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Background: Anorexia of aging (AA) is a condition in older adults that includes loss of appetite and reduced food intake. There is a lack of detailed analysis of the potential influence of educational initiatives in addressing AA. This study aimed to clarify the current state of knowledge and practice regarding AA and its relationship with the availability of continuing education opportunities among Japanese healthcare professionals involved in treating older patients., Methods: The Japan Geriatrics Society and the Japanese Association on Sarcopenia and Frailty, in collaboration with the Society on Sarcopenia, Cachexia, and Wasting Disorders, conducted an online questionnaire survey on the knowledge and practices in AA detection and management. Questions were asked in the areas of demographics, screening, definition/diagnosis, treatment, referral, and awareness, with those who 'participate' in continuing education and professional development programmes in nutrition for their patients were classified as the 'education group' and those who 'do not participate' were classified as the 'non-education group'. The results for each question were compared., Results: The analysis included 870 participants (physicians, 48%; registered dietitians, 16%; rehabilitation therapists, 14%; pharmacists, 12%; nurses, 6%; and other professionals, 5%). The education group (45%) was more likely than the non-education group (55%) to use the Mini-Nutritional Assessment Short Form (MNA-SF) to screen for AA (49% vs. 27%) and less likely not to use a validated tool (33% vs. 47%). More participants used evidence-based tools and materials for AA care (38% vs. 12%), and fewer used their clinical judgement (23% vs. 35%) or were unaware of the tools and materials (9% vs. 23%). The proportion using a team of professionals experienced in AA care were 47% and 24% of the education and non-education groups, respectively. By profession, few physicians used specific validated tools and resources for AA screening and treatment. More than half of the dietitians used the MNA-SF regardless of training opportunity availability. Regarding professional availability and team use, differences in educational opportunities were particularly large among physicians., Conclusions: Participation in continuing education programmes on nutrition is associated with responsiveness to AA screening and treatment and the availability of a team of professionals, which may influence the quality of AA treatment. Nutrition education may support the confidence of healthcare professionals working with older adults in AA with complex clinical signs and encourage them to conduct evidence-based practice., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Aim: Addressing sarcopenia and frailty in aging populations is crucial for enhancing quality of life and reducing healthcare dependence. While the importance of energy, protein, and amino acid supplementation is known, the role of minerals needs further exploration. This systematic review evaluates the effectiveness of these minerals in managing sarcopenia and frailty., Methods: We analyzed data from the Cochrane Central Register of Controlled Trials, MEDLINE, and Ichu-shi Web from January 2000 to March 2023. Studies were selected if they were interventional or observational, focused on individuals with frailty or sarcopenia who were aged 65 or older, and involved mineral supplementation. The risk of bias in these studies was assessed using the Cochrane Risk of Bias 2 tool., Results: Of the 615 studies identified, seven met the inclusion criteria. These studies mainly focused on the effects of combined nutrient supplements, with few focusing on individual minerals. The findings were mixed, demonstrating some improvements in muscle strength, activity of daily living, and cognitive functions. Notably, minerals appeared to offer benefits as part of multi-nutrient interventions, especially for cognitive and immune health, but had limited impact on muscle mass or strength when used alone. The limited number and variable outcomes of studies precluded a feasible meta-analysis., Conclusions: The effect of mineral supplementation on sarcopenia and frailty remains uncertain, suggesting a need for tailored nutritional strategies. Future studies should aim for well-designed clinical trials in order to gain a better understanding of the roles of minerals in improving muscle health and functional outcomes, leading to clearer recommendations for clinical practice. Geriatr Gerontol Int 2024; ••: ••-••., (© 2024 Japan Geriatrics Society.)

Dextran (Dx) is a biodegradable and biocompatible polysaccharide, thus promising as a drug delivery carrier for tumor therapy. Herein, we applied mechanical energy to a high molecular weight Dx to control its molecular weight and simultaneously generate mechanoradicals. The solid-state polymerization of methacrylate- or methacrylamide derivatives initiated with Dx mechanoradicals showed polymer conversion of >95%, yielding Dx-based graft copolymers with molecular weights of approximately 30,000 g mol -1 . The Dx-based graft copolymers with hydrophobic segments formed nanoparticles with a particle size of 25-35 nm in an aqueous solution. The anti-pancreatic tumor drug 5-fluorouracil (5-FU) was covalently conjugated onto the hydrophobic segments of the amphiphilic Dx, and the nanoparticles were also prepared. The drug release profile from 5-FU-conjugated nanoparticles corresponded well to the Korsmeyer-Peppas model applied to drug release from matrix substrates, and was also immensely predicted by the Logistic and Gompertz curves. The 5-FU-conjugated nanoparticles showed cytotoxicity against the pancreatic adenocarcinoma cell lines (BxPC-3) that were not significantly inferior to the 5-FU positive group. Furthermore, the fluorescein-labeled nanoparticles internalized into BxPC-3 within 6 h and actively migrated into the cytosol. These results suggest that Dx-based graft copolymers with hydrophobic segments might be used to enhance therapeutic activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Previous studies have highlighted a decline in the mental health of older adults over the course of the coronavirus disease 2019 (COVID-19) pandemic. Few studies have determined the possible causes of behavioural and psychological symptoms of dementia during COVID-19 in a comprehensive manner. We aimed to identify the challenges faced by older adults with dementia during the COVID-19 pandemic., Methods: This study adopted a qualitative approach to understanding the perceptions of healthcare professionals, such as regarding the negative effects of COVID-19 on the mental health of people with dementia. Between January and March 2022, the authors conducted individual in-depth interviews on how COVID-19 affected the stress levels, care, and self-determination of people with dementia. Qualitative data from the individual interviews were data cleansed to ensure the clarity and readability of the transcripts. The qualitative data were then analyzed by inductive manual coding using a qualitative content analysis approach. The grouping process involved reading and comparing individual labels to cluster similar labels into categories and inductively formulate themes., Results: Qualitative analysis extracted 61 different semantic units that were duplicated. Seven categories were inductively extracted using a grouping process. These were further integrated to extract the following four themes: fear of personal protective equipment (PPE), loneliness, dissatisfaction with behavioural restrictions and limitations of video calls, and family interference with service use., Discussion: People with dementia often faced mental distress during the pandemic owing to preventive measures against COVID-19, and a lack of awareness and understanding of such preventive measures worsened their distress. They experienced a severe sense of social isolation and loneliness. Findings also indicated that families tended to ignore the needs of people with dementia and their decisions and opinions regarding healthcare service use., (© 2024 Japanese Psychogeriatric Society.)

