National Institute for Longevity science

Okazaki, Japan

National Institute for Longevity science

Okazaki, Japan
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Shoji H.,National Institute for Longevity science | Shoji H.,Health Science University | Mizoguchi K.,National Institute for Longevity science
Journal of Ethnopharmacology | Year: 2013

Ethnopharmacological relevance A traditional Japanese (Kampo) medicine, yokukansan, has long been used to treat neurosis, insomnia, and night crying and irritability in children. Recently, this medicine has reported to improve the behavioral and psychological symptoms of dementia that often become problematic in patients with Alzheimer's disease and other forms of dementia. Aim of the study Several animal studies have reported that yokukansan has an anxiolytic effect. However, the underlying mechanisms are not yet understood. In the present study, we investigated the effects in rats of single and repeated administrations of yokukansan on anxiety-like behaviors, stress responses, and the brain regions involved. Materials and methods Yokukansan dissolved in water (100 or 300 mg/kg) was administered orally to F344/N male rats 1 h before each test or for two weeks before the tests began. Locomotor activity and anxiety-related behavior in the open-field test and the elevated plus-maze test, serum corticosterone levels, and restraint stress-induced c-Fos expression in various brain regions as a marker of neuronal activation were evaluated in both the vehicle-treated and yokukansan-treated rats. Results A single administration of yokukansan had no effect on locomotor activity or anxiety-like behavior; however, repeated administration decreased anxiety-like behavior in a dose-dependent manner. Neither single nor repeated administration of yokukansan had an effect on the basal or stress-induced levels of serum corticosterone. For c-Fos expression, restraint stress increased the number of c-Fos-positive cells in the subdivisions of the prefrontal cortex, amygdala, and hypothalamus. Repeated administration of yokukansan decreased the stress-induced c-Fos expression in the prelimbic cortex and the basolateral and medial amygdaloid nuclei. Conclusions The present study indicates that repeated oral administration of yokukansan has an anxiolytic effect and that this effect may be associated with attenuated neuronal activity in the medial prefrontal cortex and amygdala. © 2013 Elsevier Ireland Ltd.


Shoji H.,National Institute for Longevity science | Mizoguchi K.,National Institute for Longevity science
Behavioural Brain Research | Year: 2010

Aging is associated with dysregulation of emotional and endocrine responses in a stressful environment. To understand the developmental mechanisms of stress vulnerability with aging, we investigated the effects of repeated stress on behavioral, endocrine, and neural parameters relating to emotional and stress responses in young (3 months old) and aged (24 months old) F344/N male rats. Young and aged rats were either subjected to 1-h restraint stress for 14 consecutive days or left undisturbed. After the procedures, behaviors were examined in open-field and elevated plus-maze tests to evaluate the level of anxiety induced by aging and repeated stress. Following the behavioral tests, serum corticosterone concentrations and c-Fos immunoreactivity throughout the brain in response to acute restraint stress were examined. Control and repeatedly stressed aged rats showed more anxiety-related behaviors than control and repeatedly stressed young rats in both tests. In particular, repeatedly stressed aged rats showed more anxiety-related behaviors in the elevated plus-maze than control aged and repeatedly stressed young rats, although stressed young rats were not different from control young rats. Repeatedly stressed aged rats showed higher serum corticosterone concentrations in response to acute stress than subjects in all other conditions. In c-Fos expression, control aged rats showed decreases in c-Fos-positive cells in response to acute stress in the prefrontal cortex, medial preoptic area, bed nucleus of the stria terminalis, nucleus accumbens, medial amygdaloid nucleus, and CA3 subfield of hippocampus, whereas they showed increases in the dorsal raphe nucleus and parvocellular part of the paraventricular nucleus of the hypothalamus compared to acutely stressed control young rats. These results indicate that repeated stress enhances emotional and stress responses in aged rats but not in young rats, suggesting that aging causes organisms to become vulnerable to stress, which might be mediated by dysfunction of the brain system regulating emotional and stress responses. © 2010 Elsevier B.V.


