Age-related Differences In Response Research Articles

Enhancement of cold-stimulated thermogenesis in the corpulent rat (LA/N cp) by aminophylline.

Previous studies on obese strains of rats (e.g., Zucker and LA/N cp) have shown that they are deficient in nonshivering thermogenesis and poor in cold tolerance. Our earlier studies have established that aminophylline (AMPY; 85% theophylline-15% ethylenediamine) is effective in significantly improving cold tolerance in the lean Sprague-Dawley rat regardless of age or thermogenic capacity. The present study tested whether AMPY may be also effective in improving cold tolerance in both young (12-18 wk) and older (36-42 wk) lean and corpulent LA/N cp rats. Contrary to previous reports, however, the norepinephrine (NE)-stimulated nonshivering thermogenesis was not only present but also equal in magnitude in the corpulent rats to that of their lean controls. Further, no difference in cold tolerance was observed between the two groups regardless of age. Similarly, AMPY (18.7 mg/kg ip) significantly improved thermogenesis and cold tolerance in both lean and corpulent rats, again without any age-related difference in response. These results indicate that, despite the existence of obesity, no difference in thermogenic capacity to either NE or cold stimulation is evident in the LA/N cp rats. Thus the ontogeny of obesity in this strain may be caused by factors other than deficiency in NE- or cold-stimulated thermogenesis at the end-organ level.

Influence of aging and poly IC treatment on xenobiolic metabolism in mice

Cytochrome P-450-dependent and independent metabolism of xenobiotics in the liver of C57BL/10ScSn male mice was investigated in relation to age and the age-related differences in response to treatment with polyriboinosinic-polyribocytidylic acid (poly IC), an interferon inducing agent. Young (3 months), middle-aged (15 months) and old (27 months) animals were studied. Mean survival time of males of this strain is 30–33 months. Age-related changes in the metabolism of xenobiotics included significant decreases between middle and old age in activities of the microsomal P-450-dependent mixed function oxidases (MFO), aryl hydrocarbon hydroxylase (AHH) and p-nitroanisole (pNA) O-demethylase, but not 7-ethoxy-coumarin (7-Ec) O-deethylase. Analysis of P-450-independent enzymes revealed a significant decrease in the epoxide hydrolase activity in the microsomes and cytosol from old compared to middle-aged or young mice. Glutathione S-transferase activity towards 1-chloro-2,4-dinitrobenzene (CDNB) was lower in cytosols of middle-aged and old than young mice. Carboxy-lesterase activity was not altered by age. Hepatic microsomal protein content was significantly higher in middle-aged and old than in young mice. Intraperitoneal treatment with a single dose of 5 mg/kg poly IC 24 hours before sacrifice resulted, for mice of all age groups, in a marked inhibition of activities of all 3 microsomal cytochrome P-450-dependent enzymes, without any changes in activities of the P-450-independent enzymes. The inhibition of AHH by poly IC was much higher in old and middle-aged than in yo3ng mice, averaging 87.1%, 74.5%, and 41.9%, respectively, in the 3 age groups. Poly IC treatment increased lipid peroxidation in liver homogenates of all groups of mice. Body and liver weights were not altered in animals of the 3 age groups by poly IC treatment, but hepatic microsomal protein contents were significantly decreased.

PHARMACOKINETICS OF FENTANYL IN THE ELDERLY

SUMMARY The pharmacokinetics of fentanyl were determined in seven elderly (71–82 yr) and seven younger adults (18–41 yr) anaesthetized with thiopentone, nitrous oxide in oxygen and morphine. Fentanyl was administered as a 2-min i.v. infusion at doses of 15 μg kg−1 for elderly patients and 20 μg kg−1 for the younger patients. Plasma samples were obtained for 4 h and fentanyl concentrations determined by radio-immunoassay. Fentanyl concentration, per μg kg−1 administered, was higher in elderly than in young patients at 2 min (7.73±3.14 v. 4.54 ± 1.83 ng ml−1 (mean±SD), respectively) and at 4 min after the start of infusion (3.26 ± 1.44 v. 1.78 ±0.72 ng ml−1, respectively). Concentrations were similar at all other sampling times. Pharmacokinetic variables were determined by non-compartmental techniques. Total plasma clearance was similar for the two age groups. Volume of distribution at steady-state (VDss) was smaller in elderly patients (1.36 ± 0.44 v. 2.27 ± 0.82 litre kg −1). Despite age-related changes in VDss, plasma fentanyl concentrations for the two groups were similar throughout the 4-h sampling period except immediately following administration. These results suggest that, if there are age-related differences in response to fentanyl, the likely pharmacokinetic explanation is the higher concentration of fentanyl in the elderly immediately following its administration.

