Effects of ethanol on microsomal drug metabolism in aging female rats. I. Induction

The purpose of this study was to determine how aging affects the induction by ethanol or acetone of the hepatic microsomal monooxygenase system of female Fischer 344 rats. Young-adult, middle-aged and old rats (4, 14 and 25 months) were fed an ethanol-containing or control liquid diet for 15 days. Cytochrome P-450, cytochrome c reductase, aniline hydroxylase, nitrophenol hydroxylase, nitroanisole O-demethylase and benzphetamine N-demethylase activities were measured in hepatic microsomes. All of the drug metabolism activities except benzphetamine N-demethylase were 20-35% lower in old than in young-adult rats fed the control diet. In addition, the increase in drug metabolism produced by feeding the regular ethanol diet (36% of calories as ethanol) was 50-60% lower in the old rats. However, there was no difference in the magnitude of ethanol induction when ethanol intakes were matched. The effects of chronic acetone consumption (1.2g/day per kg body weight for 15 days) paralleled those of ethanol consumption, except that the extent of induction was greater with acetone. Acetone-induced levels of hepatic microsomal cytochrome P-450, nitrophenol hydroxylase, nitroanisole O-demethylase and aniline hydroxylase were similar in all three age groups. The results of this study indicate that induction of hepatic microsomal drug metabolism by ethanol or acetone is unaffected by the aging process.     

Effects of ethanol on microsomal drug metabolism in aging female rats. II. Inhibition

The effect of aging on the inhibition by ethanol of drug metabolism activity was examined in liver microsomes of female Fischer 344 rats aged 4, 14 and 24 months. Inhibition of aniline hydroxylase activity in microsomes from 4-month-old females occurred at low concentrations of ethanol (0.1 mM) and was predominantly competitive. Aging was associated with a significant increase in apparent Km for aniline in the absence of ethanol (24 +/- 2, 20 +/- 2 and 32 +/- 1 microM in microsomes from 4-, 14- and 24-month-old rats, respectively) and a change from competitive to non-competitive inhibition by ethanol. Inhibition of benzphetamine N-demethylase activity occurred only at high concentrations of ethanol (100 mM) and was non-competitive in nature. There were no significant effects of aging on the kinetics of the reaction or the type of inhibition produced by ethanol. Microsomal ethanol oxidation rates were measured in liver microsomes of 4-, 15- and 25-month-old Fischer 344 rats of both sexes. Ethanol oxidation in males was greater than in females and was decreased significantly in old age. Ethanol oxidation in female rats was unaffected by aging. The results suggest that significant changes in drug/ethanol interactions can occur as a consequence of aging.     

Changes in basal secretion rates of thyroxine and 3,3',5-triiodothyronine from the thyroid gland during aging of the rat.

The present experiments were carried out to examine age-related changes in the basal secretion rates of both thyroxine (T4) and 3,3',5-triiodothyronine (T3) from the thyroid gland. The experiments were performed on male Wistar rats of three different ages, i.e., (1) adult rats of 6-8 months old, (2) middle-aged rats of 25-26 months old, and (3) aged rats of 28-30 months old. The rats were anesthetized with 1.0% halothane. The thyroid venous blood as well as systemic arterial blood was collected and secretion rates of both immunoreactive T4 (iT4) and T3 (iT3) from the thyroid gland were calculated from the differences in concentrations of iT4 and iT3 in these two blood plasmas, and from the flow rate of thyroid venous blood plasma. The secretion rates of thyroid iT4 in the three different age groups were as follows: 483 +/- 68 pg/min (mean +/- S.E.) in the adult rats, 598 +/- 104 pg/min in the middle-aged rats, and 491 +/- 150 pg/min in the aged rats. There were no significant differences among the secretion rates of thyroid iT4 in these rats. The secretion rates of thyroid iT3 in the groups were as follows: 36.2 +/- 7.5 pg/min in the adult rats, 58.9 +/- 13.9 pg/min in the middle-aged rats, and 61.3 +/- 7.6 pg/min in the aged rats. The secretion rates of thyroid iT3 in both middle-aged and aged rats were approximately 1.6-1.7 times as high as the value in adult rats (p less than 0.05). These results indicate that the thyroid secretion of iT4 is well maintained, while that of iT3 increases during aging.     

Ultrastructural response of hepatocytes to thymectomy and pregnenolone-16alpha-carbonitrile.

