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Background: Elevated circulatory phosphate levels are linked to age-related muscle dysfunction, yet the mechanisms remain unclear. This study investigated the hypothesis that inflammation plays a role in connecting elevated phosphate levels to muscular dysfunction in middle-aged and older individuals and explored potential sex-based differences in these associations., Methods: The study, based on the I-Lan Longitudinal Aging Study Cohort, analyzed individuals' serum phosphate and hsCRP levels. Sex-specific analyses explored links between circulatory phosphate, inflammation, and muscle profiles (mass, handgrip strength, and walking speed). The study also examined potential mediation or synergistic effects of inflammation in the circulatory phosphate-muscle relationship., Results: The study included 2006 participants (mean age: 65.5 ± 6.5 years; 49.8 % men). Women exhibited higher circulatory phosphate levels than men. Linear analyses revealed that higher phosphate levels were significantly associated with weaker handgrip strength but not with reduced muscle mass in both men and women. In women, circulatory phosphate was not associated with inflammation (hsCRP levels), while in men, higher phosphate levels were significantly associated with higher hsCRP levels. In men, a synergistic effect was observed, where the combination of high hsCRP and elevated phosphate levels had a more pronounced impact on reducing handgrip strength than either factor alone., Conclusions: This study highlights a sex-specific association of inflammation in the mechanisms of hyperphosphatemia-related muscle weakness. The findings emphasize the importance of managing both hyperphosphatemia and chronic inflammation to mitigate their collective impact on muscle function, particularly in older men. Addressing these factors is crucial for promoting muscle health in later life., Competing Interests: Declaration of competing interest All authors declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Glucosamine (GlcN) is one of the dietary supplements used in the treatment of osteoarthritis. Endogenously, GlcN is synthesized from glucose through the hexosamine pathway. In addition to ameliorating arthritis, several biological functions of GlcN have been reported, including insulin resistance in skeletal muscle. However, the regulatory role of GlcN in skeletal muscle development is not clear. We therefore investigated the effect of GlcN on myoblast proliferation, differentiation, and myotube development and their underlying mechanisms in C2C12 cells. Myoblast proliferation was measured by MTT assay. The expressions of MyoD, myogenin (MyoG), and myosin heavy chain (MyHC) were identified as determinants of myoblast differentiation. Expressions of atrogin-1 and muscle RING-finger protein-1 (MuRF-1) were identified as markers of myotube atrophy. The results show that treatment with GlcN significantly reduced myoblast proliferation and phosphorylation of Stat3 and S6K. These findings suggest that GlcN can inhibit growth of myoblasts through inhibiting phosphorylation of Stat3 and S6K. In addition, GlcN significantly suppressed the expression of MyoD, MyoG, and MyHC, as well as myotube formation. Pretreatment of C2C12 myoblast cells with ER stress inhibitors significantly blocked GlcN-inhibited MyHC expression and myotube formation. It can be concluded that GlcN suppressed myogenic differentiation via a pathway that involved ER stress. Moreover, GlcN decreased myotube diameter and expression of MyHC, as well as increased MuRF-1 in C2C12 myotubes. Meanwhile, GlcN also reduced the expressions of phosphorylated Akt and mTOR were stimulated after GlcN treatment in C2C12 myotubes. Thus, GlcN induced skeletal muscle atrophy by inhibiting the protein synthesis pathway. Chronic GlcN infusion also caused skeletal muscle atrophy in mice. In conclusion, GlcN regulated important stages of skeletal muscle development through different signaling pathways., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Given the established association between sarcopenia and cognitive impairment was mainly in the older and oldest-old population or people with relatively limited education, this study extends the investigation to community-dwelling middle-to-old age adults in urban communities, emphasizing the need for preventive intervention for muscle health and healthy longevity., Methods: Data of 712 participants from the Gan-Dau Healthy Longevity Plan were retrieved for analysis, and all participants were stratified by age (50-64, 65-74 and 75+ years old). Possible sarcopenia was defined by 2019 consensus report of the Asian Working Group for Sarcopenia (AWGS). This study used four neuropsychological tests for analysis, i.e., Mini-Mental Status Examination (MMSE), California Verbal Learning Test II (CVLT-SF), Digital Symbol Substitution Test (DSST) and Verbal fluency (VF) for global and domain-specific cognitive function. Multivariate generalized linear models (GLMs) were employed to investigate the associations between possible sarcopenia and cognitive function in each age-specific groups., Results: The prevalence of possible sarcopenia increased with age, with 31.8 %, 37.7 %, and 55.6 % in participants aged 5064, 65-74 and, 75+ years, respectively. On the other hand, cognitive performance declined with age. In particular, among participants aged 75+ years with possible sarcopenia, their cognitive performance were poorer than robust counterparts, including MMSE (26.6 [3.4] vs. 27.4 [2.6]), CVTL-SF (total score: 21.5 [5.4] vs. 23.8 [5.5]; 30-second delayed recall: 6.0 [1.7] vs. 6.5 [1.6]), DSST (32.8 [14.3] vs. 41.3 [18.7]), and VF (12.8 [5.1] vs. 14.8 [4.9]). Multivariate generalized linear model indicated that possible sarcopenia was associated with lower MMSE (β: -0.70, p = 0.014) and lower DSST (β: -7.00, p = 0.010) in those aged 50-64 years. Moreover, possible sarcopenia was associated with lower CVLT-SF (total score β:-1.90, p = 0.028), lower DSST (β: -6.45, p < 0.001), and lower VF (β: -1.64, p=0.026) in 75+ years group., Conclusions: An association exists between possible sarcopenia and cognitive impairment, encompassing global cognition, delayed memory, verbal fluency, and executive function, among community-dwelling adults of mid-to-old age. Future research is warranted to explore the temporal alterations in this association and the potential effects of interventions aimed at fostering healthy longevity., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Tumor necrosis factor (TNF)-α is a proinflammatory cytokine involved in the pathogenesis of sarcopenia, but its