Association between plasma α-aminobutyric acid and depressive symptoms in older community-dwelling adults in Japan.

AIM: To examine the association between depressive symptoms and plasma amino acid related metaboli in older adults. METHODS: A total of 152 older adults aged ≥65 years, residing in Niigata, Japan, were used for analysis. We evaluated depressive symptoms using the Geriatric Depression Scale-15, which has been validated in older community-dwelling individuals, and used a cut off score of ≥5 to classify participants as having depressive symptoms. We used high-performance liquid chromatography-electrospray ionization mass spectrometry to measure the concentrations of plasma amino acid-related metabolites, and carried out logistic regression analysis to assess the association between depressive symptoms and plasma amino acid-related metabolites. RESULTS: Of the 119 older adults (mean age 76.3 years) included in the analysis, 22 were classified as having depressive symptoms (depressive group). There were no significant differences in physical and cognitive impairments between participants in the depressive and non-depressive groups. The plasma α-aminobutyric acid (AABA) level was significantly lower in the depressive group than in the non-depressive group (P < 0.001). Logistic regression analysis showed the best-fit model, which included AABA, leucine, threonine, hydroxyl proline and histidine levels (area under the receiver operating characteristic curve 0.8346; 95% confidence interval 0.7365-0.9326). In particular, the plasma AABA level was strongly associated with depressive symptoms. CONCLUSIONS: Plasma AABA level is significantly associated with depression symptoms in older community-dwelling adults in Japan. Thus, plasma AABA might serve as a potential marker of depression in older adults aged ≥65 years. Geriatr Gerontol Int 2019; 19: 254-258.

iNOS inhibits hair regeneration in obese diabetic (ob/ob) mice.

Previous studies have shown that androgenic alopecia is associated with metabolic syndrome and diabetes. However, the detailed mechanism whereby diabetes causes alopecia still remains unclear. We focused on the inflammatory response that is caused by diabetes or obesity, given that inflammation is a risk factor for hair loss. Inducible nitric oxide synthase (iNOS) is known to be upregulated under conditions of acute or chronic inflammation. To clarify the potential role of iNOS in diabetes-related alopecia, we generated obese diabetic iNOS-deficient (ob/ob; iNOS-KO mice). We observed that ob/ob; iNOS-KO mice were potentiated for the transition from telogen (rest phase) to anagen (growth phase) in the hair cycle compared with iNOS-proficient ob/ob mice. To determine the effect of nitric oxide (NO) on the hair cycle, we administered an iNOS inhibitor intraperitoneally (compound 1400 W, 10 mg/kg) or topically (10% aminoguanidine) in ob/ob mice. We observed that iNOS inhibitors promoted anagen transition in ob/ob mice. Next, we administered an NO donor (S-nitrosoglutathione, GSNO), to test whether NO has the telogen elongation effects. The NO donor was sufficient to induce telogen elongation in wild-type mice. Together, our data indicate that iNOS-derived NO plays a role in telogen elongation under the inflammatory conditions associated with diabetes in mice.

Donepezil is associated with decreased in-hospital mortality as a result of pneumonia among older patients with dementia: A retrospective cohort study.

AIM: Pneumonia is one of the major causes of mortality in older adults. As the average lifespan has extended and new modalities to prevent or treat pneumonia are developed, the factors that affect the length of hospital stay (LHS) and in-hospital mortality of older patients with pneumonia have changed. The object of the present study was to determine the factors associated with LHS and mortality as a result of pneumonia among older patients with dementia. METHODS: With a retrospective cohort study design, we used the data derived from the Japanese Administrative Database and diagnosis procedure combination/per diem payment system (DPC/PDPS) database. There were 39 336 admissions of older patients for pneumonia between August 2010 and March 2012. Patients with incomplete data were excluded, leaving 25 602 patients for analysis. RESULTS: Having dementia decreased mortality (OR 0.71, P < 0.001) and increased LHS. Multiple logistic regression analysis identified donepezil as an independent factor that decreased mortality in patients with dementia (OR 0.36, P < 0.001). Donepezil was prescribed for 28.7% of these patients, and their mortality rate was significantly lower than those of patients with dementia who were not treated with donepezil and of patients without dementia. The mortality rate was higher for patients with dementia who were not treated with donepezil compared with patients who did not have dementia. All other factors that influenced LHS and mortality were similar to those reported by others. CONCLUSIONS: Donepezil seems to decrease in-hospital mortality as a result of pneumonia among older patients with dementia. Geriatr Gerontol Int 2018; 18: 269-275.

