Biomedical subjects

William E Sonntag

Publications and source records attributed to William E Sonntag.

At least 19 recordsLinked to original sources

PubMed2006

Growth hormone and IGF-I modulate local cerebral glucose utilization and ATP levels in a model of adult-onset growth hormone deficiency.

Decreases in plasma IGF-I levels that occur with age have been hypothesized to contribute to the genesis of brain aging. However, support for this hypothesis would be strengthened by evidence that growth hormone (GH)/IGF-I deficiency in young animals produces a phenotype similar to that found in aged animals. As a result, we developed a unique model of adult-onset GH/IGF-I deficiency by using dwarf rats specifically deficient in GH and IGF-I. The deficiency in plasma IGF-I is similar to that observed with age (e.g., 50% decrease), and replacement of GH restores levels of IGF-I to that found in young animals with normal GH levels. The present study employs this model to investigate the effects of circulating GH and IGF-I on local cerebral glucose utilization (LCGU). Analysis of LCGU indicated that GH/IGF-I-deficient animals exhibit a 29% decrease in glucose metabolism in many brain regions, especially those involved in hippocampally dependent processes of learning and memory. Similarly, a high correlation between plasma IGF-I levels and glucose metabolism was found in these areas. The deficiency in LCGU was not associated with alterations in GLUT1, GLUT3, or hexokinase activity. A 15% decrease in ATP levels was also found in hippocampus of GH-deficient animals, providing compelling data that circulating GH and IGF-I have significant effects on the regulation of glucose utilization and energy metabolism in the brain. Furthermore, our results provide important data to support the conclusion that deficiencies in circulating GH/IGF-I contribute to the genesis of brain aging.

Adenosine Triphosphate↗

PubMed2006

Adult-onset deficiency in growth hormone and insulin-like growth factor-I decreases survival of dentate granule neurons: insights into the regulation of adult hippocampal neurogenesis.

Insulin-like growth factor-I (IGF-I), long thought to provide critical trophic support during development, also has emerged as a candidate for regulating ongoing neuronal production in adulthood. Whether and how IGF-I influences each phase of neurogenesis, however, remains unclear. In the current study, we used a selective model of growth hormone (GH) and plasma IGF-I deficiency to evaluate the role of GH and IGF-I in regulating cell proliferation, survival, and neuronal differentiation in the adult dentate gyrus. GH/IGF-I-deficient dwarf rats of the Lewis strain were made GH/IGF-I replete throughout development via twice daily injections of GH, and then GH/IGF-I deficiency was initiated in adulthood by removing animals from GH treatment. Bromodeoxyuridine (BrdU) labeling revealed no effect of GH/IGF-I deficiency on cell proliferation, but adult-onset depletion of GH and plasma IGF-I significantly reduced the survival of newly generated cells in the dentate gyrus. Colabeling for BrdU and markers of immature and mature neurons revealed a selective effect of GH/IGF-I deficiency on the survival of more mature new neurons. The number of BrdU-labeled cells expressing the immature neuronal marker TUC-4 did not differ between GH/IGF-I-deficient and -replete animals, but the number expressing only the marker of maturity NeuN was lower in depleted animals. Taken together, results from the present study suggest that, under conditions of short-term GH/IGF-I deficiency during adulthood, dentate granule cells continue to be produced, to commit to a neuronal fate, and to begin the process of neuronal maturation, whereas survival of the new neurons is impaired.

Analysis of Variance↗

PubMed2006

Effects of chronic growth hormone and insulin-like growth factor 1 deficiency on osteoarthritis severity in rat knee joints.