short half-life and inconsistent reproducibility limit the potential of TNF-α to be an ideal sarcopenia biomarker. Anti-TNF-α, a natural consequent autoantibody to TNF-α, is an indicator of relatively prolonged TNF-α exposure, has more stable concentrations than TNF-α and should be a better alternative as a biomarker of sarcopenia. Data from 484 participants from the I-Lan Longitudinal Aging Study were used for this study, and sarcopenia was defined by the Asian Working Group for Sarcopenia 2019 consensus. Plasma levels of anti-TNF-α were determined by a sandwich ELISA approach, and levels of TNF-α were determined by an immunoassay. Compared to nonsarcopenic participants, 43 sarcopenic participants had higher levels of anti-TNF-α (0.73 ± 0.19 vs. 0.79 ± 0.25 OD, p = 0.045). Plasma levels of anti-TNF-α were positively correlated with TNF-α (r = 0.24, p < 0.001), and plasma levels of anti-TNF-α were positively correlated with adiposity (r = 0.16, p < 0.001) and negatively correlated with lean body mass (r = -0.14, p = 0.003). Individuals with increasing levels of anti-TNF-α had higher odds of being sarcopenic (OR 5.4, 95 % CI: 1.1-25.8, p = 0.035), and these associations were stronger among women and younger adults. An association between TNF-α and sarcopenia was noted only in middle-aged adults (OR 6.2, 95 % CI: 1.8-21.7, p = 0.004). Plasma anti-TNF-α levels were positively correlated with TNF-α and were significantly associated with sarcopenia. Anti-TNF-α may be a more appropriate biomarker than TNF-α for sarcopenia, but further investigations are needed to confirm its roles in sarcopenia diagnosis and treatment response evaluation., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To investigate the relationship between dietary diversity and healthy aging (in terms of mobility performance, physical functions, cognitive functions, and depressive symptoms) among community-dwelling middle-aged and older adults by using a nationally representative population-based cohort study., Methods: Data from 3213 study participants in the Taiwan Longitudinal Study on Aging (TLSA) were retrieved for analysis, and all participants were divided into five groups according to the quintile of dietary variety scores (DVSs). In the 4-year follow-up study, multivariate logistic regression models were applied to investigate the associations between DVS subgroups and declines in mobility performance, physical function (activities of daily living (ADLs) and instrumental activities of daily living (IADLs)), cognitive function and depressive symptoms., Results: In this study, the DVS quintile identified people who were significantly vulnerable in diet quality. Among those in the lowest DVS quintile, the proportions consuming seafood, eggs, and beans/legumes per week were 0.3 %, 7.8 % and 12.6 %, respectively, while among those in the highest DVS quintile, the proportions were 40.2 %, 83.1 %, and 82.7 %, respectively. "Inverse" dose-response associations were observed between the DVS and the risks of decline in mobility performance, physical function (ADLs and IADLs), cognitive function, and depressive symptoms. These risks decreased with the higher DVS quintile group as compared to the lowest DVS quintile group. Even after adjustments for demographics, health behaviors (e.g., physical activity) and comorbidities, participants in the highest DVS quintile group were still associated with the lowest risk of decline in ADLs (adjusted odds ratio (aOR) 0.59 [95 % confidence interval (CI) 0.37-0.94], p < 0.05) and IADLs (aOR 0.53 [0.39-0.73], p < 0.01). However, no such association was observed in the risk of worsened mobility performance, cognitive function and depressive symptoms., Conclusions: In conclusion, higher dietary diversity has protective effects in declines in multidimensional outcomes associated with healthy aging, particularly physical functions (ADL and IADL), among community-dwelling middle-aged and older adults. Intervention studies are needed to confirm the causal relationships between dietary diversity and healthy aging., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Sarcopenia, defined as age-related diminution of muscle mass and strength, is a key determinant of frailty status and progression. We investigated the hypothesis that changing masseter muscle structure with advancing age may contribute to the development of frailty., Methods: Study data were excerpted from the I-Lan Longitudinal Aging Study, a research cohort of community-dwelling residents aged ≥53 years from Yilan (I-Lan) County, Taiwan. The study sample comprised 56 subjects classified as frail, 41 pre-frail, and 41 robust, according to Cardiovascular Health Study criteria; all groups were matched by age and sex. Masseter muscle volume was quantified based on T1-weighted magnetic resonance imaging, and adjusted for height to derive the masseter volume index (MVI). Appendicular skeletal muscle mass index (SMI) was determined by dual-energy X-ray absorptiometry, and used to derive the height-adjusted skeletal mass index (SMI). Nutrition status was assessed with the Mini-Nutritional Assessment (MNA) form., Results: The MVI was significantly smaller in frail versus pre-frail subjects. Among frail individuals, only the MVI was significantly correlated with MNA scores. MVI, but not SMI, was associated with increased risk of being frail versus pre-frail. An MVI cut-off score of 9.5 cm 3 /m 2 in males discriminated frail from pre-frail status with acceptable sensitivity and specificity. Low MVI was associated with the frailty criteria of slowness., Conclusions: MVI is a potential clinical index for evaluating phenotypic frailty. Diminished masseter muscle volume may predispose pre-frail/frail elders to depletion of physical reserves, consequent to its detrimental effect on oral functioning and nutrient intake., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Functional ability and intrinsic capacity are key elements of healthy aging, in which exercise and good nutrition play important roles. This 12-week double-blinded randomized controlled trial enrolled community-dwelling adults aged 50 years and older to examine the effects of Sarcojoint®, a comprehensive formula for the musculoskeletal system, plus resistance exercise on muscle mass. This study intended to enroll 80 participants with a randomly selected subsample of 32 participants (16 from the intervention group and 16 from controls) for magnetic resonance imaging (MRI) to assess the cross-sectional area of the bilateral mid-thighs. The participants were then randomly assigned to the intervention group (Sarcojoint® 1 package twice a day) and control group (vitamin