Changes in movement and ataxic gait with development in genetically ataxic mice: a comparison with the level of cerebellar cyclic nucleotide

Spontaneous movement and ataxic gait in ataxic mice showing various pathological changes in the cerebellum were investigated according to developmental stage by the open-field method of comparison with normal mice. As the cerebellum contains relatively high levels of cyclic nucleotide, its concentrations was measured by radioimmunoassay to elucidate the correlation between spontaneous movement and ataxic gait and the neurological changes. The movements of Rolling Mouse Nagoya (RMN), Weaver and Reeler mice without Purkinje Cell Degeneration (PCD) were found to decrease at 4 and 12 weeks of age. The degree of ataxic gait worsen in RMN, was unchanged in Reeler and improved in Weaver and PCD mice. The cerebellar c-GMP concentration of ataxic mice was decreased, while no significant changes in c-AMP concentration were found in comparison with normal mice. With development, the level of cerebellar c-GMP in Weaver mice increased, but this was not apparent in RMN, Reeler or PCD mice. The results of this investigation indicated that there may be some relation between the degree of ataxic gait and the level of cerebellar c-GMP in Weaver mice.     

Biochemical studies on monoamine contents in spinal cord of patients with multiple system atrophy

Monoamine contents were measured in the cervical spinal cord of patients with multiple system atrophy (MSA) by high-performance liquid chromatography with electrochemical detection. The concentrations of noradrenaline (NA) and its metabolite 4-methyl-4-hydroxyphenylglycol (MHPG) were highest in ventral horn compared with other regions of the spinal cord in controls. Both NA and MHPG contents were reduced in all regions in 4 MSA patients. But in one case (case 5), which did not show an autonomic dysfunction, NA as well as MHPG level was similar to controls. Similarly, the concentrations of 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were highest in ventral horn and reduced in all regions in 4 MSA patients who showed mild motor weakness. In one case (case 5), which revealed clinical motor weakness associated with fasciculation and areflexia and pathological degeneration of ventral horn, 5-HT content showed higher values than controls whereas the 5-HIAA level was lower than controls. These results probably indicate that the cell loss of supraspinal monoaminergic nuclei may be one of the causes responsible for neurological dysfunction such as autonomic failures and motor weakness in MSA.     

Elevated immunoreactive-somatostatin levels in the brain of ataxic mutant mice

Immunoreactive-somatostatin (IR-SRIF) levels were investigated in the brain of 4 types of ataxic mice (Rolling Mouse Nagoya, Weaver, PCD, Staggerer) with different cerebellar pathologies. IR-SRIF concentrations (ng/mg) were found to be significantly elevated in both cerebellum and cerebrum of all ataxic mutant mice, IR-SRIF (ng/organ) was found to be increased in the cerebellum and cerebrum in Rolling Mouse Nagoya and PCD compared with control mice. The gel-filtration profile (Sephadex G-50) in the cerebellar extracts of Rolling Mouse Nagoya proved to be identical to that of control mice. Three peaks of IR-SRIF were found to be uniformly elevated in Rolling Mouse Nagoya, with the highest peak coinciding with authentic somatostatin-14. The present results suggest that elevated levels of IR-SRIF in the brain may play a role in the mechanism underlying the manifestation of ataxia in ataxic mutant mice, especially in Rolling Mouse Nagoya and PCD.     

Relationship between hypothalamic noradrenergic neuronal activity and serum 3-methoxy-4-hydroxyphenylethylene glycol in the rat