In young female rats, thymectomy causes RER alterations and a slight increase in SER. PCN augments SER in the hepatocytes of both intact and thymectomized rats. Thymectomy prolongs zoxazolamine paralysis and PCN treatment decreases the duration of zoxazolamine paralysis both in intact and operated rats.     

Metabolism of Diazepam and Ethosuximide in rats with malaria and endotoxin-induced fever

We have investigated the effects of malaria infection with rodent parasite Plasmodium berghei and fever induced by Escherischia coli endotoxin on the metabolism of diazepam to temazepam by rat liver microsomes, and on the clearance of ethosuximide in vivo in the rat. Livers from malaria-infected (parasitaemia =36.8+/- 7.6% endotoxin-treated or saline-treated (control) rats (N=5 per treatment) were used to prepare microsomes. These were incubated with diazepam (10-600ū M) for 10 minutes in an NADPH-generating system. V( max), K(m ) and the intrinsic clearance V(max )/K(m ) for the production of temazepam were determined. In separate experiments, ethosuximide (5mg/kg) was administered via the tail vein to control, malaria-infected and endotoxin-treated rats (parasitaemia=43.8+/- 5 %) under light ether anesthesia (N=5 per treatment). Total clearance of ethosuximmide was estimated form a single blood sample obtained 24h after drug administration. Diazepam metabolism was not affected by malaria infection or fever (V(max ):1.31+/- 0.34,0.73+/- 0.27 and 1.07+/- 0.78 nmol/min/mg protein; K( m): 158.7 +/- 63.7, 175.3+/- 44.9 and 190.0+/- 81.8ūM; Intrinsic clearance/whole liver: 0.31+/- 0.16, 0.26+/- 0.1 and 0.29+/- 0.1ml/min in livers from control, malaria-infected and endotoxin-treated rats respectively; P>0.05). Similarly, clearance of ethosuximide in vivo was not affected by malaria infection or fever (1.3+/- 0.2, 1.3+/- 0.01 and 1.4+/- 0.4 ml/min/kg in control, malaria-infected and endotoxin-treated rats respectively; p>0.05). These results suggest that malaria infection and fever have no effect on the activities of the CYP3A isozymes thought to be involved in the metabolism of diazepam and ethosuximide.     

The effects of age on the pharmacokinetics and biotransformation of theophylline in vivo and in vitro in the Mongolian gerbil (Meriones unguiculatus).

The effect of post maturational aging on the in vivo disposition of theophylline was examined in the Mongolian gerbils (Meriones unguiculatus) aged 30-39 (old), 12-18 (middle-aged) and 3 (young) months following a 20 mg/kg i.p. dose. Biotransformation of theophylline was also examined in liver microsomes from non-induced and 3-methylcholanthrene induced gerbils. Analysis of theophylline plasma kinetics showed decreased clearance, increased half-life and increased volume of distribution in old vs. young animals. Clearance to the 1,3-dimethyluric acid metabolite was similar for all age groups, while clearance to the 1-methyluric acid metabolite was significantly lower in the middle-aged group compared to that of young and old gerbils. Urinary recovery of 1-methylurate was increased in old vs. young and middle-aged animals while recovery of theophylline was decreased. 3-Methylcholanthrene induction resulted in decreased recovery of theophylline and increased recovery of 1,3-dimethylurate and 1-methylurate in young and middle-aged gerbils compared to non-induced controls. Decreased microsomal protein content was observed in old vs. young and middle-aged gerbils and an age-related decrease in cytochrome P-450 content (nmol P-450/g liver) was also observed. The rate of dimethylurate formation was decreased 37% in microsomes from old vs. young and middle-aged gerbils. 3-Methylcholanthrene administration resulted in a 2- and 1.5-fold increase in the rate of 1,3-dimethylurate formation in young and middle-aged gerbils, respectively. The results of these experiments indicate that the Mongolian gerbil may be useful for the study of the biochemical mechanisms underlying age-related changes in the biotransformation and kinetics of theophylline.     

Substrate specificity of age-related changes in the inducibility of hepatic microsomal monooxygenases in middle-aged rats

Hepatic microsomal monooxygenase induction was investigated in young-adult and middle-aged male Fischer 344 rats. Monooxygenase components and drug metabolism activities were determined in liver microsomes prepared from rats treated with phenobarbital (PB), β-naphthoflavone (BNF) or methyltestosterone (MT) and compared with values from untreated rats. PB and BNF effects on cytochrome P-450 concentration and cytochrome c reductase activity were similar in young-adult and middle-aged animals. However, the extent of cytochrome P-450 induction by MT was less in the older animals. The age-related changes in induction of drug metabolism activities differed with different substrates for the monooxygenase system. In contrast to the inducibility of benzphetamine N-demethylation and aniline hydroxylation, which was dimished in the older rats, the inducibility of nitroanisole O-demethylation was enhanced. The results imply that qualitative changes in the microsomal enzyme system occurred as the animals progresses from young to middle adulthood.     

