control mice, whereas much smaller differences were observed in older animals. The relative percentage of CD4+ cells was reduced (P<0.01) in 3-month-old pituitary-grafted mice, compared with sham-operated Dwarf mice, while no differences were observed between sham- operated Dwarf and normal mice. Pituitary grafting did not affect the numbers of CD8+ cells. In 11-month-old animals, the relative percentages of CD4+ and CD8+ cells were greater (P<0.05) in sham-operated Dwarf than in normal mice but not affected by pituitary grafting. At 3 months of age, proliferation of splenocytes in response to Con A was increased (P<0.05) in sham-operated Dwarfs and reduced (P<0.05) in pituitary-grafted Dwarfs compared with normal mice. In contrast, PHA stimulation of splenocytes was decreased (P<0.05) in sham-operated compared with normal, and was still lower in mice receiving an ectopic pituitary. Substantially different responses were obtained in 11-month-old animals. In response to Con A, splenocytes from sham-operated Dwarfs exhibited a reduced (P<0.05) proliferative capacity as compared with normals, and proliferation was increased in pituitary-grafted as compared with sham-operated Dwarfs. In the presence of PHA, the proliferative capacity of splenocytes was greater (P<0.05) in sham-operated Dwarfs as compared to normals and pituitary grafting normalized this parameter. These results demonstrate differential effects of PRL deficiency (sham-operated Dwarfs versus normal) and of PRL replacement (pituitary-grafted versus sham-operated) in young as compared with old Dwarf mice on immune system activation.

Melissa A. Kennedy - One of the best experts on this subject based on the ideXlab platform.

  • Long-living Ames Dwarf Mouse hepatocytes readily undergo apoptosis.
    Experimental gerontology, 2003
    Co-Authors: Melissa A. Kennedy, Sharlene G. Rakoczy, Holly M. Brown-borg
    Abstract:

    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

  • long living Ames Dwarf Mouse hepatocytes readily undergo apoptosis
    Experimental Gerontology, 2003
    Co-Authors: Melissa A. Kennedy, Sharlene Rakoczy, Holly M Brownborg
    Abstract:

    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<0.05) while Bcl-2 protein levels were significantly higher in Dwarf liver at 24 months of age. Bax protein levels were markedly elevated in several tissues at different ages and Bcl-2/Bax ratios were lower in many Dwarf tissues. In culture, peroxide-treated Dwarf hepatocytes showed lower viability (p<0.03) and higher caspase-3 activity induction when compared to peroxide-treated wild-type cells. Peroxide-treated Dwarf hepatocytes frequently showed morphological characteristics reminiscent of apoptosis, which were not observed in peroxide-treated wild-type hepatocytes. This suggests that when experiencing an oxidative challenge, Ames Dwarf hepatocytes more readily undergo apoptosis than wild-type cells, providing an advantage to Dwarf mice, whereby they more efficiently eliminate damaged cells, thus contributing to their longer lives.

Sharlene G. Rakoczy - One of the best experts on this subject based on the ideXlab platform.

  • The Ames Dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice
    Neurobiology of aging, 2016
    Co-Authors: Kendra L. Puig, Sharlene G. Rakoczy, Holly M. Brown-borg, Joshua A. Kulas, Whitney Franklin, Giulio Taglialatela, Colin K. Combs
    Abstract:

    APP/PS1 double transgenic mice expressing human mutant amyloid precursor protein (APP) and presenilin-1 (PS1) demonstrate robust brain amyloid beta (Aβ) peptide containing plaque deposition, increased markers of oxidative stress, behavioral dysfunction, and proinflammatory gliosis. On the other hand, lack of growth hormone, prolactin, and thyroid-stimulating hormone due to a recessive mutation in the Prop 1 gene (Prop1df) in Ames Dwarf mice results in a phenotype characterized by potentiated antioxidant mechanisms, improved learning and memory, and significantly increased longevity in homozygous mice. Based on this, we hypothesized that a similar hormone deficiency might attenuate disease changes in the brains of APP/PS1 mice. To test this idea, APP/PS1 mice were crossed to the Ames Dwarf Mouse line. APP/PS1, wild-type, df/+, df/df, df/+/APP/PS1, and df/df/APP/PS1 mice were compared at 6 months of age through behavioral testing and assessing amyloid burden, reactive gliosis, and brain cytokine levels. df/df mice demonstrated lower brain growth hormone and insulin-like growth factor 1 concentrations. This correlated with decreased astrogliosis and microgliosis in the df/df/APP/PS1 mice and, surprisingly, reduced Aβ plaque deposition and Aβ 1-40 and Aβ 1-42 concentrations. The df/df/APP/PS1 mice also demonstrated significantly elevated brain levels of multiple cytokines in spite of the attenuated gliosis. These data indicate that the df/df/APP/PS1 line is a unique resource in which to study aging and resistance to disease and suggest that the affected pituitary hormones may have a role in regulating disease progression.

  • Expression of DNA Methyltransferases Is Influenced by Growth Hormone in the Long-Living Ames Dwarf Mouse In Vivo and In Vitro
    The journals of gerontology. Series A Biological sciences and medical sciences, 2013
    Co-Authors: Vanessa Armstrong, Sharlene G. Rakoczy, Lalida Rojanathammanee, Holly M. Brown-borg
    Abstract:

    Methyltransferase expression and DNA methylation are linked to aging and age-related disease. We utilized 3-, 12-, and 24-month-old Ames Dwarf and their wild-type siblings to examine the genotype and age-related differences in the expression of methyltransferase enzymes related to DNA methylation in the liver, glycine-N-methyltransferase and DNA methyltransferase (DNMT). We found that DNMT proteins and transcripts are differentially expressed in Dwarf mice compared with wild-type siblings that can be attributed to age and/or genotype. However, DNMT1 protein expression is drastically reduced compared with wild-type controls at every age. DNMT3a protein levels coincide with differences observed in DNMT activity. Growth hormone appears to modulate expression of DNMT1 and 3a in Dwarf liver tissue and primary hepatocytes. Therefore, growth hormone may contribute to age-related processes, DNA methylation, and, ultimately, longevity.

  • Long-lived Ames Dwarf Mouse exhibits increased antioxidant defense in skeletal muscle.
    Mechanisms of ageing and development, 2004
    Co-Authors: Mark Romanick, Sharlene G. Rakoczy, Holly M. Brown-borg
    Abstract:

    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.

  • Long-living Ames Dwarf Mouse hepatocytes readily undergo apoptosis.
    Experimental gerontology, 2003
    Co-Authors: Melissa A. Kennedy, Sharlene G. Rakoczy, Holly M. Brown-borg
    Abstract:

    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