Metabolic enrichment of omega-3 polyunsaturated fatty acids does not reduce the onset of idiopathic knee osteoarthritis in mice.

OBJECTIVE: We evaluated the effect of a reduction in the systemic ratio of n-6:n-3 polyunsaturated fatty acids (PUFAs) on changes in inflammation, glucose metabolism, and the idiopathic development of knee osteoarthritis (OA) in mice. We hypothesized that a lower ratio of n-6:n-3 PUFAs would protect against OA markers in cartilage and synovium, but not bone. DESIGN: Male and female fat-1 transgenic mice (Fat-1), which convert dietary n-6 to n-3 PUFAs endogenously, and their wild-type (WT) littermates were fed an n-6 PUFA enriched diet for 9-14 months. The effect of gender and genotype on serum PUFAs, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and glucose tolerance was tested by 2-factor analysis of variance (ANOVA). Cortical and trabecular subchondral bone changes were documented by micro-focal computed tomography (CT), and knee OA was assessed by semi-quantitative histomorphometry grading. RESULTS: The n-6:n-3 ratio was reduced 12-fold and 7-fold in male and female Fat-1 mice, respectively, compared to WT littermates. IL-6 and TNF-α levels were reduced modestly in Fat-1 mice. However, these systemic changes did not reduce osteophyte development, synovial hyperplasia, or cartilage degeneration. Also the fat-1 transgene did not alter subchondral cortical or trabecular bone morphology or bone mineral density. CONCLUSIONS: Reducing the systemic n-6:n-3 ratio does not slow idiopathic changes in cartilage, synovium, or bone associated with early-stage knee OA in mice. The anti-inflammatory and anti-catabolic effects of n-3 PUFAs previously reported for cartilage may be more evident at later stages of disease or in post-traumatic and other inflammatory models of OA.

Cognitive performance and age-related changes in the hippocampal proteome.

Declining cognitive performance is associated with increasing age, even in the absence of overt pathological processes. We and others have reported that declining cognitive performance is associated with age-related changes in brain glucose utilization, long-term potentiation and paired-pulse facilitation, protein expression, neurotransmitter levels, and trophic factors. However, it is unclear whether these changes are causes or symptoms of the underlying alterations in dendritic and synaptic morphology that occur with age. In this study, we examined the hippocampal proteome for age- and cognition-associated changes in behaviorally stratified young and old rats, using two-dimensional in-gel electrophoresis and MS/MS. Comparison of old cognitively intact with old cognitively impaired animals revealed additional changes that would not have been detected otherwise. Interestingly, not all age-related changes in protein expression were associated with cognitive decline, and distinct differences in protein expression were found when comparing old cognitively intact with old cognitively impaired rats. A large number of protein changes with age were related to the glycolysis/gluconeogenesis pathway. In total, the proteomic changes suggest that age-related alterations act synergistically with other perturbations to result in cognitive decline. This study also demonstrates the importance of examining behaviorally-defined animals in proteomic studies, as comparison of young to old animals regardless of behavioral performance would have failed to detect many cognitive impairment-specific protein expression changes evident when behavioral stratification data were used.

Discussing modern poultry farming systems-insights into citizen's lay theories.

A growing public concern, especially about animal welfare problems in poultry farming systems in the EU, has been addressed by numerous (mostly quantitative) studies. However, in-depth research about the underlying reasons for the lack of acceptance concerning modern poultry farming is rare. Debates on animal welfare are often polarized. Thus, this study involved 8 exploratory focus group discussions in 4 German cities. To understand the different positions and to simulate controversial debates on animal welfare, the study includes vegetarians/vegans (as a critical and involved group) and meat eaters. The actual level of knowledge about modern poultry production among participants was heterogeneous, varying between detailed specialized knowledge and misinformation. It was found that improvements for poultry animal welfare that have already been achieved, such as the ban of conventional cages for laying hens in the EU, were not yet recognized by the wider public. A central finding was that participants mostly use lay theories and conclude that the actual poultry husbandry systems make a high use of antibiotics necessary, which has a negative influence on the meat products and, thus, endangers consumer health. The results also indicate that an industrialized agri-food system (rather than farmers) is held primarily responsible for the perceived problems in the poultry value chain. Furthermore, participants are aware of their responsibility and also blame their buying behavior.