It has been suggested that the circulating levels of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), a major end metabolite of noradrenaline (NA), may provide an index of central NA neuronal activity. The aim of this study was to examine in the rat the relationship between serum MHPG and hypothalamic NA neuronal activity during basal conditions, and when hypothalamic NA neuronal activity was stimulated or suppressed. Hypothalamic NA neuronal activity was assessed from the concentrations of the primary neuronal NA metabolite 3,4-dihydroxyphenylethyleneglycol (DHPG), MHPG, and the DHPG/NA and MHPG/NA ratios. Following 2-deoxyglucose (2DG) and cysteamine administration, hypothalamic NA neuronal activity and serum MHPG rose significantly. In contrast, hypothalamic NA neuronal activity and serum MHPG fell significantly in gentled rats. Serum MHPG correlated significantly with hypothalamic DHPG and the DHPG/NA ratio in control rats, and with hypothalamic DHPG, MHPG, and the DHPG/NA and MHPG/NA ratios in gentled, 2DG- and cysteamine-treated rats. In the latter two groups, serum MHPG also correlated significantly with serum glucose, which is itself closely related to hypothalamic NA neuronal activity. These studies demonstrate a significant relationship between serum MHPG and hypothalamic NA neuronal activity in the rat, so that serum MHPG provides an index of hypothalamic NA neuronal activity in the rat.     

Postmortem Stability of Brain 3-Methoxy-4-Hydroxyphenylethyleneglycol and 3,4-Dihydroxyphenylethyleneglycol in the Rat and Mouse

Abstract: To assess the postmortem stability of brain 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and 3,4-dihydroxyphenylethyleneglycol (DHPG) levels, groups of rats and mice were killed by cervical dislocation and left at either 21° or 4°C for intervals of up to 24 h until removal and freezing of whole brain. Whole brain free and total MHPG and DHPG levels were determined simultaneously by gas chromatography-mass fragmentography (GC-MF). By 2 h after death, statistically significant decrements occurred in rat brain free DHPG (20%), total MHPG (21%), and total DHPG (11%) at 4°C, but free MHPG increased significantly (50%) compared with controls. At 21°C, rat brain total MHPG increased compared with controls at 2 h (15%) but decreased at 4 h (15%) and 8 h (15%), whereas free MHPG levels were increased at these times. Although brain total and conjugated DHPG levels showed little change, free DHPG levels were reduced at all times. In mouse brain no significant changes occurred in free MHPG and DHPG by 24 h at 4°C. At 21°C, mouse brain DHPG levels decreased whereas MHPG concentrations increased over the 8-h period of study. These findings demonstrate the occurrence of significant postmortem time- and temperature-dependent changes in brain MHPG and DHPG concentrations and indicate caution in the interpretation of changes in these metabolites in studies employing human postmortem brain tissue.     

Catecholamine Content Changes in Brain Regions of Spontaneously Hypertensive Rats Under Immobilization Stress

We compared the effect of immobilization stress on noradrenaline (NA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) content in two brain regions--diencephalon and pons-medulla oblongata--in young and adult spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). In SHR, NA content decreased with time after the onset of the stress, whereas levels of its metabolite MHPG increased. In WKY, NA and MHPG showed no change. The MHPG/NA ratio in both regions increased relative to the duration of the stress in SHR, whereas it remained almost constant in WKY. The rate of increase in the ratio was much higher in the diencephalon of adult (12-week-old) than of young (4-week-old) SHR. In SHR, NA turnover in the brain is readily affected by environmental stress, and these changes in the noradrenergic system may induce or sustain hypertension.     

Effects of DSP-4 on monoamine and monoamine metabolite levels and on beta adrenoceptor binding kinetics in rat brain at different times after administration

Effects of DSP-4 on noradrenaline (NA), 3-methoxy-4-hydroxyphenyl glycol (MHPG), serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) levels and on beta adrenoceptor binding kinetics (Bmax and K_D) in rat hippocampus, cortex and hypothalamus were studied between 24 hours and 14 days after systemic administration. Beta adrenoceptor numbers in hippocampus and cortex, but not in hypothalamus, were significantly increased after DSP-4. No significant changes in K_D values were observed in hypothalamus, but significant increases in this parameter were measured in hippocampus and cortex. NA and MHPG levels were significantly decreased in all three brain regions, but MHPG/NA ratios were increased in hippocampus, decreased in cortex and unchanged in hypothalamus. Very prominent increases in 5-HIAA levels were observed in all three brain regions, but only at one day after DSP-4. The greatest increases in 5-HIAA levels occurred in the hippocampus, but this effect of DPS-4 appeared to be slightly diminished by pre-treatment with fluoxetine. In cortex and hippocampus 5-HT levels were slightly, but significantly decreased after DSP-4.     