Increased plasma proline concentrations are associated with sarcopenia in the elderly.

BACKGROUND AND PURPOSE: Metabolome analyses have shown that plasma amino acid profiles reflect various pathological conditions, such as cancer and diabetes mellitus. It remains unclear, however, whether plasma amino acid profiles change in patients with sarcopenia. This study therefore aimed to investigate whether sarcopenia-specific changes occur in plasma amino acid profiles. METHODS: A total of 153 community-dwelling and seven institutionalized elderly individuals (56 men, 104 women; mean age, 77.7±7.0 years) were recruited for this cross-sectional analysis. We performed a comprehensive geriatric assessment, which included an evaluation of hand grip strength, gait speed, muscle mass and blood chemistry, including the concentration of 18 amino acids. RESULTS: Twenty-eight of the 160 participants met the criteria for sarcopenia established by the Asian Working Group on Sarcopenia in Older People. Univariate analysis revealed associations between the presence of sarcopenia and a higher plasma concentration of proline and glutamine, lower concentrations of histidine and tryptophan. Multivariable analysis revealed that a higher concentration of proline was the only variable independently associated with sarcopenia. CONCLUSIONS: The plasma concentration of proline may be useful for understanding the underlying pathophysiology of sarcopenia.

Evaluation of human nonmercaptalbumin as a marker for oxidative stress and its association with various parameters in blood.

Oxidative status of albumin was not a useful biomarker for oxidative stress in practical use due to time-consuming measuring method. We evaluated oxidized, human nonmercaptalbumin measured more quickly than ever by a novel method using anion-exchange HPLC. In 60 subjects taking a general health examination, mean serum human nonmercaptalbumin level was 25.1 ± 3.0% with no gender difference but positive correlation with age. There were no links between human nonmercaptalbumin and C-reactive protein, γ-glutamyltransferase or iron, reportedly associated with oxidative stress. Human nonmercaptalbumin correlated with systolic blood pressure, pulse pressure and body mass index among physical findings. Positive correlations were observed between human nonmercaptalbumin and AST, LDH, BUN, or creatinine, suggesting that oxidative stress may link with liver injury and renal function. Human nonmercaptalbumin correlated with uric acid in female but not in male, suggesting that higher uric acid levels may be associated with increased oxidative stress only in female. As another gender difference, white blood cell counts correlated with human nonmercaptalbumin in female, while the parameters for red blood cells correlated with human nonmercaptalbumin in male. In conclusion, serum human nonmercaptalbumin level in healthy subjects was approximately 25% as previously reported. Oxidative stress may be closely associated with hypertension, obesity, liver injury, renal function, and anemia.

Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1α and mTORC1: Role of protein farnesylation.

Metabolic derangements are a clinically significant complication of major trauma (e.g., burn injury) and include various aspects of metabolism, such as insulin resistance, muscle wasting, mitochondrial dysfunction and hyperlactatemia. Nonetheless, the molecular pathogenesis and the relation between these diverse metabolic alterations are poorly understood. We have previously shown that burn increases farnesyltransferase (FTase) expression and protein farnesylation and that FTase inhibitor (FTI) prevents burn-induced hyperlactatemia, insulin resistance, and increased proteolysis in mouse skeletal muscle. In this study, we found that burn injury activated mTORC1 and hypoxia-inducible factor (HIF)-1α, which paralleled dysfunction, morphological alterations (i.e., enlargement, partial loss of cristae structure) and impairment of respiratory supercomplex assembly of the mitochondria, and ER stress. FTI reversed or ameliorated all of these alterations in burned mice. These findings indicate that these burn-induced changes, which encompass various aspects of metabolism, may be linked to one another and require protein farnesylation. Our results provide evidence of involvement of the mTORC1-HIF-1α pathway in burn-induced metabolic derangements. Our study identifies protein farnesylation as a potential hub of the signaling network affecting multiple aspects of metabolic alterations after burn injury and as a novel potential molecular target to improve the clinical outcome of severely burned patients.

