Multimorbidity measures associated with cognitive function among community-dwelling older Chinese adults.

INTRODUCTION: Older adults with multimorbidity are at high risk of cognitive impairment development. There is a lack of research on the associations between different multimorbidity measures and cognitive function among older Chinese adults living in the community. METHODS: We used the Chinese Longitudinal Healthy Longevity Survey from 2002 to 2018 and included data on dementia-free participants aged ≥65 years. Multimorbidity measures included condition counts, multimorbidity patterns, and trajectories. The association of multimorbidity measures with cognitive function was examined by generalized estimating equation and linear and logistic regression models. RESULTS: Among 14,093 participants at baseline, 43.2% had multimorbidity. Multimorbidity patterns were grouped into cancer-inflammatory, cardiometabolic, and sensory patterns. Multimorbidity trajectories were classified as "onset-condition," "newly developing," and "severe condition." The Mini-Mental State Examination scores were significantly lower for participants with more chronic conditions, with cancer-inflammatory/cardiometabolic/sensory patterns, and with developing multimorbidity trajectories. DISCUSSION: Condition counts, sensory pattern, cardiometabolic pattern, cancer-inflammatory pattern, and multimorbidity developmental trajectories were prospectively associated with cognitive function. HIGHLIGHTS: Elderly individuals with a higher number of chronic conditions were associated with lower MMSE scores in the Chinese Longitudinal Healthy Longevity Survey data. MMSE scores were significantly lower for participants with specific multimorbidity patterns. Individuals with developing trajectories of multimorbidity were associated with lower MMSE scores and a higher risk of mild cognitive impairment.

KLF13 restrains Dll4-muscular Notch2 axis to improve the muscle atrophy.

BACKGROUND: Muscle atrophy can cause muscle dysfunction and weakness. Krüppel-like factor 13 (KLF13), a central regulator of cellular energy metabolism, is highly expressed in skeletal muscles and implicated in the pathogenesis of several diseases. This study investigated the role of KLF13 in muscle atrophy, which could be a novel therapeutic target. METHODS: The effects of gene knockdown and pharmacological targeting of KLF13 on skeletal muscle atrophy were investigated using cell-based and animal models. Clofoctol, an antibiotic and KLF13 agonist, was also investigated as a candidate for repurposing. The mechanisms related to skeletal muscle atrophy were assessed by measuring the expression levels and activation statuses of key regulatory pathways and validated using gene knockdown and RNA sequencing. RESULTS: In a dexamethasone-induced muscle atrophy mouse model, the KLF13 knockout group had decreased muscle strength (N) (1.77 ± 0.10 vs. 1.48 ± 0.16, P < 0.01), muscle weight (%) [gastrocnemius (Gas): 76.0 ± 5.69 vs. 60.7 ± 7.23, P < 0.001; tibialis anterior (TA): 75.8 ± 6.21 vs. 67.5 ± 5.01, P < 0.05], and exhaustive running distance (m) (495.5 ± 64.8 vs. 315.5 ± 60.9, P < 0.05) compared with the control group. KLF13 overexpression preserved muscle mass (Gas: 100 ± 6.38 vs. 120 ± 14.4, P < 0.01) and the exhaustive running distance (423.8 ± 59.04 vs. 530.2 ± 77.45, P < 0.05) in an in vivo diabetes-induced skeletal muscle atrophy model. Clofoctol treatment protected against dexamethasone-induced muscle atrophy. Myotubes treated with dexamethasone, an atrophy-inducing glucocorticoid, were aggravated by KLF13 knockout, but anti-atrophic effects were achieved by inducing KLF13 overexpression. We performed a transcriptome analysis and luciferase reporter assays to further explore this mechanism, finding that delta-like 4 (Dll4) was a novel target gene of KLF13. The KLF13 transcript repressed Dll4, inhibiting the Dll4-Notch2 axis and preventing muscle atrophy. Dexamethasone inhibited KLF13 expression by inhibiting myogenic differentiation 1 (i.e., MYOD1)-mediated KLF13 transcriptional activation and promoting F-Box and WD repeat domain containing 7 (i.e., FBXW7)-mediated KLF13 ubiquitination. CONCLUSIONS: This study sheds new light on the mechanisms underlying skeletal muscle atrophy and potential drug targets. KLF13 regulates muscle atrophy and is a potential therapeutic target. Clofoctol is an attractive compound for repurposing studies to treat skeletal muscle atrophy.