B as placebo) at a 1: 1 ratio. All the participants were required to undergo a regular exercise program (45 min at the gym per week and two sessions of 30-min exercise at home). The data from 66 participants (68.1 ± 7.1 years and 16.7% males; intervention group: 32, control group: 34) were available for analysis. The whole study was pre-registered and data reporting followed Consolidated Standards of Reporting Trials with the primary endpoints of muscle mass, 30-s chair-rise test, and gait speed. Results of MRI were the subgroup analysis to examine muscle mass and intramuscular adiposity. The baseline characteristics of all the participants between groups were similar, as well as those of the MRI subgroups. Within-group comparisons showed that the intervention group, but not the control group, significantly reduced the total body fat percentage (34.3 ± 5.5 vs. 35.0 ± 5.4%, P = 0.021). Serum vitamin D was increased in the intervention group (24.1 ± 6.1 vs. 21.1 ± 7.0 ng/mL; P = 0.025) and was reduced in the control group (18.0 ± 5.2 vs. 20.2 ± 5.8 ng/mL; P = 0.006). The physical performance tests of both groups were significantly improved. The between-group analysis showed no significant differences in 30-s chair stand test, handgrip strength and appendicular muscle mass. The sub-group analysis showed significant improvement in the serum levels of vitamin D (6.70 ± 8.20 vs. -0.50 ± 3.90 ng/mL; P = 0.001) and the mid-thigh cross-sectional area of the nondominant legs (165.4 ± 291.4 vs. -61.1 ± 195.0 mm 2 ; P = 0.034) in the intervention group. In conclusion, Sarcojoint® plus resistance exercise significantly increased muscle mass and serum levels of vitamin D, but not significantly better in muscle strength and physical performance than controls. More investigations are needed to evaluate the long-term effects of Sarcojoint® on middle-aged and older adults., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: As a biomarker for anemia and nutritional status, hemoglobin may play various roles in the development of sarcopenia, but studies evaluating these roles are scarce. Hence, this study aimed to explore the associations between hemoglobin levels and sarcopenia and its components and to determine optimal cutoffs of hemoglobin for identifying sarcopenia., Methods: Data from 730 participants identified from the I-Lan Longitudinal Aging Study were retrieved. Anemia was defined by the World Health Organization criteria as a hemoglobin level <13 g/dL in men and <12 g/dL in women, and anemia status was divided into 5 groups (1 g/dL below cutoff, 0-1 g/dL below cutoff, 0-1 g/dL above cutoff, 1-2 g/dL above cutoff, and 2 g/dL above cutoff) for trend analysis. Sarcopenia was defined by the Asian Working Group for Sarcopenia 2019 criteria., Results: In total, 118 (16.2%) participants were anemic, and 62 (8.5%) participants were sarcopenic. A higher hemoglobin level was significantly associated with faster gait speed (p-trend, 0.037) and stronger handgrip strength (p-trend, 0.003). Anemia was significantly associated with sarcopenia (OR: 2.4, 95% CI: 1.2-4.9), weakness (OR: 1.6, 95% CI: 1.0-2.5) and slowness (OR: 2.0, 95% CI: 1.1-3.4). Stronger correlations between anemia and sarcopenia were found in men and those with severe disease burden., Conclusions: Hemoglobin levels were independently associated with sarcopenia, and the associations were stronger for muscle function than for muscle mass and in men than in women. Older adults with anemia had a higher risk of sarcopenia and muscle weakness, and further intervention studies are needed to clarify the causal relationship between anemia and sarcopenia., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: To investigate the prognostic significance of hospitalization-associated muscle weakness for short-term and long-term functional declines among oldest old hospitalized patients., Methods: We conducted a retrospective cohort study in the Geriatric Evaluation and Management Unit (GEMU) of a tertiary medical center in Taiwan. Data from patients admitted to the GEMU were collected, including demographic characteristics, underlying diseases, functional assessments, and nutritional status. Handgrip strength was measured at admission and before discharge, and hospitalization-associated muscle weakness was defined accordingly. Functional status was ascertained by a telephone survey, and functional decline was defined based on a comparison with each patient's functional status before discharge., Results: Overall, data from 555 patients were retrieved, and 431 patients (mean age: 86.0 ± 6.2 years, 78.5% males) were included in the study, with a mean Barthel Index score of 74.7 ± 20.8, Mini-Mental State Examination (MMSE) score of 19.1 ± 6.8, Geriatric Depression Scale (GDS-5) score of 2.2 ± 1.6, Mini-Nutritional Assessment-Short Form (MNA-SF) score of 8.9 ± 3.0, Cumulative Illness Rating Scale-Geriatric (CIRS-G) score of 2.2 ± 0.9, and the regular use of 6.7 ± 3.5 medications. Patients with a 1-month postdischarge functional decline had significantly lower body weight and body mass index, more severe frailty and more hospitalization-associated muscle weakness. Patients with a 6-month postdischarge functional decline had lower body weight, BMI, MMSE scores, MNA-SF scores, handgrip strength, Barthel Index scores, and Braden Scale scores. BMI (OR: 0.815, 95% CI: 0.691-0.962, P = 0.015) and hospitalization-associated muscle weakness (OR: 1.227, 95% CI: 1.147-1.332, P < 0.001) were significantly associated with a 1-month postdischarge functional decline. Hospitalization-associated muscle weakness (OR: 1.067, 95% CI: 1.035-1.101, P < 0.001), the risk of pressure sores (Braden Scale, OR: 0.767, 95% CI: 0.646-0.910, P = 0.002), and BMI (OR: 0.914, 95% CI: 0.838-0.998, P = 0.045) were independently associated with a 6-month postdischarge functional decline., Conclusions: Hospitalization-associated muscle weakness significantly predicts functional decline among oldest old patients hospitalized for acute conditions. Further interventional studies are needed to examine the causal relationship between hospitalization-associated muscle weakness and clinical outcomes., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Handgrip strength is associated with mild cognitive impairment. Tumor necrosis factor [TNF]-α and interleukin [IL]-6 were pro-inflammatory cytokines influencing the severity of initial neurological deficit. Visfatin is a novel adipokine and has a strong correlation with inflammation. The relationships of TNF-α, IL-6 and visfatin are not consistent, and no study has investigated them in the elderly patients with cognitive