Coffee consumption in aged mice increases energy production and decreases hepatic mTOR levels.

OBJECTIVE: Coffee, one of the world's most consumed beverages, has many benefits. Some studies have reported the effects of coffee on aging. The aim of this study was to investigate the locomotor activity, energy metabolism, and lipid metabolism of aged (20-mo-old) mice given coffee. METHODS: Aged C57 BL/6 NCr mice were divided into three groups: controls that were not given coffee (n = 9), a group that received 0.1% caffeinated coffee (n = 9), and a group that received 0.1% decaffeinated coffee (n = 9). This regimen continued for 17 wk until mice reached the age of 24 mo. RESULTS: Regular and decaffeinated coffee consumption decreased plasma-free fatty acid levels, increased hepatic adenosine triphosphate content, and decreased total mammalian target of rapamycin (mTOR) and phosphorylated mTOR (p-mTOR) protein content in the liver. However, no differences were found in the protein or activity levels of Akt, adenosine monophosphate-activated protein kinase (AMPK), p70 S6 kinase, or sterol regulatory element-binding protein 1, proteins that are upstream or downstream of the mTOR complex 1 (mTORC1)-related pathways. Regular coffee consumption increased food and water intake, locomotor activity, the volume of carbon dioxide production, and the respiration exchange ratio. CONCLUSION: Regular and decaffeinated coffee consumption decreased hepatic total mTOR and p-mTOR levels independently of Akt and AMPK pathways in aged mice. Because decreased mTORC1 activity is known to have antiaging effects, coffee consumption during old age may retard aging. Moreover, coffee consumption by the aged population had a positive effect on behavioral energy and lipid metabolism.

Impact of age on left ventricular geometry and diastolic function in elderly patients with treated hypertension.

PURPOSE: Left ventricular (LV) remodelling is observed in numerous patients with hypertension and is a principal cause of heart failure in elderly patients. The aim of this study was to determine the relationships between age and structural/functional LV remodelling observed in elderly hypertensive patients. METHODS: A total of 557 elderly hypertensive patients (mean age: 74.0 ± 8.6 years) with preserved LV systolic function underwent echocardiography and 24-hour blood pressure (BP) measurement. RESULTS: Overall, 41.1% of patients had LV hypertrophy, 77.9% had increased relative wall thickness (RWT) defined as RWT >0.42, and 31.8% had both. Logistic analysis of the entire study population showed that increased RWT was associated with both 24-hour systolic BP (odds ratio (OR) 1.38, 95% confidence interval (CI) 1.12 to 1.70) and age (OR 1.32, 95%CI 1.08 to 1.61), whereas increased RWT was associated only with age (OR 1.61, 95%CI 1.23 to 2.11) after excluding patients with LV hypertrophy. Univariate and multivariate linear regression analyses of all patients showed that LV diastolic echocardiographic parameters were consistently associated with age (p ≤ .001) alone, even considering LV structural changes. CONCLUSIONS: Age was independently correlated with LV concentric/functional changes regardless of LV hypertrophy, suggesting that ageing is independently involved in the progression of LV remodelling.

iNOS as a Driver of Inflammation and Apoptosis in Mouse Skeletal Muscle after Burn Injury: Possible Involvement of Sirt1 S-Nitrosylation-Mediated Acetylation of p65 NF-κB and p53.