Cystatin C is a predictor for long-term All-Cause and Cardiovascular Mortality in US Adults with Metabolic Syndrome.

OBJECTIVE: This study examined the relationship between Cystatin C (CysC) levels and all-cause, CVD, and cancer mortality in US metabolic syndrome (MetS) patients. METHODS: The 1999-2002 National Health and Nutrition Examination Survey (NHANES) prospective cohort research included 1,980 MetS participants. To assess CysC levels and all-cause, CVD, and cancer mortality, fitted curves, Kaplan-Meier survival curves, cox regression analysis, and ROC curves were performed. RESULTS: During a mean follow-up of 15.3 ± 5.4 years, a total of 819 deaths occurred. The fitted and Kaplan-Meier survival curves revealed that greater CysC levels were linked to higher all-cause, CVD, and cancer mortality rates (P<0.05). After adjusting for variables, CysC level was associated with all-cause, CVD, and cancer mortality at 1.63 (1.42-1.88), 1.53 (1.19-1.95), and 1.53 (1∼2.32), respectively (P<0.05). Later tertile models showed consistent results. High CysC tertile participants showed higher risk of all-cause mortality (HR 1.87; 1.43-2.45), CVD mortality (HR 1.97, 1.15∼3.38), and cancer mortality (HR 1.72, 1.01∼2.91) compared to those in the lowest tertile (P<0.05). Subgroup studies by sex and other characteristics confirmed the findings. CysC demonstrated the higher predictive efficacy across mortality outcomes, followed by eGFR, outperforming Urea nitrogen, Creatinine, Uric acid, and CRP. CysC alone exhibited substantial predictive value for all-cause (AUC 0.773; P<0.05) and CVD mortality (AUC 0.726; P<0.05). Combining CysC with age enhanced the predictive value for all-cause mortality to 0.861 and CVD mortality to 0.771 (P<0.05). CONCLUSION: MetS patients with elevated CysC levels have a higher risk of all-cause, CVD, and cancer death. CysC may predict MetS all-cause and CVD mortality.

Association of Handgrip Strength with Hip Fracture and Falls in Community-dwelling Middle-aged and Older Adults: A 4-Year Longitudinal Study.

OBJECTIVE: Hip fracture and falls are significant health concerns. Handgrip strength (HGS) is closely associated with overall muscle strength and physical health. However, the longitudinal relationship between HGS and the risk of hip fractures and falls remains unclear, particularly regarding gender differences. This longitudinal study aimed to investigate the association between HGS and the risk of hip fracture and falls in individuals aged 45 years and above, considering gender-specific differences over a 4-year period. METHODS: This study included 10,092 participants (4471 men and 5621 women) aged 45 years and above from the China Health and Retirement Longitudinal Study (CHARLS). Incidents of hip fractures and falls were recorded during a 4-year follow-up, along with various demographic and clinical factors. Participants were categorized into five groups based on their HGS quintiles. Logistic regression models were employed to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) to assess the relationship between HGS and hip fracture/fall risk. RESULTS: During the 4-year follow-up period, 223 cases of hip fracture (2.2%) and 1831 cases of falls (18.1%) were documented. Notably, higher HGS demonstrated a strong inverse association with the risk of hip fracture in both males and females (p < 0.05). In comparison to the lowest HGS quintile, the adjusted odds ratios (ORs) for hip fracture were 0.46 (0.27-0.78) for the total population, 0.4 (0.19-0.81) for males and 0.48 (0.23-0.98) for females in the highest HGS quintile. Furthermore, a profound and statistically significant negative correlation between HGS and falls was detected (p < 0.05). The adjusted ORs for falls in the highest HGS quintile, compared to the lowest quintile, were 0.62 (0.51-0.76) in the overall population, 0.59 (0.44-0.78) in males, and 0.78 (0.62-0.99) in females. CONCLUSION: Our findings highlight the significant inverse association between HGS and the risk of hip fracture and falls in both males and females aged 45 years and above. Assessing handgrip strength may serve as a valuable tool for predicting fracture and fall risk.

