Jacob A Panici

Publications (12)51.76 Total impact

• Source

  Available from: James M Harper

  Article: Early life growth hormone treatment shortens longevity and decreases cellular stress resistance in long-lived mutant mice.

  Jacob A Panici, James M Harper, Richard A Miller, Andrzej Bartke, Adam Spong, Michal M Masternak
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  ABSTRACT: Hypopituitary Ames dwarf mice were injected either with growth hormone (GH) or thyroxine for a 6-wk period to see whether this intervention would reverse their long life span or the resistance of their cells to lethal stresses. Ames dwarf mice survived 987 ± 24 d (median), longer than nonmutant control mice (664 ± 48), but GH-injected dwarf mice did not differ from controls (707 ± 9). Fibroblast cells from Ames dwarf mice were more resistant to cadmium than cells from nonmutant controls (LD(50) values of 9.98 ± 1.7 and 3.9 ± 0.8, respectively), but GH injections into Ames dwarf mice restored the normal level of cadmium resistance (LD(50)=5.8 ± 0.9). Similar restoration of normal resistance was observed for fibroblasts exposed to paraquat, methyl methanesulfonate, and rotenone (P<0.05 in each case for contrast of GH-treated vs. untreated dwarf mice; P<0.05 for dwarf vs. nonmutant control mice.) T4 injections into Ames dwarf mice, in contrast, did not restore normal life span. We conclude that the remarkable life-span extension of Ames dwarf mice, and the stress resistance of cells from these mice, depends on low levels of GH exposure in juvenile and very young adult mice.
  The FASEB Journal 12/2010; 24(12):5073-9. · 5.71 Impact Factor
• Article: The effects of growth hormone (GH) treatment on GH and insulin/IGF-1 signaling in long-lived Ames dwarf mice.

  Michal M Masternak, Jacob A Panici, Feiya Wang, Zhihui Wang, Adam Spong
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  ABSTRACT: The disruption of the growth hormone (GH) axis in mice promotes insulin sensitivity and is strongly correlated with extended longevity. Ames dwarf (Prop1(df), df/df) mice are GH, prolactin (PRL), and thyrotropin (TSH) deficient and live approximately 50% longer than their normal siblings. To investigate the effects of GH on insulin and GH signaling pathways, we subjected these dwarf mice to twice-daily GH injections (6 microg/g/d) starting at the age of 2 weeks and continuing for 6 weeks. This produced the expected activation of the GH signaling pathway and stimulated somatic growth of the Ames dwarf mice. However, concomitantly with increased growth and increased production of insulinlike growth factor-1, the GH treatment strongly inhibited the insulin signaling pathway by decreasing insulin sensitivity of the dwarf mice. This suggests that improving growth of these animals may negatively affect both their healthspan and longevity by causing insulin resistance.
  The Journals of Gerontology Series A Biological Sciences and Medical Sciences 11/2009; 65(1):24-30. · 4.60 Impact Factor
• Article: Is altered expression of hepatic insulin-related genes in growth hormone receptor knockout mice due to GH resistance or a difference in biological life spans?

  Jacob A Panici, Feiya Wang, Michael S Bonkowski, Adam Spong, Andrzej Bartke, Ludmila Pawlikowska, Pui-Yan Kwok, Michal M Masternak
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  ABSTRACT: Growth hormone receptor knockout (GHRKO) mice live about 40%-55% longer than their normal (N) littermates. Previous studies of 21-month-old GHRKO and N mice showed major alterations of the hepatic expression of genes involved in insulin signaling. Differences detected at this age may have been caused by the knockout of the growth hormone receptor (GHR) or by differences in biological age between GHRKO and N mice. To address this question, we compared GHRKO and N mice at ages corresponding to the same percentage of median life span to see if the differences of gene expression persisted. Comparison of GHRKO and N mice at approximately 50% of biological life span showed significant differences in hepatic expression of all 14 analyzed genes. We conclude that these changes are due to disruption of GHR gene and the consequent suppression of growth hormone signaling rather than to differences in "biological age" between mutant and normal animals sampled at the same chronological age.
  The Journals of Gerontology Series A Biological Sciences and Medical Sciences 09/2009; 64(11):1126-33. · 4.60 Impact Factor
• Article: Insulin sensitivity as a key mediator of growth hormone actions on longevity.