Consumer interest in environmental impact, safety, health and animal welfare aspects of modern pig production: Results of a cross-national choice experiment.

Are consumers interested in aspects of pig production and do they take these into account in their buying decisions when such information is available? Samples of consumers in Germany and Poland selected the two - for them - most important out of a list of ten production characteristics, relating to animal welfare, health and safety, and environmental issues. In a subsequent choice experiment, the relative weight these characteristics had in consumers' choices was estimated. Relative importance of production characteristics varied between consumer segments, with the production interested segment being bigger in Germany than in Poland. With the exception of one animal welfare related criterion in Germany, those production characteristics that consumers perceive as most important relate to health and safety aspects rather than to animal welfare and environmental impact.

Growth hormone and aging: Regulation, signal transduction and replacement therapy.

It is widely accepted that during the aging process a number of alterations occur at the molecular, cellular, and tissue levels, ranging from an alteration in receptor signal transduction and gene expression to structural and morphological changes in various tissues. There is abundant empirical and scientific evidence to support the hypothesis that many of these aging processes are closely related to a decline in hormone concentrations and/or hormone action, but the etiology of these deficiencies remains elusive. GH and insulinlike growth factor-I (IGF-I) are two potent anabolic hormones that decrease with age and appear to contribute to the loss of tissue function that is associated with normal aging. In this review, age-related changes in the regulation of these hormones are detailed as well as relatively new information on mechanisms of tissue resistance to GH. Finally, the potential use of GH as a therapeutic intervention to delay physiological changes associated with age is discussed.

Impaired ability of old male rats to secrete growth hormone in vivo but not in vitro in response to hpGRF(1-44).

The capacity of hpGRF (1-44) to induce release of GH in young (3-4 month old) versus old (19-21 month old) male rats was compared in vivo and in vitro. Injection of 1 ug/kg hpGRF to rats anesthetized with sodium pentobarbital increased plasma GH concentrations in young animals to greater than 1600 ng/ml within 5 min, and a dose of 10 ug/kg hpGRF increased GH levels to approximately 1900 ng/ml at 10 min. In old rats, plasma GH concentrations were increased after hpGRF but the increases were significantly lower than in the young rats at 5, 10, and 20 min after injection (P less than 0.01). The total GH released in old animals was calculated to be approximately 50% of that in young animals. In vitro release of GH from anterior pituitary slices incubated with hpGRF was also compared between young and old animals. After 20 min incubation with hpGRF (10(-9) or 10(-7) M) or vehicle, both young and old animals demonstrated a dose related and equivalent increase in GH release. These results indicate a reduced capacity of hpGRF to stimulate GH release in vivo in aged as compared to young male rats. This decline is believed to be due to a hypothalamic influence on the anterior pituitary since the in vitro response of anterior pituitary tissue to hpGRF was similar in young and old rats. The reduced response to hpGRF in old male rats in vivo may be due to increased release of or enhanced sensitivity to somatostatin.

Decreases in growth hormone receptor signal transduction contribute to the decline in insulin-like growth factor I gene expression with age.

Several investigations have clearly indicated that plasma concentrations of insulin-like growth factor I (IGF-I) decrease with age and contribute to the decrease in tissue function that is characteristic of aging animals and man. Plasma IGF-I is regulated by GH released from the pituitary gland, and although data demonstrate a decline in GH secretion with age, GH receptor (GHR) density in liver tissue has been reported to increase. In this study, the effects of aging on GHR signal transduction were assessed in hepatic tissue to determine whether alterations in the response to GH contribute to the decline in IGF-I. Liver slices from female C57BL/6 mice (10, 17, and 31 months old) were prepared in medium and stimulated with GH. Basal GHR binding increased more than 2-fold in 31-month-old animals compared to that in either 10- or 17-month-old animals (P < 0.01), whereas the Ka values were similar in the three age groups. However, GH (2 nM)-induced IGF-I gene expression decreased dramatically with age (P < 0.01). In 10-month-old animals, GH-induced phosphorylation of the GHR complex was maximal 10 min after the addition of hormone, whereas GH-induced MAP kinase activity was maximal at 15 min. GH-induced JAK2 kinase and GHR complex phosphorylation as well as MAP kinase activity were significantly lower in 31-month-old animals than in either the 10- or 17-month-old groups (P < 0.05). The results of this study demonstrate that GH induces phosphorylation of JAK2 and the GHR complex, activates MAP kinase, and increases the expression of IGF-I messenger RNA in liver. In 17-month-old animals, decreases in IGF-I gene expression were evident that were not directly associated with diminished GHR complex phosphorylation or MAP kinase activity. By 31 months, there was a decrease in IGF-I gene expression that was associated with a marked decline in JAK2 and GHR complex phosphorylation. These data suggest that the signal transduction pathway for GH is impaired with age and that these changes may contribute to the decline in IGF-I gene expression.

