Caloric restriction in non-human primates: a progress report.
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Aging↗
Biomedical subjects
D K Ingram
Publications and source records attributed to D K Ingram.
NMDA receptor channel antagonism by dizocilpine (MK-801) impairs performance of rats in aversively motivated complex maze tasks.
To determine the involvement of the N-methyl-D-aspartate (NMDA) receptor in shock-motivated complex maze performance, the drug dizocilpine (DIZO; a.k.a. MK-801) was administered a) to naive, 3-month-old male F-344 rats prior to acquisition (AQ) in the 14-unit T-maze (Experiment 1), and b) to well-trained 11-month-old male F-344 rats prior to testing in a delayed-matching-to-sample (DMTS) task in the detour maze (Experiment 2). For Experiment 1, rats first were pretrained in a straight runway on one-way active avoidance (13/15 correct avoidances) for a maximum of 30 trials. On the following day, either DIZO 0.025 (n = 8), 0.05 (n = 8), 0.1 (n = 8), mg/kg, or saline (SAL; n = 15) was administered subcutaneously (SC) 20 min prior to 15 AQ trials in the shock-motivated 14-unit T-maze. The highest dose disrupted all measures of maze performance including errors, alternation errors, runtime, shock duration and frequency, but also produced marked motor ataxia. The 0.05-mg/kg group displayed significant impairment in AQ of this task but only on the cognitive measures, errors and alternation errors, and the 0.025-mg/kg group was impaired on the alternation measure only. One week later, the 15 SAL rats were divided into 2 groups and tested on retention with either SAL or 0.05 mg/kg DIZO. No effects on maze performance were observed. For Experiment 2, after receiving extensive pretraining in the shock-motivated detour maze, 7 rats were exposed to a novel sequence of 4 problems (P) during each of 7 daily sessions. Performance was evaluated 20 min after SC injection of either DIZO--0.025, 0.05, 0.125 mg/kg, or SAL. The 0.125-mg/kg dose caused extreme motor ataxia which precluded testing during that session. The 0.05-mg/kg but not the 0.025-mg/kg dose significantly disrupted performance on both error and trials to criterion measures. Both problem and interaction effects were significant. Disruption was most evident on two specific problems, those involving a side change from the first to second detour. Also, rats had more difficulty switching sides from problem to problem (few errors on P-1 and most on P-4), suggesting proactive interference effects. In sum, DIZO was observed to significantly disrupt performance in both mazes in a dose-related manner similar to effects observed in previous studies following administration of the anticholinergic drug scopolamine. For the 14-unit T-maze, the present results simulate age-related deficits previously found in acquisition of that task.
Aging↗
Parietal cortex lesions do not impair retention performance of rats in a 14-unit T-maze unless hippocampal damage is present.
Young male F-344 rats, pretrained in a straight runway to avoid shock, were then trained in a shock-motivated 14-unit T-maze. One day after maze acquisition, extensive parietal cortex lesions (PC) or sham operations (CON) were performed to assess possible involvement of parietal cortex in the age-related impairment previously observed in this task. Twelve days after surgery, a first 10-trial retention session in the 14-unit T-maze was conducted. One day later the vibrissae of half the rats in each group were clipped to examine involvement of the damaged barrel cortex field in maze performance of rats with PC lesions. The following day a second 10-trial retention session occurred. Finally, retention of the straight runway avoidance response was tested. Histological verification revealed a group with consistent parietal damage but also a subgroup with relatively small lesions to dorsal or lateral hippocampus in addition to parietal damage (PC + HIP). Behavioral results revealed virtually perfect maze retention for CON and PC rats. In contrast, PC + HIP rats were severely impaired in maze retention performance. Retention of the straight runway avoidance response was perfect in CON and PC rats but was impaired in PC + HIP rats. Vibrissae clipping did not affect error performance in the maze but led to a transitory increase in runtime. Overall, the results indicate that parietal lobe damage shortly after acquisition does not impair retention performance of young rats in the 14-unit T-maze, unless hippocampal damage is also evident. Thus, parietal lobe dysfunction alone would not appear to be involved in the age-related retention impairment previously observed in this task.
