Magnesium (Mg) deficiency is associated with increased risk and malignancy in colorectal cancer (CRC), yet the underlying mechanisms remain elusive. Here, we used genomic, proteomic, and phosphoproteomic data to elucidate the impact of Mg deficiency on CRC. Genomic analysis identified 160 genes with higher mutation frequencies in Low-Mg tumors, including key driver genes such as KMT2C and ERBB3. Unexpectedly, initiation driver genes of CRC, such as TP53 and APC, displayed higher mutation frequencies in High-Mg tumors. Additionally, proteomic and phosphoproteomic data indicated that low Mg content in tumors may activate epithelial-mesenchymal transition (EMT) by modulating inflammation or remodeling the phosphoproteome of cancer cells. Notably, we observed a negative correlation between the phosphorylation of DBN1 at S142 (DBN1S142p) and Mg content. A mutation in S142 to D (DBN1S142D) mimicking DBN1S142p up-regulated MMP2 and enhanced cell migration, while treatment with MgCl2 reduced DBN1S142p, thereby reversing this phenotype. Mechanistically, Mg2+ attenuated the DBN1-ACTN4 interaction by decreasing DBN1S142p, which in turn enhanced the binding of ACTN4 to F-actin and promoted F-actin polymerization, ultimately reducing MMP2 expression. These findings shed new light on the crucial role of Mg deficiency in CRC progression and suggest that Mg supplementation may be a promising preventive and therapeutic strategy for CRC.

The incidence of intestinal diseases increases with age, yet the mechanisms governing gut aging and its link to diseases, such as colorectal cancer (CRC), remain elusive. In this study, while considering age, sex and proximal–distal variations, we used a multi-omics approach in non-human primates ( Macaca fascicularis ) to shed light on the heterogeneity of intestinal aging and identify potential regulators of gut aging. We explored the roles of several regulators, including those from tryptophan metabolism, in intestinal function and lifespan in Caenorhabditis elegans . Suggesting conservation of region specificity, tryptophan metabolism via the kynurenine and serotonin (5-HT) pathways varied between the proximal and distal colon, and, using a mouse colitis model, we observed that distal colitis was more sensitive to 5-HT treatment. Additionally, using proteomics analysis of human CRC samples, we identified links between gut aging and CRC, with high HPX levels predicting poor prognosis in older patients with CRC. Together, this work provides potential targets for preventing gut aging and associated diseases.

INTRODUCTION:This study addresses the urgent need for non-invasive early-onset Alzheimer's disease (EOAD) prediction. Using optical coherence tomography angiography (OCTA), we present a choriocapillaris model sensitive to EOAD, correlating with serum biomarkers. METHODS:Eighty-four EOAD patients and 73 controls were assigned to swept-source OCTA (SS-OCTA) or the spectral domain OCTA (SD-OCTA) cohorts. Our hypothesis on choriocapillaris predictive potential in EOAD was tested and validated in these two cohorts. RESULTS:Both cohorts revealed diminished choriocapillaris signals, demonstrating the highest discriminatory capability (area under the receiver operating characteristic curve: SS-OCTA 0.913, SD-OCTA 0.991; P < 0.001). A sparser SS-OCTA choriocapillaris correlated with increased serum amyloid beta (Aβ)42, Aβ42/40, and phosphorylated tau (p-tau)181 levels (all P < 0.05). Apolipoprotein E status did not affect choriocapillaris measurement. DISCUSSION:The choriocapillaris, observed in both cohorts, proves sensitive to EOAD diagnosis, and correlates with serum Aβ and p-tau181 levels, suggesting its potential as a diagnostic tool for identifying and tracking microvascular changes in EOAD. HIGHLIGHTS:Optical coherence tomography angiography may be applied for non-invasive screening of Alzheimer's disease (AD). Choriocapillaris demonstrates high sensitivity and specificity for early-onset AD diagnosis. Microvascular dynamics abnormalities are associated with AD.

Patent foramen ovale (PFO) is a congenital defect in the partition between two atria, which may cause right-to-left shunt (RLS), leading to neurological chronic diseases with episodic manifestations (NCDEMs), such as migraine and epilepsy. However, whether PFO closure was effective in improving NCDEMs and the mechanism were unclear. Twenty-eight patients with migraine or epilepsy who underwent PFO closure were recruited. Notably, approximately half of patients received 50% or more reduction in seizure or headache attacks. Meanwhile, the postoperative blood oxygen partial pressure and oxygen saturation were elevated after PFO closure. Multisite (peripheral, right, and left atrial) and multitimepoint (before and after surgery) plasma proteomics from patients showed that the levels of free hemoglobin and cell adhesion molecules (CAMs) were significantly increased after PFO closure, which may be related to the relief of the hypoxic state. Furtherly, the omics data from multiple brain regions of mice revealed that a large number of proteins were differentially expressed in the occipital region in response to PFO, including redox molecules and CAMs, suggesting PFO-caused hypoxia may have great impacts on occipital region. Collectively, PFO may cause NCDEMs due to RLS-induced hypoxia, and PFO closure could prevent RLS to improve migraine and epilepsy.

