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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.

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.

Key summary points Aim This study concerns an investigation of whether social isolation is associated with the new onset of physical frailty among healthy Japanese older adults. Findings Fourfold higher risk of developing prefrailty during 1-year follow-up. Friendship-related social isolation increases the risk of prefrailty. Message Improving the social isolation of friendship may prevent the transition to frailty. Purpose Social factors are often overlooked when considering physical frailty. The purpose of this study was to determine whether social isolation is associated with new onset of physical frailty among healthy Japanese older adults. Methods This was a 1-year prospective cohort study conducted in Japan from August 2014 to August 2015. The participants were 229 Japanese older people (106 men, 123 women, mean age = 69.3 ± 4.2 years) who did not have prefrailty or frailty at baseline and who were current students or graduates of a community college for older people in Japan. Social isolation was assessed using the Lubben Social Network Scale-6 in terms of overall social isolation, family-related social isolation, and friendship-related social isolation. Frailty was categorized using the Fried frailty criteria. The association between new onset of physical frailty and baseline characteristics, including social isolation, was investigated. Results At 1-year follow-up, 180 (78.6%) of the participants remained robust, while 49 (21.4%) were identified as prefrail; no participants were identified as frail. Prefrailty was only associated with friendship-related social isolation (odds ratio: 4.58, 95% confidence interval 2.11–9.92, P  < 0.001) at baseline. No significant associations were observed for any other baseline characteristics, including overall social isolation, family-related social isolation, comorbidities, body composition, and physical function. Conclusion Older adults with friendship-related social isolation are four times more likely to develop prefrailty from robust during the 1-year follow-up. The results suggest that friendship-related social isolation increases the risk of healthy older adults transitioning from robust to prefrail.

The effects of social frailty on diet and nutrition are under-investigated. Our study aimed to assess the association between social frailty and diet quality, diet quantity, and nutrition over a 3-year period in community-dwelling older Japanese adults. This prospective cohort study recruited individuals aged ≥60 years from a community college and followed up 666 participants annually. Social frailty was determined using a 4-item questionnaire. Diet quantity (energy and macronutrient intake) and diet quality (dietary diversity score and Diet Quality Index-International) were assessed using a food frequency questionnaire. Nutrition was evaluated using the Mini-Nutritional Assessment (MNA). Out of the 666 participants (56.5% women), 250 (37.5%) were categorized as having social prefrailty or frailty. Regarding diet quantity, energy intake (β = −1.59kcal/kg/day, p < 0.01) and nutrient intake (protein intake, β = −0.08g/kg/day; fat intake, β = −0.06g/kg/day; carbohydrate intake, β = −0.18g/kg/day; fiber intake, β = −0.01g/kg/day; all p < 0.05) were lower in men with social prefrailty or frailty than in men with social robustness. Dietary diversity score (β = −0.25, p = 0.01) and MNA score (β = −0.32, p = 0.04) decreased in men with social prefrailty or frailty. However, these associations were not observed in women. Social frailty is associated with lower dietary intake, poor diet quality, and poor nutrition among community-dwelling older men. Future studies are required to determine the benefits of sex-specific interventions targeting social frailty on nutritional outcomes.

To identify similarities and differences in the clinical features of adult Japanese patients with individual anti-aminoacyl-tRNA synthetase antibodies (anti-ARS Abs). This was a retrospective analysis of 166 adult Japanese patients with anti-ARS Abs detected by immunoprecipitation assays. These patients had visited Kanazawa University Hospital or collaborating medical centers from 2003 to 2009. Anti-ARS Ab specificity included anti-Jo-1 (36%), anti-EJ (23%), anti-PL-7 (18%), anti-PL-12 (11%), anti-KS (8%), and anti-OJ (5%). These anti-ARS Abs were mutually exclusive, except for one serum Ab that had both anti-PL-7 and PL-12 reactivity. Myositis was closely associated with anti-Jo-1, anti-EJ, and anti-PL-7, while interstitial lung disease (ILD) was correlated with all 6 anti-ARS Abs. Dermatomyositis (DM)-specific skin manifestations (heliotrope rash and Gottron's sign) were frequently observed in patients with anti-Jo-1, anti-EJ, anti-PL-7, and anti-PL-12. Therefore, most clinical diagnoses were polymyositis or DM for anti-Jo-1, anti-EJ, and anti-PL-7; clinically amyopathic DM or ILD for anti-PL-12; and ILD for anti-KS and anti-OJ. Patients with anti-Jo-1, anti-EJ, and anti-PL-7 developed myositis later if they had ILD alone at the time of disease onset, and most patients with anti-ARS Abs eventually developed ILD if they did not have ILD at disease onset. Patients with anti-ARS Abs are relatively homogeneous. However, the distribution and timing of myositis, ILD, and rashes differ among patients with individual anti-ARS Abs. Thus, identification of individual anti-ARS Abs is beneficial to define this rather homogeneous subset and to predict clinical outcomes within the \"anti-synthetase syndrome.\"