Aging↗
Effects of intermittent feeding upon body weight and lifespan in inbred mice: interaction of genotype and age.
Beginning at either 1.5, 6 or 10 months of age, male mice from the A/J and C57BL/6J strains and their F1 hybrid, B6AF1/J were fed a diet (4.2 kcal/g) either ad libitum every day or in a restricted fashion by ad libitum feeding every other day. Relative to estimates for ad libitum controls, the body weights of the intermittently-fed restricted C57BL/6J and hybrid mice were reduced and mean and maximum life span were incremented when the every-other-day regimen was initiated at 1.5 or 6 months of age. When every-other-day feeding was introduced at 10 months of age, again both these genotypes lost body weight relative to controls; however, mean life span was not significantly affected although maximum life span was increased. Among A/J mice, intermittent feeding did not reduce body weight relative to ad libitum controls when introduced at 1.5 or 10 months of age; however, this treatment did increase mean and maximum life span when begun at 1.5 months, while it decreased mean and maximum life span when begun at 10 months. When restricted feeding was introduced to this genotype at 6 months of age, body weight reduction compared to control values was apparent at some ages, but the treatment had no significant effects on mean or maximum life span. These results illustrate that the effects of particular regimens of dietary restriction on body weight and life span are greatly dependent upon the genotype and age of initiation. Moreover, when examining the relationship of body weight to life span both between and within the various groups, it was clear that the complexity of this relationship made it difficult to predict that lower body weight would induce life span increment.
Aging↗
Complex maze performance in rats: effects of noradrenergic depletion and cholinergic blockade.
Noradrenergic (NA) involvement in acquisition (AQ) and retention (RET) of a shock-motivated 14-unit T-maze after intraperitoneal (ip) administration of DSP4, a neurotoxin that depletes forebrain NA, was evaluated in 2 experiments using 3-month-old male F-344 rats. Depletion of cortical NA level in DSP4-treated rats was verified by neurochemical assay and by latency to postdecapitation clonus reflex. In Experiment 1, DSP4 (50 mg/kg ip) rats did not differ from saline-treated (SAL) rats on any measure of maze performance (errors, alternation errors, run time, shock duration, or shock frequency) during AQ (DSP4 2 weeks prior to testing) nor during a RET test 2-3 weeks later (DSP4 immediately after the last AQ trial or 1 week after AQ). In Experiment 2, DSP4 and scopolamine (SCOP), a cholinergic (ACh) antagonist, were administered in combination to test for an NA-ACh interaction. DSP4 (50 mg/kg ip 2 weeks prior to AQ) again had no effect on AQ performance nor did DSP4 interact with either dose of SCOP (0.25 or 0.5 mg/kg ip 30 min prior to AQ) to further impair performance. Similar to previous studies SCOP impaired all measures of maze performance except shock duration. These experiments provide further evidence for involvement of ACh systems in the learning of this task and in the age-related impairments previously observed, but they suggest that central NA systems may not be involved directly or interactively with ACh systems required for efficient performance in this maze.
Acetylcholine↗
Dietary restriction and aging: the initiation of a primate study.