OBJECTIVE: To determine the effects of chronic deficiency of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) on osteoarthritis (OA) severity. METHODS: Thirty-five rats were divided into 4 treatment groups at 4 weeks of age: 1 control group (normal GH/IGF-1 levels [heterozygous]) and 3 groups of dwarves with a genetic mutation that results in GH deficiency. The first dwarf group received GH for 64 weeks (GH replete) and the second received GH until 14 weeks of age, followed by saline for 50 weeks (adult-onset GH/IGF-1 deficiency [AO-GHD]). The third dwarf group received saline injections only (lifetime GH deficient [GHD]). Sections of the medial knee joint compartment were graded and measured histologically; data were summarized using factor analysis, and treatment effects were assessed using analysis of variance and adjusting for body weight. RESULTS: Terminal IGF-1 levels and body weights were significantly affected by treatment (P = 0.002 and P < 0.001, respectively). Factor analysis yielded a total of 5 factors, the first 3 of which were not significantly affected by treatment. Factor 4 (weighted by medial tibial plateau articular cartilage width and area) was significantly affected by treatment (P < 0.012), with larger values in the AO-GHD group than in the GHD group (P < 0.05). Factor 5 (weighted primarily by articular cartilage structure and loss of toluidine blue staining scores) also was significantly affected by treatment (P < 0.001), and was significantly lower (less severe lesions) in the GH replete group than in all other treatment groups (P < 0.05). Despite the presence of cartilage lesions, osteophytes and subchondral sclerosis were not observed in GH/IGF-1-deficient animals. CONCLUSION: These results indicate that chronic GH/IGF-1 deficiency causes an increased severity of articular cartilage lesions of OA without the bony lesions normally seen in this disease.

Animals↗

PubMed2006

Growth hormone replacement attenuates diastolic dysfunction and cardiac angiotensin II expression in senescent rats.

We tested the hypothesis that long-term growth hormone (GH) replacement in aged rats would preserve diastolic function and attenuate left ventricular remodeling associated with normal aging. Male Brown Norway x F344 rats were randomized to receive twice daily injections of porcine GH (200 microg/injection, subcutaneous) or saline from 24 to 30 months of age. Adult rats (6- to 9-months old) received saline injections throughout the study. Thirty-month-old, saline-treated rats exhibited low levels of insulin-like growth factor 1 (IGF-1), impaired diastolic left ventricular filling (Doppler), increased cardiac angiotensin II (Ang II), reduced plasma Ang II, and increased cardiac collagen. GH administration in old rats restored IGF-1 and diastolic indices to values comparable to those of adults. These effects were associated with reduced cardiac Ang II and attenuations in cardiac collagen. Age-related decreases in GH and IGF-1 may contribute to the decline in diastolic function of aging, in part through alterations in renin-angiotensin system-mediated ventricular remodeling.

Aging↗

PubMed2006

Spatial learning and memory deficits after whole-brain irradiation are associated with changes in NMDA receptor subunits in the hippocampus.

Whole-brain irradiation is used for the treatment of brain tumors, but can it also induce neural changes, with progressive dementia occurring in 20-50% of long-term survivors. The present study investigated whether 45 Gy of whole-brain irradiation delivered to 12-month-old Fischer 344 x Brown Norway rats as nine fractions over 4.5 weeks leads to impaired Morris water maze (MWM) performance 12 months later. Compared to sham-irradiated rats, the irradiated rats demonstrated impaired MWM performance. The relative levels of the NR1 and NR2A but not the NR2B subunits of the NMDA receptor were significantly higher in hippocampal CA1 of irradiated rats compared to control rats. No significant differences were detected for these NMDA subunits in CA3 or dentate gyrus. Further analysis of CA1 revealed that the relative levels of the GluR1 and GluR2 subunits of the AMPA receptor and synaptophysin were not altered by whole-brain irradiation. In summary, a clinically relevant regimen of fractionated whole-brain irradiation led to significant impairments in spatial learning and reference memory and alterations in the relative levels of subunits of the NMDA, but not the AMPA, receptors in hippocampal CA1. These findings suggest for the first time that radiation-induced cognitive impairments may be associated with alterations in glutamate receptor composition.

Animals↗

PubMed2005

Growth hormone administration to aged animals reduces disulfide glutathione levels in hippocampus.

