Murine Model Of Aging Research Articles

Production of Nitric Oxide, but Not Prostacyclin, Is Reduced in Klotho Mice

A novel murine model of aging (kl /kl mice) has been developed by in vivo mutagenesis. We analyzed endothelial function in this strain. Ring preparations of the thoracic aorta were obtained from 6- to 9-week old wild-type (+ /+) and heterozygous (kl /+) klotho mice. The aortas of kl / + mice showed an exaggerated contractile response to norepinephrine and attenuated vasodilator responses to acetylcholine and lecithinized superoxide dismutase (SOD) compared to + / + mice. The response to sodium nitroprusside was unaltered in kl / + mice. The contraction in response to norepinephrine was augmented by treatment with N°-nitro-L-arginine methyl ester (L-NAME, 10-5 M) to a greater extent in + / + mice than in kl / + mice. Treatment with L-NAME abolished the vasodilator responses to both acetylcholine and lecithinized SOD. NO metabolites (NO2- and NO3-) and cGMP concentrations in the urine were significantly reduced in kl/ + mice compared to + / + mice. However, the urinary excretion of 6-keto-prostaglandin F1α was unaltered. There was little immunostaining for NO synthase and vascular endothelial growth factor (VEGF) in the aorta of kl/+ mice. No immunostaining for NO synthase was noted in the aorta of kl /kl mice. The expression of the klotho gene product may have a role in the regulation of VEGF expression and is tightly linked to endothelial release of NO.

Depressive Behavior and Alterations in Receptors for Dopamine and 5-Hydroxytryptamine in the Brain of the Senescence Accelerated Mouse (SAM)-P10

The senescence accelerated mouse (SAM) is known as a murine model of aging. SAM consists of senescence accelerated-prone mouse (SAMP) and senescence accelerated-resistant mouse (SAMR). Previous studies reported that SAMP 10 exhibits age-related learning impairments and behavioral depression in a tail suspension test after 7 months. We investigated the changes in emotional behavior in a forced swimming test and in receptors for dopamine and 5-hydroxytryptamine (5-HT) in SAMP10. SAMP10 at 8 months showed an increase of immobility in the test compared with SAMR1. Treatment with desipramine (25 mg/kg, i.p., 3 days) in SAMP10 caused a decrease in immobility. In the cortex from SAMP10, [3H]quinpirole binding to D2/D3 dopamine receptors increased significantly compared with control SAMR1. In the hippocampus from SAMP10, [3H]8-hydroxy DPAT binding to 5-HT1A receptor increased. In midbrains from SAMP10, bindings of [3H]quinpirole and [3H]8-hydroxy DPAT increased. [3H]SCH23390 binding to D1/D5 receptors and [3H]ketanserin binding to 5-HT2 receptor in brain regions examined in SAMP10 were similar to those in SAMR1. The present findings represent the first neurochemical evidence of an increase of D2/D3 and 5-HT1A receptors in SAMP10. SAMP10 may be a useful model of aging associated depressive behavior.

Depressive behavior and alterations in receptors for dopamine and 5-hydroxytryptamine in the brain of the senescence accelerated mouse (SAM)-P10.

The senescence accelerated mouse (SAM) is known as a murine model of aging. SAM consists of senescence accelerated-prone mouse (SAMP) and senescence accelerated-resistant mouse (SAMR). Previous studies reported that SAMP10 exhibits age-related learning impairments and behavioral depression in a tail suspension test after 7 months. We investigated the changes in emotional behavior in a forced swimming test and in receptors for dopamine and 5-hydroxytryptamine (5-HT) in SAMP10. SAMP10 at 8 months showed an increase of immobility in the test compared with SAMR1. Treatment with desipramine (25 mg/kg, i.p., 3 days) in SAMP10 caused a decrease in immobility. In the cortex from SAMP10, [3H]quinpirole binding to D2/D3 dopamine receptors increased significantly compared with control SAMR1. In the hippocampus from SAMP10, [3H]8-hydroxy DPAT binding to 5-HT1A receptor increased. In midbrains from SAMP10, bindings of [3H]quinpirole and [3H]8-hydroxy DPAT increased. [3H]SCH23390 binding to D1/D5 receptors and [3H]ketanserin binding to 5-HT2 receptor in brain regions examined in SAMP10 were similar to those in SAMR1. The present findings represent the first neurochemical evidence of an increase of D2/D3 and 5-HT1A receptors in SAMP10. SAMP10 may be a useful model of aging associated depressive behavior.