In vivo regulation of dopamine and noradrenaline release by alpha2A-adrenoceptors in the mouse nucleus accumbens

The present study investigated the role of alpha2A-adrenoceptor (alpha2A-AR) subtype in the regulation of noradrenaline (NA) and dopamine (DA) release in the nucleus accumbens (NAc). The effect of locally infused and systemically injected alpha2-AR agonist, dexmedetomidine (DMT), and alpha2-AR antagonist, atipamezole, on NA and DA release was investigated in alpha2A-AR knockout and control mice by using in vivo microdialysis. In addition, we compared the drug effects on DA and NA release in the NAc to their effect on locomotor activity. Baseline NA and DA concentrations did not differ between genotypes. Local infusion of DMT decreased, in a concentration-dependent manner, NA, but not DA, levels in the control mice. However, systemic injection of DMT decreased both NA and DA levels in the control mice. In both cases DMT had no effects on transmitter release in alpha2A-AR knockout mice. Our results suggest that alpha2-ARs regulate the release of NA, but not DA, at the terminal level in the NAc. However, alpha2-ARs regulate DA release in the NAc indirectly by their effect on DA neurones in the ventral tegmental area via an unknown mechanism. In both cases the regulation is mediated by alpha2A-adrenoceptor subtype. Also the modulation of locomotor activity by alpha2-AR agonist and antagonist seems to be mediated via alpha2A-adrenoceptors.     

The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

Reactive oxygen species are implicated in age‐associated neurodegeneration, although direct in vivo evidence is lacking. We recently showed that mice with a mutation in the Inner Mitochondrial Membrane Peptidase 2‐like (Immp2l) gene had elevated levels of mitochondrial superoxide, impaired fertility and age‐associated phenotypes, including kyphosis and ataxia. Here we show that ataxia and cerebellar hypoplasia occur in old mutant mice (> 16 months). Cerebellar granule neurons (CGNs) are significantly underrepresented; Purkinje cells and cells in the molecular layer are not affected. Treating mutant mice with the mitochondria‐targeted antioxidant SkQ1 from 6 weeks to 21 months protected cerebellar granule neurons. Apoptotic granule neurons were observed in mutant mice but not in age‐matched normal control mice or SkQ1‐treated mice. Old mutant mice showed increased serum protein carbonyl content, cerebellar 4‐hydroxynonenal (HNE), and nitrotyrosine modification compared to old normal control mice. SOD2 expression was increased in Purkinje cells but decreased in granule neurons of old mutant mice. Mitochondrial marker protein VDAC1 also was decreased in CGNs of old mutant mice, suggesting decreased mitochondrial number. SkQ1 treatment decreased HNE and nitrotyrosine modification, and restored SOD2 and VDAC1 expression in CGNs of old mutant mice. Neuronal expression of nitric oxide synthase was increased in cerebella of young mutant mice but decreased in old mutant mice. Our work provides evidence for a causal role of oxidative stress in neurodegeneration of Immp2l mutant mice. The Immp2l mutant mouse model could be valuable in elucidating the role of oxidative stress in age‐associated neurodegeneration.     

Involvement of noradrenergic transmission in the PVN on CREB activation, TORC1 levels, and pituitary-adrenal axis activity during morphine withdrawal

Experimental and clinical findings have shown that administration of adrenoceptor antagonists alleviated different aspects of drug withdrawal and dependence. The present study tested the hypothesis that changes in CREB activation and phosphorylated TORC1 levels in the hypothalamic paraventricular nucleus (PVN) after naloxone-precipitated morphine withdrawal as well as the HPA axis activity arises from α(1)- and/or β-adrenoceptor activation. The effects of morphine dependence and withdrawal on CREB phosphorylation (pCREB), phosphorylated TORC1 (pTORC1), and HPA axis response were measured by Western-blot, immunohistochemistry and radioimmunoassay in rats pretreated with prazosin (α(1)-adrenoceptor antagonist) or propranolol (β-adrenoceptor antagonist). In addition, the effects of morphine withdrawal on MHPG (the main NA metabolite at the central nervous system) and NA content and turnover were evaluated by HPLC. We found an increase in MHPG and NA turnover in morphine-withdrawn rats, which were accompanied by increased pCREB immunoreactivity and plasma corticosterone concentrations. Levels of the inactive form of TORC1 (pTORC1) were decreased during withdrawal. Prazosin but not propranolol blocked the rise in pCREB level and the decrease in pTORC1 immunoreactivity. In addition, the HPA axis response to morphine withdrawal was attenuated in prazosin-pretreated rats. Present results suggest that, during acute morphine withdrawal, NA may control the HPA axis activity through CREB activation at the PVN level. We concluded that the combined increase in CREB phosphorylation and decrease in pTORC1 levels might represent, in part, two of the mechanisms of CREB activation at the PVN during morphine withdrawal.     