Numerous SARS-CoV-2 variant strains with altered characteristics have emerged since the onset of the COVID-19 pandemic. Remdesivir (RDV), a ribonucleotide analogue inhibitor of viral RNA polymerase, has become a valuable therapeutic agent. However, immunosuppressed hosts may respond inadequately to RDV and develop chronic persistent infections. A patient with respiratory failure caused by interstitial pneumonia, who had undergone transplantation of the left lung, developed COVID-19 caused by Omicron BA.5 strain with persistent chronic viral shedding, showing viral fusogenicity. Genome-wide sequencing analyses revealed the occurrence of several viral mutations after RDV treatment, followed by dynamic changes in the viral populations. The C799F mutation in nsp12 was found to play a pivotal role in conferring RDV resistance, preventing RDV-triphosphate from entering the active site of RNA-dependent RNA polymerase. The occurrence of diverse mutations is a characteristic of SARS-CoV-2, which mutates frequently. Herein, we describe the clinical case of an immunosuppressed host in whom inadequate treatment resulted in highly diverse SARS-CoV-2 mutations that threatened the patient’s health due to the development of drug-resistant variants. In this study, the authors report the case of a patient who underwent lung transplantation and subsequently developed COVID-19 that resulted in persistent infection. Following antiviral treatment, SARS-CoV-2 (BA.5) showed dynamic genetic diversity with remdesivir resistant mutations leading to enhanced fusogenicity.

BackgroundMetformin (Met) is the first-line treatment for type 2 diabetes mellitus and plays an effective role in treating various diseases, such as cardiovascular disease, neurodegenerative disease, cancer, and aging. However, the underlying mechanism of Met-dependent antitumor immunity remains to be elucidated.MethodsMitoTEMPO, a scavenger of mitochondrial superoxide, abolished the antitumor effect of Met, but not antiprogrammed cell death (PD-1) antibody (Ab) treatment. Consequently, we studied the mechanism of the Met-induced antitumor effect. Expressions of glucose transporter (Glut)-1, mitochondrial reactive oxygen species (mtROS), interferon (IFN)-γ, Ki67, autophagy markers, activation markers for NF-E2-related factor 2 (Nrf2), and mammalian target of rapamaycin complex 1 (mTORC1) in CD8+ tumor-infiltrating T lymphocytes (CD8TILs) were examined by flow cytometry analysis. In addition, conditional knockout mice for Nrf2 and p62 were used to detect these markers, together with the monitoring of in vivo tumor growth. RNA sequencing was performed for CD8TILs and tumor cells. Melanoma cells containing an IFN-γ receptor (IFNγR) cytoplasmic domain deletion mutant was overexpressed and used for characterization of the metabolic profile of those tumor cells using a Seahorse Flux Analyzer.ResultsMet administration elevates mtROS and cell surface Glut-1, resulting in the production of IFN-γ in CD8TILs. mtROS activates Nrf2 in a glycolysis-dependent manner, inducing activation of autophagy, glutaminolysis, mTORC1, and p62/SQSTM1. mTORC1-dependent phosphorylation of p62 at serine 351 (p-p62(S351)) is also involved in activation of Nrf2. Conditional deletion of Nrf2 in CD8TILs abrogates mTORC1 activation and antitumor immunity by Met. In synergy with the effect of anti-PD-1 Ab, Met boosts CD8TIL proliferation and IFN-γ secretion, resulting in decreased glycolysis and oxidative phosphorylation in tumor cells. Consequently, Glut-1 is elevated in CD8TILs, together with the expansion of activated dendritic cells. Moreover, tumor cells lacking in IFNγR signaling abolish IFN-γ production and proliferation of CD8TILs.ConclusionsWe found that Met stimulates production of mtROS, which triggers Glut-1 elevation and Nrf2 activation in CD8TILs. Nrf2 activates mTORC1, whereas mTORC1 activates Nrf2 in a p-p62(S351)-dependent manner, thus creating a feedback loop that ensures CD8TILs’ proliferation. In combination with anti-PD-1 Ab, Met stimulates robust proliferation of CD8TILs and IFN-γ secretion, resulting in an IFN-γ-dependent reprogramming of the tumor microenvironment.