Mizoguchi K.,National Institute for Longevity science | Tanaka Y.,National Institute for Longevity science | Tabira T.,National Institute for Longevity science
Journal of Ethnopharmacology | Year: 2010

Aim of the study: Aging is thought to affect emotions including anxiety, and a herbal medicine, yokukansan (YKS), is used to treat emotional disturbances associated with age-related neurodegenerative disorders such as Alzheimer's disease, but its pharmacological properties have not been fully understood. The present study was designed to examine whether YKS improves age-related anxiety using F344/N aged rats. Moreover, the effects of YKS on liver function were examined. Materials and methods: YKS was administered to 21-month-old aged rats for 3 months. Locomotor activity of young control (4 months old), aged control (24 months old), and YKS-treated aged rats was examined, and the anxiety-related responses of these animals were evaluated by counting the number of excrements during locomotor activity measurement and in the elevated plus-maze test. The extracellular concentrations of serotonin and dopamine in the prefrontal cortex (PFC) were also measured using a microdialysis technique. Moreover, concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and ammonia (NH 3) in plasma were measured. Results: Although locomotor activity did not change among any experimental groups, the number of excrements was significantly increased in aged rats compared to young rats, and this increase was significantly improved by YKS treatment. Aged rats also showed significant decreases in time and frequency in the open arm of the elevated plus-maze, and these decreases were significantly improved by YKS treatment. Extracellular concentrations of serotonin and dopamine in the aged PFC were significantly decreased; serotonin was increased over the level of young rats and dopamine was partially improved by YKS treatment, respectively. In addition, YKS improved age-related increase in NH 3 concentration, but did not affect AST and ALT. Conclusions: YKS has improving activity for age-related increased anxiety and enhances serotonergic and dopaminergic transmissions in the aged PFC. These mechanisms provide information important for the treatment of anxiety in the elderly. Furthermore, the present data confirm partially the Kampo concept "liver disease". © 2009 Elsevier Ireland Ltd. All rights reserved.


Shoji H.,National Institute for Longevity science | Mizoguchi K.,National Institute for Longevity science
Physiology and Behavior | Year: 2011

Aging is generally associated with cognitive dysfunction and alterations in emotional response. Moreover, in social situations, aging decreases social interaction with unfamiliar individuals, suggesting the decline of social cognition/motivation and a high level of anxiety. Although it is known that isolation housing has various effects on subsequent behavior, including social interaction depending on the age at isolation, the effects of isolation on aged subjects have not been examined. In the present study, we investigated the effects of aging and different periods of isolation housing on social interaction in male F344/N rats. Young (3-4. months old) and aged (24-25. months old) rats were either group-housed or socially isolated for 2 or 4. weeks. The rats were tested with age-matched and group-housed unfamiliar males in a social interaction test, and social (e.g. approach/following and sniffing) and non-social behaviors (e.g. self-grooming and ambulation) were recorded. The results indicated that group-housed aged rats showed less approach/following, sniffing, and ambulation than group-housed young rats. Moreover, in young rats, isolation housing gradually increased approach/following and sniffing depending on the isolation period. In contrast, in aged rats, more prolonged isolation (4. weeks) attenuated the 2-week isolation-induced increase of sniffing behavior and had no effect on approach/following. The present study suggests that aging decreases social investigation and induces high emotional response to a novel social environment, and that the behaviors can be differentially affected by social isolation depending on the age at isolation and the period of isolation. © 2010 Elsevier Inc.


Hirose K.,Hiroshima University | Shimoda N.,National Institute for Longevity science | Kikuchi Y.,Hiroshima University
Epigenetics | Year: 2013

Although dedifferentiation, transformation of differentiated cells into progenitor cells, is a critical step in the regeneration of amphibians and fish, the molecular mechanisms underlying this process, including epigenetic changes, remain unclear. Dot blot assays and immunohistochemical analyses revealed that, during regeneration of zebrafish fin, the levels of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are transiently reduced in blastema cells and cells adjacent to the amputation plane at 30 h post-amputation (hpa), and the level of 5mC, but not 5hmC, is almost restored by 72 hpa. We observed that the dedifferentiated cells showed reduced levels of 5mC and 5hmC independent of cell proliferation by 24 hpa. Furthermore, expressions of the proposed demethylation- and DNA repair-related genes were detected during fin regeneration. Taken together, our findings illustrate that the transient reduction of 5mC and 5hmC in dedifferentiated cells is associated with active demethylation during regeneration of zebrafish fin. © 2013 Landes Bioscience.