Systemic growth hormone (GH) and insulin-like growth factor-1 (IGF-1), potent anabolic hormones, decrease with age. In humans and animal models, administration of growth hormone or IGF-1 to aged subjects improves learning and memory, suggesting that the age-related decline in cognitive performance results, in part, from peripheral GH/IGF-1 deficiency. However, the cellular mechanisms by which GH/IGF-1 effect cognitive function are unknown. We propose that the effects of these hormones may be mediated by increasing cellular redox potential resulting in reduced oxidative stress. Because the most abundant endogenous antioxidant is glutathione (GSH), we assessed GSH and disulfide glutathione (GSSH) levels in hippocampus and frontal cortex of young (4-month-old) and aged (30-month-old) male Fisher 344xBrown Norway rats treated with porcine growth hormone (200microg/animal, twice/daily) or vehicle. We report that hippocampal levels of GSSG increase with age (0.54+/-0.08 to 1.55+/-0.24nmolGSSG/mgprotein, p<0.05) and growth hormone treatment ameliorates both the age-related rise in GSSG (1.55+/-0.24 to 0.87+/-0.24nmolGSSG/mgprotein, p<0.05) and the decline in GSH/GSSG ratios. Analysis of GSSG reductase activity in aged animals indicated no effect of either age or growth hormone treatment (p=0.81). Although similar age-related increases in GSSG and decreases in GSH/GSSG ratios were evident in frontal cortex, growth hormone had no effect. Subsequently, we assessed whether the effects of age and growth hormone treatment result from modulating trace metal accumulation. Thirteen metals were analyzed in hippocampus and frontal cortex by inductive coupled plasma mass spectrometry. Aluminum, copper, iron, manganese and zinc levels increased with age (p<0.05 each) but growth hormone replacement had no effect on metal accumulation. Our results indicate that growth hormone replacement attenuates the age-related increase in oxidative stress in hippocampus without effects on glutathione reductase or trace metal accumulation. We conclude that the age-related decline in circulating growth hormone and IGF-1 contribute to increased oxidative stress in hippocampus with age.

Aging↗

PubMed2005

Growth, metabolism, and blood pressure disturbances during aging in transgenic rats with altered brain renin-angiotensin systems.

Transgenic rats with targeted decreased glial expression of angiotensinogen (ASrAogen rats) did not show an increase in systolic pressure compared with Sprague-Dawley (SD) rats during aging (15-69 wk of age). ASrAogen animals had lower body weights throughout the study, similar to reports for animals with systemic knockout of angiotensinogen or treated long term with renin-angiotensin system (RAS) blockers. Further characterization of indexes of growth and metabolism in ASrAogen rats compared with (mRen2)27 and SD rats, which express elevated versus normal brain and tissue angiotensin II levels, respectively, revealed that serum leptin was 100-200% higher in SD and (mRen2)27 rats at 46 wk and 69 wk of age. Consistent with low serum leptin, ASrAogen rats had higher food intake (73%) compared with SD or (mRen2)27 rats. (mRen2)27 rats had higher resting insulin levels than ASrAogen rats at all ages. Insulin levels were constant during aging in ASrAogen rats, whereas an increase occurred in SD rats, leading to higher insulin levels at 46 and 69 wk of age compared with ASrAogen rats. IGF-1 was comparable among strains at all ages, but (mRen2)27 rats had longer and ASrAogen rats had shorter tail lengths versus SD rats at 15 wk of age. In conclusion, reduced expression of glial angiotensinogen blunts the age-dependent rise in insulin levels and weight gain, findings that mimic the effects of long-term systemic blockade of the RAS or systemic knockout of angiotensinogen. These data implicate glial angiotensinogen in the regulation of body metabolism as well as hormonal mechanisms regulating blood pressure.

Aging↗

PubMed2005

Adult-onset growth hormone and insulin-like growth factor I deficiency reduces neoplastic disease, modifies age-related pathology, and increases life span.