Age-related differences in response to acute cold challenge (−10°C) in male F344 rats

Male F344 rats, 3, 12, and 24 months of age, were acclimated to either 5°C (CA) or 23°C (non-CA). At the end of acclimation, all CA rats exhibited higher basal oxygen uptake than the non-CA when measured at 28°C. When challenged by a 3-hour exposure to −10°C, significant difference in tolerance to cold was observed not only between the CA and non-CA rats but among the different age groups. The 3-month-olds tolerated cold better than 12-month-olds, and the 12-month-olds did better than the 24-month-olds. The ranking order for cold tolerance in −10°C was: 3-month CA > 12-month CA > 3-month non-CA = 12-month non-CA = 24-month CA > 24-month non-CA. Total 3-hour O 2 uptake decreased progressively with advancing age. Heat productions were doubled in −10°C in all age groups, and all CA rats had higher heat production than non-CAs. The increase of heat production in −10°C was insufficient to maintain body temperature in all animals. All animals had loss of body heat content, the loss becoming greater with advancing age. Non-CA rats had greater loss of heat content or faster decline of colonic temperature than the CAs. Significant strain-related difference in cold tolerance was noted between the F344 and Sprague-Dawley (S-D) rats, because 24-month-old non-CA male F344 rats still exhibited a better tolerance to −10°C than 3-month-old CA S-D rats.

Developmental differences in reactions to children labeled mentally retarded

In an attempt to examine age-related differences in response to the mental retardation label, 48 4th and 5th graders and 48 11th and 12th graders were told of a child of their own age and sex who was either labeled mentally retarded or unlabeled and who performed either competently or incompetently in giving a report. Incompetent target children were viewed more negatively than competent ones at both grade levels. The mental retardation label had less generalized impacts, leading girls but not boys (a) to cite lack of ability as the reason for a retarded child's failure, and (b) to hold low expectations that retarded targets would hold jobs, marry, or have children. A developmental shift in responses to the label was evident only on a trait perception measure; younger children stigmatized retarded targets, while older children granted special dispensation of a failing retarded child by viewing him or her more positively than a similarly incompetent but unlabeled child. Since only adolescent boys showed special dispensation, even though girls were more generally attentive to the label, both sex and age differences warrant further examination.

Post-natal developmental changes in myocardial contractility of the female wistar rat

The intrinsic contractile properties of papillary muscles isolated from female Wistar rats during post-natal development were examined. In addition, the myocardial responsiveness to certain inotropic interventions was studied. In muscles from 60-day-old animals, the velocity of shortening was markedly greater than muscles from animals ⩾ 180 days old. These findings occured in the presence and absence of added norepinephrine or calcium and over a wide range of contraction frequency. No major age-related differences in responsiveness to the various inotropic agents was observed. Isometric tension was significantly higher in muscles from animals ⩾ 180 days of age when compared to 60-day-old rats. Thus, post-natal development profoundly affects the intrinsic contractile state of cardiac muscle, with the force of contraction increasing and the speed of shortening decreasing as animals age.

The electrophysiological properties of normal neonatal and adult canine cardiac Purkinje fibers.