impairment., Methods: This study included patients aged ≥75 years at the emergency department from August 2018 to February 2019. All patients underwent comprehensive geriatric assessment and blood tests for fasting plasma TNF-α, IL-6 and visfatin levels., Results: We enrolled 106 elderly patients with a mean age of 87.3 years, including 62 (58.4%) patients in cognitive impairment group (Mini-Mental State Examination [MMSE] < 24) and 44 (41.5%) patients in the non-cognitive impairment group. Compared to the non-cognitive impairment group, the cognitive impairment group had significantly lower handgrip strength, and significantly higher TNF-α, IL-6 and visfatin levels. TNF-α positively correlated with IL-6. Both TNF-α and IL-6 negatively correlated with Barthel index and MMSE. Handgrip strength negatively correlated with TNF-α but positively correlated with Barthel index and MMSE scores. Backward and stepwise multiple logistic regression analyses showed that the independent predictor for cognitive impairment was handgrip strength and age., Conclusion: The cognitive impairment group had significantly higher serum TNF-α, IL-6, and visfatin levels. The independent predictors of cognitive impairment were handgrip strength and age. Handgrip strength negatively correlated with TNF-α and IL-6 but positively with Barthel index and MMSE scores., (Copyright © 2020. Published by Elsevier Inc.)

Objective: The optimal time after hip fracture to start prophylactic anti-osteoporosis medications (AOMs) remains uncertain, especially in real-world practice. Therefore, we investigated how timing of AOMs initiation affects the risk of subsequent osteoporotic fractures, and what factors influence timing of AOMs prescription., Method: Patients ≥50 years old with diagnostic codes indicating hospitalization for hip fracture (n = 77,930) were identified from the Taiwan National Health Insurance Research Database; 9986 who were prescribed AOMs ≤1 year after a newly-diagnosed hip fracture were grouped into those who started AOMs from: ≤14 days (very early); 15-84 days (early); 85-252 days (late); and 253-365 days (very late). Associations with fracture-related hospitalizations after an index fracture were analyzed using a multivariate, time-dependent Cox proportional hazards model, and between-group differences compared by log-rank testing. Factors influencing timing of AOMs initiation were elucidated using multivariate logistic regression analyses., Results: Compared to AOMs initiation from 15 to 84 days, initiation after 252 days was associated with significantly increased risk of fracture-related hospitalization (HR = 1.93, 95% CI 1.29-2.89). Both sensitivity and pre-specified subgroup analyses yield similar results. Among patients with high adherence to AOMs, the increased risk of subsequent fracture-related hospitalization among very late users was profound (HR = 2.56, 95% CI 1.41-4.64)., Conclusion: Timing of AOMs initiation was significantly associated with age, index year, index hospital length of stay as well as the accreditation level and geographic region of index hospital. After adjusting factors associated with timing of AOMs initiation and patients' adherence, the anti-fracture benefit of AOMs still depends crucially on the timely initiation of AOMs., Competing Interests: Declaration of competing interest All authors state that they have no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Both serum homocysteine and high sensitivity C - reactive protein (hsCRP) are inflammatory markers related to vascular aging. Little was known about relationship between hsCRP and homocysteine and sarcopenia. The study aimed to explore the association between these two biomarkers and sarcopenia and its components., Methods: Data of 1582 participants excerpted from first wave of I-Lan Longitudinal Aging Study. Sarcopenia was defined according to criteria of the Asian Working Group of Sarcopenia. Logistic regression was employed to examine the aforementioned associations., Results: High levels of homocysteine (OR 1.9, 95% CI 1.0-3.6) and hsCRP (OR 3.9, 95% CI 2.2-6.9) were independently associated with sarcopenia. Both biomarkers were significantly associated with weakness (OR 2.9, 95%CI 2.1-4.0 for high level of homocysteine; OR 1.6, 95% CI 1.2-2.0 for high level of hsCRP) and slowness (OR 2.0, 95%CI 1.3-3.0 for high level of homocysteine; OR1.5, 95% CI1.1-2.2 for high level of hsCRP). Stronger associations between high levels of homocysteine and sarcopenia were noted in the women., Conclusion: The study confirmed positive association between homocysteine, hsCRP and sarcopenia and further highlighted potential roles of both biomarkers in sarcopenia development. Intervention studies are needed to evaluate potential therapeutic benefits of lowering homocysteine and hsCRP in managing sarcopenia., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cardiovascular disease imposes substantial burdens of morbidity and mortality that increase with population aging. Estimating cardiometabolic risk accurately and expediently is challenging, and no single biomarker is satisfactory; hence, we investigated the potential of serum activin A for this purpose. Study data were collected from 433 community-dwelling adults age ≥53 years from Yilan County, Taiwan. Data included: demographics and medical history; physical measurements (blood pressure, body mass index, waist circumference); comprehensive functional assessments (frailty, cognitive function, depressive symptoms, nutritional status); fasting blood biochemistry (glucose, high-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein, insulin-like growth factor-1, activin A, stratified into high, medium and low tertiles, and others); and dual-energy X-ray absorptiometry. Metabolic syndrome was considered a proxy for overall cardiometabolic risk. Subjects mean age was 69.3 ± 9.2 years, 48.3% were males. Compared to women, men had higher systolic blood pressure, education levels, relative appendicular skeletal muscle mass, waist circumference, physical activity, walking speed, free androgen index, and levels of serum uric acid, alanine aminotransferase, and dehydroepiandrosterone sulfate. High activin A was significantly associated with age, relative appendicular skeletal muscle mass in both gender, waist circumference in women, current alcohol drinking, hypertension, and Charlson Comorbidity Index. There were dose-dependent relationships (low to high) between serum activin A and frailty, cognitive impairment, malnutrition, metabolic syndrome, uric acid, and high-sensitivity C-reactive protein. Logistic regression analyses showed older age, serum uric acid, and metabolic