BACKGROUND:The role of the liver, a vital metabolic organ, in ocular health and the corresponding mechanisms remains unclear. This study aimed to examine the association between liver function and retinal thickness, and whether metabolic signatures (MS) of liver function mediate these associations. METHODS:We used data from 31019 participants in UK Biobank. Liver function was measured using seven serum-based circulating biomarkers: alanine transaminase, aspartate transaminase, gamma-glutamyltransferase, alkaline phosphatase, total bilirubin, total protein, and albumin levels. Retinal thickness was measured using optical coherence tomography, including the retinal nerve fiber layer, ganglion cell-inner plexiform layer, inner nuclear layer, inner nuclear layer-external limiting membrane, external limiting membrane-inner and outer photoreceptor segments, inner and outer photoreceptor segments-retinal pigment epithelium (ISOSRPE), and retinal pigment epithelium (RPE). The circulating metabolome was quantified using nuclear magnetic resonance spectroscopy. A linear regression model and formal mediation analyses were performed. RESULTS:We find that abnormal liver function is significantly associated with increased RPE thickness (β [SE]: 0.094(0.034); P = 0.021) and decreased ISOSRPE thickness (β [SE]: -0.172 (0.048); P < 0.001), after adjusting for demographic, lifestyle factors, best-corrected visual acuity, and intraocular pressures. Among the 249 metabolites, 23 are selected using lasso regression to construct MS for liver function. The mediation proportion of MS in association between liver function and ISOSRPE thickness is 28.6% (P = 0.004). Among the 23 metabolites, six play a significant mediating role in the association between liver function and ISOSRPE thickness, with mediation proportions ranging from 3.20% to 16.4%. CONCLUSION:This study demonstrates significant associations of liver function with retinal thickness and reveals potential underlying metabolomic mechanisms, providing insights into the liver-eye axis.

Background With global aging, cognitive impairment, including Alzheimer's disease and related dementias, has become a critical public health challenge, driving the need for convenient screening tools to facilitate early intervention. Objective This study aimed to develop an efficient and noninvasive risk assessment model for identifying potential cognitive impairment in the elderly using machine learning algorithms based on comprehensive geriatric assessment (CGA). Methods We included 1410 participants aged 50 and older from geriatric clinics and community. Feature selection was performed on the CGA indicators using a combination of expert knowledge and machine learning. Logistic regression (LR), naive Bayes, support vector machines, neural networks, and random forests were comprehensively evaluated based on common classification performance metrics. The optimal machine learning algorithms and feature subset are used to construct the final prediction model. Shapley Additive exPlanations (SHAP) was used to explain the model. Results Thirteen noninvasive predictors were identified, including 'Bathing', 'Age', 'Caregiver', 'Sleep duration', 'Homekeeping', 'Right Ear', 'Stand BWEO', 'Hobbies', 'Focusing Difficulty', 'UI effect', and 'Housework'. The LR model performed best on the test set, with an AUC of 0.877 and high accuracy (0.815), sensitivity (0.767), and specificity (0.827). The SHAP results illustrated the role of these key features in cognitive impairment, which is highly consistent with clinical knowledge.Conclusions This study identifies convenient, noninvasive predictors for screening-oriented prediction of cognitive impairment, develops an efficient machine learning model, and employs SHAP analysis for interpretation. This facilitates widespread screening, providing guidance for early detection and intervention in high-risk populations.

