Melinda Ramsey

Disruption of the insulin/IGF-I pathway increases life span in invertebrates. However, effects of decreased IGF-I signaling in mammalian models remain controversial. Using a rodent model with a specific and limited deficiency of GH and IGF-I, we report that GH and IGF-I deficiency throughout life [GH deficiency (GHD)] has no effect on life span compared with normal, heterozygous animals. However, treatment of GHD animals with GH from 4-14 wk of age [adult-onset (AO) GHD] increased median and maximal life span by 14% and 12%, respectively. Analysis of end-of-life pathology indicated that deficiency of these hormones decreased tumor incidence in GHD and AO-GHD animals (18 and 30%, respectively) compared with heterozygous animals and decreased the severity of, and eliminated deaths from, chronic nephropathy. Total disease burden was reduced by 24% in GHD and 16% in AO-GHD animals. Interestingly, the incidence of intracranial hemorrhage increased by 154 and 198% in GHD and AO-GHD animals, respectively, compared with heterozygous animals. Deaths from intracranial hemorrhage in AO-GHD animals were delayed by 14 wk accounting for the increased life span compared with GHD animals. The presence of GH and IGF-I was necessary to maximize reproductive fitness and growth of offspring early in life and to maintain cognitive function and prevent cartilage degeneration later in life. The diverse effects of GH and IGF-I are consistent with a model of antagonistic pleiotropy and suggest that, in response to a deficiency of these hormones, increased life span is derived at the risk of functional impairments and tissue degeneration.

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.