syndrome were significantly associated with medium and high activin-A status, whereas, skeletal muscle mass, insulin-like growth factor-1 and dehydroepiandrosterone sulphate were associated with high, but not medium, serum activin A. This discovery of a dose-dependent association between serum activin A levels, age, and metabolic syndrome, suggests activin A may be a biomarker of overall cardiometabolic risk; however, further studies are needed to evaluate its potential applications in assessing and managing cardiometabolic risk., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Since the operational definition of "cognitive frailty" was first proposed in 2013 by the International Academy of Nutrition and Aging and the International Association of Gerontology and Geriatrics, several studies have been carried out using this cognitive frailty model. In this review, we examined the available clinical and epidemiological evidence for cognitive frailty. Despite its low prevalence (1.0-1.8%) in the community setting, cognitive frailty has been associated with a high risk of disability, poor quality of life, and death; while cognitive frailty appears to be associated with a high risk of dementia, there is no clear evidence for this association. Again, while the prevalence of cognitive frailty appears to have increased in the clinical setting, to date, very few studies evaluated the impact of cognitive frailty. While a new definition of cognitive frailty was proposed in 2015 to incorporate "reversible" and "potential reversible" subtypes, there is a paucity of epidemiological evidence to support this definition. In conclusion, there is no consensus on the definition of cognitive frailty for use in clinical and community settings or on which measures to be used for detecting cognitive impairment. Further study is required to formulate effective preventive strategies for disability in the elderly., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Muscle mass and strength ineluctably decline with advancing age. Yet, the impact of ethnicity on the pattern of changes and their magnitude is unclear. The aims of the present study were to analyze age- and gender-specific changes in measures of muscle mass and strength among community-living persons and to identify differences between Caucasian and Asian participants., Methods: The Italian survey ("Longevity Check-up"), conducted during Milan EXPO 2015, consisted of a population assessment aimed at evaluating the prevalence of specific health metrics in persons outside of a conventional research setting (n=1924), with a special focus on muscle mass and strength. The Taiwanese survey used the first-wave sampling from the I-Lan Longitudinal Aging Study (ILAS) collected from August 2011 to August 2013 (n=1839). ILAS was designed to explore the interrelationship between sarcopenia and frailty in community-dwelling older people in Taiwan. In both studies, muscle mass was estimated by measuring the calf circumference (CC), whereas muscle strength was assessed by handgrip strength testing., Results: The mean age of the 1924 Italian participants was 62.5years (standard deviation 8.3, range from 50 to 98years), of whom 1031 (53.6%) were women. Similarly, the mean age of the Taiwanese sample was 63.9years (standard deviation 9.3, range from 50 to 92years), with 966 (52.5%) women. CC declined with age in both genders and was significantly greater among Italian participants compared with Taiwanese people in all age groups. A similar effect of age was observed for muscle strength. As for CC, muscle strength was significantly greater among Italian persons relative to Taiwanese participants., Conclusion: Muscle mass and strength declined with age in both ethnic groups. Caucasians showed greater muscle mass and performed better than their Asian counterparts. However, the age at which declines began to appear and the rate of decline during aging were comparable between the two populations., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The efficacy and safety of ZOSTAVAX in subjects 60 years of age and older was established in the Shingles Prevention Study (SPS) and in subjects 50 to 59 years of age in the ZOSTAVAX Efficacy and Safety Trial (ZEST). We evaluated the safety and immunogenicity of ZOSTAVAX in a total of 150 Taiwanese subjects ≥50 years of age, who received a single dose of ZOSTAVAX. gpELISA was used to determine geometric mean titers (GMT) of the varicella-zoster virus (VZV) antibody. The geometric mean fold rise (GMFR) of the VZV antibody from the pre-vaccination to the 4 week post-vaccination time point was calculated. There was an overall increase in GMT from 128.45 to 391.85 at 4 weeks post-vaccination. The estimated GMFR was 3.05 (95% CI: 2.60 to 3.57).There were no serious adverse events for 28 days following vaccination. This study demonstrated the safety and immunogenicity of ZOSTAVAX among healthy Taiwanese adults., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The overexpression of ATP-binding cassette (ABC) transporters often leads to the development of multidrug resistance (MDR), which is the major factor contributing to the failure of chemotherapy. The objective of this study was to investigate the enhancement of CEP-33779, a small-molecule inhibitor of Janus kinase 2 (JAK2), on the efficacy of conventional chemotherapeutic agents in MDR cells with overexpression of P-glycoprotein (ABCB1), multidrug resistance-associated protein 1 (ABCC1) and breast cancer resistance protein (ABCG2). Our results showed that CEP-33779, at nontoxic concentrations, significantly sensitized ABCB1 overexpressing MDR cells to its anticancer substrates. CEP-33779 significantly increased intracellular accumulation and decreased the efflux of doxorubicin by inhibiting the ABCB1 transport function. Furthermore, CEP-33779 did not alter the expression of ABCB1 both at protein and mRNA levels but did stimulate the activity of ABCB1 ATPase. CEP-33779 was predicted to bind within the large hydrophobic cavity of homology modeled ABCB1. In addition, the down-regulation of JAK2 by shRNA altered neither the expression of ABCB1 nor the cytotoxic effect of chemotherapeutic agents in ABCB1-overexpressing cells. Significantly, CEP-33779 enhanced the efficacy of vincristine against the ABCB1-overexpressing and drug resistant KBv200 cell xenograft in nude mice. In conclusion, we conclude that CEP-33779 enhances the efficacy of substrate drugs in ABCB1-overexpressing cells by directly inhibiting ABCB1 transport function. The findings encouraged to further study on the combination therapy of CEP-33779 with conventional chemotherapeutic agents in ABCB1 