Chronic low-grade inflammation has emerged as the pivotal driver connecting metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) to neurodegenerative disorders, a pathological continuum increasingly recognized as “Type 3 Diabetes Mellitus” (T3DM). Diet, as a primary modifiable lifestyle factor, plays a dual role as both an inflammatory trigger and a potential therapeutic target. This review systematically delineates the methodological evolution of dietary inflammatory indices, shifting from the reductionist, nutrient-centric logic of the Dietary Inflammatory Index (DII) to the systemic, “food-matrix-based” logic of the recently proposed Food Inflammation Index (FII). We provide an in-depth mechanistic synthesis of the gut-metabolism-brain axis, illustrating how high-inflammatory diets initiate a malignant cascade: beginning with gut dysbiosis and barrier leakage, followed by immunometabolic reprogramming of adipose tissue, and culminating in the “Trojan Horse” effect at the blood–brain barrier. This process facilitates amyloid-beta accumulation and bioenergetic crises, forming the molecular basis of T3DM. While the DII remains an irreplaceable tool for large-scale historical and cross-cultural epidemiological research, we argue that the FII represents an important methodological advancement toward precision nutrition. By quantifying intra-group heterogeneity and capturing whole-food effects, the FII is designed to address the clinical “translation bottleneck” of nutrient-based assessments. Furthermore, we explore the clinical integration of the Food Inflammation Scores of Individuals (FISI) with digital health platforms and artificial intelligence, proposing novel, pre-emptive tools such as Children’s FISI (C-FISI) and Pregnancy FISI (P-FISI) for life-cycle management. This review bridges the gap between nutrition science and neuro-metabolic pathology, providing a novel theoretical framework and practical tools for the integrated management of MetS and the early prevention of T3DM.

The estimated glucose disposal rate (eGDR) is a novel indicator of insulin resistance that reflects the body’s ability to process glucose. The association between eGDR and sarcopenia in adults remains unclear. This study investigated the relationship between eGDR and sarcopenia to support the improved clinical identification of the condition. We analysed data from the 2011 to 2018 cycles of the National Health and Nutrition Examination Survey (NHANES). The final analytical sample comprised 7,147 participants. After applying survey weights, the population was 49.5

Ferroptosis has been implicated in skeletal muscle aging. Nevertheless, specific ferroptosis-related genes (FRGs) governing skeletal muscle aging remain unclear. The aim of this study was to identify ferroptosis-related marker genes associated with skeletal muscle aging, uncovering potential therapeutic targets for skeletal muscle aging. Data from GSE38718 was utilized to identify differentially expressed FRGs (DE-FRGs) in aging versus normal human skeletal muscle by the least absolute shrinkage and selection operator (LASSO) and the support vector machine recursive feature elimination (SVM-RFE) algorithms. Validation was conducted using RT-qPCR and Western blot in aging mouse muscle and D-galactose (D-gal)-treated C2C12 cells. SLC38A1 was identified as a significantly downregulated marker for aging skeletal muscle. Overexpression of SLC38A1 mitigated cellular aging in D-gal treated C2C12 cells. In both D-gal treated and sh-SLC38A1 C2C12 cells, increased ROS levels, elevated mtROS, higher intracellular iron concentrations, and intensified lipid peroxidation were observed. In contrast, SLC38A1 overexpression markedly reduced the accumulation of ROS, mtROS, iron concentration, and lipid peroxidation associated with D-gal treatment in these cells. In conclusion, through screening analyses and validation experiments, we identified SLC38A1 as a ferroptosis-related regulator for skeletal muscle aging.

Cerebral small vessel disease (CSVD) is a global brain disorder that is characterized by a series of clinical, neuroimaging, and neuropathological manifestations. However, the molecular pathophysiological mechanisms of CSVD have not been thoroughly investigated. Liquid chromatography-tandem mass spectrometry-based proteomics has broad application prospects in biomedicine. It is used to elucidate disease-related molecular processes and pathophysiological pathways, thus providing an important opportunity to explore the pathophysiological mechanisms of CSVD. Serum samples were obtained from 96 participants (58 with CSVD and 38 controls) consecutively recruited from The First Affiliated Hospital of Zhengzhou University. After removing high-abundance proteins, the serum samples were analyzed using high-resolution mass spectrometry. Bioinformatics methods were used for in-depth analysis of the obtained proteomic data, and the results were verified experimentally. Compared with the control group, 52 proteins were differentially expressed in the sera of the CSVD group. Furthermore, analyses indicated the involvement of these differentially expressed proteins in CSVD through participation in the overactivation of complement and coagulation cascades and dysregulation of insulin-like growth factor-binding proteins. The proteomic biomarker panel identified by the machine learning model combined with clinical features is expected to facilitate the diagnosis of CSVD (AUC = 0.947, 95