Inflammation and apoptosis develop in skeletal muscle after major trauma, including burn injury, and play a pivotal role in insulin resistance and muscle wasting. We and others have shown that inducible nitric oxide synthase (iNOS), a major mediator of inflammation, plays an important role in stress (e.g., burn)-induced insulin resistance. However, it remains to be determined how iNOS induces insulin resistance. Moreover, the interrelation between inflammatory response and apoptosis is poorly understood, although they often develop simultaneously. Nuclear factor (NF)-κB and p53 are key regulators of inflammation and apoptosis, respectively. Sirt1 inhibits p65 NF-κB and p53 by deacetylating these transcription factors. Recently, we have shown that iNOS induces S-nitrosylation of Sirt1, which inactivates Sirt1 and thereby increases acetylation and activity of p65 NF-κB and p53 in various cell types, including skeletal muscle cells. Here, we show that iNOS enhances burn-induced inflammatory response and apoptotic change in mouse skeletal muscle along with S-nitrosylation of Sirt1. Burn injury induced robust expression of iNOS in skeletal muscle and gene disruption of iNOS significantly inhibited burn-induced increases in inflammatory gene expression and apoptotic change. In parallel, burn increased Sirt1 S-nitrosylation and acetylation and DNA-binding capacity of p65 NF-κB and p53, all of which were reversed or ameliorated by iNOS deficiency. These results indicate that iNOS functions not only as a downstream effector but also as an upstream enhancer of burn-induced inflammatory response, at least in part, by Sirt1 S-nitrosylation-dependent activation (acetylation) of p65 NF-κB. Our data suggest that Sirt1 S-nitrosylation may play a role in iNOS-mediated enhanced inflammatory response and apoptotic change, which, in turn, contribute to muscle wasting and supposedly to insulin resistance after burn injury.

Age-related changes of vitamin E: α-tocopherol levels in plasma and various tissues of mice and hepatic α-tocopherol transfer protein.

PURPOSE: Despite numerous studies on the RRR- and all-rac-α-tocopherol isoform of vitamin E (VE) during aging, this relationship has not been examined in specific tissues. Since α-tocopherol is the most abundant of VE's eight isoforms, and VE is an important antioxidant that impacts the aging process, we analyzed α-tocopherol levels in plasma and tissues of mice at progressive ages. Moreover, we examined protein and mRNA expression levels of hepatic α-tocopherol transfer protein (α-TTP), which specifically binds α-tocopherol, during aging. METHODS: The α-tocopherol levels in plasma, liver, cerebrum, hippocampus, cerebellum, heart, kidney, epididymal adipose tissue, testis, pancreas, soleus muscle, plantaris muscle, and duodenum from male C57BL/6NCr mice at 3, 6, 12, 18, and 24 months of age were determined by HPLC and fluorescence detection. Also, hepatic α-TTP protein and mRNA expression levels were analyzed by Western blot and qPCR, respectively. RESULTS: Tissue-specific, age-related changes of α-tocopherol levels normalized by tissue weight were observed in the liver, cerebrum, hippocampus, cerebellum, heart, kidney, and epididymal adipose tissue. Specifically, α-tocopherol levels in epididymal adipose tissue increased greatly as mice aged from 6 to 24 months. Although hepatic α-TTP protein levels also showed age-related changes, α-TTP mRNA expression levels measured after overnight fasting were not altered. CONCLUSIONS: In this study, we determined that α-tocopherol levels and hepatic α-TTP protein levels of mice undergo significant tissue-specific, age-related changes. This is the first report to investigate VE in terms of the α-tocopherol levels in plasma and various tissues of mice and hepatic α-TTP protein levels during aging.

Induction of peptidylarginine deiminase 2 and 3 by dibutyryl cAMP via cAMP-PKA signaling in human astrocytoma U-251MG cells.

Peptidylarginine deiminases (PADs) are posttranslational modification enzymes that citrullinate (deiminate) protein arginine residues in a calcium-dependent manner, yielding citrulline residues. Enzymatic citrullination abolishes positive charges of native protein molecules, inevitably causing significant alterations in their structure and function. Previously, we reported the abnormal accumulation of citrullinated proteins and an increase of PAD2 content in hippocampi of patients with Alzheimer disease. In this study, we investigated PAD expression by using dibutyryl cAMP (dbcAMP) in human astrocytoma U-251MG cells. Under normal culture conditions, PAD2 and PAD3 mRNA expression is detectable with quantitative PCR in U-251MG cells. The addition of dbcAMP in a dose-dependent manner significantly increased this mRNA expression and protein levels. Moreover, PAD enzyme activity also increased significantly and dose-dependently. Furthermore, the expression of PAD2 and PAD3 mRNA was inhibited by the cAMP-dependent PKA inhibitor KT5720, suggesting that such expression of dbcAMP-induced PAD2 and PAD3 mRNA is mediated by the cAMP-PKA signaling pathway in U-251MG cells. This is the first report to document the PAD2 and PAD3 mRNA expression induced by dbcAMP and to attribute the induction of these genes to mediation by the cAMP-PKA signaling pathway in U-251MG cells. © 2016 Wiley Periodicals, Inc.