Inomata M.,Asahi University | Niida S.,National Institute for Longevity science | Shibata K.-I.,Hokkaido University | Into T.,Asahi University
Cellular and Molecular Life Sciences | Year: 2012

Toll-like receptor (TLR) signaling is linked to autophagy that facilitates elimination of intracellular pathogens. However, it is largely unknown whether autophagy controls TLR signaling. Here, we report that poly (I: C) stimulation induces selective autophagic degradation of the TLR adaptor molecule TRIF and the signaling molecule TRAF6, which is revealed by gene silencing of the ubiquitin- editing enzyme A20. This type of autophagy induced formation of autophagosomes and could be suppressed by an autophagy inhibitor and lysosomal inhibitors. However, this autophagy was not associated with canonical autophagic processes, including involvement of Beclin-1 and conversion of LC3-I to LC3-II. Through screening of TRIF-interacting 'autophagy receptors' in human cells, we identified that NDP52 mediated the selective autophagic degradation of TRIF and TRAF6 but not TRAF3. NDP52 was polyubiquitinated by TRAF6 and was involved in aggregation of TRAF6, which may result in the selective degradation. Intriguingly, only under the condition of A20 silencing, NDP52 could effectively suppress poly (I: C) - induced proinflammatory gene expression. Thus, this study clarifies a selective autophagic mechanism mediated by NDP52 that works downstream of TRIF-TRAF6. Furthermore, although A20 is known as a signaling fine-tuner to prevent excess TLR signaling, it paradoxically downregulates the fine-tuning effect of NDP52 on TLR signaling. © 2011 Springer Basel AG.


Suzuki T.,National Institute for Longevity science | Yoshida H.,Tokyo Metropolitan University
Osteoporosis International | Year: 2010

This study aimed to determine whether low bone mineral density (BMD) at the femoral neck independently predicts all-cause mortality in elderly Japanese women. A prospective cohort study of 271 women aged 67-89 years was conducted. A Cox proportional hazard model was used to examine independent associations between BMD and total mortality. During a 12-year follow-up period, the mortality risk (as measured by hazard ratio [HR]) was significantly increased in the three categories of baseline BMD (diagnostic criteria of osteoporosis, tertile of BMD, and quartile of BMD). After adjusting for major potential confounding variables for mortality, significantly increased mortality risks were found in subjects with osteoporosis (HR = 2.17, p = 0.032), in subjects in the lowest tertile (HR = 2.57, p = 0.007), and in subjects in the lowest quartile (HR = 3.13, p = 0.014], respectively. Our findings suggest that preventive strategies should be considered to increase and maintain high BMD at the femoral neck in the elderly women not only to prevent hip fractures but also probably to reduce mortality risk. Introduction: Several longitudinal studies with Caucasian subjects have suggested that osteoporosis is associated with increased mortality. This study aimed to determine whether low bone mineral density (BMD) at the femoral neck independently predicts all-cause mortality in elderly Japanese community-dwelling women. Method: A prospective cohort study of 271 women aged 67-89 years was conducted. A Cox proportional hazard model was used to examine independent associations between BMD at both the femoral neck and the trochanter and total mortality. Results: During a 12-year follow-up period, 81 of 271 women (29.9%) died. An independent and significant relationship was found between baseline BMD at the femoral neck and mortality risk. The mortality risk (as measured by HR) was increased by 2.80-fold (95% confidence interval [CI] 1.55-5.06; p < 0.01) in the subjects with osteoporosis or by 2.94-fold (95% CI 1.64-5.26; p < 0.001) in subjects in the lowest tertile or by 3.61-fold (95% CI 1.77-7.41; p < 0.001) in subjects in the lowest quartile of BMD, respectively. After adjusting for major potential confounding factors for mortality such as age, body mass index, blood pressure, blood variables, medical history, alcohol drinking, and smoking status, those in the subjects with osteoporosis (HR = 2.17 [95% CI 1.07-4.41], p = 0.032), in the lowest tertile (HR = 2.57 [95% CI 1.29-5.15], p = 0.007), or in the lowest quartile (HR = 3.13 [95% CI 1.26-7.73], p = 0.014] had a significantly increased risk of mortality. BMD measurement at the trochanter showed similar but weaker results. Conclusions: Our findings suggest that preventive strategies should be considered to increase and maintain high BMD at the femoral neck in elderly subjects not only to prevent osteoporosis and its associated fractures but also probably to reduce mortality risk. © 2009 International Osteoporosis Foundation and National Osteoporosis Foundation.


Matsuzaki K.,Kyoto University | Kato K.,Nagoya City University | Kato K.,Japan Institute for Molecular Science | Yanagisawa K.,National Institute for Longevity science
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2010