Evidence indicates that exposure to environmental chemicals may be related to frailty; however, most existing research has focused on single-exposure scenarios. This study aims to systematically evaluate the relationships between multiple environmental toxin exposures and frailty using a comprehensive exposure group approach and to investigate potential mechanisms mediated by systemic inflammation. Data from 2354 participants in the 2013-2016 National Health and Nutrition Examination Survey (NHANES) were analyzed. Environmental toxins were categorized into 10 groups, encompassing 61 substances. Frailty was assessed using a 36-item Frailty Index (FI). We applied an exposure‑wide association study (ExWAS; to screen for individual toxin-frailty associations) and deletion/substitution/addition (DSA; to identify key exposures in multi‑exposure contexts) models, and used Bayesian kernel machine regression (BKMR; to evaluate joint relationships and potential interactions among selected exposures). The role of systemic inflammation was evaluated through mediation analysis. Of the 2354 adults analyzed, 657 (27.9 %) were classified as frailty. ExWAS and DSA models identified total nicotine equivalent-2, tungsten, cobalt, tin, and N-acetyl-S-(2-carboxyethyl)-L-cysteine as significant exposures associated with frailty. BKMR analysis revealed a positive correlation between key exposures and frailty. Mediation analysis indicated that systemic inflammation mediated 2.5-14.6 % of these associations. To our knowledge, this is the first comprehensive study to report associations between three categories of five environmental toxins and frailty in U.S. adults, with inflammation potentially serving as a partial mediator. These findings are critical for identifying hazardous environmental chemicals and developing targeted strategies to promote healthy aging.

Objectives:Symptomatic intracranial hemorrhage (sICH) following endovascular thrombectomy (EVT) for acute ischemic stroke due to anterior circulation large vessel occlusion (AIS-LVO) significantly impacts clinical outcomes. Contrast enhancement (CE) on immediate post-EVT non-contrast CT (NCCT) may reflect blood-brain barrier disruption, but its volumetric correlation with sICH and functional independence remains underexplored. Methods:We performed a retrospective screening on consecutive AIS-LVO patients who had CE on NCCT immediately within 2 h after EVT. The quantitative volume of CE was calculated by using 3D Slicer software. Multivariable logistic regression was performed to achieve the risk factors of sICH and functional independence. The discrimination and calibration of the multivariable models were assessed using the area under the receiver operator characteristic curve, fivefold cross-validation, calibration curve, and decision curve analysis. Results:In this study, 111 patients were enrolled in the final analysis. According to the restricted cubic spline, 10.6 mL was the optimal threshold of CE volume dichotomization for patients with AIS-LVO. In multivariate regression analysis, the CE+ group (CE volume beyond 10.6 mL) was significantly associated with sICH (aOR: 5.24, 95% CI: 1.45-18.99, p = 0.012) and functional independence (10.9% vs. 51.8%; aOR 0.05, 95% CI: 0.01-0.28, p < 0.001). The multivariable models demonstrated good discrimination and calibration in this cohort, as well as the fivefold cross-validation. Conclusion:Volumetric quantification of CE on immediate post-EVT NCCT serves as a novel biomarker for early sICH risk stratification and functional prognosis in AIS-LVO. Incorporating CE volume into predictive models enhances clinical utility, enabling timely diagnosis and intervention.

Dyslipidaemia has been implicated in osteonecrosis through some clinical studies. However, a direct causal relationship between hyperlipidaemia and osteonecrosis remains unconfirmed, and whether lipid-lowering agents could be used to treat osteonecrosis remains unclear. This study aimed to investigate the causal role of lipid traits in osteonecrosis using Mendelian randomisation (MR) analysis, assess the potential effects and mechanisms of lipid-lowering drug targets on osteonecrosis risk and validate these findings through experimental approaches. Genome-wide association study (GWAS) data were used to analyse lipid traits, drug targets and FinnGen osteonecrosis. Statin effects were further studied in a rat model of steroid-induced osteonecrosis and in vitro cell models. MR analysis revealed a significant association between LDL-C and increased osteonecrosis risk. Genetic mimicry of HMGCR inhibitors was associated with reduced osteonecrosis risk, which was validated through colocalisation. Stem cell growth factor-β (SCGF-β) was identified as a mediator of 21.3% of HMGCR inhibitors' effect on osteonecrosis risk. Further studies confirmed simvastatin's alleviating effect on SONFH, suggesting that simvastatin promotes osteogenesis and inhibits adipogenesis of mesenchymal stem cells (MSCs), partly mediated by SCGF-β upregulation, which activates the Wnt signalling pathway. Our findings supported dyslipidaemia as a causal factor for osteonecrosis, highlighting HMGCR as a promising therapeutic target.