Introduction: We examined the efficacy of a multidomain intervention in preventing cognitive decline among Japanese older adults with mild cognitive impairment (MCI)., Methods: Participants aged 65-85 years with MCI were randomized into intervention (management of vascular risk factors, exercise, nutritional counseling, and cognitive training) and control groups. The primary outcome was changes in the cognitive composite score over a period of 18 months., Results: Of 531 participants, 406 completed the trial. The between-group difference in composite score changes was 0.047 (95% CI: -0.029 to 0.124). Secondary analyses indicated positive impacts of interventions on several secondary health outcomes. The interventions appeared to be particularly effective for individuals with high attendance during exercise sessions and those with the apolipoprotein E ε4 allele and elevated plasma glial fibrillary acidic protein levels., Discussion: The multidomain intervention showed no efficacy in preventing cognitive decline. Further research on more efficient strategies and suitable target populations is required., Highlights: This trial evaluated the efficacy of multidomain intervention in individuals with MCI. The trial did not show a significant difference in preplanned cognitive outcomes. Interventions had positive effects on a wide range of secondary health outcomes. Those with adequate adherence or high risk of dementia benefited from interventions., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Exposure to chronic psychosocial stress is a risk factor for metabolic disorders. Because dipeptidyl peptidase-4 (DPP4) and cysteinyl cathepsin K (CTSK) play important roles in human pathobiology, we investigated the role(s) of DPP4 in stress-related adipocyte differentiation, with a focus on the glucagon-like peptide-1 (GLP-1)/adiponectin-CTSK axis in vivo and in vitro. Plasma and inguinal adipose tissue from non-stress wild-type (DPP4 +/+ ), DPP4-knockout (DPP4 -/- ) and CTSK-knockout (CTSK -/- ) mice, and stressed DPP4 +/+ , DPP4 -/- , CTSK -/- , and DPP4 +/+ mice underwent stress exposure plus GLP-1 receptor agonist exenatide loading for 2 weeks and then were analyzed for stress-related biological and/or morphological alterations. On day 14 under chronic stress, stress decreased the weights of adipose tissue and resulted in harmful changes in the plasma levels of DPP4, GLP-1, CTSK, adiponectin, and tumor necrosis factor-α proteins and the adipose tissue levels of CTSK, preadipocyte factor-1, fatty acid binding protein-4, CCAAT/enhancer binding protein-α, GLP-1 receptor, peroxisome proliferator-activated receptor-γ, perilipin2, secreted frizzled-related protein-4, Wnt5α, Wnt11 and β-catenin proteins and/or mRNAs as well as macrophage infiltration in adipose tissue; these changes were rectified by DPP4 deletion. GLP-1 receptor activation and CTSK deletion mimic the adipose benefits of DPP4 deficiency. In vitro, CTSK silencing and overexpression respectively prevented and facilitated stress serum and oxidative stress-induced adipocyte differentiation accompanied with changes in the levels of pref-1, C/EBP-α, and PPAR-γ in 3T3-L1 cells. Thus, these findings indicated that increased DPP4 plays an essential role in stress-related adipocyte differentiation, possibly through a negative regulation of GLP-1/adiponectin-CTSK axis activation in mice under chronic stress conditions., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Background: Exposure to chronic psychological stress (CPS) is a risk factor for thrombotic cardiocerebrovascular diseases (CCVDs). The expression and activity of the cysteine cathepsin K (CTSK) are upregulated in stressed cardiovascular tissues, and we investigated whether CTSK is involved in chronic stress-related thrombosis, focusing on stress serum-induced endothelial apoptosis., Methods and Results: Eight-week-old wild-type male mice (CTSK +/+ ) randomly divided to non-stress and 3-week restraint stress groups received a left carotid artery iron chloride3 (FeCl 3 )-induced thrombosis injury for biological and morphological evaluations at specific timepoints. On day 21 post-stress/injury, the stress had enhanced the arterial thrombi weights and lengths, in addition to harmful alterations of plasma ADAMTS13, von Willebrand factor, and plasminogen activation inhibitor-1, plus injured-artery endothelial loss and CTSK protein/mRNA expression. The stressed CTSK +/+ mice had increased levels of injured arterial cleaved Notch1, Hes1, cleaved caspase8, matrix metalloproteinase-9/-2, angiotensin type 1 receptor, galactin3, p16 IN4A , p22phox, gp91 phox , intracellular adhesion molecule-1, TNF-α, MCP-1, and TLR-4 proteins and/or genes. Pharmacological and genetic inhibitions of CTSK ameliorated the stress-induced thrombus formation and the observed molecular and morphological changes. In cultured HUVECs, CTSK overexpression and silencing respectively increased and mitigated stressed-serum- and H 2 O 2 -induced apoptosis associated with apoptosis-related protein changes. Recombinant human CTSK degraded γ-secretase substrate in a dose-dependent manor and activated Notch1 and Hes1 expression upregulation., Conclusions: CTSK appeared to contribute to stress-related thrombosis in mice subjected to FeCl 3 stress, possibly via the modulation of vascular inflammation, oxidative production and apoptosis, suggesting that CTSK could be an effective therapeutic target for CPS-related thrombotic events in patients with CCVDs., (© 2024. The Author(s).)

Background: There are few reports about the perceptions of the regional quota called Chiikiwaku medical students and graduates., Method: Eighty-four medical students and 41 graduates were enrolled in A prefecture. The questionnaire comprised 22 items scored on a 7-point Likert scale, focusing on perceptions of merit and demerit of Chiikiwaku . The data were collected online., Results: Chiikiwaku students scored higher on an item such as 'regional quotas are a solution to the doctor shortage'. Chiikiwaku graduates felt more burdened than Chiikiwaku students., Conclusion: Our results suggested that the perception of Chiikiwaku was different between Chiikiwaku students and graduates., Competing Interests: M.S, N.T, and K.M are members of the Graduate School of Medicine Endowed Chairs in Nagoya University, which is endowed by Aichi prefecture government and Nagoya city government. The other authors declare no conflicts of interest associated with this manuscript. Kei Miyazaki is an Editorial Board member of Journal of General and Family Medicine and a co‐author of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication., (© 2024 The Authors. Journal of General and Family Medicine published by John Wiley & Sons Australia, Ltd on behalf of Japan Primary Care Association.)

Sarcopenia has a significant impact on falls, physical function, activities of daily living, and quality of life in older adults, and its prevention and treatment are becoming increasingly important as the global population ages. In addition to primary age-related sarcopenia, activity-related sarcopenia, disease-related sarcopenia, and nutrition-related sarcopenia have been proposed as secondary sarcopenia. Polypharmacy and potentially inappropriate medication based on multiple diseases cause health problems in older patients. In some cases, drugs used for therapeutic or preventive purposes act on skeletal muscle as adverse drug reactions and induce sarcopenia. Although sarcopenia caused by these adverse drug reactions may be more common in older patients, in particular those taking many medications, drug-related sarcopenia has not yet received much attention. This review summarizes drugs that may induce sarcopenia and emphasizes the importance of drug-related sarcopenia as a secondary sarcopenia. Geriatr Gerontol Int 2024; 24: 195-203., (© 2023 Japan Geriatrics Society.)

Introduction: Patient empowerment, as part of patient-centered care, is important in the treatment of diabetes. However, this concept is still not well-understood by healthcare professionals, because it differs substantially from traditional approaches. We developed the "Diabetes Theater" workshop to promote a better understanding of patient empowerment. The present study sought to characterize the learning experience and impact of Diabetes Theater on participants' perceptions regarding patient empowerment., Methods: We analyzed the data using mixed methods. Quantitative data were collected using a questionnaire with a five-item, 11-point Likert scale derived from the Diabetes Attitude Scale. The qualitative component asked the question "If you had to tell your colleagues at work two things you felt or learned at the Diabetes Theater, what would they be?" Quantitative data were analyzed using t tests, and free-text responses were analyzed using Steps for Coding and Theorization., Results: We received 131 responses. Nurses were the most numerous respondents, followed by dietitians, physicians, and pharmacists. Scores for the five items after participation increased in the direction of promoting participants' understanding of and attitudes toward patient empowerment compared to pre-participation. Scores for most questions increased significantly, regardless of the participants' occupation. In their answers to the open-ended questions, participants reported that they had learned about patient empowerment., Discussion: Diabetes Theater appears to be a useful method for healthcare professionals to accurately understand the philosophy of patient empowerment in diabetes., Competing Interests: Conflict of interestKentaro Okazaki, Mina Suematu and Noriyuki Takahashi declare that their past (KO) and current (MS and NT) affiliations were established by donations from Aichi Prefecture and Nagoya City, Japan., (© The Japan Diabetes Society 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Exposure to chronic psychological stress (CPS) is an intractable risk factor for inflammatory and metabolic diseases. Lysosomal cysteinyl cathepsins play an important role in human pathobiology. Given that cathepsin S (CTSS) is upregulated in the stressed vascular and adipose tissues, we investigated whether CTSS participates in chronic stress-induced skeletal muscle mass loss and dysfunction, with a special focus on muscle protein metabolic imbalance and apoptosis. Eight-week-old male wildtype (CTSS +/+ ) and CTSS-knockout (CTSS -/- ) mice were randomly assigned to non-stress and variable-stress groups. CTSS +/+ stressed mice showed significant losses of muscle mass, dysfunction, and fiber area, plus significant mitochondrial damage. In this setting, stressed muscle in CTSS +/+ mice presented harmful alterations in the levels of insulin receptor substrate 2 protein content (IRS-2), phospho-phosphatidylinositol 3-kinase, phospho-protein kinase B, and phospho-mammalian target of rapamycin, forkhead box-1, muscle RING-finger protein-1 protein, mitochondrial biogenesis-related peroxisome proliferator-activated receptor-γ coactivator-α, and apoptosis-related B-cell lymphoma 2 and cleaved caspase-3; these alterations were prevented by CTSS deletion. Pharmacological CTSS inhibition mimics its genetic deficiency-mediated muscle benefits. In C 2 C 12 cells, CTSS silencing prevented stressed serum- and oxidative stress-induced IRS-2 protein reduction, loss of the myotube myosin heavy chain content, and apoptosis accompanied by a rectification of investigated molecular harmful changes; these changes were accelerated by CTSS overexpression. These findings demonstrated that CTSS plays a role in IRS-2-related protein anabolism and catabolism and cell apoptosis in stress-induced muscle wasting, suggesting a novel therapeutic strategy for the control of chronic stress-related muscle disease in mice under our experimental conditions by regulating CTSS activity., (© 2023. The Author(s).)