Diet-induced non-alcoholic fatty liver disease affects expression of major cytochrome P450 genes in a mouse model.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is associated with impaired liver function, and resveratrol could suppress NAFLD progression. This study examined the effects of NAFLD on the expression of major cytochrome P450 (CYP) subtypes in the liver and whether the expression could be attenuated by resveratrol. METHODS: C57BL/6 mice (male, 10 weeks of age) were fed a high-fat and high-sucrose (HFHS) diet to induce NAFLD. Major Cyp subtype mRNA expression in the liver was measured by real-time RT-PCR. KEY FINDINGS: Body and liver weights at 4 and 12 weeks were significantly higher in mice fed the HFHS diet compared with control. The HFHS diet significantly increased the accumulation of cholesterol and triglycerides at 12 weeks. Under this condition, the HFHS diet increased the expression of Cyp1a2 and decreased that of Cyp3a11 at 1 week and thereafter. On the other hand, Cyp1a1, 2b10 and 2c29 mRNA expression levels in the liver were significantly increased at 12 weeks only. Resveratrol (0.05% (w/w) in diet) slightly suppressed lipid accumulation in the liver, but failed to recover impaired Cyp gene expression levels in NAFLD. CONCLUSIONS: Drug metabolism may be impaired in NAFLD, and each Cyp subtype is regulated in a different manner.

Sulforaphane promotes murine hair growth by accelerating the degradation of dihydrotestosterone.

Dihydrotestosterone (DHT) causes the regression of human hair follicles in the parietal scalp, leading to androgenic alopecia (AGA). Sulforaphane (SFN) increases the expression of DHT degrading enzymes, such as 3α-hydroxysteroid dehydrogenases (3α-HSDs), and, therefore, SFN treatment may improve AGA. To determine the effects of SFN on hair growth, we administered SFN (10 mg/kg BW, IP) or vehicle (DMSO) to ob/ob mice for six weeks and examined hair regeneration and the plasma levels of testosterone and DHT. We also tested the effects of SFN on the expression of two forms of 3α-HSD, aldo-keto reductase 1c21 and dehydrogenase/reductase (SDR family) member 9, both in vitro and in vivo. SNF significantly enhanced hair regeneration in ob/ob mice. The mice treated with SFN showed lower plasma levels of testosterone and DHT than those treated with vehicle. SFN increased the mRNA and protein levels of the two forms of 3α-HSD in the liver of the mice and in cultured murine hepatocyte Hepa1c1c7 cells. These results suggest that SFN treatment increases the amount of 3α-HSDs in the liver, accelerates the degradation of blood DHT, and subsequently blocks the suppression of hair growth by DHT.

Voluntary Exercise Can Ameliorate Insulin Resistance by Reducing iNOS-Mediated S-Nitrosylation of Akt in the Liver in Obese Rats.

Voluntary exercise can ameliorate insulin resistance. The underlying mechanism, however, remains to be elucidated. We previously demonstrated that inducible nitric oxide synthase (iNOS) in the liver plays an important role in hepatic insulin resistance in the setting of obesity. In this study, we tried to verify our hypothesis that voluntary exercise improves insulin resistance by reducing the expression of iNOS and subsequent S-nitrosylation of key molecules of glucose metabolism in the liver. Twenty-one Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus, and 18 non-diabetic control Long-Evans Tokushima Otsuka (LETO) rats were randomly assigned to a sedentary group or exercise group subjected to voluntary wheel running for 20 weeks. The voluntary exercise significantly reduced the fasting blood glucose and HOMA-IR in the OLETF rats. In addition, the exercise decreased the amount of iNOS mRNA in the liver in the OLETF rats. Moreover, exercise reduced the levels of S-nitrosylated Akt in the liver, which were increased in the OLETF rats, to those observed in the LETO rats. These findings support our hypothesis that voluntary exercise improves insulin resistance, at least partly, by suppressing the iNOS expression and subsequent S-nitrosylation of Akt, a key molecule of the signal transduction pathways in glucose metabolism in the liver.