PurposeGrowing evidence suggests that thyroid hormones play an important role in the process of sarcopenia during aging. The aim of our study was to investigate whether thyroid hormones have an association with age-related sarcopenia in euthyroid geriatric patients with Hashimoto’s thyroiditis (HT).MethodsA total of 442 euthyroid older patients with Hashimoto’s thyroiditis were included in this cross-sectional study. Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia (AWGS) 2019 criteria. Body composition, grip strength and gait speed were assessed in participants. Concentrations of thyroid hormones were determined by immunoassays. Logistic regression analyses were carried out to assess the association between free T3 (FT3) levels and sarcopenia risk.ResultsCompared to non-sarcopenic patients, FT3 levels were found to be lower in the sarcopenic group (2.92 pg/ml vs 3.00 pg/ml, p<0.05). Multiple linear regression analysis showed a significant positive association between FT3 and hand grip strength, gait speed, skeletal muscle mass. Multivariable logistic regression analysis showed that FT3 levels were independently associated with sarcopenia (odds ratio 0.533 [95% confidence interval 0.343, 0.829], p=0.005) and low gait speed, low hand grip strength, low skeletal muscle index.ConclusionHigher FT3 levels within normal range was positively associated with skeletal muscle mass, hand grip strength and physical function in elderly euthyroid individuals with HT.

Temporal lobe epilepsy (TLE), the most common type of drug-resistant epilepsy, severely affects quality of life. However, the underlying mechanism of TLE remains unclear and deserves further exploration. Sorbs2, a key synaptic regulatory protein, plays an important role in the regulation of synaptic transmission in the mammalian brain. In this study, we aimed to investigate the expression pattern of Sorbs2 in a kainic acid (KA)-induced TLE mouse model and in patients with TLE to further determine whether Sorbs2 is involved in seizure activity and to explore the potential mechanism by which Sorbs2 affects seizures in this TLE mouse model. First, we found that the expression of Sorbs2 was obviously increased in the hippocampus and cortex of a TLE mouse model and in the temporal cortex of TLE patients, indicating an abnormal expression pattern of Sorbs2 in TLE. Importantly, subsequent behavioral analyses and local field potential (LFP) analyses of a TLE mouse model demonstrated that the downregulation of hippocampal Sorbs2 could prolong the latency to spontaneous recurrent seizures (SRSs) and protect against SRSs. We also found that the knockdown of Sorbs2 in the hippocampus could decrease excitatory synaptic transmission in pyramidal neurons (PNs) in the hippocampal CA1 region and reduce the expression levels of the AMPAR subunits GluA1 and GluA2. Thus, we speculated that Sorbs2 may promote epileptogenesis and the development of TLE by affecting AMPAR-mediated excitatory synaptic transmission in PNs in the CA1 region. Therefore, reducing the expression of hippocampal Sorbs2 could restrain epileptogenesis and the development of TLE.

Scavenger receptor class B type I (SR-BI) is abundant in adult mouse and human brains, but its function in the central nervous system (CNS) remains unclear. This study explored the role of SR-BI in epilepsy and its possible underlying mechanism. Expression patterns of SR-BI in the brains of mice with kainic acid (KA)-induced epilepsy were detected using immunofluorescence staining, quantitative real-time polymerase chain reaction (qPCR), and Western blotting(WB). Behavioral analysis was performed by 24-hour video monitoring and hippocampal local field potential (LFP) recordings were employed to verify the role of SR-BI in epileptogenesis. RNA sequencing (RNA-seq) was used to obtain biological information on SR-BI in the CNS. WB, qPCR, and co-immunoprecipitation (Co-IP) were performed to identify the relationship between SR-BI and the gabapentin receptor α2δ-1.The results showed that SR-BI was primarily co-localized with astrocytes and its expression was down-regulated in the hippocampus of KA mice. Notably, overexpressing SR-BI alleviated the epileptic behavioral phenotype in KA mice. Hippocampal transcriptomic analysis revealed 1043 differentially expressed genes (DEGs) in the SR-BI-overexpressing group. Most DEGs confirmed by RNA-seq analysis were associated with synapses, neuronal projections, neuron development, and ion binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that the DEGs were enriched in the glutamatergic synapse pathway. Furthermore, the gabapentin receptor α2δ-1 decreased with SR-BI overexpression in epileptic mice. Overall, these findings highlight the important role of SR-BI in regulating epileptogenesis and that the gabapentin receptor α2δ-1 is a potential downstream target of SR-BI.