Acute neutral endopeptidase inhibition is natriuretic in old rats.

Neutral endopeptidase 24.11 (NEP) inhibitors prevent breakdown of atrial natriuretic peptide (ANP), and may be useful therapeutically, in sodium overload states as often occurs in the aged. However, age-dependent changes in ANP/NEP may limit the activity of these agents in the elderly. To investigate this we conducted experiments in young, middle aged and old conscious male rats, studied in the baseline euvolemic state and during acute NEP inhibition (NEPI). NEPI produced a marked increase in sodium excretion (>100%) in all groups, regardless of age. A selective, potassium sparing effect was also seen, only in the middle-aged and old rats. Although baseline hemodynamics were affected by age with mean blood pressure, BP, and renal vascular resistance (RVR) being higher in old versus young (131+/-5 vs. 115+/-3 mmHg; P<0.05 and 29+/-3 vs. 20+/-1 mmHg/ml per min per 100 g body weight (BW); P<0.02, respectively); NEPI produced similar mild pressor and significant renal vasoconstrictor effects in all age groups. Despite the tendency of NEPI to reduce renal perfusion, this is an effective method of increasing sodium excretion in all age groups while the potassium sparing actions seen selectively in the older rats may increase the usefulness of NEPI as a diuretic agent for the elderly.     

Effect of age and carbon tetrachloride on cytokine concentrations in rat liver.

Interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) concentrations were measured in livers of young-adult and old rats administered carbon tetrachloride or vehicle. IL-1beta levels were higher and IL-6 levels were lower in old rats than in young-adult rats. Carbon tetrachloride treatment increased IL-1beta and decreased TNF-alpha and IL-6. The elevation in IL-1beta was diminished by aging. These results indicate that the increase in carbon tetrachloride hepatotoxicity that occurs in old age could be related to a dysregulation of inflammatory cytokines.     

The long-acting cholinesterase inhibitor heptyl-physostigmine attenuates the scopolamine-induced learning impairment of rats in a 14-unit T-maze.

Heptyl-physostigmine (heptyl-Phy), a new carbamate derivative of physostigmine (Phy), has been assessed for potential clinical value by evaluating its in vitro activity against human erythrocyte acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE), its duration of in vivo activity against rat plasma AChE, and its effects on attenuating a scopolamine-induced impairment in learning performance of young rats in a 14-unit T-maze. Heptyl-Phy demonstrated potent cholinesterase inhibition, with activity similar to that of Phy against AChE, IC50 values 21.7 +/- 2.0 nM and 27.9 +/- 2.4 nM, respectively, and significantly greater than that of Phy against BChE, IC50 values 5.0 +/- 0.1 nM and 16.0 +/- 2.9 nM, respectively. Heptyl-Phy achieved maximum AChE inhibition of 92.5% at 60 min and maintained a high and relatively constant inhibition for more than 8 h. For analysis of effects on learning performance, heptyl-Phy at 1.0, 1.5, 2.0 or 3.0 mg/kg, or vehicle was administered i.p. to 52 3-month-old male Fischer-344 rats 60 min prior to maze training. Thirty minutes prior to training, each animal received either 0.9% NaCl or scopolamine hydrochloride (0.75 mg/kg). Only a 2.0 mg/kg dose of heptyl-Phy significantly reduced the number of errors in scopolamine-treated rats. The other doses did not improve any aspect of maze performance. Although the therapeutic window of heptyl-Phy did not appear wide enough for clinical use, the longer duration of action of heptyl-Phy would appear beneficial.     

Effects of septal lesion on lordosis response induced by estradiol in middle-aged and old female rats

Long-Evans female rats were divided into three age groups: 10 young rats (5 months of age), 7 middle-aged rats (10-13 months of age) and 6 old rats (21-27 months of age). The rats were ovariectomized and immediately implanted subcutaneously with a silastic capsule filled with estradiol benzoate (E2). Lordosis response was compared in each animal before and after the septal lesion. Serum E2 levels were 197 +/- 27 pg/ml (mean +/- SEM), 192 +/- 81 pg/ml and 405 +/- 83 pg/ml in young, middle-aged and old rats respectively. When serum E2 levels were adjusted by analysis of covariance, LQ (lordosis quotient) was 42, 36 and 61 in young, middle-aged and old rats respectively before the septal lesion and 98, 68 and 88 respectively after the septal lesion. The extent of potentiation of lordosis after the septal lesion was less in middle-aged and old rats than young rats. These results indicate that an enhanced lordosis response in aged rats is partly due to high circulating E2 levels and partly due to disinhibition of the septal region on lordosis.     