To maintain and restore skeletal muscle mass and function is essential for healthy aging. We have found that myonectin acts as a cardioprotective myokine. Here, we investigate the effect of myonectin on skeletal muscle atrophy in various male mouse models of muscle dysfunction. Disruption of myonectin exacerbates skeletal muscle atrophy in age-associated, sciatic denervation-induced or dexamethasone (DEX)-induced muscle atrophy models. Myonectin deficiency also contributes to exacerbated mitochondrial dysfunction and reduces expression of mitochondrial biogenesis-associated genes including PGC1α in denervated muscle. Myonectin supplementation attenuates denervation-induced muscle atrophy via activation of AMPK. Myonectin also reverses DEX-induced atrophy of cultured myotubes through the AMPK/PGC1α signaling. Furthermore, myonectin treatment suppresses muscle atrophy in senescence-accelerated mouse prone (SAMP) 8 mouse model of accelerated aging or mdx mouse model of Duchenne muscular dystrophy. These data indicate that myonectin can ameliorate skeletal muscle dysfunction through AMPK/PGC1α-dependent mechanisms, suggesting that myonectin could represent a therapeutic target of muscle atrophy., (© 2023. Springer Nature Limited.)

This study aimed to examine the effectiveness of early rehabilitation in patients with femoral neck fractures admitted to acute care settings in Japan using the data registered with the Japan Association of Rehabilitation Databases (JARD). We included data for 401 patients (out of 3088 patients) aged ≥ 65 years (85 males, 316 females) from nine hospitals who sustained a femoral neck fracture between July 2005 and September 2015. Using the number of days until surgery or the number of days until the start of rehabilitation or both as the explanatory variables, and the indoor mobility at discharge as the outcome variable, we calculated the adjusted rate ratio (ARR) and 95% confidence interval (CI) using Poisson regression analysis (age, sex, cognitive impairment, concurrent symptoms, and previous history of fracture adjusted as covariates). The ARR for independent walking at the discharge of the early-rehabilitation group (starting rehabilitation within two days after the injury) was significantly higher (ARR: 2.01, 95% CI: 1.34-3.02) than that of the non-early rehabilitation group. These results suggest that early acute-phase rehabilitation after a femoral neck fracture in older patients allows for better ambulatory ability at discharge, regardless of the time to surgery., Competing Interests: We declare no conflict of interest related to this study.

Cathepsin S (CTSS) is a widely expressed cysteinyl protease that has garnered attention because of its enzymatic and non-enzymatic functions under inflammatory and metabolic pathological conditions. Here, we examined whether CTSS participates in stress-related skeletal muscle mass loss and dysfunction, focusing on protein metabolic imbalance. Eight-week-old male wildtype (CTSS +/+ ) and CTSS-knockout (CTSS -/- ) mice were randomly assigned to non-stress and variable-stress groups for 2 weeks, and then processed for morphological and biochemical studies. Compared with non-stressed mice, stressed CTSS +/+ mice showed significant losses of muscle mass, muscle function, and muscle fiber area. In this setting, the stress-induced harmful changes in the levels of oxidative stress-related (gp91 phox and p22 phox ,), inflammation-related (SDF-1, CXCR4, IL-1β, TNF-α, MCP-1, ICAM-1, and VCAM-1), mitochondrial biogenesis-related (PPAR-γ and PGC-1α) genes and/or proteins and protein metabolism-related (p-PI3K, p-Akt, p-FoxO3α, MuRF-1, and MAFbx1) proteins; and these alterations were rectified by CTSS deletion. Metabolomic analysis revealed that stressed CTSS -/- mice exhibited a significant improvement in the levels of glutamine metabolism pathway products. Thus, these findings indicated that CTSS can control chronic stress-related skeletal muscle atrophy and dysfunction by modulating protein metabolic imbalance, and thus CTSS was suggested to be a promising new therapeutic target for chronic stress-related muscular diseases., (© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Older patients are prone to multimorbidity or related polypharmacy, which may cause various adverse drug reactions (ADRs) and a high incidence of drug-related health problems. Although not often noted, ADRs include nutrition-related adverse reactions. Aging, multiple illnesses, mental and psychological problems, declining physical function, and environmental factors can lead to decreased food intake and increased metabolic stress in older people, resulting in energy imbalances that cause malnutrition. ADRs can lead to appetite loss, followed by decreased food intake, which in turn causes malnutrition and deficiencies of various nutrients. However, these nutrition-related ADRs have received less attention. This review article describes drug-nutrition interactions, with a particular focus on older patients. Geriatr Gerontol Int 2023; 23: 465-477., (© 2023 Japan Geriatrics Society.)

Background: Exposure to chronic psychological stress is a risk factor for metabolic cardiovascular disease. Given the important role of lysosomal CTSS (cathepsin S) in human pathobiology, we examined the role of CTSS in stress-related thrombosis, focusing on inflammation, oxidative stress, and apoptosis., Methods: Six-week-old wild-type mice (CTSS +/+ ) and CTSS-deficient mice (CTSS -/- ) randomly assigned to nonstress and 2-week immobilization stress groups underwent iron chloride3 (FeCl 3 )-induced carotid thrombosis surgery for morphological and biochemical studies., Results: On day 14 poststress/surgery, stress had increased the lengths and weights of thrombi in the CTSS +/+ mice, plus harmful changes in the levels of PAI-1 (plasminogen activation inhibitor-1), ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 13 motifs), and vWF (von Willebrand factor) and arterial tissue CTSS expression. Compared to the nonstressed CTSS +/+ mice, the stressed CTSS -/- mice had decreased levels of PAI-1, vWF, TNF (tumor necrosis factor)-α, interleukin-1β, toll-like receptor-4, cleaved-caspase 3, cytochrome c , p16 INK4A , gp91 phox , p22 phox , ICAM-1 (intercellular adhesion molecule-1), MCP-1 (monocyte chemoattractant protein-1), MyD88 (myeloid differentiation primary response 88), and MMP (matrix metalloproteinase)-2/-9 and increased levels of ADAMTS13, SOD (superoxide dismutase)-1/-2, eNOS (endothelial NO synthase), p-Akt (phospho-protein kinase B), Bcl-2 (B-cell lymphoma-2), p-GSK3α/β (phospho-glycogen synthase kinases alpha and beta), and p-Erk1/2 (phospho-extracellular signal-regulated kinase 1 and 2) mRNAs and/or proteins. CTSS deletion also reduced the arterial thrombus area and endothelial loss. A pharmacological inhibition of CTSS exerted a vasculoprotective action. In vitro, CTSS silencing and overexpression, respectively, reduced and increased the stressed serum and oxidative stress-induced apoptosis of human umbilical vein endothelial cells, and they altered apoptosis-related proteins., Conclusions: CTSS inhibition appeared to improve the stress-related thrombosis in mice that underwent FeCl 3 -induction surgery, possibly by reducing vascular inflammation, oxidative stress, and apoptosis. CTSS could thus become a candidate therapeutic target for chronic psychological stress-related thrombotic events in metabolic cardiovascular disease., Competing Interests: Disclosures None.