Magnesium Depletion Score and Metabolic Syndrome in US Adults: Analysis of NHANES 2003-2018.

BACKGROUND: The association between magnesium status and metabolic syndrome remains unclear. This study aimed to examine the relationship between the kidney reabsorption-related magnesium depletion score (MDS) and metabolic syndrome among US adults. METHODS: We analyzed data from 15,565 adults participating in the National Health and Nutrition Examination Survey (NHANES) 2003-2018. Metabolic syndrome was defined according to the National Cholesterol Education Program's Adult Treatment Panel III report. The MDS is a scoring system developed to predict the status of magnesium deficiency that fully considers the pathophysiological factors influencing the kidneys' reabsorption capability. Weighted univariate and multivariate logistic regression were used to assess the association between MDS and metabolic syndrome. Restricted cubic spline analysis was conducted to characterize dose-response relationships. Stratified analyses by sociodemographic and lifestyle factors were also performed. RESULTS: In both univariate and multivariate analyses, higher MDS was significantly associated with increased odds of metabolic syndrome. Each unit increase in MDS was associated with approximately a 30% higher risk for metabolic syndrome, even after adjusting for confounding factors (OR 1.31; 95% CI 1.17-1.45). Restricted cubic spline graphs depicted a linear dose-response relationship across the MDS range. This positive correlation remained consistent across various population subgroups and exhibited no significant interaction by age, gender, race, adiposity, smoking status, or alcohol consumption. CONCLUSIONS: Higher urinary magnesium loss as quantified by MDS may be an independent linear risk factor for metabolic syndrome in US adults, irrespective of sociodemographic and behavioral factors. Optimizing magnesium nutritional status could potentially confer benefits to patients with metabolic syndrome.

The association of handgrip strength with all-cause and cardiovascular mortality: results from the National Health and Nutrition Examination Survey database prospective cohort study with propensity score matching.

Objective: To investigate the association between handgrip strength (HGS) with all-cause and cardiovascular disease (CVD) mortality in US adults. Method: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) prospective cohort study (2011-2014) with 10,470 participants. The cox regression analysis, Kaplan-Meier survival curves, fitted curves, ROC curves, and propensity score-matched analysis (PSM) with inverse probability of treatment weighting (IPTW), SMRW (PSM with repeated weights), PA (pairwise algorithm), and OW (overlap weighting) regression analysis were performed to assess the relationship between HGS and all-cause and CVD mortality. Results: The low HGSs (men <37.4 kg, women <24 kg), was found to be associated with higher all-cause and CVD mortality in a reverse J-shaped curve (p < 0.05). Adjusting for multiple covariates including age, BMI, race, education level, marriage status, smoking and alcohol use, and various comorbidities, the hazard ratio (HR) for all-cause mortality in the lowest HGS quintile 1 (Q1) was 3.45 (2.14-5.58) for men and 3.3 (1.88-5.79) for women. For CVD mortality, the HR was 2.99 (1.07-8.37) for men and 10.35 (2.29-46.78) for women. The area under the curve (AUC) for HGS alone as a predictor of all-cause mortality was 0.791 (0.768-0.814) for men and 0.780 (0.752-0.807) for women (p < 0.05), while the AUC for HGS and age was 0.851 (0.830-0.871) for men and 0.848 (0.826-0.869) for women (p < 0.05). For CVD mortality, the AUC for HGS alone was 0.785 (95% CI 0.738-0.833) for men and 0.821 (95% CI 0.777-0.865) for women (p < 0.05), while the AUC for HGS and age as predictors of all-cause mortality was 0.853 (0.861-0.891) for men and 0.859 (0.821-0.896) for women (p < 0.05). The HGS Q1 (men <37.4 kg and women <24 kg) was matched separately for PSM. After univariate, multivariate Cox regression models, PSM, IPTW, SMRW, PA, and OW analyses, women had 2.37-3.12 and 2.92-5.12 HRs with low HGS for all-cause and CVD mortality, while men had 2.21-2.82 and 2.33-2.85 for all-cause and CVD mortality, respectively (p < 0.05). Conclusion: Adults with low HGS exhibited a significantly increased risk of both all-cause and CVD mortality, regardless of gender. Additionally, low HGS served as an independent risk factor and predictor for both all-cause and CVD mortality.