Decreased pulsatile release of growth hormone in old male rats.

Pulsatile release of GH was compared in young (4-5 months old) and old (18-20 months old) male Sprague-Dawley rats using indwelling atrial cannulae. More than 57% of the young rats exhibited GH pulses greater than 300 ng/ml plasma, whereas only 7% of the old animals had GH pulses of similar amplitude. Trough GH values were not different between young and old rats, but during the 10.5-h sampling period, mean GH concentrations in young male rats were significantly greater than those in old male rats (175.3 +/- 20.9 vs. 70.2 +/- 7.6 ng/ml; P < 0.01). In another experiment, pituitary GH and hypothalamic somatostatin content were measured in young and old rats. The pituitary GH content was significantly greater in young than in old males (1187 +/- 95 vs. 670 +/- 93 microgram; P < 0.01). The immunoreactive somatostatin content in caudal areas of the hypothalamus was also greater in young than in old male rats (100.2 +/- 4.2 vs. 79.0 +/- 5.1 ng; P < 0.01). These observations demonstrate that GH secretion is depressed in old male rats, and this is associated with diminished pulsatile release of GH. The results also suggest that a relationship exists among the reduction in somatostatin content, pituitary GH content, and attenuated GH secretion in old male rats.

Diminished diurnal secretion of adrenocorticotropin (ACTH), but not corticosterone, in old male rats: possible relation to increased adrenal sensitivity to ACTH in vivo.

The diurnal secretion of ACTH and corticosterone was examined in chronically cannulated young (3-4 months old), middle-aged (10-12 months old), and old (22-24 months old) Fischer 344 male rats. Plasma corticosterone in young rats increased from baseline concentrations of 78 +/- 5 to a maximum of 171 +/- 24 ng/ml at 1730 h and declined to basal levels by 1930 h. Middle-aged and old rats demonstrated a similar magnitude and time course of corticosterone release. However, comparison of the relative concentrations of ACTH released during the diurnal surge revealed that old rats secreted 35% less ACTH than young or middle-aged animals (P less than 0.05). Age-related changes in the sensitivity of the adrenal gland to a submaximal dose of ACTH were tested in dexamethasone-pretreated animals at 1100 and 1700 h in a separate experiment. Plasma corticosterone levels were significantly greater after ACTH administration (1 mIU/kg ACTHAR, iv) at 1700 h in both young and old rats compared to 1100 h values (P less than 0.05), and levels 20 min post-ACTH injection at 1700 h were significantly greater in old than young or middle-aged rats at the same time (P less than 0.05). These results demonstrate that 1) there are no age-related changes in the diurnal secretion of corticosterone in Fischer 344 male rats; 2) there is a decline in the peak level of ACTH during the diurnal surge of old compared to young animals; and 3) adrenal sensitivity to ACTH at 1700 h is greater in old compared to young or middle-aged rats. We hypothesize that the greater increase in adrenal sensitivity to ACTH is responsible for the maintenance of the corticosterone rhythm in the presence of diminished ACTH concentrations in older rats.

Decreases in cerebral microvasculature with age are associated with the decline in growth hormone and insulin-like growth factor 1.