Werner syndrome is an adult-onset progeria syndrome that results in various complications. This study aimed to clarify the profile and secular variation of the disease. Fifty-one patients were enrolled and registered in the Werner Syndrome Registry. Their data were collected annually following registration. A cross-sectional analysis at registration and a longitudinal analysis between the baseline and each subsequent year was performed. Pearson's chi-squared and Wilcoxon signed-rank tests were used. Malignant neoplasms were observed from the fifth decade of life (mean onset: 49.7 years) and were observed in approximately 30% of patients during the 3-year survey period. Regarding renal function, the mean estimated glomerular filtration rate calculated from serum creatinine (eGFRcre) and eGFRcys, which were calculated from cystatin C in the first year, were 98.3 and 83.2 mL/min/1.73 m 2 , respectively, and differed depending on the index used. In longitudinal analysis, the average eGFRcre for the first and fourth years was 74.8 and 63.4 mL/min/1.73 m 2 , showing a rapid decline. Secular changes in Werner syndrome in multiple patients were identified. The prevalence of malignant neoplasms is high, and renal function may decline rapidly. It is, therefore, necessary to carry out active and detailed examinations and pay attention to the type and dose of the drugs used.

Objective: This quick literature review aimed to organize information on the detailed components of total pain in older people with advanced dementia in a holistic manner. Materials and Methods: The authors analyzed qualitative data from relevant clinical guidelines or textbooks, focusing on certain types of pain and distress in older people with advanced dementia, followed by an expert panel review by research team members. In the search, the authors defined a person with advanced dementia as having a functional assessment staging tool scale score greater than or equal to six. Results: The model covered a wide variety of pain, from physical pain to dementia-related psychological and spiritual aspects of total pain, including living environment change, stigma, discrimination, lack of communication and understanding, loss of sense of control and dignity, and cultural distress. It also identified physical appearance as an important factor in dying with dignity, as established by existing research on individuals with incurable cancers. Conclusion: The conceptual model of total pain in people with advanced dementia is expected to help turn healthcare professionals' attention to physical, psychological, social, and spiritual contributors to total pain in advanced dementia., (©2023 The Japanese Association of Rural Medicine.)

Advance care planning (ACP) for people with dementia, as with other diseases, is a necessary process to realize medical treatment and care in the final stage of a person's life. On the other hand, dementia, a disease that is expected to make it difficult for people to make decisions on their own in the future, has a long course, and is characterized by uncertainty regarding the course of the disease, which may also be a limiting factor in the implementation of ACP for people with dementia. On the other hand, the uncertainties may also be a reason for implementing ACP. This paper reviews reports on ACP initiatives for people with dementia from many countries and presents their characteristics, cultural and customary influences, effects, facilitating and inhibiting factors, and recommendations for implementation, with the aim of promoting future ACP initiatives for people with dementia. The aim of the study was to promote future ACP initiatives for people with dementia.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease of the central nervous system. Although recent reports have noted that cognitive impairment is common in NMOSD, little longitudinal information is available on the trajectories of cognitive function in the disease. Here, we report a case of a 55-year-old woman with an 11-year history of NMOSD who visited our memory clinic for progressive memory loss. She was diagnosed with early-onset Alzheimer disease based on amyloid and tau positron emission tomography imaging biomarkers. This is the first report of early-onset Alzheimer disease in a patient with NMOSD. Complications of Alzheimer disease should be considered when patients with NMOSD exhibit rapid cognitive decline. More longitudinal studies of NMOSD with cognitive impairment are needed., Competing Interests: The authors declare no conflicts of interest.

Background: Young bone marrow transplantation (YBMT) has been shown to stimulate vascular regeneration in pathological conditions, including ageing. Here, we investigated the benefits and mechanisms of the preventive effects of YBMT on loss of muscle mass and function in a senescence-associated mouse prone 10 (SAMP10) model, with a special focus on the role of growth differentiation factor 11 (GDF-11)., Methods: Nine-week-old male SAMP10 mice were randomly assigned to a non-YBMT group (n = 6) and a YBMT group (n = 7) that received the bone marrow of 8-week-old C57BL/6 mice., Results: Compared to the non-YBMT mice, the YBMT mice showed the following significant increases (all P < 0.05 in 6-7 mice): endurance capacity (>61.3%); grip strength (>37.9%), percentage of slow myosin heavy chain fibres (>14.9-15.9%). The YBMT also increased the amounts of proteins or mRNAs for insulin receptor substrate 1, p-Akt, p-extracellular signal-regulated protein kinase1/2, p-mammalian target of rapamycin, Bcl-2, peroxisom proliferator-activated receptor-γ coactivator (PGC-1α), plus cytochrome c oxidase IV and the numbers of proliferating cells (n = 5-7, P < 0.05) and CD34+/integrin-α7+ muscle stem cells (n = 5-6, P < 0.05). The YMBT significantly decreased the levels of gp91phox, caspase-9 proteins and apoptotic cells (n = 5-7, P < 0.05) in both muscles; these beneficial changes were diminished by the blocking of GDF-11 (n = 5-6, P < 0.05). An administration of mouse recombinant GDF-11 improved the YBMT-mediated muscle benefits (n = 5-6, P < 0.05). Cell therapy with young bone marrow from green fluorescent protein (GFP) transgenic mice exhibited GFP+ myofibres in aged muscle tissues., Conclusions: These findings suggest that YBMT can prevent muscle wasting and dysfunction by mitigating apoptosis and proliferation via a modulation of GDF-11 signalling and mitochondrial dysfunction in SAMP10 mice., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Competing Interests: Declaration of Competing Interest Dr. Kawashima receives grants from Otsuka Pharmaceutical Co., Ltd., TAIHO Phamaceutical Co., Ltd., Chugai Phamaceutical Co., Ltd., EA Pharma Co., Ltd., Eisai Co., Ltd., AbbVie Inc., and Mitsubishi Tanabe Pharma Corporation, which are unrelated to the submitted work. Dr. Ando receives grants and personal fees from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Nippon Kayaku Co., Ltd., Yakult Honsha Co., Ltd., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Ltd., and Eisai Co., Ltd., grants from Mochida Pharmaceutical Co., Ltd., personal fees from Eli Lilly Japan K·K., Novartis Pharma K.K., Bayer Holding Ltd., Bristol-Myers Squibb, Sawai Pharmaceutical Co., Ltd., Roche Diagnostics K.K., MSD K.K, Astellas Pharma Inc., Otsuka Holdings Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., and Hisamitsu Pharmaceutical Co., Inc., which are unrelated to the submitted work. All other authors have no disclosures or conflicts of interest.

Background: Loss of skeletal muscle mass is associated with numerous factors such as metabolic diseases, lack of independence, and mortality in older adults. Therefore, developing simple, safe, and reliable tools for assessing skeletal muscle mass is needed. Some studies recently reported that the risks of the incidence of geriatric conditions could be estimated by analyzing older adults' gait; however, no studies have assessed the association between gait parameters and skeletal muscle loss in older adults. In this study, we applied machine learning approach to the gait parameters derived from three-dimensional skeletal models to distinguish older adults' low skeletal muscle mass. We also identified the most important gait parameters for detecting low muscle mass., Methods: Sixty-six community-dwelling older adults were recruited. Thirty-two gait parameters were created using a three-dimensional skeletal model involving 10-meter comfortable walking. After skeletal muscle mass measurement using a bioimpedance analyzer, low muscle mass was judged in accordance with the guideline of the Asia Working Group for Sarcopenia. The eXtreme gradient boosting (XGBoost) model was applied to discriminate between low and high skeletal muscle mass., Results: Eleven subjects had a low muscle mass. The c-statistics, sensitivity, specificity, precision of the final model were 0.7, 59.5%, 81.4%, and 70.5%, respectively. The top three dominant gait parameters were, in order of strongest effect, stride length, hip dynamic range of motion, and trunk rotation variability., Conclusion: Machine learning-based gait analysis is a useful approach to determine the low skeletal muscle mass of community-dwelling older adults., Competing Interests: Declarations of interest None., (Copyright © 2022. Published by Elsevier B.V.)