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.

Aging↗

PubMed2005

Growth hormone and insulin-like growth factor-1 (IGF-1) and their influence on cognitive aging.

The concept that growth hormone and IGF-1 are required for normal development of the mammalian body and, more recently the brain, is supported by a vast experimental literature. IGF-1 crosses the blood-brain barrier and in recent years, much attention has focused on age-related decreases in serum growth hormone and IGF-1 as potential mechanisms that may influence cognitive function in the elderly. However, interventional studies are needed to establish a definite link between these hormones and function of the aging brain. In rodents, long-term growth hormone/IGF-1 replacement improves learning and memory in aged rats. While the exact mechanism underlying these cognitive improvements is unknown, growth hormone and IGF-1 replacement to aged animals increases neurogenesis, vascular density, and glucose utilization, and alters NMDA receptor subunit composition in brain areas that are implicated in learning and memory. While these observations offer valuable insight into the influence of growth hormone and IGF-1 on neuronal events in the aged mammal, additional functional studies are required to link these changes to cognitive improvements.

Aging↗

PubMed2005

Dendritic stability in a model of adult-onset IGF-I deficiency.

OBJECTIVE: A significant decrease in plasma levels of insulin-like growth factor-I (IGF-I) is one of the most robust hallmarks of aging and may contribute to functional changes associated with senescence. This study examined the role of IGF-I in the maintenance of adult dendritic morphology. DESIGN: We utilized a model of the aging-related decrease in plasma IGF-I to examine whether such a decrease, in itself, leads to dendritic changes in the cerebral cortex. The dw/dw rat, originally of the Lewis strain, suffers from a spontaneous mutation in which growth hormone (GH) production is severely decreased. Since GH is responsible for the production of circulating IGF-I by the liver, these animals are deficient in plasma IGF-I. Homozygous dw/dw rats were administered porcine GH to sustain IGF-I levels during development and then GH injections were stopped as adults in order to examine the effects of adult-onset GH and IGF-I deficiency. Animals sacrificed after two or eight weeks of GH and IGF-I deficiency were compared to age-matched dw/dw animals that received GH both developmentally and throughout adulthood (GH/IGF-I replete). The dendritic arbors of pyramidal neurons in cingulate cortex were labeled by intracellular injection and reconstructed in three dimensions. RESULTS: Comparing GH/IGF-I replete and deficient dw/dw rats, we found no differences in the apical or basal arbors of either layer two or layer five pyramidal neurons. CONCLUSIONS: These findings indicate that a decrease in plasma levels of IGF-I is not sufficient in itself to produce dendritic changes like those seen in aging animals.

Aging↗

PubMed2005

Functional characterization of des-IGF-1 action at excitatory synapses in the CA1 region of rat hippocampus.

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.

Androstadienes↗

PubMed2004

Angiotensin-converting enzyme inhibition, body composition, and physical performance in aged rats.

This study was designed to test the effects of angiotensin-converting enzyme (ACE) inhibition on body composition and physical performance in aged rats. Male Brown Norway x F344 rats were randomized to receive daily injections of enalapril (40 mg/kg or 80 mg/kg) or saline from 24 to 30 months of age. Body composition was determined using dual-energy X-ray absorptiometry (DXA), and physical performance was assessed using the grip strength and inclined plane procedures. Performance measures were assessed at baseline and monthly thereafter. DXA was performed at baseline, 3 months, and 6 months of follow-up. Compared with the enalapril groups, the saline group experienced a greater 6-month decline in the physical performance measures. Lean body mass declined in both groups; however, the enalapril groups also experienced a significant loss of fat mass. These results suggest that ACE inhibition may prevent age-related declines in physical performance, which may be mediated by a reduction in body fat mass.

Age Factors↗

PubMed2003

Microvascular plasticity in aging.