  Michal M Masternak, Jacob A Panici, Michael S Bonkowski, Larry F Hughes, Andrzej Bartke
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  ABSTRACT: Reduced insulin sensitivity and glucose intolerance have been long suspected of having important involvement in aging. Here we report that in studies of calorie restriction (CR) effects in mutant (Prop1(df) and growth hormone receptor knockout [GHRKO]) and normal mice, insulin sensitivity was strongly associated with longevity. Of particular interest was enhancement of the already increased insulin sensitivity in CR df/df mice in which longevity was also further extended and the lack of changes in insulin sensitivity in calorically restricted GHRKO mice in which there was no further increase in average life span. We suggest that enhanced insulin sensitivity, in conjunction with reduced insulin levels, may represent an important (although almost certainly not exclusive) mechanism of increased longevity in hypopituitary, growth hormone (GH)-resistant, and calorie-restricted animals. We also report that the effects of GH treatment on insulin sensitivity may be limited to the period of GH administration.
  The Journals of Gerontology Series A Biological Sciences and Medical Sciences 06/2009; 64(5):516-21. · 4.60 Impact Factor
• Source

  Available from: Vanesa Jiménez-Ortega

  Article: Effects of every-other-day feeding on prolactin regulatory mechanism in transgenic human growth hormone mice.

  Vanesa Jiménez-Ortega, Michal M Masternak, Jacob A Panici, Zhihui Wang, Andrzej Bartke, Ana I Esquifino
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  ABSTRACT: Transgenic mice overexpressing human growth hormone (hGH) exhibit accelerated aging with functional hyperprolactinemia and greatly depressed endogenous prolactin. Calorie restriction (CR) is widely recognized as the most effective experimental intervention to delay aging. The aim of the present work was to analyze the effects of lifelong overexpression of hGH on prolactin-gene expression as well as the dopamine production at the pituitary level and discern whether this mechanism changes as a function of feeding patterns. Ten-month-old mice fed every other day (EOD) were killed after one day of fasting. The results confirmed typical phenotypic features of these transgenic mice: an increase in body weight, very high hGH plasma concentrations, and hyperinsulinemia. There was a marked inhibition of the expression of the prolactin gene, together with an increased tyrosine hydroxylase (TH) and the long isoform of dopamine receptor type 2 (D2LR) gene expression at the pituitary level. These parameters were not affected by the EOD feeding pattern. These data may suggest an autocrine or paracrine effect of dopamine at the hypophyseal level on prolactin secretion that is independent of the feeding pattern.
  Experimental Biology and Medicine 05/2008; 233(4):434-8. · 2.64 Impact Factor
• Article: Effects of caloric restriction and growth hormone resistance on insulin-related intermediates in the skeletal muscle.

  Khalid A Al-Regaiey, Michal M Masternak, Michael S Bonkowski, Jacob A Panici, John J Kopchick, Andrzej Bartke
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  ABSTRACT: Growth hormone receptor-deficient (GHRKO) mice are long-lived and have reduced insulin-like growth factor (IGF)-1 and insulin levels and enhanced insulin sensitivity thus resembling the phenotype of animals subjected to calorie restriction (CR). In contrast to its effects in normal mice, CR does not improve insulin sensitivity or increase longevity in GHRKO males. In an attempt to identify mechanisms underlying this differential response to CR, effects of CR on the expression of insulin-related genes were compared in GHRKO and normal mice. In addition to changes detected in both genotypes, and responses unique to GHRKO mice, the levels of Akt2 and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1alpha) were increased and levels of phosphorylated c-Jun N-terminal kinase (JNK)1 were reduced in response to CR only in normal mice. These changes may be related to mechanisms of improving insulin sensitivity and life expectancy.
  The Journals of Gerontology Series A Biological Sciences and Medical Sciences 02/2007; 62(1):18-26. · 4.60 Impact Factor
• Article: Long-lived growth hormone receptor knockout mice show a delay in age-related changes of body composition and bone characteristics.