Objectives: Muscle ultrasound is a non-invasive technique that enables identification of the quantity and quality of muscle tissue. It has been used not only for diagnosis of sarcopenia but also for prediction of outcomes in clinical practice. There is now increasing awareness that muscle changes detected during acute hospitalization indicate acute sarcopenia leading to worse outcomes. However, to our knowledge, few studies have investigated this in hospitalized older adults. The aim of this study was to determine whether muscle changes on muscle ultrasound can predict poor outcomes in acute hospitalized older adults., Methods: This prospective, observational cohort study involved 145 acute hospitalized older adults. Bilateral anterior thigh thickness (BATT), echo intensity (EI), and corrected EI of the quadriceps were assessed on admission and 7 d later. The primary outcome was mortality, and the secondary outcomes were hospital-associated complications and decline in activities of daily living (ADLs) at 3 mo after discharge., Results: Changes in BATT, EI, and corrected EI at 7 d after admission were found in 0.2%, 0.0%, and 0.2% of cases, respectively. The respective rates for mortality, hospital-associated complications, and ADL decline were 8.7%, 52.8%, and 43%, respectively. Multivariable logistic regression analysis showed that the BATT value at admission tended to be associated with mortality. Changes in BATT, EI, and collected EI were not associated with adverse outcomes., Conclusions: Acute muscle changes on muscle ultrasound were not associated with mortality, ADL decline, or hospital-associated complications in acute hospitalized older adults. More research in various settings is needed to clarify the value of muscle ultrasound in clinical practice., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: To elucidate recent prescription trends for older adults and the background underlying changes over time with a particular focus on the prevalence of polypharmacy and potentially inappropriate medications (PIMs)., Methods: We cross-sectionally collected prescription data of patients aged ≧65 years who visited chain pharmacies dispensing prescribed drugs from all types of outpatient settings for one month in two sampling periods (October, 2014 and December, 2019), and the data were analysed. Prevalence of polypharmacy and factors associated with PIMs between the two periods were investigated., Results: The average number of drugs prescribed decreased over time (4.05 ± 3.24 in 2014 vs. 3.98 ± 3.16 in 2019, p < 0.001), as did the prevalence of polypharmacy (50.1% in 2014 vs. 48.2% in 2019, p < 0.001). Meanwhile, the prevalence of PIMs exhibited a marked increase (overall: 26.8% in 2014 vs. 43.7% in 2019, aged 65-74: 25.6% in 2014 vs. 40.3% in 2019, aged 75-84: 27.4% in 2014 vs. 43.9% in 2019), which was the most pronounced in patients aged over 85 (29.4% in 2014 vs. 53.0% in 2019). The number of classes of drugs positively associated with PIMs in 2019 increased from that in 2014. The increasing trend was most prominently observed in the oldest age category (over 85 years, 2 in 2014 vs. 6 in 2019)., Conclusions: The comparison of monthly prescribing data with an interval of 5 years suggested an increasing trend in the prevalence of PIMs, contrary to the declining prevalence of polypharmacy., (Copyright © 2022. Published by Elsevier B.V.)

Accumulating evidence from anatomical and neuroimaging studies suggests that the cerebellum is engaged in a variety of motor and cognitive tasks. Given its various functions, a key question is whether the cerebellum also plays an important role in the brain's integrative functions. Here, we hypothesize the existence of connector regions, also known as connector hubs, where multiple resting state networks converged in the cerebellum. To verify this, we employed a recently developed voxel-level network measure called functional connectivity overlap ratio (FCOR), which could be used to quantify the spatial extent of a region's connection to several large-scale cortical networks. Using resting state functional MRI data from 101 healthy participants, cerebellar FCOR maps were constructed and used to identify the locations of connector hubs in the cerebellum. Results showed that a number of cerebellar regions exhibited strong connectivity with multiple functional networks, verifying our hypothesis. These highly connected regions were located in the posterior cerebellum, especially in lobules VI, VII, and IX, and mainly connected to the core neurocognitive networks such as default mode and executive control networks. Regions associated with the sensorimotor network were also localized in lobule V, VI, and VIII, albeit in small clusters. These cerebellar connector hubs may play an essential role in the processing of information across the core neurocognitive networks., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Chronic psychological stress is a risk factor for kidney disease, including kidney dysfunction and hypertension. Lysosomal CatK (cathepsin K) participates in various human pathobiologies. We investigated the role of CatK in kidney remodeling and hypertension in response to 5/6 nephrectomy injury in mice with or without chronic stress., Methods: Male 7-week-old WT (wild type; CatK +/+ ) and CatK-deficient (CatK -/- ) mice that were or were not subjected to chronic stress underwent 5/6 nephrectomy. At 8 weeks post-stress/surgery, the stress was observed to have accelerated injury-induced glomerulosclerosis, proteinuria, and blood pressure elevation., Results: Compared with the nonstressed mice, the stressed mice showed increased levels of TLR (Toll-like receptor)-2/4, p22 phox , gp91 phox , CatK, MMP (matrix metalloproteinase)-2/9, collagen type I and III genes, PPAR-γ (peroxisome proliferator-activated receptor-gamma), NLRP-3 (NOD-like receptor thermal protein domain associated protein 3), p21, p16, and cleaved caspase-8 proteins, podocyte foot process effacement, macrophage accumulation, apoptosis, and decreased levels of Bcl-2 (B cell lymphoma 2) and Sirt1, as well as decreased glomerular desmin expression in the kidneys. These harmful changes were retarded by the genetic or pharmacological inhibition of CatK. Consistently, CatK inhibition ameliorated 5/6 nephrectomy-related kidney injury and dysfunction. In mesangial cells, CatK silencing or overexpression, respectively, reduced or increased the PPAR-γ and cleaved caspase-8 protein levels, providing evidence and a mechanistic explanation of CatK's involvement in PPAR-γ/caspase-8-mediated cell apoptosis in response to superoxide and stressed serum., Conclusions: These results demonstrate that CatK plays an essential role in kidney remodeling and hypertension in response to 5/6 nephrectomy or stress, possibly via a reduction of glomerular inflammation, apoptosis, and fibrosis, suggesting a novel therapeutic strategy for controlling kidney injury in mice under chronic psychological stress conditions.

Individuals with mild cognitive impairment (MCI) often make qualitative errors on the Clock Drawing Test (CDT), and these errors are reported to be associated with lower scores on neuropsychological assessments. Gait speed is also closely associated with cognitive dysfunction. However, the association between CDT errors and gait speed has not been investigated in individuals with MCI. Therefore, in this study, we explored the association between gait speed and qualitative errors on the CDT. Participants were 196 outpatients at a memory clinic with a clinical dementia rating of 0.5. The CDT was evaluated using the method of Cahn et al. The participants were divided into tertiles of normal and maximum gait speeds. The CDT error types of stimulus-bound response, conceptual deficit (CD), and planning deficit were found in 24.5%, 29.6%, and 30.1% of the participants, respectively. CD was found in 43.6% of the slowest tertile of maximum gait and in 22.2% of the fastest tertile. Multiple linear regression analysis gait speeds as objective continuous variables revealed that CD was significantly negatively associated with maximum gait, but not with normal gait. No other error types were associated with gait speeds. Only CD type error on the CDT was negatively associated with maximum gait speed, but not normal gait speed in the current study. The association between the qualitative error on the CDT and gait speed provides further basis of the clinical importance of qualitative assessments of CDT., (© 2022. The Author(s).)