Japan as the front-runner of super-aged societies: Perspectives from medicine and medical care in Japan.

BACKGROUND: The demographic structure of a country changes dramatically with increasing trends toward general population aging and declining birth rates. In Japan, the percentage of the elderly population (aged ≥65 years) reached 25% in 2013; it is expected to exceed 30% in 2025 and reach 39.9% in 2060. The national total population has been decreasing steadily since its peak reached in 2008, and it is expected to fall to the order of 80 million in 2060. Of the total population, those aged ≥75 years accounted for 12.3% as of 2013, and this is expected to reach 26.9% in 2060. As the demographic structure changes, the disease structure changes, and therefore the medical care demand changes. To accommodate the medical care demand changes, it is necessary to secure a system for providing medical care. Japan has thus far attained remarkable achievements in medical care, seeking a better prognosis for survival; however, its medical care demand is anticipated to change both qualitatively and quantitatively. As diseases in the elderly, particularly in the old-old population, are often intractable, conventional medical care must be upgraded to one suitable for an aged society. What is required to this end is a shift from "cure-seeking medical care" focusing on disease treatment on an organ-specific basis to "cure and support-seeking medical care" with treatments reprioritized to maximize the quality of life (QOL) for the patient, or a change from "hospital-centered medical care" to "community-oriented medical care" in correlation with nursing care and welfare. CURRENT SITUATION AND PROBLEMS: (1) Necessity for a paradigm shift to "cure-and-support seeking medical care" In addition to the process of aging with functional deterioration of multiple organs, the elderly often suffer from systemically disordering diseases, such as lifestyle-related diseases, as well as geriatric syndrome and daily activity dysfunction; therefore, integrated and comprehensive medical care is required. In addition, with regard to diseases in the elderly, not only their acute stage, but also their chronic and intermediate stages must be emphasized in their treatment. Aiming to achieve a complete cure of disease by exploring the cause and implementing radical treatment, the conventional medical care model is difficult to apply to the medical care of the elderly; medical care suitable for the elderly is required. (2) Spread of home-based care and the necessity for human resources development Many elderly people want to continue to live in their house and their community where they have been living for a long time, even with disease. There are increasing needs for QOL-emphasizing home-based care for patients in the intermediate stage after completion of acute stage treatment, or for end-of-life care. Hence, there is a demand for a shift to "community-oriented medical care" for providing comprehensive care supported with medical and nursing resources available in the community. As the percentage of the elderly population (aged ≥65 years) and the availability of medical care resources vary considerably among different regions, it is important that specialists in the fields of public health, medical care, nursing care, and welfare work on establishing a collaborative system suitable for the local characteristics of each region by making the best use of their own specialties. (3) Necessity for establishing a department of gerontology or geriatric medicine at each medical school In line with the increasing number of elderly people, it is necessary to upgrade the systems for educating and nurturing physicians engaged in healthcare and nursing care for the elderly. It is also necessary to develop the organic cooperation with other medical and nursing care professionals, such as registered nurses and care workers. At present, just approximately 30% of medical schools in Japan have a department specializing in medical care for the elderly and relevant medical education; there is an urgent need to improve the situation, as the majority of universities do not provide any such education. (4) Necessity for establishing a medical center for promoting medical care provider collaboration, multidisciplinary training and a means to increase public awareness In the medical care for the elderly, comprehensive care must be provided from the viewpoints of both healthcare and nursing care; to improve the quality of such care services, multidisciplinary collaboration and team-based medicine are indispensable. Therefore, physicians, nurses, therapists, pharmacists, dieticians, care managers, and other health care professionals who have thorough knowledge about medical care for the elderly are of utmost necessity. In reality, however, the collaboration of these health care professionals is unsatisfactory, and the degree of understanding of team-based medicine by each medical professional is low. Therefore, as in the case of the establishment of cancer