BACKGROUND:Altered mitophagy has been observed in various neurological disorders, such as epilepsy. The role of mitophagy in causing neuronal damage during epileptic episodes is significant, and recent research has indicated that GLS2 plays a crucial role in regulating autophagy. However, exactly how GLS2 affects epilepsy is still unclear. AIMS:To investigate the expression and distribution characteristics of GLS2 in epilepsy, and then observed the changes in behavior and electrophysiology caused by overexpression of GLS2 in epileptic mice, and determined whether GLS2 regulated seizure-like changes in the mouse model through the protective mechanism of mitophagy. RESULTS:The expression of GLS2 in a kainic acid (KA)-induced epileptic mouse model and aglutamate-inducedneuronal excitatory damage in HT22 cells model was downregulation. In brief, overexpression of GLS2 can alleviate epileptic activity. Subsequently, we demonstrated that GLS2 interacts with mitophagy-related proteins in a KA-induced epilepsy mouse model. Mechanistically, overexpression of GLS2 inhibited mitophagy in epileptic mice, downregulating the expression of LC3 and reducing ROS production. CONCLUSIONS:This study proves the GLS2 expression pattern is abnormal in epileptic mice. The function of mitophagy in hippocampal neurons is affected by GLS2, and overexpression of GLS2 can reduce the occurrence of seizure-like events (SLEs) by altering mitophagy function. Thus, GLS2 might control seizures, and our findings provide a fresh avenue for antiepileptic treatment and offer novel insights into treating and preventing epilepsy.

Information exchange between neurons and astrocytes mediated by extracellular vesicles (EVs) is known to play a key role in the pathogenesis of central nervous system diseases. A key driver of epilepsy is the dysregulation of intersynaptic excitatory neurotransmitters mediated by astrocytes. Thus, we investigated the potential association between neuronal EV microRNAs (miRNAs) and astrocyte glutamate uptake ability in epilepsy. Here, we showed that astrocytes were able to engulf epileptogenic neuronal EVs, inducing a significant increase in the glutamate concentration in the extracellular fluid of astrocytes, which was linked to a decrease in glutamate transporter-1 (GLT-1) protein expression. Using sequencing and gene ontology (GO) functional analysis, miR-181c-5p was found to be the most significantly upregulated miRNA in epileptogenic neuronal EVs and was linked to glutamate metabolism. Moreover, we found that neuronal EV-derived miR-181c-5p interacted with protein kinase C-delta (PKCδ), downregulated PKCδ and GLT-1 protein expression and increased glutamate concentrations in astrocytes both in vitro and in vivo. Our findings demonstrated that epileptogenic neuronal EVs carrying miR-181c-5p decrease the glutamate uptake ability of astrocytes, thus promoting susceptibility to epilepsy.

Background:piRNAs play key roles in various diseases. However, the role of piRNAs in sporadic Parkinson's disease (PD) remains unclear. This study was conducted to explore key piRNAs that can be used as biomarkers for sporadic Parkinson's disease. Methods:Differentially expressed piRNAs (DEPs) and their interaction were investigated using bioinformatics analysis, while the diagnostic value and expression of the selected piRNAs were detected. Results:42 DEPs were screened between PD and controls. Moreover, most of the physiological piRNA-piRNA interactions and linkages in normal samples had been altered in the sporadic PD samples. 14 overlapping piRNAs were selected, and six key piRNA biomarkers were screened. The different expressions of piR-hsa-327831, piR-hsa-1968818, piR-hsa-3770447, piR-hsa-1325354, and piR-hsa-2524778 had high efficiency and sensitivity in the diagnosis of PD. Conclusion:PiR-hsa-327831, piR-hsa-1968818, piR-hsa-3770447, piR-hsa-1325354, piR-hsa-758566 and piR-hsa-2524778 could be biomarkers of PD.

