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Impaired glucose tolerance characterized by postprandial hyperglycemia, which occurs frequently in elderly persons and represents an important preliminary step in diabetes mellitus, poses an independent risk factor for the development of atherosclerosis. Endothelial cellular senescence is reported to precede atherosclerosis. We reported that continuous high glucose stimulus causes endothelial senescence more markedly than hypertension or dyslipidemia stimulus. In the present study, we evaluated the effect of fluctuating glucose levels on human endothelial senescence. Constant high glucose increased senescence-associated-β-galactosidase (SA-β-gal) activity, a widely used marker for cellular senescence. Interestingly, in intermittent high glucose, this effect was more pronounced as well as increase of p21 and p16INK4a , senescence related proteins with DNA damage. However, telomerase was not activated and telomere length was not shortened, thus stress-induced senescence was shown. However, constant high glucose activated telomerase and shortened telomere length, which suggested replicative senescence. Intermittent but not constant high glucose strikingly up-regulated the expression of p22phox, an NADPH oxidase component, increasing superoxide. The small interfering RNA of p22phox undermined the increase in SA-β-gal activity induced by intermittent high glucose. Conclusively, intermittent high glucose can promote vascular endothelial senescence more than constant high glucose, which is in partially dependent on superoxide overproduction.

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 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.

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. Here the authors show that myonectin functions as a protective factor against age-associated, disuse-induced or steroid-induced muscle atrophy, suggesting that myonectin represents a therapeutic target for preventing skeletal muscle dysfunction.

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.

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.

Nutritional support effectively prevents and treats sarcopenia; however, the influence of overall dietary patterns on sarcopenia parameters is less investigated. This study aimed to determine the association between adherence to Mediterranean-style diet (MD), Dietary Approaches to Stop Hypertension (DASH), Japanese Food Guide Spinning Top (JFG-ST), and modified JFG-ST (mJFG-ST) and muscle mass, muscle strength, and physical performance in community-dwelling Japanese elderly. This prospective cohort study recruited individuals aged over 60 years from a community college in Nagoya, Japan. A total of 666 participants were followed up annually from 2014 to 2017. Demographic data, anthropometric measurements, and sarcopenia parameters including walking speed (WS), hand grip strength in the dominant hand (HGS), and skeletal mass index (SMI) were recorded. Self-recall dietary intake was assessed using a validated food frequency questionnaire comprising 29 food groups. Adherence to MD, DASH, JFG-ST, and mJFG-ST was determined by tertiles. At baseline, the mean age of all participants (56.5% women) was 69.4±4.4 years. WS, HGS, and SMI were 1.4±0.2 (m/s), 28.9±8.1 (kg), and 6.7±1.0 (kg/m2), respectively. In longitudinal analysis, participants with higher JFG-ST adherence scores were more likely to have higher SMI (Q3 vs. Q1: mean difference, 0.048; p=0.04) after adjustment, and its benefits were more evident in men (Q2 vs. Q1: mean difference, 0.098; p=0.047; Q3 vs. Q1: mean difference, 0.091; p=0.017) than in women. WS and HGS were not associated with any type of dietary pattern. Adherence to JFG-ST was positively associated with SMI in Japanese community-dwelling elderly adults aged over 60 years, specifically in men. The country-specific dietary recommendations are required to be developed for sarcopenia prevention.

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.

Healthy aging is associated with structural and functional changes in the brain even in individuals who are free of neurodegenerative diseases. Using resting state functional magnetic resonance imaging data from a carefully selected cohort of participants, we examined cross sectional changes in the functional organization of several large-scale brain networks over the adult lifespan and its potential association with general cognitive performance. Converging results from multiple analyses at the voxel, node, and network levels showed widespread reorganization of functional brain networks with increasing age. Specifically, the primary processing (visual and sensorimotor) and visuospatial (dorsal attention) networks showed diminished network integrity, while the so-called core neurocognitive (executive control, salience, and default mode) and basal ganglia networks exhibited relatively preserved between-network connections. The visuospatial and precuneus networks also showed significantly more widespread increased connectivity with other networks. Graph analysis suggested that this reorganization progressed towards a more integrated network topology. General cognitive performance, assessed by Addenbrooke’s Cognitive Examination-Revised total score, was positively correlated with between-network connectivity among the core neurocognitive and basal ganglia networks and the integrity of the primary processing and visuospatial networks. Mediation analyses further indicated that the observed association between aging and relative decline in cognitive performance could be mediated by changes in relevant functional connectivity measures. Overall, these findings provided further evidence supporting widespread age-related brain network reorganization and its potential association with general cognitive performance during healthy aging.

Although potentially inappropriate medications (PIMs) have been linked to poor health outcomes, country-specific PIM criteria have not been compared. Thus, we compared the identification of PIMs between the Screening Tool for Older Person's Appropriate Prescriptions for Japanese (STOPP-J) and the 2015 American Geriatrics Society Beers Criteria in elderly patients receiving home-based medical services. A 5-year prospective cohort study was conducted with 196 patients receiving home-based medical services. Data were collected using questionnaires and chart reviews and included detailed information on prescription medication. STOPP-J and the Beers Criteria were used to categorize PIM and non-PIM recipients. All-cause mortality and first hospitalization were compared using a multivariate Cox regression model. PIMs were detected in 132 patients (67.3%) by STOPP-J and in 141 patients (71.9%) by the Beers Criteria, and the mean numbers of PIMs were 1.3 ± 1.3 and 1.2 ± 1.1, respectively. The three most frequently prescribed STOPP-J PIMs were hypnotics (26.8%), diuretics (25.6%), and NSAIDs (12.6%), compared with proton pump inhibitors (PPIs) (29.8%), hypnotics (26%), and NSAIDs (8.1%) according to the Beers Criteria. STOPP-J PIMs were associated with all-cause mortality (HR 3.01, 95% CI 1.37-6.64) and hospitalization (HR 1.91, 95% CI 1.17-3.09); neither was associated with Beers Criteria PIMs. Using a modified Beers Criteria (excluding PPIs), PIMs were correlated with first hospitalization (HR 1.91, 95% CI 1.17-3.09). PIMs categorized by STOPP-J are associated with hospitalization and mortality in Japanese patients receiving home-based medical services. PPIs, commonly used for acid-related diseases, do not seem to have deleterious effects on health outcomes. Country-oriented, medication-specific criteria would be of considerable clinical utility.