Juvenile (1 yr) and adult (3-5 yr) male rhesus monkeys (Macaca mulatta) and juvenile (1-4 yr) and adult (5-10 yr) male squirrel monkeys (Saimiri sciureus) were fed a diet at or near ad libitum levels based on recommended caloric intake for age and body weight or fed 30% less of the same diet with this restriction gradually introduced over a 3-mo period. Analysis of body weights among these respective control and experimental groups from the first year of the study indicated that the monkeys undergoing dietary restriction were gaining weight at a markedly slower rate compared to control values. Actual food intake among diet-restricted groups had been reduced 22-24% below control levels. Periodic analysis of hematology and blood chemistry measurements over the first year of the study detected few significant differences between control and experimental groups to indicate that diet restriction was not detrimental to general health. When values obtained from hematology and blood chemistry measurements of juvenile and adult groups (control and experimental groups combined) were compared to ad libitum fed old monkeys from each species (greater than 18 yr for rhesus; greater than 10 yr for squirrel monkeys), many significant age differences were noted. Among the largest and most consistent findings in both species were age-related decreases in concentrations of lymphocytes, serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, and phosphates as well as the albumin/globulin ratio and the blood urea nitrogen/creatinine ratio. Age-related increases in serum globulin and creatinine concentrations were also found. These parameters as well as many others being implemented in the study will be monitored further to determine if diet restriction affects the rate of development as well as aging as observed in numerous rodent studies applying such nutritional manipulations.
Aging↗
Comparison of retention performance between young rats with fimbria-fornix lesions and aged rats in a 14-unit T-maze.
Young (3-months) and aged (24-months) male F-344 rats were pretrained in one-way active avoidance in a straight runway for 3 days. Then two 10-trial daily sessions were given in a 14-unit T-maze in which the response requirement was to negotiate each of 5 maze segments within 10 s to avoid footshock. One day or one week after acquisition, bilateral electrolytic lesions were made in the fimbria-fornix of young rats (1-day lesion or 1-week lesion). Corresponding sham operations were made for remaining young rats (1-day sham or 1-week sham). Aged animals did not receive any surgical treatment. One week after surgery, a 10-trial retention test was conducted to assess the lesion effects on retention and to manipulate the interval between acquisition and lesions. Aged animals were tested in the maze 1 week after acquisition. Results revealed that rats with fimbria-fornix lesions exhibited significant impairment compared to sham-operated groups on all retention performance measures including errors, runtime, number of shocks, duration of shock, and alternation errors. The number of errors and alternation errors of lesioned animals were still higher than those of sham-operated animals at the second half of the retention test, whereas other non-cognitive measures for lesioned animals recovered to control levels. The interval between acquisition training and lesions had no influence on retention performance. Although performance of aged rats during acquisition and retention trials was significantly worse than that of young controls and lesioned animals, a similar recovery pattern during retention testing was found for young rats with fimbria-fornix lesions and aged rats, i.e. both groups showed significant declines in non-cognitive measures with less decline in cognitive measures. These results suggest that the fimbria-fornix is partially involved in retention of 14-unit T-maze performance and that the age-related retention deficit observed in this task may be related to impaired transmission through this pathway.
Aging↗
Retention of maze performance inversely correlates with N-methyl-D-aspartate receptor number in hippocampus and frontal neocortex in the rat.
The N-methyl-D-aspartate (NMDA) receptor may play a critical role in learning and memory. In the present study, a significant correlation was found between the number of NMDA-displaceable, Na+-independent L-[3H]glutamate binding sites in the hippocampus and neocortex of young rats and the mean number of errors during retention, but not acquisition, in a 14-unit T-maze.
Animals↗
Food restriction prevents an age-associated increase in rat liver beta-adrenergic receptors.
In male Wistar rats fed ad libitum (24% protein, 4.5 Kcal/gm), the [125I]iodopindolol binding capacity of the beta-adrenergic receptors in liver of 24-month-old animals is 3-4 times greater than that of 6-month-old counterparts. In rats fed the same diet, on alternate days from weaning, the receptor capacity did not increase significantly between 6 and 24 months (10.20 +/- 0.55 vs 9.20 +/- 0.72 fmol/mg) or between 24 and 30 months. This was not due to acute dietary deprivation, as rats food-restricted for only 2 weeks, at 23.5 months of age, also showed elevated receptor capacities compared to 6-month-old ad libitum fed animals. Moreover, intermittent feeding produced no significant effects among 6-month-old animals, whether restricted since weaning or for two weeks prior to sacrifice. Many biochemical parameters that decrease with aging in rats fed ad libitum are prevented by dietary restriction. Our results demonstrate that a reproducible biochemical process that increases with aging is also prevented with dietary restriction. The age-related, liver beta-receptor increase may be a potentially reliable marker for studying biochemical perturbations that modify life span.