  Michael S Bonkowski, Richard W Pamenter, Juliana S Rocha, Michal M Masternak, Jacob A Panici, Andrzej Bartke
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  ABSTRACT: There is conflicting information on the physiological role of growth hormone (GH) in the control of aging. This study reports dual-energy x-ray absorptiometry (DXA) measurements of body composition and bone characteristics in young, adult, and aged long-lived GH receptor knockout (GHR-KO) and normal mice to determine the effects of GH resistance during aging. Compared to controls, GHR-KO mice showed an increased percentage of body fat. GHR-KO mice have reduced total-body bone mineral density (BMD), bone mineral content, and bone area, but these parameters increased with age. In addition, GHR-KO mice have decreased femur length, femur BMD, and lower lumbar BMD compared to controls in all age groups. These parameters also continued to increase with age. Our results indicate that GH resistance alters body composition, bone growth, and bone maintenance during aging in GHR-KO mice.
  The Journals of Gerontology Series A Biological Sciences and Medical Sciences 07/2006; 61(6):562-7. · 4.60 Impact Factor
• Article: Caloric restriction and growth hormone receptor knockout: effects on expression of genes involved in insulin action in the heart.

  Michal M Masternak, Khalid A Al-Regaiey, Marc Michael Del Rosario Lim, Vanesa Jimenez-Ortega, Jacob A Panici, Michael S Bonkowski, John J Kopchick, Zhihui Wang, Andrzej Bartke
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  ABSTRACT: Blockade of growth hormone (GH), decreased insulin-like growth factor-1 (IGF1) action and increased insulin sensitivity are associated with life extension and an apparent slowing of the aging process. We examined expression of genes involved in insulin action, IR, IRS1, IRS2, IGF1, IGF1R, GLUT4, PPARs and RXRs in the hearts of normal and GHR-/- (KO) mice fed ad libitum or subjected to 30% caloric restriction (CR). CR increased the cardiac expression of IR, IRS1, IGF1, IGF1R and GLUT4 in normal mice and IRS1, GLUT4, PPARalpha and PPARbeta/delta in GHR-KO animals. Expression of IR, IRS1, IRS2, IGF1, GLUT4, PPARgamma and PPARalpha did not differ between GHR-KO and normal mice. These unexpected results suggest that CR may lead to major modifications of insulin action in the heart, but high insulin sensitivity of GHR-KO mice is not associated with alterations in the levels of most of the examined molecules related to intracellular insulin signaling.
  Experimental Gerontology 05/2006; 41(4):417-29. · 3.74 Impact Factor
• Article: Effects of caloric restriction and growth hormone resistance on the expression level of peroxisome proliferator-activated receptors superfamily in liver of normal and long-lived growth hormone receptor/binding protein knockout mice.

  Michal M Masternak, Khalid A Al-Regaiey, Marc Michael Del Rosario Lim, Vanesa Jimenez-Ortega, Jacob A Panici, Michael S Bonkowski, John J Kopchick, Andrzej Bartke
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  ABSTRACT: Growth hormone receptor/binding protein knockout (GHR-KO) mice live approximately 40% longer than their normal siblings do. These mice have dramatically reduced plasma levels of insulin-like growth factor 1 (IGF1) and enhanced insulin sensitivity. We examined the expression level of peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors family genes in the livers of normal and GHR-KO mice fed ad libitum or subjected to long-term 30% caloric restriction (CR). The levels of PPARgamma and PPARalpha messenger RNA and proteins and the levels of retinoid X receptors messenger RNA were elevated in long-lived GHR-KO mice as compared to normal mice with no major effect of CR in either genotype. These findings suggest that enhanced insulin sensitivity of GHR-KO mice may be related to the altered actions of PPARs family members in the liver. The results also indicate that CR may increase insulin sensitivity through a different mechanism.
  The Journals of Gerontology Series A Biological Sciences and Medical Sciences 12/2005; 60(11):1394-8. · 4.60 Impact Factor
• Article: Caloric restriction results in decreased expression of peroxisome proliferator-activated receptor superfamily in muscle of normal and long-lived growth hormone receptor/binding protein knockout mice.