Objectives: Frailty is a state of increased vulnerability to poor resolution of homeostasis after a stressor. We hypothesized that frail older adults would tend to have electrolyte imbalances because they should have many stressors together with fragile physiological systems. In this study, we aimed to determine whether older adults with higher Frailty Index scores have electrolyte imbalances and to establish which domains of the Frailty Index are correlated with electrolyte imbalances., Design: A cross-sectional study., Setting and Participants: A total of 4204 older adults aged 70 years or over who visited the Japanese National Center for Geriatrics and Gerontology., Methods: We calculated the 50-item Frailty Index with the following domains: comorbidities, cognitive function and mood, basic and instrumental activities of daily living, physical function, nutrition, and fall risks from physical weakness and comorbidities. Participants were categorized into four groups: a non-frail group (Frailty Index ≤0.2), mildly frail group (0.20 < Frailty Index ≤0.3), moderately frail group (0.3 < Frailty Index ≤0.4), and severely frail group (0.4 < Frailty Index). Their serum sodium, potassium, calcium, and phosphorus concentrations were measured. A multiple regression model was used to explore the relationship of electrolyte imbalances with the Frailty Index and to determine which frailty domains are correlated with electrolyte imbalances., Results: Compared with the non-frail group, the mildly and moderately frail groups tended to have hypernatremia and hypophosphatemia, whereas the severely frail group tended to have dysnatremia, hypokalemia, and hypophosphatemia. The estimated odds ratios increased by 15%-52% for each electrolyte imbalance as the Frailty Index increased by 0.1. The Frailty Index domains of cognitive function, activities of daily living, and nutrition were correlated with more than three kinds of electrolyte imbalances, the domains of physical function and fall risks from physical weakness were correlated with three kinds of electrolyte imbalances, and the domains of comorbidities and fall risks from comorbidities were correlated with two kinds of electrolyte imbalances., Conclusions: Older adults with higher Frailty Index scores tend to have electrolyte imbalances., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Skeletal muscle mass and function losses in aging individuals are associated with quality of life deterioration and disability. Mesenchymal stromal cells exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in aging-related degenerative disease., Methods and Results: We investigated the efficacy of umbilical cord-derived mesenchymal stromal cells (UC-MSCs) on sarcopenia-related skeletal muscle atrophy and dysfunction in senescence-accelerated mouse prone 10 (SAMP10) mice. We randomly assigned 24-week-old male SAMP10 mice to a UC-MSC treatment group and control group. At 12 weeks post-injection, the UC-MSC treatment had ameliorated sarcopenia-related muscle changes in performance, morphological structures, and mitochondria biogenesis, and it enhanced the amounts of proteins or mRNAs for myosin heavy chain, phospho-AMP-activated protein kinase, phospho-mammalian target of rapamycin, phospho-extracellular signal-regulated kinase1/2, peroxisome proliferator-activated receptor-γ coactivator, GLUT-4, COX-IV, and hepatocyte growth factor in both gastrocnemius and soleus muscles, and it reduced the levels of proteins or mRNAs for cathepsin K, cleaved caspase-3/-8, tumor necrosis factor-α, monocyte chemoattractant protein-1, and gp91 phox mRNAs. The UC-MSC treatment retarded mitochondria damage, cell apoptosis, and macrophage infiltrations, and it enhanced desmin/laminin expression and proliferating and CD34 + /Integrin α 7 + cells in both types of skeletal muscle of the SAMP10 mice. In vitro, we observed increased levels of HGF, PAX-7, and MoyD mRNAs at the 4th passage of UC-MSCs., Conclusions: Our results suggest that UC-MSCs can improve sarcopenia-related skeletal muscle atrophy and dysfunction via anti-apoptosis, anti-inflammatory, and mitochondrial biogenesis mechanisms that might be mediated by an AMPK-PGC1-α axis, indicating that UC-MSCs may provide a promising treatment for sarcopenia/muscle diseases., (© 2022. The Author(s).)

Werner syndrome (WS) is a progeroid syndrome caused by mutations in the WRN gene, which encodes the RecQ type DNA helicase for the unwinding of unusual DNA structures and is implicated in DNA replication, DNA repair, and telomere maintenance. patients with WS are prone to develop malignant neoplasms, including hematological malignancies. However, the pathogenesis of WS-associated hematological malignancies remains uncharacterized. Here we investigated the somatic gene mutations in WS-associated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Whole-exome sequencing (WES) of 4 patients with WS with MDS/AML revealed that all patients had somatic mutations in TP53 but no other recurrent mutations in MDS/AML. TP53 mutations were identified at low allele frequencies at more than one year before the MDS/AML stage. All 4 patients had complex chromosomal abnormalities including those that involved TP53. Targeted sequencing of nine patients with WS without apparent blood abnormalities did not detect recurrent mutations in MDS/AML except for a PPM1D mutation. These results suggest that patients with WS are apt to acquire TP53 mutations and/or chromosomal abnormalities involving TP53, rather than other MDS/AML-related mutations. TP53 mutations are frequently associated with prior exposure to chemotherapy; however, all four patients with WS with TP53 mutations/deletions had not received any prior chemotherapy, suggesting a pathogenic link between WRN mutations and p53 insufficiency. These results indicate that WS hematopoietic stem cells with WRN insufficiency acquire competitive fitness by inactivating p53, which may cause complex chromosomal abnormalities and the subsequent development of myeloid malignancies. These findings promote our understanding of the pathogenesis of myeloid malignancies associated with progeria., (Copyright © 2022 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

To treat older patients with hypertension, it is important to detect cognitive impairment at an early stage because of its potential influence on treatment efficacy and functional prognosis. In this study, we aimed to identify the incidence and determinants of cognitive impairment in hypertensive patients aged 65 years and above who visited our outpatient clinic and were not previously diagnosed with cognitive impairment. Among 312 patients with hypertension, we found that 35% (n = 109) and 7.7% (n = 24) had cognitive impairment and dementia, respectively, as defined by the Mini-Mental State Examination (≤27 or ≤23, respectively). Patients with cognitive impairment were older, had lower levels of education, and had lower instrumental activities of daily living (IADL) scores than those without cognitive impairment. Multiple regression analysis revealed that age and IADL were associated with cognitive impairment in patients with hypertension. Regarding the treatment of hypertension, the office and home blood pressure levels, number of antihypertensive medications prescribed, and proportion of the use of each antihypertensive drug was equivalent between patients with and without cognitive impairment. Finally, patients with unrecognized cognitive impairment showed distinct clinical characteristics, including high antihypertensive medication burden and preserved IADL, when compared to hypertensive patients in the different cohorts of definitive mild cognitive impairment of a similar age. These findings suggest that older hypertensive patients are at a high risk of masked cognitive decline, even if they are functionally independent., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Background: Cachexia is a complicated metabolic disorder that is characterize by progressive atrophy of skeletal muscle. Cathepsin K (CTSK) is a widely expressed cysteine protease that has garnered attention because of its enzymatic and non-enzymatic functions in signalling in various pathological conditions. Here, we examined whether CTSK participates in cancer-induced skeletal muscle loss and dysfunction, focusing on protein metabolic imbalance., Methods: Male 9-week-old wild-type (CTSK +/+ , n = 10) and CTSK-knockout (CTSK -/- , n = 10) mice were injected subcutaneously with Lewis lung carcinoma cells (LLC; 5 × 10 5 ) or saline, respectively. The mice were then subjected to muscle mass and muscle function measurements. HE staining, immunostaining, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and western blotting were used to explore the CTSK expression and IRS1/Akt pathway in the gastrocnemius muscle at various time points. In vitro measurements included CTSK expression, IRS1/Akt pathway-related target molecule expressions, and the diameter of C2C12 myotubes with or without LLC-conditioned medium (LCM). An IRS1 ubiquitin assay, and truncation, co-immunoprecipitation, and co-localization experiments were also performed., Results: CTSK +/+ cachectic animals exhibited loss of skeletal muscle mass (muscle weight loss of 15%, n = 10, P < 0.01), muscle dysfunction (grip strength loss > 15%, n = 10, P < 0.01), and fibre area (average area reduction > 30%, n = 5, P < 0.01). Compared with that of non-cachectic CTSK +/+ mice, the skeletal muscle of cachectic CTSK +/+ mice exhibited greater degradation of insulin receptor substrate 1 (IRS1, P < 0.01). In this setting, cachectic muscles exhibited decreases in the phosphorylation levels of protein kinase B (Akt 308 , P < 0.01; Akt 473 , P < 0.05) and anabolic-related proteins (the mammalian target of rapamycin, P < 0.01) and increased levels of catabolism-related proteins (muscle RING-finger protein-1, P < 0.01; MAFbx1, P < 0.01) in CTSK +/+ mice (n = 3). Although there was no difference in LLC tumour growth (n = 10, P = 0.44), CTSK deletion mitigated the IRS1 degradation, loss of the skeletal muscle mass (n = 10, P < 0.01), and dysfunction (n = 10, P < 0.01). In vitro, CTSK silencing prevented the IRS1 ubiquitination and loss of the myotube myosin heavy chain content (P < 0.01) induced by LCM, and these changes were accelerated by CTSK overexpression even without LCM. Immunoprecipitation showed that CTSK selectively acted on IRS1 in the region of amino acids 268 to 574. The results of co-transfection of IRS1-N-FLAG or IRS1-C-FLAG with CTSK suggested that CTSK selectively cleaves IRS1 and causes ubiquitination-related degradation of IRS1., Conclusions: These results demonstrate that CTSK plays a novel role in IRS1 ubiquitination in LLC-induced muscle wasting, and suggest that CTSK could be an effective therapeutic target for cancer-related cachexia., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Pannexin (PANX) family proteins form large-pore channels that mediate purinergic signaling. We analyzed the cryo-EM structures of human PANX1 in lipid nanodiscs to elucidate the gating mechanism and its regulation by the amino terminus in phospholipids. The wild-type channel has an amino-terminal funnel in the pore, but in the presence of the inhibitor probenecid, a cytoplasmically oriented amino terminus and phospholipids obstruct the pore. Functional analysis using whole-cell patch-clamp and oocyte voltage clamp showed that PANX1 lacking the amino terminus did not open and had a dominant negative effect on channel activity, thus confirming that the amino-terminal domain played an essential role in channel opening. These observations suggest that dynamic conformational changes in the amino terminus of human PANX1 are associated with lipid movement in and out of the pore. Moreover, the data provide insight into the gating mechanism of PANX1 and, more broadly, other large-pore channels.