Protective effect of IL-18 on kainate- and IL-1 beta-induced cerebellar ataxia in mice

The pathogenesis of sporadic cerebellar ataxia remains unknown. In this study, we demonstrate that proinflammatory cytokines, IL-18 and IL-1beta, reciprocally regulate kainate-induced cerebellar ataxia in mice. We show that systemic administration of kainate activated IL-1beta and IL-18 predominantly in the cerebellum of mice, which was accompanied with ataxia. Mice deficient in caspase-1, IL-1R type I, or MyD88 were resistant to kainate-induced ataxia, while IL-18- or IL-18R alpha-deficient mice displayed significant delay of recovery from ataxia. A direct intracerebellar injection of IL-1beta-induced ataxia and intracerebellar coinjection of IL-18 counteracted the effect of IL-1beta. Our data firstly show that IL-18 and IL-1beta display differential direct regulation in kainate-induced ataxia in mice. Our results might contribute toward the development of a new therapeutic strategy for cerebellar ataxia in humans.     

Relative Importance of 3-Methoxy-4-Hydroxyphenylglycol and 3,4-Dihydroxyphenylglycol as Norepinephrine Metabolites in Rat, Monkey, and Humans

Abstract: A gas chromatographic-mass spectrometric assay, which allowed simultaneous measurement of 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG), was used to show that the concentration of MHPG in primate CNS far exceeded that of DHPG and that both metabolites were mainly in the unconjugated form. In rat brain, DHPG concentration was generally higher than that of MHPG, and both existed predominantly as conjugates. Rat and primate plasma contained more MHPG than DHPG. In plasma of primates but not of rats, higher proportions of the metabolites were conjugated, compared to those in brain. Significant correlations existed between MHPG and DHPG in rat brain, monkey brain, human plasma, and both monkey CSF and plasma. In monkeys, a significant CSF-plasma correlation was found for MHPG, but not for DHPG. Acute administration of piperoxane raised rat brain MHPG and DHPG concentration; desipramine prevented this rise in DHPG, but not in MHPG. Desipramine alone decreased DHPG, but not MHPG, concentration. Piperoxane increased monkey brain MHPG, but not DHPG, concentration. These data suggest that DHPG is a valuable metabolite to measure when assessing norepinephrine metabolism in the rat. Under certain conditions, measurement of rat brain MHPG and DHPG may provide information concerning the site of norepinephrine metabolism. However, in primates the importance of monitoring DHPG, in addition to MHPG, is uncertain.     

Decreased Brain Protein Levels of Cytochrome Oxidase Subunits in Alzheimer's Disease and in Hereditary Spinocerebella Ataxia Disorders

Abstract : Controversy exists as to the clinical importance, cause, and disease specificity of the cytochrome oxidase (CO) activity reduction observed in some patients with Alzheimer's disease (AD). Although it is assumed that the enzyme is present in normal amount in AD, no direct measurements of specific CO protein subunits have been conducted. We measured protein levels of CO subunits encoded by mitochondrial (COX I, COX II) and nuclear (COX IV, COX VIc) DNA in autopsied brain of patients with AD whom we previously reported had decreased cerebral cortical CO activity. To assess disease specificity, groups of patients with spinocerebellar ataxia type I and Friedreich's ataxia were also included. As compared with the controls, mean protein concentrations of all four CO subunits were significantly decreased (-19 to -47%) in temporal and parietal cortices in the AD group but were not significantly reduced (-12 to -17%) in occipital cortex. The magnitude of the reduction in protein levels of the CO subunits encoded by mitochondrial DNA (-42 to -47%) generally exceeded that encoded by nuclear DNA (-19 to -43%). In the spinocerebellar ataxia disorders, COX I and COX II levels were significantly decreased in cerebellar cortex (-22 to -32%) but were normal or close to normal in cerebral cortex, an area relatively unaffected by neurodegeneration. We conclude that protein levels of mitochondrial- and nuclear-encoded CO subunits are moderately reduced in degenerating but not in relatively spared brain areas in AD and that the decrease is not specific to this disorder. The simplest explanation for our findings is that CO is decreased in human brain disorders as a secondary event in brain areas having reduced neuronal activity or neuronal/synaptic elements consequent to the primary neurodegenerative process.     