Triple-negative breast cancer (TNBC) is one of the breast cancer subtype that displays a high risk of early recurrence and short overall survival. Improvement of the prognosis of patients with TNBC requires identifying a predictive factor of recurrence, which would make it possible to provide beneficial personalized treatment. However, no clinically reliable predictive factor is currently known. In this study, we investigated the predictive factor of recurrence in TNBC using matrix-assisted laser desorption/ionization-imaging mass spectrometry for lipid profiling of breast cancer specimens obtained from three and six patients with recurrent and non-recurrent TNBC, respectively. The signal for phosphatidylcholine (PC) (32:1) at m/z 732.5 was significantly higher in the recurrence group compared to the non-recurrence group (P = 0.024). PC (32:1) was more abundant in the cancer epithelial area than it was in the surrounding stroma, suggesting that abnormal lipid metabolism was associated with malignant transformation. Our results indicate PC (32:1) as a candidate predictive factor of TNBC recurrence. A future prospective study investigating whether personalized therapy based on PC (32:1) intensity improves the prognosis of patients with TNBC is recommended.

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neurodegenerative disease. This multicenter, randomized phase 3 study evaluated the efficacy and safety of 0.3 mg/kg intravenous mogamulizumab, a monoclonal antibody targeting-CC chemokine receptor 4, every 12 weeks in HAM/TSP patients. This study comprised a 24-week double-blind, placebo-controlled period, 24-week open-label period, and extension treatment period. The primary endpoint was the proportion of patients with a ≥ 1-grade improvement in the Osame motor disability score (OMDS). Secondary endpoints were changes in HTLV-1 proviral load, 10-m timed walk, cerebrospinal fluid (CSF) neopterin levels, and safety. The exploratory endpoint was CSF chemokine C-X-C motif ligand 10 (CXCL10) levels. Thirty-four and 33 patients were randomized to mogamulizumab and placebo arms, respectively. At the end of the double-blind period, no significant difference was found in the OMDS improvement rate or other secondary efficacy endpoints assessing motor activities. However, the mogamulizumab arm showed a significant decrease in HTLV-1 proviral load (− 59.39 ± 29.91% vs. placebo 2.32 ± 36.31%) and CSF neopterin ( p  < 0.001)/CXCL10 levels ( p  = 0.004). The baseline OMDS pattern and the 60–80% HTLV-1 proviral load reduction were sustained through the open-label and extension treatment periods. Although a higher incidence of rash (69.2%) was reported, the safety profile was similar compared with a previous phase 1/2a study. We found no significant difference in clinical benefit; however, mogamulizumab may provide long-term clinical benefit by preventing disease progression, as CSF neopterin/CXCL10 levels are associated with long-term prognosis in HAM/TSP. Clinical Trial Registration Number: NCT03191526 (registered date: 6-June-2017).

Vertical profiles of dissolved oxygen (DO) and water temperature (WT) measured bi-monthly for 36 years (1980–2015) near the deepest part of a warm monomictic lake were analyzed with special reference to yearly minimum DO at bottom (DOmin). DOmin changed yearly (3.0 ± 1.2 mg l −1 ) and significant differences in DOmin were not observed between Period I (1980–1993; cooler and worse in water quality) and Period II (1994–2015; warmer and better in water quality). This unclear trend in DOmin was probably due to the offsetting influences between warming induced by global warming and oligotrophication attempted by local governments etc. for the study period. DOmin was positively correlated with disturbance time (timing of last cold water intrusion observed from Mar to Aug), which could be related to the start of DO depletion at bottom. Thus, the linear model using this parameter could predict yearly DOmin fairly well for the entire study period (r 2  = 0.60). In addition, DOmin and time of disturbance were correlated negatively with water density at bottom in Jan and positively with water density equilibrated to air temperature (AT) in Mar. Higher lake water density after full depth mixing advances the disturbance time. In contrast, lower AT in Mar and/or higher density of influent water after Mar delays the time likely due to the larger amount of snowfall in the watershed. Further, DOmin was positively correlated with maximum wind velocity in Sep which probably induced the recovery of DO. Multiple-regression models to predict DOmin using these meteorological and water quality parameters were developed (r 2  ≥ 0.38, worse performances than the model using disturbance time) to forecast future trends of DOmin through global warming and/or climate change. Significant influences of water or sediment oxygen demands on DOmin were not detected. We also discuss the applicability of the proposed models.