The aging brain undergoes structural changes even in very healthy individuals. Quantifying these changes could help disentangle pathologic changes from those associated with the normal human aging process. Using longitudinal magnetic resonance imaging (MRI) data from 227 carefully selected healthy human cohort with age ranging from 50 to 80 years old at baseline scan, we quantified age-related volumetric changes in the brain of healthy human older adults. Longitudinally, the rates of tissue loss in total gray matter (GM) and white matter (WM) were 2497.5 and 2579.8 mm 3 per year, respectively. Across the whole brain, the rates of GM decline varied with regions in the frontal and parietal lobes having faster rates of decline, whereas some regions in the occipital and temporal lobes appeared relatively preserved. In contrast, cross-sectional changes were mainly observed in the temporal-occipital regions. Similar longitudinal atrophic changes were also observed in subcortical regions including thalamus, hippocampus, putamen, and caudate, whereas the pallidum showed an increasing volume with age. Overall, regions maturing late in development (frontal, parietal) are more vulnerable to longitudinal decline, whereas those that fully mature in the early stage (temporal, occipital) are mainly affected by cross-sectional changes in healthy older cohort. This may suggest that, for a successful healthy aging, the former needs to be maximally developed at an earlier age to compensate for the longitudinal decline later in life and the latter to remain relatively preserved even in old age, consistent with both concepts of reserve and brain maintenance., (Copyright © 2022 Bagarinao et al.)

This prospective, cross-sectional, cohort observational study was conducted to evaluate the associations between sedentary behavior and arteriosclerosis-related vascular issues in community-dwelling frail older adults. We included 116 Japanese community-dwelling older adults (92 females and 24 males) who availed daycare at two long-term care insurance facilities in the cities of Yokkaichi and Handa between 2017 and 2019. An unpaired t -test and the chi-square test were used for intergroup comparisons. Logistic regression analysis was conducted with cardio-ankle vascular index as the dependent variable, sedentary behavior as the explanatory variable, and the other evaluated factors as covariates. Long-time sedentary behavior (based on the median value for all participants) was associated with high cardio-ankle vascular index after adjusting for age, sex, body mass index, ankle-brachial index, and walking MET-minutes in 1 week (odds ratio 3.086, 95% confidence interval 1.275-7.467, p =0.012). After adjusting for other variables (care needs certificate, skeletal muscle mass index, body fat percentage, grip strength, 4-m walking duration, etc), there was a significant association between long-time sedentary behavior and high cardio-ankle vascular index values (odds ratio 4.977, 95% confidence interval 1.497-16.554, p =0.009). The results study confirmed an association between long-time sedentary behavior in frail older adults and the degree of arterial stiffness assessed by the cardio-ankle vascular index. Interventions in older adults that focus on daily sedentary time to prevent the onset and exacerbation of geriatric syndromes secondary to the progression of arteriosclerosis warrant further investigation., Competing Interests: The authors report no conflicts of interest.

Aim: This study performed anthropometric measurements for Werner syndrome (WS) using bioelectrical impedance analysis and compared them with the Japanese reference data., Methods: The analytical sample included nine participants with WS (four men, five women, 49.6 ± 9.3 years, SD). The height-corrected appendicular skeletal muscle mass index (SMI), upper- and lower-limb muscle mass index (USMI/LSMI) of the patients with WS were compared with the Japanese reference data (40-79 years). The body mass index, SMI, height-corrected fat mass index (FMI) and fat-free mass index (FFMI) were compared with the reference data of Japanese older adults (65-94 years). The SMIs of WS were also compared with the diagnostic criteria for sarcopenia., Results: The SMI and USMI/LSMI of all participants with WS were lower than the Japanese reference data corresponding to gender and age, and the rate of decrease was more pronounced for USMI than for LSMI. The body mass index, SMI and FFMI for all the WS cases were lower than those for the older Japanese, while the FMI was higher in men with WS but lower in women than the reference data of the older Japanese. The SMI was below the cut-off value for the diagnosis of sarcopenia in all patients with WS., Conclusion: The SMI for WS is comparable with that for sarcopenia and significantly lower than that for healthy individuals of the same age and older adults. The USMI was significantly lower than LSMI in patients with WS, and FMI was higher in male patients with WS and lower in women than in healthy older people. Geriatr Gerontol Int 2022; 22: 75-80., (© 2021 Japan Geriatrics Society.)

Older adults have physical and metabolic characteristics, and there are many differences in nutritional outcomes from middle-aged adults. In addition, there are many factors that cause malnutrition peculiar to the older adults, which are not seen in middle-aged adults, and it is easy for them to lose weight and become malnourished. Therefore, nutritional management needs to take into account the age of each subject. Uniform nutritional management can even cause poor health outcomes. The concept of frailty, especially phenotype frailty, and sarcopenia, which have been advocated with the aging of the population and the extension of life expectancy around the world, is very important in considering the extension of healthy life expectancy. In other words, in the super-aged society, frailty and sarcopenia have been emphasized as factors of functional decline, physical dysfunction, and the need for long-term care in addition to the well-known diseases such as cardiovascular disease, malignant tumors, and infectious disease. In fact, these two conditions are strongly associated with the increased risk of new disease development, falls, fractures, disability, hospitalization and death in the older adults. These two conditions are primarily associated with malnutrition and decreased dietary protein intake, and may recover to robustness again with appropriate interventions such as nutritional therapy. Therefore, undernutrition measures are more important for prevention of frailty and sarcopenia than measures for obesity against metabolic syndrome in the older adults, especially in the late-stage older people.