To determine the basis for age-related changes that occur in the transmembrane action potentials (AP) of canine cardiac Purkinje fibers (PF), we used standard microelectrode techniques to study PF from normal neonatal and adult beagles. As previously shown, neonatal PF AP have a less negative maximum diastolic potential (MDP), a lower AP amplitude (amp) and maximum upstroke velocity of phase 0 (Vmax), and shorter AP duration measured at 50% and 100% repolarization than have those of adults. Further, the termination of phase 1 and the peak of phase 2 occur at more positive levels of membrane potential in neonatal PF. The less negative MDP in neonatal PF is associated with a lower intracellular potassium activity (aKi) as demonstrated with a K+-sensitive microelectrode. Neonatal PF showed greater depression of AP amp and Vmax during superfusion with the rapid Na+ channel blocker, tetrodotoxin (TTX), than did adult PF. The attainment of more negative voltages at the termination of phase 1 in adult compared to neonatal PF was not attributable to age-related differences in response to changes in drive cycle length, temperature, or external Cl- concentration. However, 4-aminopyridine, a blocker of the early, repolarizing potassium current, altered this variable in adult and not in neonatal PF. The effects of verapamil and AHR-2666, both slow inward current blockers; of TTX, which blocks a background inward Na+ current; and of TEA+, which blocks repolarizing K+ current, were studied on AP repolarization. Adult PF AP were more sensitive to the effects of AHR-2666, verapamil, and TEA+ and less sensitive to the effects of TTX than neonates.

Age-related changes in body temperature responses to morphine in rats

Body temperature responses to morphine were studied in rats of thr three age groups: young (3–5 months old), mature (10–12 months old), and senescent (26–28 months old). A low dose of morphine (5 mg/kg s.c.) produced hyperthermia in all three age groups, but the senescent rats displayed the greates increase in body temperature. In contrast, the senescent rats displayed the least hypothermic response to a high dose of morphine (25 mg/kg s.c.). The age-related differences in response to morphine were specific since all age groups responded similarly to ethanol (1.5 g/kg i.p.). In response to thermic stress, senescent rats developed exaggerated hyperthermia during heat stress and hypothermia during cold stress, indicating no peripheral impairment of ability to conserve or dissipate heat. Age-related differences in response to morphine appear to result from alterations in central thermoregulatory mechanisms.

The effects of mechanical immobilization on sutural development in the growing rabbit.

Methyl-2-cyanoacrylate was used to mechanically immobilize the coronal suture unilaterally in a series of New Zealand white rabbits at varying ages. The animals were separated into groups; some were sacrificed at 30 day and some at 60 days postoperatively. Amalgam markers were placed in the parietal and frontal bones across the coronal suture, and were measured immediately after surgery and at the time of sacrifice to confirm mechanical immobility. The animals were studied radiographically and histologically in order to document the presence or absence of sutural bone union. Based on the results of this study, it appears that immobilization of the coronal suture results in the formation of an ectocranial periosteal bone bridge in rabbits less than 8 weeks of age. Bone union was not found in animals older than 8 weeks of age. This age-related difference in response is believed to be due to decreased periosteal depository activity on the ectocranial surface of the calvaria once the brain ceases to expand actively. Furthermore, bone union or synostosis was never seen within or across the internal portion of the sutural ligament. It is suggested, therefore, that sutural immobilization at young ages in the rabbit does not result in sutural synostosis and that the term "periosteal bone bridge" should be used when referring to this biological response.

Age-related differences in response to ethanol in the rat

Female rats, aged 2–3, 11–12, and 18–20 months were tested for cin old rats, but blood alcohol levels at time of awakening were lowest in older, compared with younger animals, suggesting a greater responsiveness of brain tissues to the hypnotic effects of ethanol in older rats or, alternatively, a more rapid development of central acute tolerance in younger subjects. Lower doses of ethanol (.75–1.5 g/kg) were observed to produce greater hypothermia and impairment of motor performance in older animals. Although blood alcohol levels were higher in older animals following the injection (1 g/kg, IP) of ethanol, there was no age-related effect on rate of ethanol disappearance. Doses of ethanol that produced comparable blood levels in old (1.0 g/kg) and young (1.5 g/kg) animals also produced a similar degree of motor impairment. Thus, the greater effects produced by moderate doses of ethanol (around 1.0 g/kg) in older rats can be attributed to the higher peak drug levels achieved in those animals. Differential responses to hypnotic doses of ethanol may involve, additionally, a greater responsiveness of brain tissue to that drug in older animals.