Understanding the bases of aging-related cognitive decline remains a central challenge in neurobiology. Quantitative studies reveal little change in the number of neurons or synapses in most of the brain but their ongoing replacement is reduced, resulting in a significant loss of neuronal plasticity with senescence. Aging also may alter neuronal function and plasticity in ways that are not evident from anatomical studies of neurons and their connections. Since the nervous system is dependent upon a consistent blood supply, any aging-related changes in the microvasculature could affect neuronal function. Several studies suggest that, as the nervous system ages, there is a rarefaction of the microvasculature in some regions of the brain, as well as changes in the structure of the remaining vessels. These changes contribute to a decline in cerebral blood flow (CBF) that reduces metabolic support for neural signaling, particularly when levels of neuronal activity are high. In addition to direct effects on the microvasculature, aging reduces microvascular plasticity and the ability of the vessels to respond appropriately to changes in metabolic demand. This loss of microvascular plasticity has significance beyond metabolic support for neuronal signaling, since neurogenesis in the adult brain is regulated coordinately with capillary growth.

Aging↗

PubMed2002

Of worms, flies, dwarfs, and things that go bump in the night.

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.

Animals↗

PubMed2002

Growth hormone, insulin-like growth factor-1 and the aging cardiovascular system.

There is a large body of evidence that biological aging is related to a series of long-term catabolic processes resulting in decreased function and structural integrity of several physiological systems, among which is the cardiovascular system. These changes in the aging phenotype are correlated with a decline in the amplitude of pulsatile growth hormone secretion and the resulting decrease in plasma levels of its anabolic mediator, insulin like growth factor-1 (IGF-1). The relationship between growth hormone and biological aging is supported by studies demonstrating that growth hormone administration to old animals and humans raises plasma IGF-1 and results in increases in skeletal muscle and lean body mass, a decrease in adiposity, increased immune function, improvements in learning and memory, and increases in cardiovascular function. Since growth hormone and IGF-1 exert potent effects on the heart and vasculature, the relationship between age-related changes in cardiovascular function and the decline in growth hormone levels with age have become of interest. Among the age-related changes in the cardiovascular system are decreases in myocyte number, accumulation of fibrosis and collagen, decreases in stress-induced cardiac function through deterioration of the myocardial conduction system and beta-adrenergic receptor function, decreases in exercise capacity, vessel rarefaction, decreased arterial compliance and endothelial dysfunction leading to alterations in blood flow. Growth hormone has been found to exert potent effects on cardiovascular function in young animals and reverses many of the deficits in cardiovascular function in aged animals and humans. Nevertheless, it has been difficult to separate the effects of growth hormone deficiency from age-related diseases and associated pathologies. The development of novel animal models and additional research are required in order to elucidate the specific effects of growth hormone deficiency and assess its contribution to cardiovascular impairments and biological aging.

Aged↗

PubMed2002

A critical analysis of the role of growth hormone and IGF-1 in aging and lifespan.

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.

Aging↗

PubMed2002

Insulin-like growth factor-1 does not ameliorate the age-related decline in presumptive inhibitory synapses in layer 2 of rat sensorimotor cortex.

Four old (29 months) Brown Norway x Fischer 344 (BN x F344) rats received intracerebroventricular infusion of insulin-like growth factor-1 (IGF-1) and four middle-aged (18 months) and four old (29 months) rats received infusion of saline for 28 days. Sensorimotor cortex containing layer 2 was blocked and processed for electron microscopy. Thin (700 A) and semithin (1 microm) sections were collected from the same anatomical space for quantification of synapses and neurons, respectively, using the physical disector. Numerical density (Nv) of presumptive inhibitory synapses in layer 2 of sensorimotor cortex has been reported to decline with age Poe et al., 2001; Brunso-Bechtold et al. [Brain Res. 872 (2000) 125]. Infusion of IGF-1 did not affect the density of synapses or neurons when old IGF-1 animals were compared with old saline animals.

Aging↗

PubMed2002

Models of growth hormone and IGF-1 deficiency: applications to studies of aging processes and life-span determination.

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.

Aging↗