Diabetes has been regarded as an independent risk factor for Alzheimer’s disease (AD). Liraglutide could improve cognition in AD mouse models, but its precise mechanism remains unclear. In this study, we used STZ-induced diabetic rats and HT-22 cells to investigate the effects of liraglutide. The MWM test, MTT assay, ELISA, western blot, and immunofluorescence were used in this research. Diabetic rats induced by STZ displayed a longer escape latency and entered the target zone less frequently (p < 0.05) in the MWM test. Intraperitoneal injection of liraglutide improved the cognition of diabetic rats (p < 0.05) and reduced Aβ42 expression in the hippocampus (p < 0.05). In vivo experiments showed that HT-22 cell viability decreased in the HG group, but liraglutide (100 nmol/L and 1 μmol/L) enhanced HT-22 cell viability (p < 0.05). Oxidative stress markers were upregulated in HT-22 cells in the HG group, while liraglutide treatment significantly reduced these markers (p < 0.05). Western blot and immunofluorescence analyses demonstrated increased levels of Aβ, BACE1, and γ-secretase in HT-22 cells in the HG group (p < 0.05), whereas these levels were reduced in the liraglutide treatment group (p < 0.05). These effects were reversed by the nuclear factor kappa B (NF-κB) and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitors (p < 0.05). These findings suggest that liraglutide improved the cognition of diabetic rats and might exert its protective effects by reducing oxidative stress, downregulating BACE1 and γ-secretase expression, and decreasing Aβ deposition via the NF-κB and ERK1/2 pathways.

老年人的抑郁症是一种常见且严重的健康问题,它通常与慢性疾病共存,容易导致老年人的认知功能及机体功能状况恶化.由于慢性疾病的并发症状,老年人的抑郁症状经常被忽视和治疗不充分.抗抑郁药物和心理疗法已显示出对老年性抑郁症的效果,但在老年入中的局限性更加明显.基于音乐的干预是一个系统的干预过程,对抑郁症状有积极的影响,老年人尤其受益于这种非侵入性治疗.已经探索了多种音乐干预方法,从音乐聆听法到休闲歌唱法,再到由受过专门训练的音乐治疗师进行的音乐干预,它们具备无创、高安全性、良好的依从性及成本效益比等特点.本文综述了不同形式的音乐干预方法应用在老年人常见慢性疾病合并抑郁症中的效果,总结了音乐干预在国内医疗保健机构普及应用时面临的问题和挑战.

Background: According to previous studies, myelin damage may be involved in the occurrence of depression. However, to date, no study has quantitatively investigated the changes in myelinated fibers and myelin sheaths in the hippocampal formation (HF) and hippocampal subfields in the context of depression. Methods: Male Sprague-Dawley (SD) rats (aged 4-5 weeks) were evenly divided into the control group and chronic unpredictable stress (CUS) group. Behavioral tests were performed, and then changes in myelinated fibers and myelin ultrastructure in hippocampal subfields in depression model rats were investigated using modern stereological methods and transmission electron microscopy techniques. Results: After a four-week CUS protocol, CUS rats showed depressive-like and anxiety-like behaviors. The total length and total volume of myelinated fibers were reduced in the CA1 region and DG in the CUS group compared with the control group. The total volumes of myelin sheaths and axons in the CA1 region but not in the DG were significantly lower in the CUS group than in the control group. The decrease in the total length of myelinated nerve fibers in the CA1 region in CUS rats was mainly due to a decrease in the length of myelinated fibers with a myelin sheath thickness of 0.15 mu m-0.20 mu m. Limitations: The exact relationship between the degeneration of myelin sheaths and depression-like, anxiety-like behaviors needs to be further investigated. Conclusions: CUS induces depression- and anxiety-like behaviors, and the demyelination in the CA1 region induced by 4 weeks of CUS might be an important structural basis for these behaviors.

