RESUMEN
Insulin-like growth factor-1 (IGF-1) and growth hormone play a major role in the growth and development of tissues throughout the mammalian body. Plasma IGF-1 concentrations peak during puberty and decline with age. We have determined that chronic treatments to restore plasma IGF-1 concentrations to adult levels attenuate spatial learning deficits in aged rats, but little is known of the acute actions of IGF-1 in the brain. To this end, we utilized hippocampal slices from young Sprague-Dawley rats to characterize the acute effects of des-IGF-1 on excitatory synaptic transmission in the CA1 region. We observed a 40% increase in field excitatory postsynaptic potential (fEPSP) slope with application of des-IGF-1 (40 ng/ml) and used whole cell patch-clamp recordings to determine that this enhancement was due to a postsynaptic mechanism involving alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) but not N-methyl-D-aspartate receptors. Furthermore, the enhancement was completely blocked by the broad-spectrum tyrosine kinase inhibitor, genistein (220 microM), and significantly reduced by the PI3K blockers wortmannin (1 microM) and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (10 microM), suggesting that the effect was predominantly dependent on PI3K activation. This characterization of the acute actions of des-IGF-1 at hippocampal excitatory synapses may provide insight into the mechanism by which long-term increases in plasma IGF-1 impart cognitive benefits in aged rats. Increases in AMPA receptor-mediated synaptic transmission may contribute directly to cognitive improvement or initiate long-term changes in synthesis of proteins such as brain-derived neurotrophic factor that are important to learning and memory.
Asunto(s)
Hipocampo/citología , Factor I del Crecimiento Similar a la Insulina/farmacología , Neuronas/efectos de los fármacos , Sinapsis/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Androstadienos/farmacología , Animales , Animales Recién Nacidos , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Estimulación Eléctrica/métodos , Inhibidores Enzimáticos/farmacología , Agonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Genisteína/farmacología , Hipocampo/fisiología , Técnicas In Vitro , Masculino , Neuronas/fisiología , Técnicas de Placa-Clamp/métodos , Ratas , Ratas Sprague-Dawley , Wortmanina , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacologíaRESUMEN
Increased plasma IGF-1 has consistently been associated with a variety of human cancers, whereas reduced levels of IGF-1 are associated with increased lifespan in other species. However, the aforementioned relationships are correlational or are derived from animal models that are not specific for growth hormone/IGF-1 excess or deficiency. This study was designed to assess the effects of physiological changes in growth hormone and IGF-1 expression on dimethylbenzanthracine (DMBA)-induced mammary carcinogenesis. At 50 days of age, female heterozygous (dw/+) and growth hormone deficient dwarf (dw/dw) rats of the Lewis strain received a single dose of DMBA (80 micro g/g of body weight) via oral gavage. Animals were assigned to one of four experimental groups: a) heterozygous animals (normal size), b) dwarf animals administered vehicle, c) dwarf animals administered low levels of porcine growth hormone (50 micro g twice daily), and d) dwarf animals administered high levels of porcine growth hormone (200 micro g twice daily). At study termination, heterozygous animals exhibited a 70% incidence of mammary tumors, whereas no tumors were observed in saline-treated dwarf animals. Administration of either 100 micro g or 400 micro g growth hormone/day resulted in a dose dependent increase in incidence of mammary tumors (83 and 100%, respectively). Furthermore, heterozygous animals exhibited 1.5 +/- 0.25 tumors per tumor-bearing animal, whereas dwarf animals administered 100 micro g and 400 micro g growth hormone per day had 1.9 +/- 0.63 and 3.4 +/- 0.83 tumors per animal, respectively. The present study demonstrates that DMBA-induced carcinogenesis is dependent on critical plasma levels of growth hormone and IGF-1, and that growth hormone/IGF-1 deficient animals are resistant to DMBA-induced carcinogenesis.
Asunto(s)
9,10-Dimetil-1,2-benzantraceno , Carcinógenos , Enanismo/inmunología , Enanismo/metabolismo , Hormona del Crecimiento/deficiencia , Neoplasias Mamarias Experimentales/inducido químicamente , Animales , Enanismo/genética , Femenino , Heterocigoto , Inmunidad Innata , Factor I del Crecimiento Similar a la Insulina/deficiencia , Ratas , Ratas Endogámicas Lew , Valores de ReferenciaRESUMEN
Studies in Caenorhabditis elegans demonstrate that disruption of the daf-2 signaling pathways extends lifespan. Similarities among the daf-2 pathway, insulin-like signaling in flies and yeast, and the mammalian insulin-like growth factor 1 (IGF-1) signaling cascade raise the possibility that modifications to IGF-1 signaling could also extend lifespan in mammals. In fact, growth hormone (GH)/IGF-1-deficient dwarf mice do live significantly longer than their wild-type counterparts. However, multiple endocrine deficiencies and developmental anomalies inherent in these models confound this interpretation. Here, we critique the current mammalian models of GH/IGF-1 deficiency and discuss the actions of GH/IGF-1 on biological aging and lifespan.
Asunto(s)
Envejecimiento/fisiología , Hormona del Crecimiento/fisiología , Factor I del Crecimiento Similar a la Insulina/fisiología , Animales , Caenorhabditis elegans/fisiología , Proteínas de Caenorhabditis elegans , Enanismo/metabolismo , Hormona del Crecimiento/deficiencia , Factor I del Crecimiento Similar a la Insulina/deficiencia , Ratones , Modelos Animales , Ratas , Receptor de Insulina/fisiologíaRESUMEN
The remarkable progress in understanding the genetic basis of life-span determination in invertebrates indicates that impairments in the insulin-insulin-like growth factor 1 (IGF-1) signaling cascade increase longevity. Similarities among insulin and IGF-1-like signaling pathways in invertebrates and mammals raise the possibility that modifications of these pathways may extend life span in mammals. Investigators using Ames, Snell, and growth hormone receptor knockout models have concluded that decreased growth hormone and IGF-1 are responsible for increased life span. In this review, we critique the dwarf models and, based on multiple endocrine deficiencies and developmental anomalies, conclude that these models may not be sufficient to assess the consequences of growth hormone or IGF-1 deficiency on either biological aging or life span. We attempt to resolve some of these issues by presenting an alternative animal model of growth hormone-IGF-1 deficiency. Finally, we propose an integrated explanation of growth hormone and IGF-1's contribution to the aging phenotype and life-span determination.
Asunto(s)
Envejecimiento/fisiología , Hormona del Crecimiento/deficiencia , Factor I del Crecimiento Similar a la Insulina/deficiencia , Longevidad/fisiología , Animales , Modelos Animales de Enfermedad , Enanismo/metabolismo , Enanismo/fisiopatología , Crecimiento , HumanosRESUMEN
Studies over the past several years have found that antagonism of the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway increases life-span in Caenorhabditis elegans and Drosophila. However, a persistent problem in these studies is the fact that the genetic mutation has effects on the development of the organism as well as on reproductive function. These effects act as potential confounding variables that complicate the interpretation of results. Kenyon and colleagues circumvent these issues by suppressing the insulin/IGF-1-like daf-2 signaling pathway at specific stages in the life-span of C. elegans. The results of their investigation challenge our understanding of the evolution of aging and provide opportunities for future studies in mammalian models.