Several reports have demonstrated that cerebral blood flow decreases with age and may contribute to neurodegenerative changes found in aging animals and man. Because GH and insulin-like growth factor 1 (IGF-1) decrease with age and have an important role in vascular maintenance and remodeling, we hypothesized that the decrease in cerebral blood flow is associated with a rarefaction of cerebral blood vessels resulting from a decline in GH and IGF-1. Measurements of vascular density (number of vessels/cortical surface area) in both Brown-Norway and Fisher 344/Brown-Norway rats were made at 5, 13, and 29 months of age using chronic cranial window chambers that allowed viewing of the cortical surface and its corresponding vasculature. Correlations were made with plasma levels of IGF-1. In Brown-Norway rats, arteriolar density decreased from 15.53 +/- 1.08 to 9.49 +/- 0.62 endpoints/mm2 in 7- and 29-month-old animals, respectively (P < 0.05). A decline was observed also in arteriolar anastomoses [3.05 +/- 0.21 to 1.42 +/- 0.24 connections/mm2 in 7- and 29-month-old animals (P < 0.05)]. Venular density did not decrease with age. Similar changes were observed in Fisher 344/Brown-Norway rats. The number of cortical surface arterioles was correlated with plasma IGF-1 levels at the time of vascular mapping (r = 0.772, P < 0.05), and injection of bovine GH (0.25 mg/kg, s.c., twice daily for 35 days) to 30-month-old animals increased both plasma IGF-1 and the number of cortical arterioles. These data indicate that: 1) vascular density on the surface of the cortex decreases with age; 2) vascular density is correlated with plasma levels of IGF-1; and 3) injection of GH increases cortical vascular density in older animals. We conclude that GH and IGF-1 have an important role in the decline in vascular density with age and suggest that decreases in vascular density may have important implications for the age-related decline in cerebral blood flow and brain function.

Decreased ability of old male rats to secrete luteinizing hormone (LH) is not due to alterations in pituitary LH-releasing hormone receptors.

The present study was undertaken to determine if the diminished release of LH in male rats with age in response to castration or LHRH injection is due to alternations in the number or affinity of LHRH receptors in the pituitary. Young (3-4 months old) and old (18-20 months) male Sprague-Dawley rats were killed 0, 2, 4, and 8 days after castration. Serum was collected for determination of LH concentrations, and anterior pituitaries were removed for analysis of LHRH receptors. The numbers and affinity constants of receptors were determined by Scatchard analysis using iodinated des-Gly10-[D-Ala6]LHRH ethylamide (LHRH-a) as ligand. Plasma LH in young rats increased from 54 ng/ml in intact animals to 319 ng/ml 8 days after castration, but in old animals, LH increased only from 47 to 119 ng/ml during the same period (P less than 0.01). However, there were no age-related differences in LHRH receptors in intact animals, and both young and old animals showed similar increases in pituitary LHRH receptors after castration when expressed either as receptors per pituitary (young, 132 +/- 27 to 262 +/- 43 fmol/pituitary; old, 175 +/- 27 to 299 +/- 19 fmol/pituitary) or as receptors per mg protein (young, 420 +/- 48 to 847 +/- 172 fmol/mg protein; old, 432 +/- 38 to 866 +/- 62 fmol/mg protein). Receptor affinity was not statistically different in intact young or old animals (4.51 +/- 0.41 X 10(9) and 4.51 +/- 1.23 X 10(9) M1, respectively), and receptor affinity increased in both groups in response to castration. The capacity of young and old male rats to produce LHRH receptors in response to exogenous LHRH was tested in a second experiment. Animals were castrated and given daily injections of testosterone propionate (500 micrograms/kg, im) for 13 days. Beginning on day 9, LHRH-a (250 micrograms/kg, sc) was injected for 5 days. The rises in serum LH after a single injection of LHRH-a were similar in young and old animals on the first and fifth days of LHRH-a treatment. LHRH receptors at the cessation of hormone therapy also increased similarly in both young and old animals in response to LHRH-a (715 +/- 135 and 811 +/- 203 fmol/mg protein, respectively). Receptor affinity was not statistically different in young (6.27 +/- 0.40 X 10(9) M-1) or old (6.67 +/- 0.79 X 10(9) M-1) animals. In a third experiment, male rats were castrated and given injections of LHRH (166 ng/kg) at 30-min intervals for 4.5 h.(ABSTRACT TRUNCATED AT 400 WORDS)

Insulin-like growth factor-1 selectively increases glucose utilization in brains of aged animals.