Beneficial effects of sigma agonists on the age-related learning impairment in the senescence-accelerated mouse (SAM)

A beneficial effect of sigma (σ) agonists was previously described on several pharmacological models of learning impairments. We examined this effect in senescence-accelerated mice (SAM), which has been developed as a murine model of aging and cognitive dysfunction. SAMP8/Ta (P8, senescence-prone substrain), 10–12 months of age, showed significant impairments in mnemonic capacities, as compared to age-matched SAMR1/Ta controls (R1, senescence-resistant substrain). Tests included open-field behavior, spontaneous alternation performances in the Y-maze, step-down passive avoidance and place learning after repetitive training in a water-maze. Pretreatment with the σ agonists JO-1784 (igmesine) or PRE-084, at 0.1–3 mg/kg, s.c., significantly improved spontaneous alternation and passive avoidance performances in P8. JO-1784 or PRE-084, at 1 mg/kg, also improved place learning in the water-maze, and retention, in term of escape latency. The implication of σ sites was indicated by the lack of significant effect of JO-1783, the inactive enantiomer of JO-1784, and by the ability of BMY-14802 (5 mg/kg, i.p.) to antagonize the effects on passive avoidance of JO-1784 (0.5 mg/kg) or PRE-084 (1 mg/kg). Subchronic treatments with JO-1784 (0.5 mg/kg/day) or PRE-084 (1 mg/kg/day) during 10 days, allowed a significant improvement of learning during training in the water-maze, but retention was not significantly ameliorated. These results confirmed the interest of the SAM substrains as an experimental model for senile memory impairment and showed that σ agonists could improve the quality of learning, although they seem less effective on long-term memory retrieval upon chronic administration.

A novel murine model of aging, Senescence-Accelerated Mouse (SAM)

Senescence-Accelerated Mouse (SAM) has been under development by our research team at Kyoto University since 1970, based on the AKR/J strain donated by the Jackson Laboratory in 1968. The SAM mouse has an accelerated senescence and age-associated pathologies such as senile amyloidosis, senile osteoporosis, degenerative joint disease, cataract, deficits in learning and memory, brain atrophy, hyperinflation of lungs, hearing impairment and so on. SAM research is advancing world-wide and attempts are being made to clarify fundamental mechanisms involved in primary aging processes, pathogenesis of age-associated pathologies and effective methods to modulate or ameliorate the advance of senescence and disease processes involved in age-associated pathologies.

Molecular biological approaches to aging in Japan: an overview

Progress in molecular biological investigations of aging in Japan is overviewed. Emphasis is put on studies which, in the author's opinin, appear to have considerable relevance to a definition of aging, i.e. functional decline of cells and tissues with advancing age. (1) Changes in the nucllear DNA, most significantly in methylation, and deletions of mitochondrial DNA have been shown to occur with age. (2) Various aspects of protein metabolism have been investigated, i.e. the fidelity of translation, accumulation of altered enzymes, oxidative damage, and half-lives and degradation of proteins. (3) Japanese researchers have made significant contributions to the understanding of the chemical structure and the mechanisms of generation of paired helical filaments in Alzheimer's disease. Also, studies on β-amyloid peptide are noteworthy. (4) Murine models of aging were developed and molecular biological investigations on them are progressing. Nematodes and fruit flies are also used as models.(5) Changes in gene expression with age have attracted considerable interest.

Age-related changes in transmitter glutamate and NMDA receptor/channels in the brain of senescence-accelerated mouse

The senescence-accelerated mouse (SAM-P/8) is known as a murine model of aging and memory dysfunction. In the hippocampus and cerebral cortex of P/8, the contents of glutamic acid and glutamine were significantly higher than those of normal strain R/1 during 2 and 14 months. High K +-evoked endogenous glutamic acid release from the slices of P/8 was increased in comparison with R/1 at 9 and 11 months. In addition, the B max of [ 3H]dizocilpine (MK-801, channel blocker for N- methyl- d-aspartic acid receptor/channel) binding in the cerebral cortex was age-dependently decreased in P/8 but not in R/1. These results suggest that synaptic dysfunctions in the glutamatergic system occur in the CNS of SAM-P/8.

Effects of Bifemelane Hydrochloride, a Brain Function Improver, on Muscarinic Receptors in the CNS of Senescence-Accelerated Mouse.

Senescence-accelerated mouse (SAM-P/8) is known as a murine model of aging and memory dysfunction, compared with control mouse (SAM-R/1). In the hippocampus of 9-month-old SAM-P/8, the Bmax of [3H]QNB binding was decreased compared with that of SAM-R/1 at the same age. Single and repeated administrations of bifemelane to SAM-P/8 induced an increase in the Bmax of [3H]QNB binding in the hippocampus. From these results, bifemelane seems to exert pharmacological effects through possible activation of the cholinergic system in the hippocampus of SAM.

Ligand-binding characteristics of [ 3H]QNB, [ 3H]prazosin, [ 3H]rauwolscine, [ 3H]TCP and [ 3H]nitrendipine to cerebral cortical and hippocampal membranes of senescence accelerated mouse

The senescence accelerated mouse (SAM) is known as a murine model of aging and memory dysfunction. In the cerebral cortical membranes of male 9-month-old SAM mice, the B max values of [ 3H]rauwolscine and [ 3H]nitrendipine binding, and the values of both K d and B max of [ 3H]TCP binding in the accelerated aging strain SAM-P 8 were significantly increased compared with the values in the control strain SAM-R 1 . In hippocampal membranes, however, the B max values of [ 3H]quinuclidinyl benzilate and [ 3H]nitrendipine binding were significantly decreased in SAM-P 8 compared with those in SAM-R 1 . These results suggest that muscarinic acetylcholine receptors, α 2-adrenoceptors, N- methyl- d-aspartate receptor channels and L-type Ca 2+ channels are changed in cerebral cortex and hippocampus in SAM-P 8 at 9 months.