Background: Findings from recent meta-analyses of anti-osteoporosis drugs have shown that there is no association of anti-osteoporosis drugs with overall mortality, possibly because of population limitations such as age, sex, the presence or absence of fractures, and other parameters, which are associated with increased mortality in the elderly. There is no report about possible associations between anti-osteoporosis drugs and overall mortality in the old (ages ≥ 50 years) or oldest (ages ≥ 75 years) population. The purpose of using anti-osteoporosis drugs is not only to improve bone mineral density and reduce fractures, but also to prolong life expectancy, especially in the old or oldest population. We determined the association between anti-osteoporosis drugs and overall mortality in the old and oldest populations, and determined the effects of different demographic parameters.Methods: We searched Web of Science, Embase, the Cochrane Database, and PubMed from inception to January 10, 2021, for trials reporting the effects of anti-osteoporosis drugs on overall mortality. The effects of calcium and vitamin D were excluded. We included all randomized trials comparing interventions with different anti-osteoporosis drugs, and we included elderly (ages ≥ 50 years) without other metabolic bone diseases. We pooled data using a fixed effects meta-analysis with weighted mean differences and reported 95% confidence intervals (CIs). We also used the I² statistic to assess heterogeneity in the results of individual studies. The primary endpoint was the total number of people in the drug treatment and placebo groups, and the number of deaths during the follow-up periods. Findings: Of 23,242 citations identified by the search strategy, 25 studies (mean duration: 3.0 years, comprising 93,782 participants; 91.4% women; average age: 73.2 years) met the inclusion criteria. A total of 21 studies were mainly comprised of Caucasians. In 25 studies, anti-osteoporosis drugs included bisphosphonate, selective estrogen receptor modulators (SERMs), parathyroid hormone analogues, receptor-activated nuclear factor-κB ligand inhibitor, anti-sclerostin antibodies. and strontium ranelate. One of the studies used two anti-osteoporosis drugs compared with placebos, while all the other studies used one anti-osteoporosis drug.In the elderly population, anti-osteoporosis drugs did not reduce individual mortalities (weight RR: 0.96; 95% CI: 0.90–1.02), with heterogeneity among trials (I² = 2%, p = 0.43); however, none of the anti-osteoporosis drugs was significantly associated with overall mortality. Stratified analyses were performed according to age and sex, with osteoporosis, and with or without fractures. In different age groups (> 65 years of age, > 75 years of age, and > 80 years of age), the associations between anti-osteoporosis drugs and overall mortalities were not significant. In the female and male groups, none of the associations between anti-osteoporosis drugs and overall mortality were significant. In the with or without osteoporosis groups, these drugs did not reduce overall mortalities. However, these drugs did show reduced mortality (RR: 0.83; 95% CI: 0.70–0.99), but only in the group with fractures.Interpretation: None of the anti-osteoporosis drugs reduced overall mortality, but in the old population with recent fractures, these drugs showed a reduced overall mortality. The association between anti-osteoporosis drugs and overall mortality did not influence by age and sex. The use of these drugs in the old and oldest populations was safe, and was effective in patients with fractures.Funding Statement: This work was supported by grants from the Chongqing Health and Family Planning Commission (No. 2015MSXM016), Chongqing Development and Reform Commission (No. [2013] 1420), and National Key Clinical Specialties Construction Program of China (No. [2013] 544).Declaration of Interests: None.

Running exercise has been shown to be associated with decreased symptoms of depression. However, the mechanisms underlying these antidepressant effects of running exercise remain relatively unclear. In the current study, we investigated the relationship between depressive symptoms in chronic unpredictable stress (CUS) model rats treated with running exercise and changes in oligodendrocytes in the hippocampus. After 4 weeks of CUS, the model group was randomly divided into a CUS standard group (18 rats) and a CUS running group (15 rats). Then, a 4-week treadmill running trial was performed with the CUS running group. In addition, the behavioral effects of exercise were investigated by means of a sucrose preference test (SPT) and an at the end of the 8th week. Immunohistochemical methods and modern stereological methods were used to precisely quantify the total number of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase)-positive (CNPase+) oligodendrocytes in each hippocampal subregion. At the behavioral level, after four weeks of running, the CUS running group displayed significantly higher consumption of sucrose water in the SPT than the CUS standard group. Unbiased stereological analyses revealed significantly higher total numbers of CNPase+ cells in the hippocampal CA3 and dentate gyrus regions in the CUS running group than in the CUS standard group, whereas there was no significant difference between the groups in the number of CNPase+ cells in the hippocampal CA1 region. The present results further confirm that exercise can alleviate symptoms and protect hippocampal oligodendrocytes in depressed rats.