Previous studies indicate that insulin-like growth factor-1 is an important neurotrophic agent and that decreases in brain concentrations of IGF-1 and the type 1 IGF receptor have an important role in the age-related decline in memory, neuronal function and possibly dendritic architecture. In this study, we assessed the effects of age and IGF-1 replacement on local cerebral glucose utilization (LCGU). Three groups of male Brown-Norway rats (7, 18 and 28 months of age) were implanted with Alzet minipumps and either saline or IGF-1 (50ng/0.5 microliter/hour) was infused into the lateral ventricle for 28 days. On day 28, LCGU was measured by infusion of 2-[(14)C]deoxyglucose during the dark phase of the light/dark cycle. Results indicate that glucose utilization significantly decreased with age throughout the brain including the anterior cingulate, sensorimotor and retrosplenial cortex, CA1, CA3 and dentate gyrus of hippocampus and several regions of the hypothalamus. Administration of IGF-1 to aged animals increased rates of LCGU in the anterior cingulate of the cortex (14.2%), CA1 region of the hippocampus (11.0%) and the arcuate nucleus of the hypothalamus (12.0%). Our results indicate that although glucose utilization decreases with age throughout the brain, the effects of IGF-1 infusion are manifest only in specific brain regions. Since IGF-1 has been shown to reverse the age-related decrease in memory, these results suggest that despite the wide distribution of the type 1 IGF receptor the actions of IGF-1 on glucose utilization are highly localized. Additionally, the close association between glucose utilization and excitatory amino acid activity suggests that IGF-1 may act on specific neural pathways to increase glutamate activity in brain regions associated with learning and memory.

Somatostatin gene expression in hypothalamus and cortex of aging male rats.

Somatostatin has been reported to decrease with age in many brain regions and these changes generally have been considered to have important implications for the regulation of both neural activity and neuroendocrine regulatory systems. The purpose of this study was to determine whether the age-related changes in somatostatin concentration in cortex and hypothalamus are attributable to alterations in the regulation of somatostatin gene expression. Hypothalamic and cortical tissue were dissected from young (3-4 month), middle-aged (12-14 month), and old (22 month) male Fischer 344 rats. Total RNA was extracted and dilutions blotted to nitrocellulose. Somatostatin cDNA in expression vector pSP65 was used to produce a 32P-labeled antisense probe for hybridization. After washing, blots were autoradiographed and analyzed by densitometry. Dilutions of total RNA were also probed with 32P-labeled oligo d(pT)16 to determine poly A +RNA levels. Data were expressed as relative somatostatin gene expression (somatostatin mRNA/poly A +RNA). Results indicated that in cortex, relative somatostatin gene expression was similar in young, middle-aged, and old animals (0.54 +/- 0.11, 0.60 +/- 0.08, and 0.51 +/- 0.04, respectively). However, somatostatin gene expression in the hypothalamus decreased consistently with age and ratios in old rats were approximately 50% of levels observed in young animals (p less than 0.05). Northern analysis of RNA revealed a single somatostatin transcript of approximately 0.65 kb in all age groups. In situ hybridization analysis of somatostatin mRNA in the hypothalamus indicated that the age-related decrease in somatostatin gene expression is a consequence of decreased expression within specific hypothalamic nuclei rather than a loss of somatostatin-containing neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Positive Feedback by Ovarian Hormones on Prolactin and LH in Old Versus Young Female Rats.

The purpose of this investigation was to determine whether any differences could be demonstrated in the ability of old versus young ovariectomized rats to release prolactin and LH in response to ovarian steroid administration. Female Long Evans rats 20-24 months of age and 4 months of age were ovariectomized. Fourteen days later, each rat was injected with estradiol benzoate, followed three days later by an injection of progesterone. Blood was collected from an intra-atrial cannula for eight hrs after progesterone treatment for radioimmunoassay of prolactin and LH. Basal plasma levels of prolactin were higher in the old than in the young rats. The young rats showed a marked rise in plasma prolactin and LH in response to progesterone, whereas the old rats exhibited no elevation in prolactin and a smaller increase in LH than in young rats. Changes in hypothalamic function in the old female rats are believed to account for the differences observed.

Effects of ovariectomy and steroid replacement on hypothalamic LHRH content in aging female rats.