Senescent changes in rodent hepatic epoxide metabolism

Age-related alterations in epoxide metabolism were examined in subcellular fractions of liver from 3-, 12- and over 24-month-old male rats and mice. Using styrene oxide as the substrate, glutathione-S-transferase activity remained unchanged while the activity of epoxide hydrase increased with age in both species. The microsomally-mediated binding of benzo[a]pyrene to DNA was also increased in the old animals. Thus, senescent rodents retain or increase their ability to metabolize epoxides. The effect on epoxide metabolism of pretreatment of the senescent rodents with polychlorinated biphenyls was also examined. Glutathione-S-transferase activity was induced only in old animals. However, epoxide hydrase activity, while inducible in all age groups of rats, increased only in young mice. Therefore, there is an age-related difference in response of epoxide metabolizing enzymes to polychlorinated biphenyl treatments between rats and mice.

Serum Immunoreactive Corticotrophin and Response to Metyrapone in Old Age in Man

Attempts have been made to establish the level of immunoreactive corticotrophin (IR-ACTH) in serum in healthy subjects with partts were investigated and the clinical and biochemical condition s of selection specified. Serum IR-ACTH was determined by a radioimmunoassay procedure using an N-terminal antibody produced against the 1--24 sequence of the conrticotrophin molecule. The morning level of serum IR-ACTH was determined in 115 fasting healthy subjects, range less than 16--210 pg/ml, median 94 pg/ml (3rd International Standard preparation). The level was found to be unchanged within the age interval 20--94 years, irrespective of sex. Thy nycterohemeral variation of the IR-ACTH concentration in serum was studied in 11 sibjects. A rhythmic variation of the IR-ACTH level was not constantly found and age-related difference in the temporal pattern was not demonstrated. In 10 young and 10 elderly subjects a metyrapone test was carried out and the IR-ACTH response was determined. The rise in serum IR-ACTH concentration varied between 20 and 739 pg/ml. Any significant age-related difference in response was not found. The interpretation of the present results with respect to the decreased secretory activity of the glucocorticoid producing system in the aged is discussed. It was concluded that the findings in this study did not indicate a primary deficiency of the axis of the glucocorticoid producing system, neither at the pituitary level nor at the adrenocortical level, as a causal factor to the decreased glucocorticoid production in old age.

Immunoreactive Corticotrophin Reserve in Old Age in Man During and After Surgical Stress

Attempts have been made to establish whether the immunoreactive corticotrophin (IR-ACTH) reserve was impaired in old age during surgical stress and whether an exhaustion of the IR-ACTH reserve could be traced postoperatively. Recognition of the degenerative changes of the senescent adenohypophysis has made this investigation essential in an effort to analyze factors responsible for the high risk involved in surgery on the aged. In the study 18 young and 14 elderly patients were subjected to elective abdominal or thoracic surgery, and the IR-ACTH response was determined. No significant age-related difference in response to surgery was found. On the 5th day after operation an intravenous metyrapone test was carried out, and the IR-ACTH response in plasma determined. In the elderly, the IR-ACTH response to metyrapone was not found to be inferior to that in the young patients. It was concluded that the IR-ACTH reserve was unimpaired during surgery in old age and that exhaustion was not in evidence based on unimpaired IR-ACTH response during repeated stress in the postoperative period. Therefore, decreased ACTH reserve seems not to be a factor involved in the higher surgical risk in the elderly.

Effect of antidiuretic hormone and theophylline on cyclic AMP in renal medulla of newborn and adult rabbits and dogs

1. Cyclic AMP concentration was measured in renal medullary slices of newborn and adult rabbits and dogs. 2. Cyclic AMP concentration increased in response to ADH and this effect was potentiated by theophylline. 3. No age related differences in responsiveness were seen in rabbit kidney. 4. Newborn dog medulla was less responsive to ADH than adult but this effect was minimized when tissue cyclic AMP concentration was factored by tissue protein rather than slice weight. 5. Immaturity of the cyclic AMP response to ADH is probably not an important factor in the decreased concentrating capacity in the newborn.