Effects of naloxone-precipitated withdrawal after a single dose of morphine on catecholamine concentrations in guinea-pig brain

The effect of naloxone-precipitated withdrawal after acute morphine was studied on the concentrations of noradrenaline (NA), 4-hydroxy-3-methoxyphenylethyleneglycol (MHPG), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and on the metabolite/parent amine ratios MHPG/NA, DOPAC/DA and HVA/DA, in eight regions of the guineapig brain. Guinea-pigs were treated with a single dose of morphine sulphate (15 mg/kg s.c.) or saline (control) and 2h later with naloxone hydrochloride (15 mg/kg s.c.) to precipitate withdrawal. The animals were decapitated at 0.5 h or 1 h after naloxone injections and their brains analysed for monoamine concentrations by HPLC-ECD. At 0.5 h after naloxone-precipitated withdrawal NA and MHPG levels, and the MHPG/NA ratio, were increased in the hypothalamus, and the NA levels were increased in the hypothalamus, medulla/pons and cortex 1 h after naloxone. Naloxoneprecipitated withdrawal also produced increased DA metabolism in the cortex, midbrain and medulla 0.5 h later, and in the cortex, hypothalamus and striatum 1 h later. Hence naloxone-precipitated withdrawal from acute morphine treatment produced a complex pattern of increased synthesis and metabolism of NA and DA which varied over time and with the brain region examined.     

Genetic factors influencing neurosensitivity to early phenobarbital administration in mice

This study was designed to assess the possible genetic determinants of neurosensitivity to early (neonatal) phenobarbital (PhB) administration and to conduct a strain comparison for the cerebellar histology of both inbred and outbred mice. HS/Ibg, C57BL/10 and DBA/1 pups were injected with 50 mg PhB/kg daily on neonatal days 2-21. On day 50, treated animals (B) of all strains had smaller brains than controls (C). Moreover, the cerebellar area was decreased in HS and C57 B mice but not in DBA mice, suggesting genotype-environment interaction. B mice from all strains had similar Purkinje cell losses. Strain comparison showed that control C57 mice had smaller brains than control HS, and DBA had smaller brains than both HS and C57. Similarly, C57 had smaller cerebellar layers than HS and DBA had smaller cerebellar layers than both HS and C57. DBA and C57 mice had fewer Purkinje cells than HS but did not differ from each other.     

Prolonged alpha-tocopherol deficiency decreases oxidative stress and unmasks alpha-tocopherol-dependent regulation of mitochondrial function in the brain

Vitamin E is the major lipid-soluble chain-breaking antioxidant in mammals and plays an important role in normal development and physiology. Deficiency (whether dietary or genetic) results in primarily nervous system pathology, including cerebellar neurodegeneration and progressive ataxia (abnormal gait). However, despite the widely acknowledged antioxidant properties of vitamin E, only a few studies have directly correlated levels of reactive oxygen species with vitamin E availability in animal models. We explored the relationship between vitamin E and reactive oxygen species in two mouse models of vitamin E deficiency: dietary deficiency and a genetic model (tocopherol transfer protein, Ttp-/- mice). Both groups of mice developed nearly complete depletion of alpha-tocopherol (the major tocopherol in vitamin E) in most organs, but not in the brain, which was relatively resistant to loss of alpha-tocopherol. F4-neuroprostanes, an index of lipid peroxidation, were unexpectedly lower in brains of deficient mice compared with controls. In vivo oxidation of dihydroethidium by superoxide radical was also significantly lower in brains of deficient animals. Superoxide production by brain mitochondria isolated from vitamin E-deficient and Ttp-/- mice, measured by electron paramagnetic resonance spectroscopy, demonstrated a biphasic dependence on exogenously added alpha-tocopherol. At low concentrations, alpha-tocopherol enhanced superoxide flux from mitochondria, a response that was reversed at higher concentrations. Here we propose a mechanism, supported by molecular modeling, to explain decreased superoxide production during alpha-tocopherol deficiency and speculate that this could be a beneficial response under conditions of alpha-tocopherol deficiency.     