To examine the role of age on the hypothalamic LHRH response to ovariectomy (ovx) and steroid replacement, young cycling (3-4 months) and old constant estrous (18-20 months) rats were ovariectomized. Two weeks later, rats were treated for 5 days with estradiol benzoate (E, 5 micrograms/kg), progesterone (P, 10 mg/kg), E + P (5 micrograms E + 10 mg/kg) or corn oil, after which time they were killed for determination of hypothalamic LHRH content. The young and old ovx rats had similar levels of LHRH in the medial basal (MBH) and anterior (AH) hypothalamus, but E treatment was only effective in increasing MBH-LHRH content in the young animals. There was no significant effect of P alone or in combination with E. In the second experiment, similar results were seen using a single dose of E (1 microgram/rat) in young and old ovx rats. In addition, the radioimmunoassay of LHRH using two different antibodies binding to different portions of LHRH gave similar results in young and old rats, suggesting that the LHRH peptide was being processed similarly in the two age groups. In conclusion, it appears that hypothalamic LHRH content of young and old ovx rats does not differ with age despite a marked attenuation of serum LH levels with age. The hypothalamus from old rats, however, is less responsive to steroid stimulation of LHRH content.

Immunoreactive beta-endorphin in the plasma, pituitary and hypothalamus of young and old male rats.

Immunoreactive beta-endorphin (IR-beta-ENDO) was measured in the plasma, pituitary, and hypothalamus of young (3-5 mo.) and old (19-23 mo.) male Sprague-Dawley rats, using a specific radioimmunoassay. Plasma IR-beta-ENDO in old male rats (3.44 +/- 0.54 ng/ml) was more than three times higher than values observed in young male rats (1.00 +/- 0.10 ng/ml). Pituitary content and concentration of IR-beta-ENDO also were significantly greater in the old (5.85 +/- 0.51 microgram/gland and 1.17 +/- 0.10 microgram/mg protein) than in the young (3.53 +/- 0.29 microgram/gland and 0.78 +/- 0.06 microgram/mg protein) male rats. The content of IR-beta-ENDO in the hypothalamus of old and young rats was nearly the same (43.45 +/- 2.47 and 49.88 +/- 6.35 ng/hypothalamus, respectively), whereas the concentration of IR-beta-ENDO in the hypothalamus of the old male rats (3.89 +/- 0.25 ng/mg protein) was approximately 50% lower than that observed in the young male rats (7,80 +/- 0.85 ng/mg protein). These changes in plasma, pituitary, and hypothalamic IR-beta-ENDO may contribute to the increase in prolactin and decrease in gonadotropins observed in old male rats, since beta-ENDO administration is known to produce these effects on prolactin and gonadotropin secretion.

Effects of moderate caloric restriction on cortical microvascular density and local cerebral blood flow in aged rats.

The present study was designed to assess the impact of moderate caloric restriction (60% of ad libitum fed animals) on cerebral vascular density and local cerebral blood flow. Vascular density was assessed in male Brown-Norway rats from 7-35 months of age using a cranial window technique. Arteriolar density, arteriole-arteriole anastomoses, and venular density decreased with age and these effects were attenuated by moderate caloric restriction. Analysis of local cerebral blood using [14C]iodoantipyrine indicated that basal blood flow decreased with age in CA1, CA3 and dentate gyrus of hippocampus; similar trends were evident in cingulate, retrosplenal, and motor cortex. Basal blood flow was increased in all brain regions of moderate caloric restricted old animals (compared to old ad libitum fed animals) and no differences were observed between ad libitum fed young and caloric restricted older animals. In response to a CO2 challenge to maximally dilate vessels, blood flow increased in young and old ad libitum fed animals, but a similar increase was not observed in caloric restricted old animals. We conclude that a decrease in cerebral vasculature is an important contributing factor in the reduction in blood flow with age. Nevertheless, vessels from young and old animals have the capacity to dilate in response to a CO2 challenge and, after CO2, no differences are observed between the two age-groups. These results are consistent with the hypothesis that aged animals fail to adequately regulate local cerebral blood flow in response to physiological stimuli. Moderate caloric restriction increases microvascular density and cerebral blood flow in aged animals but tissues exhibit little or no increase in blood flow in response to CO2 challenge. The cause of this deficient response may indicate that vessels are maximally dilated in aged calorically restricted animals or that they fail to exhibit normal regulatory control.

Expression of insulin-like growth factor-1 (IGF-1) and IGF-binding protein 2 (IGF-BP2) in the hippocampus following cytotoxic lesion of the dentate gyrus.

