Effects of aging and long-term calorie restriction on DHEA and DHEA sulfate in rhesus monkeys.
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Aging↗
Biomedical subjects
D K Ingram
Publications and source records attributed to D K Ingram.
Adenovirus-mediated gene transfer of dopamine D2 receptor cDNA into rat striatum.
A robust feature of mammalian aging associated with diminished motor control is the loss of dopamine D2 receptors from the neostriatum. Decline in this neurotransmitter receptor is also observed in neurodegenerative disorders, such as Huntington's disease and late-stage Parkinson's disease. We have constructed a replication-deficient adenoviral vector to transfer rat dopamine D2 receptor cDNA to brain as a possible therapeutic strategy. Using tissue culture cells infected with this vector, we detected dopamine D2 receptor mRNA by Northern analysis and functional receptor protein in membrane preparations as specific binding of the dopamine D2 receptor ligand, [3H]spiperone. In vivo demonstration involved autoradiographic analysis of [3H]spiperone binding in rat striatum following injection of the adenoviral vector. Dopamine D2 receptor expression was amplified markedly above normal concentrations in the injection site, whereas no increased expression was observed in sites receiving control treatments. These results demonstrate the potential of gene therapy using adenoviral vectors to transfer neurotransmitter receptor proteins to the brain to reverse deficiencies in specific neurodegenerative disorders.
Adenoviridae↗
Retrograde transfer of replication deficient recombinant adenovirus vector in the central nervous system for tracing studies.
We assessed the application of a replication deficient recombinant adenovirus vector as a retrograde tracer in neural pathway studies. The adenovirus vector, Ad. RSV betagal, containing the intracellular marker gene, beta-galactosidase, was injected directly into the laterodorsal striatum of rats. The retrograde transport of the vector from the injection site was clearly visible in the cerebral cortex, thalamic nucleus, and substantia nigra. No evidence for anterograde transport of the vector was found. When the vector was injected into the genu of the corpus callosum, little uptake of the vector by fibers was noted which suggested that uptake by fibers-of-passage should not be a problem in tracing studies. The present study demonstrates that adenoviral vectors can be useful retrograde tracers in the study of afferent connections within the central nervous system.
Adenoviruses, Human↗
Effects of aging and dietary restriction on activity of monkey serum in promoting fibroblast migration.
In order to determine whether serum modified cellular aging in vivo, we previously studied the effects of serum from various mammals of different ages on cell functions such as proliferation and migration, and reported that cell migration was more greatly inhibited by serum from old donors than cell proliferation [1]. Moreover, since dietary restriction has been reported to extend lifespan and slow the aging rate of some animals [2], we wondered whether sera from dietary restricted and control monkeys of various ages might exhibit reduced aging effects on cell migration. When serum from young adult (3-5 years old) monkeys was added to plain medium, the migration of human fetal skin fibroblasts was very strongly inhibited compared to FBS. Surprisingly, sera from adult (6-11 years old) and old (more than 18 years old) monkeys caused significantly less migration-inhibitory activity than serum from young adult monkeys although sera from adult and old monkeys were much more inhibitory to cell migration than FBS. Dietary restriction only caused marginal effects on serum migration-promoting activity in a few monkey groups. The inhibition of cell migration caused by monkey serum was not brought about by cytotoxic effects since monkey serum stimulated cell proliferation as well as fetal bovine serum. These results indicate that the effects of aging on monkey serum migration-promoting activity are much more pronounced than those of dietary restriction.
Aging↗
Maze learning in aged rats is enhanced by phenserine, a novel anticholinesterase.
A new generation of cholinesterase inhibitors is expected to overcome some limitations of the therapeutic use of anticholinesterases. Phenserine is a long-acting and selective inhibitor of acetylcholinesterase with a preferential brain uptake. We have assessed the effects of chronic phenserine tartrate treatment on performance of aged Fischer-344 rats in the 14-unit T-maze. Phenserine (1-3 mg kg-1, i.p.) treatment for 5 days significantly reduced the number of errors made in the Stone maze. Other performance variables were also improved. No side effects were noted across 5 days treatment at doses of 1-2 mg kg-1. Phenserine can therefore improve the performance of aged rats in this complex maze task without producing obvious side effects.
Aging↗
Influence of age, sex, and dietary restriction on intracellular free calcium responses of CD4+ lymphocytes in rhesus monkeys (Macaca mulatta).