mediated-MDR cancer patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In this study we developed a tissue engineered bulking agent that consisted of adipose-derived stem cells (ADSCs) and silk fibroin microspheres to treat stress urinary incontinence caused by severe intrinsic sphincter deficiency (ISD). ISD models were established by completely transection of the bilateral pudendal nerve (PNT) and confirmed by the decreased leak-point pressure (LPP) and increased lumen area of urethra. Injection of silk fibroin microspheres could recover LPP and lumen area at 4 weeks but its efficacy disappears at 8, 12 weeks. Moreover, it was exciting to find that tissue engineered bulking agent brought long-term efficacy (at 4, 8, 12 weeks post-injection) on the recovery of LPP and lumen area. Concomitantly with the function, tissue engineered bulking agent treated group also improved the urethral sphincter structure as exhibited by better tissue regeneration. The findings showed that silk fibroin microspheres alone could work effectively in short-term, while tissue engineered bulking agent that combined silk fibroin microspheres with ADSCs exhibited promising long-term efficacy. This study developed a new strategy of tissue engineered bulking agent for future ISD therapy., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Little is known about the emergency department (ED) visits from drug-related injury among older adults in Taiwan. This study seeks to identify risk factors associated with adverse drug events (ADEs) leading to ED visits., Methods: We prospectively conducted a case-control study of patients 65years and older presenting to the ED. ED visits between March 1, 2009 and Feb 28, 2010 identified by investigators for suspected ADEs were further assessed by using the Naranjo Adverse Drug Reaction probability scale. For each patient with an ADE, a control was selected and time-matched from the ED population of the study hospital. The association between the risk of adverse drug events and triage, age, gender, serum alanine transaminase (ALT), serum creatinine, number of medications, and Charlson Comorbidity Index scores were analyzed using logistic regression., Results: Of 20,628 visits, 295 ADEs were physician-documented in older adults. Independent risk factors for ADEs included number of medications (adjusted odds ratio [OR]=4.1; 95% confidence interval [CI] 2.4-6.9 for 3-7 drugs; adjusted OR=6.4; 95% CI 3.7-11.0 for 8 or more drugs) and increased concentration of serum creatinine (adjusted OR=1.5; 95% CI 1.1-2.2). Diuretics, analgesics, cardiovascular agents, anti-diabetic agents and anticoagulants were the medications most commonly associated with an ADE leading to ED visits., Conclusions: This study suggests that prevention efforts should be focused on older patients with renal insufficiency and polypharmacy who are using high risk medications such as anticoagulants, diuretics, cardiovascular agents, analgesics, and anti-diabetic agents., (© 2013. Published by Elsevier B.V. on behalf of European Federation of Internal Medicine. All rights reserved.)

Objective: To assess the risk factors for progressive deterioration of semen quality (PDSQ) in adult patients with varicocele., Methods: A total of 32 men with left varicocele and impaired semen quality (group 1) and 30 age-matched patients with left varicocele and normal semen quality (group 2) were recruited for the present study. All the subjects received conservative treatment, and the parameters for evaluation every 12 months included semen quality, peak retrograde flow (PRF) and spontaneous venous reflux by color Doppler ultrasonography, body mass index, serum concentration of follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, testicular volume and discrepancy, grade of varicocele, and scrotal temperature., Results: The mean follow-up time was 63.2 months (range 60-66). The patients in group 1 had a significantly greater PRF, lower testicular volume, greater testicular volume discrepancy, lower testosterone level, higher scrotal temperature, and greater follicle-stimulating hormone level than those in group 2 at first. The semen quality deteriorated in 28 subjects (87.5%) in group 1, but in only 6 patients (20%) in group 2 during follow-up. Furthermore, the 6 subjects with PDSQ in group 2 had greater PRF and scrotal temperature than those without., Conclusion: The rate of PDSQ was significantly greater in the varicocele patients with an initially abnormal semen quality than in those with initially normal semen quality (87.5% vs 20%). Furthermore, the varicocele patients with initially normal semen quality who had greater PRF and scrotal temperature might have a greater risk of PDSQ., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Cationic polyurethane, a biodegradable non-viral vector, protects DNA from nuclease degradation and helps to deliver genes efficiently. Oct4, a POU-domain transcription factor, is highly expressed in maintaining pluripotency and cellular reprogramming process in stem cells. SirT1, a NAD-dependent histone deacetylase, is an essential mediator of cellular longevity. Herein we demonstrated that both Oct4 and SirT1 (Oct4/SirT1) expression was decreased in an age-dependent manner in retina with aged-related macular degeneration and retinal pigment epithelium cells (RPEs). To investigate the possible rescuing role of Oct4/SirT1, polyurethane-short branch polyethylenimine (PU-PEI) was used to deliver Oct4/SirT1 into aged RPEs (aRPEs) or light-injured rat retinas. Oct4/SirT1 overexpression increased the expression of several progenitor-related genes and the self-renewal ability of aRPEs. Moreover, Oct4/SirT1 overexpression resulted in the demethylation of the Oct4 promoter and enhanced the expression of antioxidant enzymes, which was accompanied by a decrease in intracellular ROS production and hydrogen peroxide-induced oxidative stress. Importantly, PU-PEI-mediated Oct4/SirT1 gene transfer rescued retinal cell loss and improved electroretinographic responses in light-injured rat retinas. In summary, these data suggest that PU-PEI-mediated delivery of Oct4/SirT1 reprograms aRPEs into a more primitive state and results in cytoprotection by regulating the antioxidative capabilities of these cells., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Induced pluripotent stem cells (iPSCs) with four reprogramming factors (Oct-4/Sox2/Klf-4/c-Myc) have been shown to differentiate into hepatic lineages. However, it was unclear whether obviation of the c-Myc oncogene in iPSCs affected hepatic differentiation or inhibited in vivo tumor formation. In this study, we demonstrated that iPSCs