The abnormal cerebellar organization of Weaver and reeler mice does not affect the cellular distribution of three neuronal mRNAs

We used in situ hybridization of 35S-labeled antisense RNAs to study the cellular distribution of three neuronal mRNAs. We compared the expression of these RNAs in cerebellar Purkinje neurons in wild-type (C57Bl-6J) mice and in two mutants (Weaver and reeler) known to have abnormal cerebellar morphologies. In normal mice, GAD mRNA is present in four sets of neurons in the cerebellar cortex while calbindin mRNA is present only in Purkinje neurons. Proenkephalin mRNA is present in Golgi II neurons as well as in a set of neurons in the deep part of the molecular layer. Despite the dramatic differences in structural organization and inputs of Purkinje neurons in the cerebella of adult Weaver and reeler mice, the expression of these RNAs appears unchanged. These results support the hypothesis that Purkinje cell cytodifferentiation proceeds autonomously after its inception in early embryonic life.     

Increased Cerebrospinal Fluid Dopamine and 3,4-Dihydroxyphenylacetic Acid Levels in Huntington''s Disease: Evidence for an Overactive Dopaminergic Brain Transmission

Levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) in the CSF of patients with Huntington's disease (HD) were measured by HPLC. CSF DA, DOPAC, and MHPG levels were found to be increased in HD patients. Levels of HVA, 5-HIAA, and NA in the CSF of HD patients did not differ from those of controls. Changes in CSF DA and DOPAC levels were consistent with previous findings of increased DA tissue content in some brain areas of patients with HD. These results suggest that CSF DOPAC levels could be a more reliable index of overactive dopaminergic brain systems in HD than CSF HVA levels.     

Studies on the behavioral pharmacology of TRH-T in cytosine arabinoside-induced ataxic mice: a comparison with genetically ataxic mice

The effects of thyrotropin releasing hormone tartrate (TRH-T) on the behavior of cytosine arabinoside (Ara-C) induced ataxic mice were studied. The ataxic mice were prepared by injecting 50 mg/kg/day subcutaneously on the 2nd, 3rd and 4th postnatal days. Spontaneous motor activities were measured with a movement spectrum analyzer (ANIMEX-2) and the degree of ataxic gait determined by an open-field study. Cerebella from these animals were subjected to histopathologic examination at 4, 8 and 12 weeks of age. Ataxic gait became improved moderately and spontaneous motor activities increased slightly following administration of TRH-T. The effects of TRH-T on ataxia and spontaneous motility in the Ara-C injected mice varied with the age, and resembled those seen in weaver mice but not those in the Rolling mouse Nagoya. The results also suggest that the effects of TRH-T on the behavior of ataxic mice correlate with the extent of pathologic changes evoked in their cerebella.     

Cuttine edge: T cells from aged mice are resistant to depletion early during virus infection

Aging is associated with decreased expansion of T cells upon stimulation. In young mice, infection induces a transient T cell depletion followed by the development of an Ag-specific T cell response that controls the infection. We found that T cells were depleted early after infection with E55 + murine leukemia retrovirus in young, but not aged, mice. Adoptive transfer experiments showed donor T cells of young, but not aged, mice were depleted due to apoptosis in various tissues of young recipients. However, T cells of neither young nor aged donors were depleted in aged recipients. These results indicate that both environmental and intrinsic cellular properties limit depletion of T cells of aged mice and suggest a novel explanation for the decreased T cell response associated with aging.