N-methyl-D-aspartate mediated responses decrease with age in Fischer 344 rat brain.

N-Methyl-D-aspartate (NMDA) receptor-mediated responses were studied in hippocampus, cortex, and striatum of Fischer 344 rats of various ages (3-5, 12-14, or 24-28 months old; young, middle-aged, and senescent or old, respectively) to determine whether aging alters the function of NMDA receptors. NMDA-induced inhibition of muscarinic-stimulated phosphoinositide hydrolysis in hippocampus, and NMDA-stimulated release of [3H]norepinephrine (NE) or [3H]dopamine (DA) were used as indices of NMDA receptor function. The muscarinic agonist carbachol (1 mM) stimulated PI hydrolysis in hippocampi from all three age groups with no significant differences between the groups. NMDA inhibited the carbachol-evoked PI response in a concentration-dependent manner (10-100 microM) in all age groups. However, the NMDA-induced (100 microM) inhibition of the carbachol-stimulated response was markedly reduced in an age-dependent manner with losses of 25% and 53% in middle-aged and senescent rats compared to young. Concentration-effect curves for NMDA-stimulated [3H]NE release were determined using hippocampal and cortical slices from rats of the three age groups. In the hippocampus the maximal response for NMDA was significantly decreased from 6.55 fractional [3H]NE release in young to 4.51 and 4.18 in middle-aged and old rats, respectively, with no age-related changes in the potency of NMDA or slope of the curves. In cortical slices the maximal response was significantly reduced in an age-dependent manner by 23% in the senescent rats compared to the young rats. NMDA-stimulated [3H]DA release from striatal slices was significantly lower in the senescent rats at concentrations of NMDA from 500-2000 microM.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prominent decline of newborn cell proliferation, differentiation, and apoptosis in the aging dentate gyrus, in absence of an age-related hypothalamus-pituitary-adrenal axis activation

Neurogenesis and apoptosis in the hippocampal dentate gyrus (DG) occur during development and adulthood. However, little is known about how these two processes relate to each other during aging. In this study, we examined apoptosis, proliferation, migration, and survival of newborn cells in the young (2 weeks), young-adult (6 weeks), middle-aged (12 months), and old (24 months) rat DG. We also measured dentate volume and cell numbers, along with basal corticosterone and stress response parameters. We show that new cell proliferation and apoptosis slow down profoundly over this time period. Moreover, migration and differentiation into a neuronal or glial phenotype was strongly reduced from 6 weeks of age onwards; it was hardly present in middle-aged and old rats as confirmed by confocal analysis. Surprisingly, we found no correlation between cell birth and corticosterone levels or stress response parameters in any age group.     

Cellular immunosenescence in F344 rats: decreased natural killer (NK) cell activity involves changes in regulatory interactions between NK cells, interferon, prostaglandin and macrophages

Natural killer (NK) activity of F344 rat spleen cells remained constant between 1 and 18 months of age under specific pathogen-free (SPF) conditions. Between 18 and 24 months of age, however, there was a dramatic decline in activity which remained at a low baseline throughout the normal lifespan. Removal of adherent cells on G-10 Sephadex columns revealed age-related changes in adherent cell regulation of NK activity. Young (4-6 week) NK activity was consistently decreased by adherent cell removal while old (24-30 month) NK activity was slightly but reproducibly increased. Moreover, splenic macrophages from old rats purified by adherence to microexudate-coated surfaces were highly suppressive to young nonadherent NK activity. A role for endogenous prostaglandin (PG) in suppressed old rat NK activity was suggested by the effectiveness of anti-PGE2 in vivo to boost old NK activity. Although old rat NK activity was boosted to a relatively greater extent by interferon (IFN) in vitro than was young NK activity, IFN-boosted NK activity of old rats was much more sensitive to PGE2 inhibition than was IFN-boosted young rat NK activity. IFN treatment in vitro or poly(I:C) treatment in vivo induced protection against PGE2 inhibition of NK activity in young rats, while no resistance to PGE2 inhibition was induced in old rat NK cells by similar treatments. In vivo, the same protocol of IFN administration which boosted young rat NK activity further suppressed old rat activity. These results support the hypothesis that immunosuppression related to aging, which supersedes the boosting effect of IFN, involves the combined effects of suppressor macrophages (via PGE2) and intrinsic changes in effector (NK) cells which render them more sensitive to PGE2 inhibition.     