Adrenergic beta-Antagonists↗
Scopolamine in rats impairs acquisition but not retention in a 14-unit T-maze.
To follow up a previous report noting that scopolamine impaired acquisition performance of young rats in a shock-motivated 14-unit T-maze, the present study assessed the effects of muscarinic antagonism on retention aspects of the same task. The broader objective was to further the investigation of possible defects in cholinergic neurotransmission that might underlie the age-related impairments previously observed in this task. Young (3-month) male F-344 rats were given preliminary training to criterion in one-way active avoidance in a straight runway. Then on the first day of complex maze training, each rat received 5 acquisition (AQ) trials followed by a second 10-trial retention (RET) session conducted the following day. Subjects were assigned to one of eight groups receiving an intraperitoneal injection of either scopolamine hydrochloride (1.0 mg/kg) or saline as follows: (a) 30 min prior to training on the first day (PRE-AQ); (b) 30 min prior to training on both the first and second day (PRE-AQ-RET); (c) immediately after completing the trial on the first day (POST-AQ); (d) 30 min prior to testing on the second day (PRE-RET). Dependent measures included errors, alternation errors, run time, number of shocks, and total shock received. On the first day of maze training, all performance measures except for alternation errors were significantly higher for the two acquisition groups (PRE-AQ and PRE-AQ-RET) compared to all other groups which did not differ significantly.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Key questions in developing biomarkers of aging.
A series of questions is presented regarding a logical strategy for developing biomarkers of aging. The questions pertain to the conceptualization process in determining how to define aging and what extraneous and possibly confounding variables must be controlled in measuring this epiphenomenon. In addition, the investigator must consider the degree of generalization that is intended to apply to a candidate biomarker of aging. Empirical questions are also to be considered. Specifically, how will reliability and validity of the candidate biomarker be quantified and assessed? What statistical methods will be applied in this process? The need for biomarkers of aging as research tools in gerontology is argued, but the greater need for agreement on how to direct the conceptualization of this effort is also emphasized.
Aging↗
Motor performance variability during aging in rodents. Assessment of reliability and validity of individual differences.
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Aging↗
The relationship of body weight to longevity within laboratory rodent species.
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Aging↗
Co-dergocrine, cerebral glucose utilization and maze performance in middle-aged rats.
The objective of this study was to determine the effect of co-dergocrine in rats on local cerebral glucose utilization and performance in a complex T-maze. Middle-aged (12-16 months) male Fischer-344 rats were given injections of co-dergocrine (3 or 10 mg/kg, IP) 35 min before behavioral testing or the administration of 2-deoxy-D-[1-14C]glucose ([14C]DG), a radiotracer for local cerebral glucose utilization (LCGU). Both doses stimulated LCGU in the locus ceruleus and median raphe nucleus and in subcortical structures associated with learning and memory (hippocampus and subiculum). The higher dose also stimulated LCGU in motor areas (caudate-putamen, globus pallidus, internal capsule). In contrast, co-dergocrine decreased LCGU in the frontal cortex. Poorer performance in a complex maze (increased shocks, errors and run time) was observed in middle-aged as compared with younger animals (3 months). Acute co-dergocrine treatment did not improve performance of middle-aged rats in this task. Thus, in the present experimental paradigm employing single dose administration, co-dergocrine's stimulation of LCGU was not associated with an alteration of maze performance in age-matched animals.
Age Factors↗
Dietary restriction benefits learning and motor performance of aged mice.
Female C3B10RF1 mice maintained on either a control (approximately 95 kcal/week) or restricted (approximately 55 kcal/week) diet since weaning were tested in a behavioral battery at 11 to 15 or 31 to 35 months of age (middle-aged vs. aged). Age-related declines observed among control groups in tests of motor coordination (rotorod) and learning (complex maze) were prevented by the restriction regime. In addition, diet restriction increased locomotor activity in a runwheel cage among mice of both ages but did not affect exploratory activity in a novel arena.