The influence of aging and dietary restriction on increase in intracellular free calcium ([Ca2+]i) of CD4+ lymphocytes from Macaca mulatta was examined after stimulation with anti-CD3 mAb. We used a flow cytometric assay with the dye indo-1 and either direct or reciprocal immunofluorescent staining to identify CD4+ cells. After stimulation with anti-CD3 mAb, intracellular free calcium responses were reduced in CD4+ lymphocytes from old male and female ad libitum fed monkeys compared to young and adult male or female monkeys. Old female monkeys had significantly lower [Ca2+]i than did old male monkeys. The reduced responses were in part related to a decreased percentage of responding cells. Dietary restriction of males over a four-year period did not alter [Ca2+]i response compared to ad libitum fed male monkeys. Female monkeys of all ages (which were restricted only for four months) also had similar [Ca2+]i responses to ad libitum fed controls. Our data suggest that age-related changes in [Ca2+]i responses are similar between humans and M. mulatta, and that over these intervals, no effects of caloric restrictions can be detected.
Aging↗
Phenserine and ring C hetero-analogues: drug candidates for the treatment of Alzheimer's disease.
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Alzheimer Disease↗
Slowing ageing by caloric restriction.
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Aging↗
Energy balance in rhesus monkeys (Macaca mulatta) subjected to long-term dietary restriction.
Male rhesus monkeys of various age groups representative of the species life span were fed ad libitum amounts (controls) or 30% less food than control monkeys of comparable age and body weight. Despite significantly lowered energy intake and body weight, the amount of energy lost in the feces, and fecal energy density (concentration) were not altered in diet-restricted (DR) monkeys, compared to age- and weight-matched controls. Absolute energy expenditure (EE; 24-hr) was consistently lower in DR monkeys, but this trend was not statistically significant. Expressed as a function of metabolic mass (body weight, metabolic body size, lean mass), 24-hr EE was not different in monkeys subjected to long-term DR, compared to controls. Calculations of net energy (intake-loss), as an index of energy balance, revealed that energy expenditure generally exceeded energy intake in all juvenile and adult group monkeys. However, this discrepancy was not statistically different from zero, suggesting that most animals were in energy balance. Also, there was no difference between control and DR animals with respect to energy balance. Diet restriction induced significant reductions in the absolute amount of lean body mass; however, percent (of total weight) lean and fat mass did not differ from controls.
Animals↗
Aging and food restriction alter some indices of bone metabolism in male rhesus monkeys (Macaca mulatta).
Food restriction increases life span, reduces aging rate and affects a wide variety of biological functions. In rats, food restriction delays bone growth and reduces bone density and mineral content. We report the effects of aging and long-term (> 6.0 y) food restriction on several indices of bone growth and metabolism in rhesus monkeys (Macaca mulatta). Food allotments for controls approximated free access consumption, whereas food-restricted monkeys received 30% less food on a body weight basis. Cross-sectional and longitudinal age effects on serum alkaline phosphatase paralleled those reported for humans. Food restriction induced a significant delay in the developmental decline (to adult levels) in total alkaline phosphatase and significantly suppressed serum interleukin 6 concentrations, particularly in younger monkeys. Also, food restriction slowed skeletal growth, as reflected by shorter crown-rump length, and significantly reduced total body bone mineral content, but not bone mineral density, measured by dual energy X-ray absorptiometry. Analyses of serum parathyroid hormone, calcium, phosphate and osteocalcin concentrations suggested that the effects on skeletal growth were not related to alterations in calcium and phosphate homeostasis or a primary defect in bone formation. These findings suggest that long-term food restriction delays skeletal development in male rhesus monkeys while allowing the development of a reduced but otherwise normal skeleton.
Aging↗
Diet restriction in rhesus monkeys lowers fasting and glucose-stimulated glucoregulatory end points.
Male rhesus monkeys (Macaca mulatta) of different age groups representing the species life span were fed ad libitum or a 30% reduced calorie diet over a 7-yr period. During the first 2-3 yr of this longitudinal study, glucose and insulin levels were not altered by diet restriction (DR). However, reductions in fasting blood glucose became apparent in DR animals after 3-4 yr. At the end of the 6th yr of study, glycated hemoglobin was measured, and intravenous glucose tolerance tests (IVGTTs) were conducted. Maximum glucose levels reached during IVGTTs increased with age but were lower in DR animals compared with controls. Several measures of the insulin response (baseline, maximum, and integrated areas under curve) increased with age and were lower in DR monkeys. With the exception of glycated hemoglobin, which was not different in monkeys subjected to DR, these findings confirm previous studies in rodents demonstrating that DR alters glucose metabolism and may be related to the antiaging action of this intervention.
Aging↗
The correlation between neuron counts and optical density of NADPH-diaphorase histochemistry in the rat striatum: a quantitative study.