without c-Myc had the capacity to differentiate into hepatocyte-like cells (iPSC-Heps) with biological functions. As detected using planar-radionuclide imaging and Hoechst labeling assays, these iPSCs and iPSC-Heps tended to mobilize to the injured liver area in thioacetamide (TAA)-treated mice. Intravenous transplantation of both iPSCs and iPSC-Heps but not mouse embryonic fibroblasts (MEFs) reduced the hepatic necrotic area, improved liver functions, and rescued TAA-treated mice from lethal acute hepatic failure (AHF). In addition, microarray-based bioinformatics and quantitative RT-PCR showed high expression of antioxidant genes in iPSCs and iPSC-Heps compared to MEFs. In vivo and in vitro studies of NAC pretreatment confirmed that iPSCs and iPSC-Heps potentially suppressed ROS production and activated antioxidant enzymes in TAA-injured livers. Six months after transplantation in TAA-treated mice, tumor formation was not seen in non-c-Myc iPSC grafts. Therefore, reprogramming adult somatic cells without c-Myc may prevent oxidative stress-induced damage and provide a safer alternative for hepatic regeneration in AHF., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Taiwan is one of the fastest aging countries in the world. As such, the government has developed various strategies to promote an age-friendly health-care system. Health services are supported by National Health Insurance (NHI), which insures over 97% of citizens and over 99% of health-care institutes. The current health-care system has difficulties in caring for older patients with multiple comorbidities, complex care needs, functional impairments, and post-acute care needs. Taipei, an international metropolis with a well-preserved tradition of filial piety in Chinese societies, has developed various strategies to overcome the aforementioned barriers to an age-friendly health-care system. These include an emphasis on general medical care and a holistic approach in all specialties, development of a geriatrics specialty training program, development of post-acute services, and strengthening of linkages between health and social care services. Despite achievements thus far, challenges still include creating a more extensive integration between medical specialties, promotion of an interdisciplinary care model across specialties and health-care settings, and integration of health and social care services. The experiences of Taipei in developing an age-friendly health-care service system may be a culturally appropriate model for other Chinese and Asian communities., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Human longevity is a complex phenotype with a strong genetic predisposition. Increasing evidence has revealed the genetic antecedents of human longevity. This article aims to review the data of various case/control association studies that examine the difference in genetic polymorphisms between long-lived people and younger subjects across different human populations. There are more than 100 candidate genes potentially involved in human longevity; this article particularly focuses on genes of the insulin/IGF-1 pathway, FOXO3A, FOXO1A, lipoprotein metabolism (e.g., APOE and PON1), and cell-cycle regulators (e.g., TP53 and P21). Since the confirmed genetic components for human longevity are few to date, further precise assessment of the genetic contributions is required. Gaining a better understanding of the contribution of genetics to human longevity may assist in the design of improved treatment methods for age-related diseases, delay the aging process, and, ultimately, prolong the human lifespan., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The prevalence and incidence of type 2 diabetes mellitus (DM) increase with age, and its diagnosis and treatment in older people present a challenge. Applying evidence to elderly patients can be problematic, because older persons with frailty, multiple comorbidities, and functional disabilities are generally excluded from diabetes clinical trials. Frailty is characterized by multisystem decline and vulnerability to adverse health outcomes. Insulin resistance predicts frailty, and DM accelerates muscle strength loss. Geriatric diabetes care guidelines have refocused from risk factor control to geriatric syndromes. The European Diabetes Working Party guidelines for elderly type 2 DM patients consider frailty, recommending a conservative target (hemoglobin A1c <8%). Diabetic care-home residents with physical disabilities, cognitive impairment, tube feeding, and the inability to communicate pose particular challenges. Tight glycemic control for such patients increases the risk of hypoglycemia and significant functional decline; a mean hemoglobin A1c <7% did not protect them from care-home-acquired pneumonia. In conclusion, caring for elderly diabetic patients poses unique challenges. Little is known about diabetes care of elderly people with frailty, disabilities, or multiple comorbidities. The interrelationship between frailty and DM deserves further investigation. Practice guidelines for care-home residents with DM are needed to ensure quality of care., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Objectives: This study was to improve human cell growth on titanium (Ti) used for dental implants through formation of a nano-network surface oxide layer created by an electrochemical anodization treatment., Methods: An electrochemical anodization treatment was used to produce a network oxide layer on Ti surface. Surface characterization of the network layer was carried out using thin film X-ray diffractometer and field emission scanning electron microscopy. Human bone marrow mesenchymal stem cells (hMSCs) were made to express green fluorescent protein (GFP) by retroviral transduction. The GFP signal was measured in situ to assess in vitro and in vivo cell growth on Ti surfaces. In vivo experiments on Ti-supported cell growth were carried out on the back skin of nude mice. Alizarin red staining and immunofluorescent staining were used to observe cell differentiation., Results: A multilayer TiO(2) nano-network was produced rapidly on Ti surface using a simple electrochemical anodization treatment. The TiO(2) nano-network layer on the anodized Ti surfaces significantly improved in vitro and in vivo hMSC growth, as assessed by measurement of GFP fluorescence, relative to hMSC growth on untreated Ti surface. The TiO(2) nano-network layer on the anodized Ti surfaces can also induce the differentiation of hMSCs after 28-day in vivo test., Significance: The formation of TiO(2) nano-network on the Ti surfaces can increase the hMSC growth in vitro and in vivo.