Clarification of the molecular and cellular mechanisms underlying the assembly of amyloid β-protein (Aβ) into insoluble fibrils in the brain has been one of the biggest challenges in the research on Alzheimer disease (AD). We previously identified a novel Aβ species, which was characterized by its tight binding to GM1 ganglioside (GM1), in the brain showing early pathological changes of AD. The ganglioside-bound Aβ (GAβ) possessed unique characteristics, including its altered immunoreactivity, which suggests its distinct conformation from native Aβ, and its strong potency to accelerate Aβ assembly into fibrils. On the basis of these characteristics, it was hypothesized that Aβ adopts an altered conformation following interaction with GM1, leading to the generation of GAβ, and then GAβ acts as an endogenous seed for Alzheimer amyloid in the brain. To date, various in vitro and in vivo studies on GAβ have revealed how Aβ binds to gangliosides, i.e., what are the favorable physicochemical and neurobiological conditions for generating GAβ, and what is the pathological significance of ganglioside-induced Aβ assembly in the development of AD. Interestingly, GAβ is favorably generated in the unique ganglioside-enriched (clustered), raft-like microdomains; moreover, amyloid fibrils formed in the presence of gangliosides are neurotoxic. Furthermore, the conformational change of Aβ in the presence of ganglioside has been characterized by an NMR study. In this review, we focus on the recent progress of GAβ studies and highlight the possibility that ganglioside binding is the initial and common step in the development of a part of human misfolding-type amyloidoses, including AD. © 2010 Elsevier B.V. All rights reserved.


Oikawa N.,National Institute for Longevity science | Kimura N.,Japan National Institute of Biomedical Innovation | Yanagisawa K.,National Institute for Longevity science
Brain Research | Year: 2010

We elucidated how Alzheimer-type pathologies of amyloid β-protein (Aβ) and tau spatiotemporally emerge in brains of nontransgenic nonhuman primate, cynomolgus monkey, in the present study. To examine the accumulation of deposited Aβ, phosphorylated tau accumulation, intracellular tau accumulation, and neurofibrillary tangle formation, the brains, mainly temporal cortex and hippocampus, of 34 cynomolgus monkeys aged 6 to 36 years were studied by biochemical and histochemical analyses. Biochemically, first, the accumulation of insoluble Aβ was detected in the neocortical (temporal and frontal) and hippocampal regions of animals as young as mid-20s and their levels were extremely high in those of advanced age. The accumulation of phosphorylated tau in the same regions occurred before the age of 20 with poor correlation to the levels of insoluble Aβ. Histologically, intraneuronal and intraoligodendroglial tau accumulation was observed in temporal cortex and hippocampus of animals before the age of 20. In an advanced aged 36-year-old individual, argyrophilic tangles and tau-accumulated dystrophic neurites were markedly observed in the medial temporal area contiguous to limbic structures. Notably, these tau pathologies also emerged, to a lesser extent, in the temporal cortices of advanced aged animals harboring significant amounts of insoluble Aβ. These results suggest that the cynomolgus monkey can be used to elucidate the age-dependent sequence of Aβ and tau pathologies. © 2009 Elsevier B.V. All rights reserved.


Uezumi A.,Health Science University | Ikemoto-Uezumi M.,National Institute for Longevity science | Tsuchida K.,Health Science University
Frontiers in Physiology | Year: 2014

Adult skeletal muscle possesses a remarkable regenerative ability that is dependent on satellite cells. However, skeletal muscle is replaced by fatty and fibrous connective tissue in several pathological conditions. Fatty and fibrous connective tissue becomes a major cause of muscle weakness and leads to further impairment of muscle function. Because the occurrence of fatty and fibrous connective tissue is usually associated with severe destruction of muscle, the idea that dysregulation of the fate switch in satellite cells may underlie this pathological change has emerged. However, recent studies identified nonmyogenic mesenchymal progenitors in skeletal muscle and revealed that fatty and fibrous connective tissue originates from these progenitors. Later, these progenitors were also demonstrated to be the major contributor to heterotopic ossification in skeletal muscle. Because nonmyogenic mesenchymal progenitors represent a distinct cell population from satellite cells, targeting these progenitors could be an ideal therapeutic strategy that specifically prevents pathological changes of skeletal muscle, while preserving satellite cell-dependent regeneration. In addition to their roles in pathogenesis of skeletal muscle, nonmyogenic mesenchymal progenitors may play a vital role in muscle regeneration by regulating satellite cell behavior. Conversely, muscle cells appear to regulate behavior of nonmyogenic mesenchymal progenitors. Thus, these cells regulate each other reciprocally and a proper balance between them is a key determinant of muscle integrity. Furthermore, nonmyogenic mesenchymal progenitors have been shown to maintain muscle mass in a steady homeostatic condition. Understanding the nature of nonmyogenic mesenchymal progenitors will provide valuable insight into the pathophysiology of skeletal muscle. In this review, we focus on nonmyogenic mesenchymal progenitors and discuss their roles in muscle pathogenesis, regeneration, and homeostasis. © 2014 Uezumi, Ikemoto-Uezumi and Tsuchida.

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