Background: Older adults, especially those with cognitive decline, often have poor gait performance, which results in poor clinical outcomes due to falls or decreased daily physical activity. The effects of various exercises on gait performance have been studied, whereas the short-term and long-term effects of different exercise modalities remain unknown., Objective: To compare the short- and long-term effects of aerobic training (AT), resistance training (RT), and combined training (CT) on the gait performance of community-dwelling older adults with subjective cognitive decline (SCD)., Design: A four-arm, randomized controlled trial., Setting and Subjects: 388 community-dwelling older adults with SCD (mean age, 72.3 years)., Methods: Participants attended an exercise or education class twice a week for 26 weeks. 10 gait performance parameters were examined at baseline, post-intervention (Week 26), and after 26 weeks of follow-up (Week 52) using an electronic walkway system., Results: The mean adherence of exercise sessions was 82.5 to 85.9%. All exercise intervention induced an improvement in gait speed, stride time, cadence, stride length, and double-support time at Week 26 (p < .05), without significant intergroup differences among exercise interventions. However, only RT showed a significant effect on some spatiotemporal gait parameters at Week 52. The analyses for the gait variability parameters showed mild effects of all exercise interventions., Conclusion: All of the exercise programs examined had a positive short-term effect on spatiotemporal gait parameters of older adults with SCD, despite no effect on gait variability parameters. RT are most recommended when long-lasting effects are the primary aim., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We recently demonstrated that proliferin-1 (PLF-1) functions as an apoptotic cell-derived growth factor and plays an important role in vascular pathobiology. We therefore investigated its role in muscle regeneration in response to cardiotoxin injury., Methods and Results: To determine the effects of PLF-1 on muscle regeneration, we used a CTX-induced skeletal muscle injury model in 9-week-old male mice that were administered with the recombinant PLF-1 (rPLF-1) or neutralizing PLF-1 antibody. The injured muscles exhibited increased levels of PLF-1 gene expression in a time-dependent manner. On day 14 after injury, rPLF-1 supplementation ameliorated CTX-induced alterations in muscle fiber size, interstitial fibrosis, muscle regeneration capacity, and muscle performance. On day 3 postinjury, rPLF-1 increased the levels of proteins or genes for p-Akt, p-mTOR, p-GSK3 α / β , p-Erk1/2, p-p38MAPK, interleukin-10, Pax7, MyoD, and Cyclin B1, and it increased the numbers of CD34 + /integrin- α 7 + muscle stem cells and proliferating cells in the muscles and/or bone marrow of CTX mice. An enzyme-linked immunosorbent assay revealed that rPLF-1 suppressed the levels of plasma tumor necrosis factor- α and interleukin-1 β in CTX mice. PLF-1 blocking accelerated CTX-related muscle damage and dysfunction. In C2C12 myoblasts, rPLF-1 increased the levels of proteins for p-Akt, p-mTOR, p-GSK3 α / β , p-Erk1/2, and p-p38MAPK as well as cellular functions; and these effects were diminished by the depletion of PLF-1 or silencing of its mannose-6-phosphate receptor., Conclusions: These findings demonstrated that PLF-1 can improve skeletal muscle repair in response to injury, possibly via the modulation of inflammation and proliferation and regeneration, suggesting a novel therapeutic strategy for the management of skeletal muscle diseases., Competing Interests: The authors declare that they have no conflicts of interest to disclose with respect to this manuscript., (Copyright © 2021 Hiroki Goto et al.)

Aim: Cerebral small vessel disease and lower urinary tract symptoms are common in older people. However, the association between white matter hyperintensity (WMH) and overactive bladder (OAB) is not fully understood. We aimed to identify the relationship between WMH and OAB., Methods: We carried out neuropsychological testing and head magnetic resonance imaging (T2-weighted and fluid-attenuated inversion recovery) of 72 outpatients at a memory clinic and evaluated their Overactive Bladder Symptom Score. WMH was assessed using the Fazekas scale, and WMH volumes were determined using Software for Neuro-Image Processing in Experimental Research. OAB was diagnosed based on a urinary urgency score (the third question of the Overactive Bladder Symptom Score) of two or higher and a total Overactive Bladder Symptom Score of three or higher. Multivariate logistic analysis was carried out, with the presence/absence of overactive bladder as the outcome variable, and age, sex, body mass index and diabetes mellitus as covariates., Results: Of the 72 participants, 17 (24%) were diagnosed with OAB. WMH assessed by the visual rating scale was not associated with OAB. However, participants with OAB showed significantly higher WMH volume than those without OAB. Regionally, participants with OAB showed high WMH volume in the frontal, occipital and parietal lobes. Multiple logistic regression analysis showed that WMH was significantly associated with OAB (OR 1.82, 95% CI 1.11-2.98), after adjustment for clinically important confounders., Conclusions: Cerebral WMH volume is associated with OAB, independent of age, sex, body mass index and diabetes mellitus. Geriatr Gerontol Int 2021; 21: 996-1002., (© 2021 Japan Geriatrics Society.)

Background: Social frailty is associated with poor health outcomes; however, its effects on healthy aging indicators have not been adequately investigated. This study assessed the longitudinal association between social frailty and the intrinsic capacity of community-dwelling older adults., Methods: A total of 663 participants (56.7% women) aged ≥60 years from in Nagoya, Japan, were included in the study. The first measurement occurred in 2014, and annual follow-ups occurred until 2017. Social frailty was determined based on four items: financial difficulty, household status, social activity, and regular contact with others. A deficit score of 0 represented social robustness, 1 represented social prefrailty, and ≥ 2 represented social frailty. Intrinsic capacity was evaluated by the locomotion, cognition, psychological function, vitality, and sensory function domains. The longitudinal association was analyzed using generalized estimating equations., Results: The prevalence of social prefrailty and social frailty at baseline was 31.2 and 6.3%, respectively. The social prefrailty group (β = - 0.132, P < 0.001) and social frailty group (β = - 0.258, P < 0.001) were associated with a greater reduction in the composite intrinsic capacity scores than the social robustness group, especially in the cognition, psychological function, and vitality domains. Men with social prefrailty/social frailty demonstrated a greater decrease in the psychological function domain score (- 0.512 vs. - 0.278) than women. Additionally, the cognition domain score only decreased in men in the social prefrailty/social frailty group (β = - 0.122, P = 0.016)., Conclusions: Social frailty was associated with intrinsic capacity and its subdomains longitudinally. Men with social frailty were more vulnerable than women to a decline in their psychological function and cognition domains. Therefore, the advanced management of social frailty is necessary to facilitate healthy aging., (© 2021. The Author(s).)

The thalamus is critical for the brain's integrative hub functions; however, the localization and characterization of the different thalamic hubs remain unclear. Using a voxel-level network measure called functional connectivity overlap ratio (FCOR), we examined the thalamus' association with large-scale resting-state networks (RSNs) to elucidate its connector hub roles. Connections to the core-neurocognitive networks were localized in the anterior and medial parts, such as the anteroventral and mediodorsal nuclei areas. Regions functionally connected to the sensorimotor network were distinctively located around the lateral pulvinar nucleus but to a limited extent. Prominent connector hubs include the anteroventral, ventral lateral, and mediodorsal nuclei with functional connections to multiple RSNs. These findings suggest that the thalamus, with extensive connections to most of the RSNs, is well placed as a critical integrative functional hub and could play an important role for functional integration facilitating brain functions associated with primary processing and higher cognition., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Purpose: The WHO has proposed a novel model of healthy aging called intrinsic capacity (IC). However, the association between dietary patterns and IC is unclear. We aimed to investigate the prospective associations between dietary patterns and IC trajectories over a 3-year period in community-dwelling Japanese adults aged ≥ 60 years., Methods: A prospective cohort study which contained nutritional status, mental status, and physical function was used. A validated 34-item food frequency questionnaire was used to determine dietary intake and to derive five dietary patterns ("fruits and vegetables", "sugar and fat", "salt and pickles", "noodle and alcohol", and "protein-rich") using principal component analysis. The composite IC score was calculated as the mean of the locomotion Z-score, cognition Z-score, psychological Z-score, vitality Z-score, and sensory regression score. A generalized estimating equation was applied for longitudinal analysis., Results: A total of 666 enrollees were included in the analysis. The mean baseline IC was 0.07 ± 0.47. The "fruits and vegetables" dietary pattern was positively associated with composite IC score changes after adjusting for confounders (Q4 vs. Q1: mean difference [0.069], P = 0.019). Similarly, a positive correlation was observed for the "protein-rich" dietary pattern with the composite IC score changes (Q4 vs. Q1: mean difference [0.092], Q3 vs. Q1: mean difference [0.101], Q2 vs. Q1: mean difference [0.083]; all P < 0.01). However, adherence to the "sugar and fat" dietary pattern was negatively associated with composite IC score changes (Q4 vs. Q1: mean difference [- 0.072], P = 0.026). Furthermore, the percentage of animal protein to total protein intake showed a significant incremental trend in the "protein-rich" dietary pattern (P for trend < 0.001)., Conclusion: The "fruits and vegetables" and "protein-rich" (animal-based protein in particular) dietary patterns were positively associated with IC changes, whereas the "sugar and fat" dietary pattern was negatively associated with IC changes. Identification and promotion of healthy dietary patterns in older adults may inform future health policies and research., (© 2021. Springer-Verlag GmbH, DE part of Springer Nature.)