Chelonianin, originally isolated from the shrimp (Penaeus monodon), exhibits antimicrobial effects in vitro and in vivo and is used to treat infectious fish diseases. Herein, we report that the recombinant chelonianin protein fused to a fluorescent protein (rcf protein) was expressed from a stably transfected Chinese hamster ovary (CHO) cells. The in vitro experiments showed that the rcf protein exhibited antimicrobial activity against several bacteria, while the recombinant fluorescent protein alone did not. In addition, pretreatment and post-treatment with the rcf protein were both effective in promoting a significant decrease in fish mortality and decreasing the number of infectious bacteria. We utilized the quantitative reverse-transcriptase polymerase chain reaction technique to survey the levels of gene expressions of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide synthase 1 induced in response to bacterial infection in experiments with tilapia (Oreochromis mossambicus). Our results indicated that the rescue of fish treated with the rcf protein may involve regulation of TNF-alpha expression. Collectively, chelonianin inhibited the production of an inflammatory mediator and reduced mortality in fish during bacterial challenge, suggesting that it has potential as a therapeutic or prophylactic drug for use against bacterial infectious diseases.

To evaluate the potential of DNA vaccine against dengue (DEN) infection, we characterize the protective efficacy and immune responses of mice intramuscularly injected with plasmid encoding DEN-2 non-structural protein 1 (NS1). Intravenously challenged by lethal DEN-2, mice vaccinated with NS1-DNA exhibited a delay onset of paralysis, a marked decrease of morbidity, and a significant enhancement of survival. In addition to a moderate increase of NS1-specific antibody titer from immunized mice measured by ELISA, a strong priming effect on anti-NS1 response was also noticed in plasmid NS1-vaccinated mice by radioimmunoprecipitation (RIP) or immunoblot analysis. Interestingly, newborn mice from NS1-DNA-immunized dam showed stronger resistance to viral challenge, as compared to those from vector DNA or PBS-immunized dams, indicating the protective role of NS1-specific antibody. In contrast to humoral immune response, DNA immunization can elicit strong cellular immune responses, including NS1-specific T cell proliferation and cytolytic activity. The NS1-DNA-induced protection can be further augmented by co-injection of plasmid encoding interleukin 12 (IL-12), suggesting an effector role of Th1 immunity against DEN infection. In summary, our results suggest the potential of NS1-DNA vaccine against DEN infection, and indicate both NS1-specific humoral and cellular immune responses contribute to the protection.

An indirect enzyme-linked immunosorbent assay (ELISA) was developed to detect and differentiate the antibody responses to Japanese encephalitis (JE) virus nonstructural protein NS1 between infected and vaccinated individuals. The results showed that all convalescent sera from JE patients contained NS1-specific IgG antibodies, while 65 and 40% of these sera showed detectable NS1-specific IgM and IgA antibodies, respectively. Specificity analysis showed that NS1-specific IgM and IgA antibodies from JE patients do not cross-react to dengue virus NS1 glycoprotein, while IgG antibodies from 10% of JE patients showed significant cross-reaction to dengue virus NS1 glycoprotein. To differentiate infection from vaccination, the immune sera from 24 children vaccinated with inactivated JE vaccine were analyzed. The data showed that none of these immune sera had detectable NS1-specific IgG antibodies. The results demonstrated the potential application of JE NS1-specific indirect ELISA to differentiate infection from vaccination.

A pair of virulent (RP-9) and attenuated (RP-2ms) mutants of Japanese encephalitis virus (JEV) were generated from a Taiwanese isolate NT109. The mutants differed in several aspects in vitro and in vivo. RP-2ms exhibited smaller plaque than RP-9 on BHK-21 cells, and when intracerebrally injected, RP-2ms was much less neurovirulent than RP-9. As peripherally inoculated, RP-2ms lost neuroinvasiveness while RP-9 penetrated blood-brain barrier, replicated in mouse brain, and killed all the mice. Single RP-2ms immunization completely protected C3H and ICR mice from a lethal challenge with RP-9; the sera from such mice contained antibodies against JEV envelope and nonstructural 1 proteins, indicating RP-2ms had replicated in the mice Neutralizing activity against NT109 in such sera was further demonstrated by plaque reduction neutralization test. In addition, significant lymphoproliferation was detected in spleen cells from the RP-2ms-immunized mice, and cytotoxic activity in these cells specific for the MHC-matched, JEV-infected cells, but not mock cells, was also observed. Altogether, these results demonstrate that RP-2ms, a highly attenuated JEV strain, can induce a protective immunity in mice.

Two flaviviruses, Japanese encephalitis (JE) virus and Dengue (DEN) virus which have high pathogenicity for humans, continue to pose a serious public health problem in tropical and subtropical countries of the world. In order to identify the immunodominant B-cell epitopes for diagnostic application, we have prepared a series of 15-mer synthetic peptides from JE virus core protein based on computer analysis. Four linear, immunodominant epitopes corresponding to amino acids 91-105 (P78), 1-15 (P73), 8-22 (P74), and 34-48 (P75) of JE virus core proteins were identified by employing an enzyme-linked immunosorbent assay (ELISA), using high-titered immune sera from JE-vaccinated children. P78 was found to be the most immunodominant. The sero-specificity of these peptides was tested by binding to seroconverted samples from JE and DEN-1 patients. P78 and P74 belonged to group-specific epitopes which reacted with both JE and DEN-1 patient sera. P73 and P75 belonged to subcomplex-specific epitopes which reacted only with JE but not with DEN-1 patient sera. The study suggests that these peptides corresponding to the immunodominant epitopes of JE virus core protein might have the potential to be used as peptide-based diagnostic reagents for the detection and differentiation of JE and DEN antibody responses.