centers within individual regions to promote medical care for cancer, there is a demand to nurture professionals engaged in medical care for the elderly, and to establish a core facility for the promotion of multidisciplinary collaboration and team-based medicine for each region. (5) Do the people understand the paradigm shift? Currently, not only healthcare professionals, but also many citizens seek "cure-seeking medical care" aiming at a restoration of organ function; however, surveys of the elderly often show that they want to restore independent daily activity, rather than to achieve a "cure." In contrast, in the actual medical care setting, contradictory situations prevail in which the public awareness of the shift to "cure-and-support seeking medical care" is unsatisfactory, including the fact that the majority of recipients of tertiary emergency care are elderly patients. CONTENTS OF THE PROPOSAL: The Science Council of Japan has the task to propose future visions for the Japanese aging society not only from the viewpoint of the health of each individual, but also from a broader perspective, taking into account the relationship between humans and society. Various issues related to general population aging are posing serious problems, which require prompt resolution. Although we made a number of proposals at the 21st Subcommittee for Aging, the situation has not changed satisfactorily. Accordingly, the present proposals on specific solutions were designed. (1) In a super-aged society, a paradigm shift to "cure-and-support seeking medical care" should be implemented A super-aged society will consist of an unprecedented demographic structure in which the percentage of only those people aged ≥75 years will increase in the entire population. Therefore, there is an urgent need to prepare for increasing populations of persons in need of long-term care and those who are likely to become in need of long-term care. Given the consideration that "patients are not merely sick persons, but rather living persons," a paradigm shift from conventional "cure-seeking medical care" to "cure and support-seeking medical care" must be implemented. (2) Facilitate a paradigm shift to community-oriented medical care, and promote the activity of female physicians in the medical care for the elderly A paradigm shift should be promptly facilitated by reorganizing hospital functions and establishing a community comprehensive care system for home-based care to promote the participation of the elderly by themselves in care-supporting society. To further promote the collaboration of medical care and welfare, not only persons in charge of actual regional settings, but also university schools of medicine and regional core medical institutions experienced in medical care for the elderly should take the initiative to promote home-based care and facilitate a paradigm shift to community-oriented medical care. In addition, programs should also be developed to re-educate female physicians who became housewives in order to nurture them to become facilitators of geriatric medicine. (3) Physicians who are required at local medical facilities must be nurtured through the establishment of a department of gerontology or geriatric medicine at each medical school To facilitate efficient medical care services, medical education and research, and human resources development in support of expected paradigm shifts, it is considered that a department of gerontology or geriatric medicine should be established at each medical school. Furthermore, it is necessary to allocate dedicated teachers of medical care for the elderly to all medical schools, as well as to upgrade practice-participatory drills and to collaborate with a broad range of entities, including local medical institutions, and welfare and nursing care facilities. Efforts must be made to nurture locally wanted physicians through specific efforts concerning team-based medicine. (4) Promote the establishment of centers for geriatrics and gerontology (provisional name) for medical care collaboration, multidisciplinary training, and a means to increase public awareness To promote the uniform accessibility of expertise on efficient medical care that is best suited for a super-aged society, it is necessary to build a post-graduation educational system under the initiatives of the Japan Geriatrics Society and the National Center for Geriatrics and Gerontology across the nation in cooperation with regional medical schools and the Japan Medical Association. Furthermore, at least one hospital serving as a center for geriatrics and gerontology should be established in each regional block (Hokkaido, Tohoku, Koshinetsu, Hokuriku/Tokai, Kinki, Chushikoku and Kyushu/Okinawa) by making the best use of existing hospitals. Byestablishing these centers, uniform accessibility for the quality of medical care for the elderly in each region is expected. (ABSTRACT TRUNCATED).

Inflammatory stimuli induce inhibitory S-nitrosylation of the deacetylase SIRT1 to increase acetylation and activation of p53 and p65.