Serum leptin response to endogenous hyperinsulinemia in aging rats

To determine if aging is associated with altered serum leptin response to diet-induced changes in endogenous hyperinsulinemia, male Fisher 344 (F344) rats at different age groups were studied while on regular rat chow and following 10 days of experimental diets consisting of 60% of the weight as fructose or glucose. The serum leptin concentration (ng/ml) gradually increased from basal levels of 2.5+/-0.1 at age of 4 months to 3.7+/-0.1, 6.9+/-0.9, 9. 4+/-0.3 and 8.9+/-1.1 at 6, 12, 18 and 24 months of age, respectively (P<0.001). Hyperinsulinemia associated with 60% fructose diet was associated with increased serum leptin levels in 4, 12, and 24 month old rats to 5.1+/-0.8, 6.7+/-1.2, and 8.6+/-1.1, respectively (P<0.001). Feeding 60% glucose diet also was associated with increased serum leptin levels in 4, 12 and 24 month old rats to 7.6+/-0.6, 7.2+/-0.7, and 9.1+/-1.1, respectively (P<0.001). Restricting dietary intake to 60% of the calories consumed by control rats for 10 days resulted in a decrease in serum leptin to 1.0+/-0.02 in 4 month old rats and 2.5+/-0.4 in 24 month old rats (P<0.01). It is concluded that aging in F344 rats is associated with increased serum leptin concentrations. However, diet-related hyperinsulinemic effect on leptin is blunted in aging rats although leptin response to caloric restriction is maintained. The inability of aging rats to mount hyperleptinemic response to dietary changes may contribute to the age-related increase in adiposity.     

高胆固醇血症大鼠主动脉内皮细胞NF-κB的激活和血小板源生长因子B链的表达

目的　验证体外培养的内皮细胞经轻微修饰低密度脂蛋白 (mm LDL)刺激后激活细胞核因子κB(NF κB)的现象可否同样在高胆固醇血症大鼠主动脉内皮细胞内出现并促进血小板源生长因子B链 (PDGF B)的表达 ,以及年龄对NF κB PDGF B信号传导通路的影响。方法　胃饲高胆固醇乳剂建立高胆固醇血症大鼠模型 ,免疫组织化学染色法 [链霉素抗生物素蛋白 过氧化物酶 (SP)法 ]明确主动脉内皮细胞NF κB激活后发生核转位的情况 ;应用原位杂交技术观察内皮细胞PDGF BmRNA的表达 ,同时应用免疫组织化学染色法 (SP法 )观察内皮细胞合成PDGF B链的情况。结果　与对照组相比 ,胃饲高胆固醇乳剂 6周后 ,2个月龄大鼠出现高胆固醇血症 ,主动脉内皮细胞NF κB核转位的比例明显增加 ,PDGF BmRNA的表达也增多。 10个月龄对照组Wistar大鼠的主动脉内皮细胞几乎不表达PDGF BmRNA ,摄入高胆固醇乳剂 16周后 ,内皮细胞表达PDGF BmRNA明显增多。较之摄入胆固醇同时期的 2个月龄大鼠 ,NF κB的核转位及内皮细胞PDGF B链的合成均增多(0 4 6 1± 0 0 75比 0 35 0± 0 0 94 ;0 2 30± 0 0 4 0比 0 185± 0 0 37) ,其差异有显著性意义 (P <0 0 5 ;P <0 0 0 1)。结论　高胆固醇血症能激活大鼠主动脉内皮细胞的NF κB ,使核转位增多     