NADPH diaphorase (NADPH-d) histochemistry is a useful technique for examining select neuronal populations in both experimental studies and human neuropathology and also provides a simple method to localize nitric oxide synthase in the central nervous system. However, no established method exists for detecting quantitative changes of NADPH-d histochemistry under different experimental conditions. To develop a quantitative procedure, we systematically examined the properties of NADPH-d histochemistry and then investigated the correlation between the number of NADPH-d positive cells and the optical density of NADPH-d histochemistry in the rat striatum. NADPH-d activity was sensitive to specific experimental conditions, such as incubation time, fixation, and high temperature. In the striatum NADPH-d activity of neuropil was more sensitive to these conditions than were the somata. The different staining patterns of NADPH-d between the neuropil of the striatum and white matter, such as the optic tract suggest neuropil staining in the striatum is not just unspecific background staining. Increasing incubation time only increased the optical density of NADPH-d staining, in contrast, the number of NADPH-d positive cells counted was relatively consistent across incubation times. Therefore, little correlation existed between the optical density and cell number. These results indicate that when using NADPH-d histochemistry, the number of NADPH-d positive neurons is independent of the optical density of the staining, and these two parameters should be considered and treated separately when conducting quantitative analysis related to an experimental treatment.
Animals↗
Spermidine potentiates dizocilpine-induced impairment of learning performance by rats in a 14-unit T-maze.
The NMDA receptor, a ligand-gated ion channel complex, has been reported to be involved in memory processes. Learning is impaired following administration of dizocilpine, a non-competitive antagonist of the NMDA receptor. Polyamines, such as spermine and spermidine, interact with the NMDA receptor to enhance binding of dizocilpine, which blocks the ion channel. The present study assessed action of polyamines as modulators of learning via NMDA receptor activation. Dizocilpine (0.05 mg/kg) was given i.p. before maze learning, at a dose that produced a slight, nonsignificant impairment of maze learning. Pretreatment with 80 mg/kg but not 15 or 40 mg/kg spermidine (i.p.) before dizocilpine impaired maze learning compared to saline controls. Administration of 80 mg/kg spermidine without dizocilpine did not impair maze learning. The results are consistent with the view that systemic injection of a polyamine can modulate learning processes involving the NMDA receptor.
Analysis of Variance↗
New pharmacological strategies for cognitive enhancement using a rat model of age-related memory impairment.
We have developed the Stone maze paradigm for use as a rat model of memory impairment observed in normal aging and in Alzheimer's disease. Evidence produced thus far clearly implicates both the cholinergic and glutamatergic systems in acquisition performance in this complex maze task. Although results have been very inconsistent regarding the cognitive enhancing abilities of cholinomimetics for use in Alzheimer's disease, new classes of cholinesterase inhibitors may offer greater therapeutic efficacy. The use of glycine and polyamine agonists appears to be a viable strategy for positive modulation of the NMDA receptor. In addition, an approach that combines stimulation both of cholinergic and glutamatergic systems may have greater potential than agonism of either separately. Manipulation of signal transduction events might also have potential for cognitive enhancement. The influx of Ca2+ through the NMDA receptor stimulates production of NO via the action of NOS. By using NARG to block NOS activity, we have demonstrated in rats that NO production appears to influence learning in the Stone maze. We are currently exploring the age-related changes in NOS activity in specific brain regions of rats to determine if loss in the NO generating system is related to age-related memory impairment observed in the Stone maze. In addition, we are exploring pharmacological strategies for inducing NO production; however, because of the potential neurotoxicity for NO overstimulation, this strategy will present some obstacles. The identification of NO as a simple molecule serving vital physiological functions but representing potential for neurotoxicity presents an important unifying area for neurobiological investigations searching for mechanisms of normal brain aging and of age-related neuropathology, as observed in Alzheimer's disease.
Aging↗
Age-related fibrillar material in mouse brain. Assessing its potential as a biomarker of aging and as a model of human neurodegenerative disease.
We have described the age-related deposition of fibrillar material in brains of B6 mice and SAM. Since in other inbred strains similar deposits were absent or occurred only occasionally and only in aged individuals, a genetic predisposition of B6 mice and SAM to accumulate the fibrillar material is suggested. The deposits are mostly associated with astrocytic processes and have been referred to as astrocytic inclusions. HSPG- and laminin-like molecules have been identified as components of the fibrillar material. The deposits have similarities with CA in humans, but they also show some important differences; thus there is presently insufficient evidence to consider the deposits the murine equivalent of CA. Although the physiological significance of the fibrillar material is not yet clear, the awareness of the deposits appears pertinent because they might contribute to various aspects of CNS function of susceptible strains of mice, and therefore could lead to possible misinterpretations of the results of studies employing these strains. Future directions of our research will determine the potential of the murine deposits to model aspects of human neuropathology, in particular, whether the deposits may mimic the deposition of ECM molecules as an early-event in the pathogenesis of amyloid plaque formation.