Inflammation increases the abundance of inducible nitric oxide synthase (iNOS), leading to enhanced production of nitric oxide (NO), which can modify proteins by S-nitrosylation. Enhanced NO production increases the activities of the transcription factors p53 and nuclear factor κB (NF-κB) in several models of disease-associated inflammation. S-nitrosylation inhibits the activity of the protein deacetylase SIRT1. SIRT1 limits apoptosis and inflammation by deacetylating p53 and p65 (also known as RelA), a subunit of NF-κB. We showed in multiple cultured mammalian cell lines that NO donors or inflammatory stimuli induced S-nitrosylation of SIRT1 within CXXC motifs, which inhibited SIRT1 by disrupting its ability to bind zinc. Inhibition of SIRT1 reduced deacetylation and promoted activation of p53 and p65, leading to apoptosis and increased expression of proinflammatory genes. In rodent models of systemic inflammation, Parkinson's disease, or aging-related muscular atrophy, S-nitrosylation of SIRT1 correlated with increased acetylation of p53 and p65 and activation of p53 and NF-κB target genes, suggesting that S-nitrosylation of SIRT1 may represent a proinflammatory switch common to many diseases and aging.

Ascorbic acid deficiency affects genes for oxidation-reduction and lipid metabolism in livers from SMP30/GNL knockout mice.

BACKGROUND: We sought to elucidate the effect of an ascorbic acid (AA) deficiency on gene expression, because the water soluble antioxidant AA is an important bioactive substance in vivo. METHODS: We performed microarray analyses of the transcriptome in the liver from senescence marker protein-30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice, which are unable to synthesize AA in vivo. RESULTS: Our microarray analysis revealed that the AA deficiency increased gene expression related to the oxidation-reduction process, i.e., the nuclear factor, erythroid derived 2, like 2 (Nrf2) gene, which is a reactive oxygen species-sensitive transcriptional factor. Moreover, this AA deficiency increased the expression of genes for lipid metabolism including the cytochrome P450, family 7, subfamily a, polypeptide 1 (Cyp7a1), which is a late-limiting enzyme of the primary bile acid biosynthesis pathway. Although an AA deficiency increased the Cyp7a1 protein level, bile acid levels in the liver and gallbladder decreased. Since Cyp7a1 has a heme iron at the active site, AA must function as a reductant of the iron required for the continuous activation of Cyp7a1. CONCLUSIONS: This experimental evidence strongly supports a role for AA in the physiologic oxidation-reduction process and lipid metabolism including bile acid biosynthesis. GENERAL SIGNIFICANCE: Although many effects of AA supplementation have been reported, no microarray analysis of AA deficiency in vivo is available. Results from using this unique model of AA deficiency, the SMP30/GNL-KO mouse, now provide new information about formerly unknown AA functions that will implement further study of AA in vivo.

Factors associated with mental well-being of homeless people in Japan.

AIM: This study aimed to determine the frequency of low mental well-being and associated factors among homeless people in Japan. METHODS: A community-based cross-sectional study was conducted. Data were collected through in-person interviews of 423 homeless persons living in two areas of Tokyo. Mental well-being was assessed using the Japanese version of the World Health Organization-Five Well-being Index. RESULTS: The overall sample comprised 392 (92.7%) men and 31 (7.3%) women. Average age was 60.6 ± 11.9 years. The mean score on the World Health Organization-Five Well-being Index for the 396 participants with no missing values was 11.81 ± 5.35. Based on a cut-off criterion of 12/13, the frequency of low mental well-being among the participants was 57.1%. In multiple logistic regression analyses, the subjective perception of poor health (odds ratio [OR] = 3.88, 95% confidence interval [CI] = 2.32-6.49), lack of perceived emotional social support (OR = 2.77, 95% CI = 1.70-4.49), dwelling without roof (OR = 2.70, 95% CI = 1.47-4.97), and pain (OR = 1.96, 95% CI = 1.12-3.42) were significantly associated with low mental well-being in this population. CONCLUSION: The findings suggest that comprehensive intervention programs that provide supportive housing, emotional social support, and health-care services, may be needed to improve the mental well-being of homeless people.