The protective effects of melatonin in high glucose environment by alleviating autophagy and apoptosis on primary cortical neurons.

Cognitive dysfunction has been regarded as a complication of diabetes. Melatonin (MLT) shows a neuroprotective effect on various neurological diseases. However, its protective effect on cortical neurons in high glucose environment has not been reported. Our present study aims to observe the protective effect of melatonin on rat cortical neurons and its relationship with autophagy in high glucose environment. The rat primary cortical neurons injury model was induced by high glucose. The CCK-8, flow cytometry, Western blot and immunofluorescence methods were used to examine the cell viability, apoptosis rate and proteins expression. Our results showed that there were no differences in cell viability, apoptosis rate, and protein expression among the control, MLT and mannitol group. The cell viability of the glucose group was significantly lower than that of the control group, and the apoptosis rate of the glucose group was significantly higher than that of the control group. Compared with the glucose group, the glucose + melatonin group showed a significant increase in cell viability and a notable decrease in apoptosis rate. Melatonin concentration of 0.1-1 mmol/L can significantly alleviate the injury of cortical neurons caused by high glucose. Compared with the control group, the glucose group showed a significant reduction of B-cell lymphoma 2 (Bcl-2) protein expression, while remarkable elevations of Bcl2-associated X protein (Bax), cleaved Caspase-3, coiled-coil, myosin-like Bcl2-interacting protein (Beclin-1) and microtubule-associated protein 1 light chain-3B type II (LC3B-II) levels. The neurons pre-administered with melatonin obtained significantly reversed these changes induced by high glucose. The phosphorylation levels of protein kinase B (Akt), mechanistic target of rapamycin kinase (mTOR) and Unc-51 like autophagy activating kinase 1(ULK1) were decreased in the glucose group compared with the control group, whereas significant increase were observed in the glucose + MLT group, compared with the glucose group. These data indicated that melatonin has a neuroprotective effect on cortical neurons under high glucose environment, which may work by activating Akt/mTOR/ULK1 pathway and may be deeply associated with the downregulation of autophagy.

REG1A and RUNX3 Are Potential Biomarkers for Predicting the Risk of Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Clinical features are traditionally used to predict DKD, yet with low diagnostic efficacy. Most of the recent biomarkers used to predict DKD are based on transcriptomics and metabolomics; however, they also should be used in combination with many other predictive indicators. The purpose of this study was thus to identify a simplified class of blood biomarkers capable of predicting the risk of developing DKD. The Gene Expression Omnibus database was screened for DKD biomarkers, and differentially expressed genes (DEGs) in human blood and kidney were identified via gene expression analysis and the Least Absolute Shrinkage and Selection Operator regression. A comparison of the area under the curve (AUC) profiles on multiple receiver operating characteristic curves of the DEGs in DKD and other renal diseases revealed that REG1A and RUNX3 had the highest specificity for DKD diagnosis. The AUCs of the combined expression of REG1A and RUNX3 in kidney (AUC = 0.929) and blood samples (AUC = 0.917) of DKD patients were similar to each other. The AUC of blood samples from DKD patients and healthy individuals obtained for external validation further demonstrated that REG1A combined with RUNX3 had significant diagnostic efficacy (AUC=0.948). REG1A and RUNX3 expression levels were found to be positively and negatively correlated with urinary albumin creatinine ratio and estimated glomerular filtration rate, respectively. Kaplan-Meier curves also revealed the potential of REG1A and RUNX3 for predicting the risk of DKD. In conclusion, REG1A and RUNX3 may serve as biomarkers for predicting the risk of developing DKD.