Aging↗
Rodent models of memory dysfunction in Alzheimer's disease and normal aging: moving beyond the cholinergic hypothesis.
The Stone maze paradigm has been developed for use as a rat model of memory impairment observed in normal aging and in Alzheimer's disease. Results from several studies have demonstrated the involvement of both cholinergic and glutamatergic systems in acquisition performance in this complex maze task. Although results of clinical studies on the cognitive enhancing abilities of cholinomimetics for treatment of memory impairment in Alzheimer's disease have been inconsistent, new classes of cholinesterase inhibitors offer greater potential for therapeutic efficacy. The physostigimine derivative, phenserine, appears to have marked efficacy for improving learning performance of aged rats or of young rats treated with scopolamine in the Stone maze. Declines in markers of glutamatergic neurotransmission in Alzheimer's disease and in normal aging suggest that pharmacological manipulation of this system might also prove beneficial for cognitive enhancement. Treatment with glycine and/or polyamine agonists is suggested as a strategy for activating the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. In addition, the use of combined pharmacological activation of cholinergic and glutamatergic systems is suggested. Manipulation of signal transduction events should also be considered as a strategy for cognitive enhancement. The influx of Ca2+ through the channel formed by the NMDA receptor stimulates the production of the oxyradical, nitric oxide (NO*), via the action of nitric oxide synthase (NOS). Compounds that inhibit NOS activity impair acquisition in the Stone maze, suggesting an involvement of NO*. Thus, strategies for inducing NO* production to enhance cognitive performance may be beneficial. Because of the potential neurotoxicity for NO*, this strategy is not straightforward. Although many new directions beyond the cholinergic hypothesis can be suggested, each has its potential benefits which must be weighed against its risks. Nonetheless, an important unifying area for neurobiological research examining mechanisms of normal brain aging and of age-related neuropathology, as observed in Alzheimer's disease, might emerge from the identification of NO* as a simple molecule serving vital physiological functions but representing potential for neurotoxicity.
Aging↗
Thrombosis of parietal, but not striate, cortex impairs acquisition of a 14-unit T-maze in the rat.
We evaluated parietal cortex (PCTX) involvement in learning a shock-motivated, 14-unit T-maize in young F344 rats. In Experiment 1, each rat was placed into a stereotaxic instrument, and the scalp was retracted before either the photosensitive dye, rose bengal, or saline (CON) was provided via a jugular catheter. After 60 s, halogen lamps were used to illuminate the cranium bilaterally over PCTX for 40 min to activate the dye and generate a thrombus in dye-injected rats. Active avoidance pretraining in a straight runway occurred 12 days after surgery. Each rat was provided acquisition (ACQ) trials in the 14-unit T-maze 24-h later. The PCTX rats were impaired relative to CON in errors, run time, alternation errors, and shock frequency measures in the 14-unit T-maze, but not in shock duration. The thrombosis extended to areas comprising anteromedial and posterior PCTX, and also into the striate cortex (SCTX). In Experiment 2, rats were divided into four groups: a PCTX group that received bilateral illumination; PCTX+SCTX and SCTX groups that were illuminated at midline; and a CON group that received the surgery and either dye or illumination. Only PCTX differed from CON, with maze performance similar to Experiment 1. The thrombosis for the PCTX group in Experiment 2 was confined to anteromedial and posterior PCTX. Thus, PCTX, but not SCTX, was implicated in ACQ of this maze task, suggesting that PCTX might be involved in the robust age-related impairments in ACQ previously observed.
Age Factors↗
Milacemide treatment in mice enhances acquisition of a Morris-type water maze task.
The N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor appears to be involved with processes of learning and memory. A neutral amino acid binding site is known to exist on the NMDA complex. Glycine binds with high affinity to this site and has been found to potentiate NMDA activity. 2-N-Pentylaminoacetamide HCl (milacemide) is a glycine agonist that has been found to enhance performance of rodents in passive and active avoidance tasks and has improved the performance of humans in several word retrieval tasks. We evaluated the effects of milacemide on the performance of male C57BL/6J mice in a complex spatial task, the Morris water maze. Because NMDA receptor activation appears involved in induction of long-term potentiation, it was hypothesized that milacemide administration would be involved in task acquisition. Therefore, mice were treated with either milacemide (10 mg/kg) or vehicle 1 h prior to training on each of 4 consecutive days. Results indicated that mice treated with milacemide learned the task significantly faster than controls over 4 days of training, as measured by mean distance (cm) to reach the goal platform. Therefore, agonism of the glycine site on the NMDA receptor appears to facilitate performance of learning in a spatial memory task.
Acetamides↗