Aging↗
Effects of voluntary and forced exercise on thermoregulation and survival in aged C57BL/6J mice.
To evaluate the effect of exercise on thermoregulation in senescent animals, three groups of male C57BL/6J mice aged 28-30 months were tested for cold tolerance, defined as the rate of decline in colonic temperature during 3 h exposure to 10 degrees C ambient temperature. Following this test, the mice were exposed to one of the following exercise conditions: forced exercise on a treadmill for 60 min daily at a rate of 5 m/min; continuous access to voluntary exercise in wheel-activity cages, which resulted in a mean rate of 1.1 m/min; or no expressed exercise with 60 min daily placement on the non-activated treadmill. After 3 weeks, assessment of cold tolerance was repeated. A combined mortality rate of 36% was observed in the exercise groups for this period, while there were no deaths in the non-exercised group. The high mortality rate among exercised animals indicated that these regimens were hazardous for aged mice. Moreover, between tests the non-exercised group exhibited a 0.6 degree C increase in body temperature and 38% improvement in cold tolerance which could be interpreted as a normal adaptation for repeated cold exposure. In contrast, no significant change in either of these variables was observed among survivors in the exercise groups. Thus, introduction of these exercise regimens in senescent mice decreased survival and did not improve the age-related impairment in thermoregulation.
Adaptation, Physiological↗
Age comparisons of body temperature and cold tolerance among different strains of Mus musculus.
The age-related declines in colonic temperature (Tco) and cold tolerance (ability to maintain Tco when exposed to 10 degrees C for 3 h) described for C57BL/6J mice are compared to other mouse strains. Assessment of young and aged male mice of the C57BL/6J and A/J inbred strains and their F1 hybrid, B6AF1/J, as well as a pen-bred strain of Mus musculus captured from the wild revealed an aged-related decline in thermoregulation among all these strains. The degree of decline in thermoregulation was roughly correlated to differences in strain-specific lifespan. Aged mice of the relatively short-lived genotype, A/J (mean lifespan of 22 months), had the lowest Tco and poorest cold tolerance. The long-lived hybrids, B6AF1/J (mean lifespan of 29 months), demonstrated the highest Tco and the best cold tolerance among aged mice. C57BL/6J (mean lifespan of 26 months) showed an intermediate level of thermoregulation. Aged pen-bred mice demonstrated a significant decline in cold tolerance, but not a significant decline in Tco. The thermoregulatory responses of the pen-bred mice were superior to those observed among the domesticated strains. These data suggest that the age-related impairment in thermoregulation is a general phenomenon of aging in Mus musculus that is correlated with strain-specific lifespan but is possibly affected by the level of hybridization and domestication.
Aging↗
Scopolamine impairs learning performance of rats in a 14-unit T-maze.
To assess involvement of muscarinic cholinergic systems in performance of a shock-motivated 14-unit T-maze task, 3-month old Fischer-344 rats were given an IP injection of scopolamine (0.1, 0.3, 1.0 or 3.0 mg/kg), methylscopolamine (1.0 mg/kg), or saline 30 min prior to maze training on 2 consecutive days. Scopolamine, but not methylscopolamine, impaired all components of acquisition performance. Measures of error performance, run time, shock duration, and number of shocks received were significantly increased but only at the 1.0 and 3.0 mg/kg scopolamine doses. The cognitive component of the task, measured by error performance, appeared most affected. Cognitive performance deficits observed following scopolamine administration in the present study resembled age-related impairments in rats and mice previously observed in this task. The cholinergic hypothesis of geriatric memory dysfunction appears to be implicated by these findings; however, the degree to which memory systems are involved remains unclear. Other performance variables such as discriminative control of stimuli or mechanisms of attention are implicated and discussed.
Animals↗