Influence of age on 5'-nucleotidase in plasma membranes isolated from rat liver

Studies were carried out to determine the kinetic properties of 5'-nucleotidase from liver plasma membranes in rats of different ages; four groups were examined, namely rats 25 +/- 2, 60 +/- 5, 230 +/- 15 and 525 +/- 20 days old. The 5'-nucleotidase showed minimum Vmax values in young rats; differences in this kinetic parameter were not detected among the other groups. However, the Km values increased during growth and development, declined in young animals and increased again in the middle-aged. Arrhenius plots of the 5'-nucleotidase activity showed a single break at aroung 22 degrees C in developing the middle-aged animals; the break temperature decreased to 17 degrees C in the rats 230 +/- 15 days old. The pH-Vmax and pH-Km curves showed a maximum at pH 7.6 at all ages. Lipid analysis of membrane preparations was carried out. Phospholipid composition did not change markedly with age. The cholesterol level decreased between 25 +/- 2 and 60 +/- 5 days. The degree of saturation of fatty acids seemed to increase in the same period, but reached the lowest value in the young rats. The results indicate that either sphingomyelin or other phospholipids do not affect the isothermal kinetics of 5'-nucleotidase during development and aging. Furthermore, phospholipid polar groups as well as the cholesterol and fatty acids of the bulk lipid phase modulate the membrane fluidity in the same way at different ages. Finally, the modifications of the Km with age cannot be correlated with changes in the surface charge.     

The effect of donor age on human fibroblast beta-adrenergic receptor response and agonist-induced desensitization.

Aging has been associated with changes in beta-adrenergic receptor (beta-receptor) function in several tissues. The relative contribution of cellular aging and age-related changes in homeostatic regulation of receptor function is unknown. We have examined beta-receptor function in fibroblasts of young and old donors (young: mean age 31.2 +/- 0.8 years +/- S.E., n = 6; old: mean age 81.8 +/- 0.6 years +/- S.E., n = 6). Beta-receptor responses to isoproterenol (ISO), (1 microM) were similar in the two groups. The concentration of ISO required for 50% maximal beta-receptor-mediated cyclic AMP production (EC50) was similar in both groups. Fibroblast beta-receptor density was also similar in young and old groups. ISO-induced beta-receptor desensitization was both dose- and time-dependent. Submaximal desensitization by acute exposure (30 min) to ISO (1 mM) caused similar levels of beta-receptor desensitization in young (42.5 +/- 2.5%) and old (42.8 +/- 2.8%) groups and a similar increase in ISO EC50. These findings demonstrate that aging in vivo does not cause changes in fibroblast beta-receptor regulation that are retained in culture.     

Central resistance to the inhibitory effects of leptin on stimulated insulin secretion with aging

Aging is associated with resistance to the effects of leptin on food intake and energy homeostasis. We examined if old rats were resistant to the effects of leptin on glucose stimulated insulin secretion. When leptin was infused intravenously (0.5 microg/kg/min) under hyperglycemic clamp conditions (11 mM) in young (n=5) and old rats (n=10, 5 ad libitum fed and five with surgical removal of visceral fat), glucose stimulated insulin secretion was significantly decreased by 44% in the young rats, but not in old rats (31.8+/-2.8 to 17.9+/-1.0 versus 33.7+/-1.4 versus 31.0+/-1.7 and 24.7+/-1.6 versus 21.0+/-2.8 in young versus old versus old VF- respectively, p<0.01). To identify if the resistance to leptin is secondary to impaired transport across the blood brain barrier (BBB), we infused leptin into the third ventricle (intra-cerebro ventricular, ICV). ICV infusion of leptin elicited a partial effect on glucose stimulated insulin secretion in the old (25.7+/-2.5 to 15.4+/-2.4 versus 24.4+/-2.4 to 19.0+/-2.0 in young versus old, respectively) suggesting that part of the leptin resistance was beyond the BBB. Resistance to the effects of leptin on insulin secretion in aging may protect against the onset of diabetes in old subjects.     

Cerebrovascular permeability and cognition in the aging rat.

Regional cerebrovascular permeability-capillary surface area products (rPS) and brain vascular space (BVS) were measured in aging, conscious, unrestrained Sprague-Dawley rats. Three groups of animals were examined: young-mature (6 months), middle-aged (12-14 months), and old (24-26 months) rats. Complex maze learning had been previously characterized in these same animals. Maze learning declined with age. Brain vascular space did not differ significantly with age in any brain region. However, small, but significant age-dependent decreases in rPS (25-33%) were observed. These decreases occurred mainly in the old animals in the basal ganglia and parietal cortex, and in the middle-aged and old rats in the olfactory bulbs. Significant and unexpected positive average correlations between brain permeability-capillary surface area products (PS) and learning errors occurred primarily in young rats and were attributable mainly to changes in 5 of 14 brain regions; hypothalamus, hippocampus, parietal cortex, septal area and superior colliculus. The higher correlations between maze learning errors and PS in young animals may indicate dynamic regulation of this cerebrovascular parameter which is lessened with aging. Average correlations between PS and cerebral blood flow also were determined and found to be generally small and not significant for most brain regions and age groups.