Receptor binding and gene expression of several members of the IGF gene family were examined in the rat brain following lesion of the hippocampal dentate gyrus granular cells by intradentate colchicine injection. Dentate granular cell loss was accompanied by extensive reactive gliosis in the lesioned hippocampus and damaged overlying cortex, as verified by the increase in GFAP mRNA and BS-1 lectin binding. At 4 days post-lesion, 125I-IGF-2 binding was dramatically increased within the lesioned dentate gyrus and damaged overlying cortex, and corresponded temporally and anatomically with increased IGF-BP2 gene expression following the lesion. Increased IGF-BP3 gene expression was only observed in the overlying cortex at 10 days post-lesion, and corresponded with an increase in 125I-IGF-1 binding at the injured surface of the cortex. Type-2 IGF receptor mRNA expression was reduced to background levels in the lesioned dentate gyrus, suggesting that IGF-BP2 was a major component of the observed increase in 125I-IGF-2 binding. In situ hybridization also revealed a prominent increase in IGF-1 mRNA expression by 4 days post-lesion, which was localized within the lesioned dentate gyrus and damaged cortical areas, and was shown to be expressed by microglia. While no IGF-2 mRNA expression was observed within the CNS, either prior to, or following the lesion, IGF-2 mRNA expression was observed in the choroid plexus, meningeal membranes, and in blood vessel endothelium, providing a potential source for the transport of IGF-2 into the CNS. In the injured CNS, increased IGF-BP2 expression may act to maintain or transport IGF-1 or IGF-2, as well as modulate the local autocrine and paracrine actions of the IGFs. Increased microglial IGF-1 expression following colchicine treatment correlates with the timing of a number of post-traumatic events within the CNS, suggesting that IGF-1 may have a role as a neuroprotectant for surviving neurons and signal for local neuronal sprouting, as well as a role in reactive astrogliosis.

Moderate caloric restriction increases type 1 IGF receptors and protein synthesis in aging rats.

Insulin-like growth factor-1 (IGF-1) is an anabolic hormone that mediates the actions of growth hormone (GH) and is found at lower concentrations in aged animals. These decreases in GH and IGF-1 appear to have important physiological consequences for aging, since protein synthesis decreases with age, and administration of GH and/or IGF-1 has been shown to increase protein synthesis. The present study was designed to determine (a) the relationship between the age-related changes in rates of tissue protein synthesis and plasma IGF-1 concentrations, (b) type 1 IGF receptor density in tissues and (c) whether long-term moderate caloric restriction, which is known to increase life-span, affects these relationships. Male Brown Norway rats were fed ad libitum or caloric-restricted (60% ad libitum) from 14 weeks of age and sacrificed at different ages. In ad libitum fed animals there were age-related decreases in plasma IGF-1 concentrations (14%) and in the rates of protein synthesis of the heart (36%) and liver (38%). Type 1 IGF receptor density remained constant in all tissues with age. The caloric-restricted animals exhibited plasma IGF-1 concentrations 33 to 42% lower than the ad libitum fed animals. However, rates of protein synthesis increased by 70 and 30% in heart and diaphragm, and this increase was associated with 60 to 100% increases in type 1 IGF receptor densities when compared with ad libitum fed animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin-like growth factor-1 ameliorates age-related behavioral deficits.

Insulin-like growth factor-1 has been found to be involved in the regulation of several aspects of brain metabolism, neural transmission, neural growth and differentiation. Because decreased insulin-like growth factor-1 and/or its receptors are likely to contribute to age-related abnormalities in behavior, the strategy of replacing this protein is one potential therapeutic alternative. The present study was designed to assess whether cognitive deficits with ageing may be partially overcome by increasing the availability of insulin-like growth factor-1 in the brain. Fischer-344 x Brown Norway hybrid (F1) male rats of two ages (four-months-old and 32-months-old) were preoperatively trained in behavioral tasks and subsequently implanted with osmotic minipumps to infuse the insulin-like growth factor-1 (23.5 microg/pump) or a vehicle, i.c.v. Animals were retested at two weeks and four weeks after surgery. Insulin-like growth factor-1 improved working memory in the repeated acquisition task and in the object recognition task. An improvement was also observed in the place discrimination task, which assesses reference memory. Insulin-like growth factor-1 had no effect on sensorimotor skills nor exploration, but mildly reversed some age-related deficits in emotionality. These data indicate a potentially important role for insulin-like growth factor-1 in the reversal of age-related behavioral impairments in rodents.