  Michal M Masternak, Khalid A Al-Regaiey, Marc Michael Del Rosario Lim, Michael S Bonkowski, Jacob A Panici, Grzegorz K Przybylski, Andrzej Bartke
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  ABSTRACT: Resistance to growth hormone, reduced insulin-like growth factor 1 (IGF1) action, and enhanced insulin sensitivity are likely mediators of extended life span and delayed aging process in growth hormone receptor/binding protein knockout (GHR-KO) mice. Fat metabolism and genes involved in fatty acid oxidation are strongly involved in insulin action. Using real-time polymerase chain reaction and western blot we have examined expression of peroxisome proliferator-activated receptors (PPARs) and retinoid X receptor (RXR) genes in the skeletal muscle of normal and GHR-KO mice subjected to 30% caloric restriction. The results indicate that caloric restriction decreased the expression of PPARgamma, PPARalpha, and PPARbeta/delta which would lead to down-regulation of fat metabolism. This suggested metabolic change clearly does not affect whole-body insulin action. These findings suggest that whole-animal insulin sensitivity is not regulated through skeletal muscle insulin action.
  The Journals of Gerontology Series A Biological Sciences and Medical Sciences 11/2005; 60(10):1238-45. · 4.60 Impact Factor
• Article: Effect of every other day feeding diet on gene expression in normal and in long-lived Ames dwarf mice.

  Michal M Masternak, Khalid A Al-Regaiey, Michael S Bonkowski, Jacob A Panici, Andrzej Bartke
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  ABSTRACT: Ames dwarf mutant mice are long-lived, hypoinsulinemic and hypoglycemic and exhibit enhanced sensitivity to injected insulin. Their phenotypic characteristics show many similarities to animals subjected to caloric restriction (CR) but Ames dwarf mice are not CR mimetics. Reducing daily food intake by 30% prolongs longevity in both normal and Ames dwarf mice. In the present study, the animals were subjected to a different type of CR, every other day feeding (EOD). Using real-time PCR, we have examined the expression of genes related to insulin signaling in the liver of normal and dwarf mice after 9 months of EOD. The results indicate that EOD produces some changes in the insulin and IGF1 signaling pathways, and that these changes are consistent with EOD increasing insulin sensitivity.
  Experimental Gerontology 07/2005; 40(6):491-7. · 3.74 Impact Factor
• Article: Effects of caloric restriction on insulin pathway gene expression in the skeletal muscle and liver of normal and long-lived GHR-KO mice.

  Michal M Masternak, Khalid A Al-Regaiey, Marc Michael Del Rosario Lim, Vanesa Jimenez-Ortega, Jacob A Panici, Michael S Bonkowski, Andrzej Bartke
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  ABSTRACT: Growth hormone receptor/binding protein knockout (GHR-KO) mice are characterized by resistance to growth hormone (GH), reduced insulin like growth factor 1 (IGF1) levels and enhanced insulin sensitivity and markedly increased lifespan. Findings in these and other long-lived mutant mice, and in normal animals subjected to caloric restriction (CR) indicate that insulin signaling is importantly involved in the control of longevity. We have examined the mRNA expression level of genes involved in insulin/IGF1 action in the skeletal muscle and liver of normal and GHR-KO mice fed ad libitum or subjected to long term 30% CR. The levels of IR, IRS1, IRS2, GLUT4 and IGF1 message in the skeletal muscle were reduced by CR in both normal and GHR-KO mice. In the liver, the results indicate that in GHR-KO mice mRNA expression of genes related to early steps of insulin signaling is up-regulated in the liver but not in the muscle. The results also show that improved insulin sensitivity in response to CR is not due to increased mRNA expression of the above genes in either normal or GHR-KO animals.
  Experimental Gerontology 40(8-9):679-84. · 3.74 Impact Factor