Massive GGGGCC (G4C2) repeat expansion in C9orf72 and the resulting loss of C9orf72 function are the key features of ~50% of inherited amyotrophic lateral sclerosis and frontotemporal dementia cases. However, the biological function of C9orf72 remains unclear. We previously found that C9orf72 can form a stable GTPase activating protein (GAP) complex with SMCR8 (Smith-Magenis chromosome region 8). Herein, we report that the C9orf72-SMCR8 complex is a major negative regulator of primary ciliogenesis, abnormalities in which lead to ciliopathies. Mechanistically, the C9orf72-SMCR8 complex suppresses the primary cilium as a RAB8A GAP. Moreover, based on biochemical analysis, we found that C9orf72 is the RAB8A binding subunit and that SMCR8 is the GAP subunit in the complex. We further found that the C9orf72-SMCR8 complex suppressed the primary cilium in multiple tissues from mice, including but not limited to the brain, kidney, and spleen. Importantly, cells with C9orf72 or SMCR8 knocked out were more sensitive to hedgehog signaling. These results reveal the unexpected impact of C9orf72 on primary ciliogenesis and elucidate the pathogenesis of diseases caused by the loss of C9orf72 function.

GSK3 alpha and GSK30 are two GSK3 isoforms with 84% overall identity and 98% identity in their catalytic domains. GSK30 plays important roles in the pathogenesis of can-cer, while GSK3 alpha has long been considered a functionally redundant protein of GSK30. Few studies have specifically investigated the functions of GSK3 alpha. In this study, unex-pectedly, we found that the expression of GSK3 alpha, but not GSK30, was significantly correlated with the overall sur-vival of colon cancer patients in 4 independent cohorts. To decipher the roles of GSK3 alpha in colon cancer, we profiled the phosphorylation substrates of GSK3 alpha and uncovered 156 phosphosites from 130 proteins specifically regulated by GSK3 alpha. A number of these GSK3 alpha-mediated phos-phosites have never been reported before or have been incorrectly identified as substrates of GSK30. Among them, the levels of HSF1S303p, CANXS583p, MCM2S41p, POGZS425p, SRRM2T983p, and PRPF4BS431p were signifi-cantly correlated with the overall survival of colon cancer patients. Further pull-down assays identified 23 proteins, such as THRAP3, BCLAF1, and STAU1, showing strong binding affinity to GSK3 alpha. The interaction between THRAP3 and GSK3 alpha was verified by biochemical experi-ments. Notably, among the 18 phosphosites of THRAP3, phosphorylation at S248, S253, and S682 is specifically mediated by GSK3 alpha. Mutation of S248 to D (S248D), which mimics the effect of phosphorylation, obviously increased cancer cell migration and the binding affinity to proteins related to DNA damage repair. Collectively, this work not only discloses the specific function of GSK3 alpha as a kinase but also suggests GSK3 alpha as a promising therapeutic target for colon cancer.

Mental disorders are associated with dysregulated metabolism, but comprehensive investigations of their metabolic similarities and differences and their clinical relevance are few. Here, based on the plasma metabolome and lipidome of subcohort1, comprising 100 healthy participants, 55 cases with anxiety, 52 persons with depression, and 41 individuals with comorbidity, which are from WCHAT, a perspective cohort study of community-dwelling older adults aged over 50, multiple metabolites as potential risk factors of mental disorders were identified. Furthermore, participants with mental illnesses were classified into three subtypes (S1, S2, and S3) by unsupervised classification with lipidomic data. Among them, S1 showed higher triacylglycerol and lower sphingomyelin, while S2 displayed opposite features. The metabolic profile of S3 was like that of the normal group. Compared with S3, individuals in S1 and S2 had worse quality of life, and suffered more from sleep and cognitive disorders. Notably, an assessment of 6,467 individuals from the WCHAT showed an age-related increase in the incidence of depression. Seventeen depression-related metabolites were significantly correlated with age, which were validated in an independent subcohort2. Collectively, this work highlights the clinical relevance of metabolic perturbation in mental disorders, and age-related metabolic disturbances may be a bridge-linking aging and depressive.

IntroductionMotoric cognitive risk syndrome (MCR) is characterized by subjective cognitive complaints (SCCs) and slow gait (SG). Metabolomics and lipidomics may potentiate disclosure of the underlying mechanisms of MCR.MethodsThis was a cross-sectional study from the West China Health and Aging Trend cohort study (WCHAT). The operational definition of MCR is the presence of SCCs and SG without dementia or mobility disability. The test and analysis were based on untargeted metabolomics and lipidomics, consensus clustering, lasso regression and 10-fold cross-validation.ResultsThis study enrolled 6,031 individuals for clinical analysis and 577 plasma samples for omics analysis. The overall prevalence of MCR was 9.7%, and the prevalence of MCR-only, assessed cognitive impairment-only (CI-only) and MCR-CI were 7.5, 13.3, and 2.1%, respectively. By consensus clustering analysis, MCR-only was clustered into three metabolic subtypes, MCR-I, MCR-II and MCR-III. Clinically, body fat mass (OR = 0.89, CI = 0.82–0.96) was negatively correlated with MCR-I, and comorbidity (OR = 2.19, CI = 1.10–4.38) was positively correlated with MCR-III. Diabetes mellitus had the highest ORs above 1 in MCR-II and MCR-III (OR = 3.18, CI = 1.02–9.91; OR = 2.83, CI = 1.33–6.04, respectively). The risk metabolites of MCR-III showed relatively high similarity with those of cognitive impairment. Notably, L-proline, L-cystine, ADMA, and N1-acetylspermidine were significantly changed in MCR-only, and PC(40:3), SM(32:1), TG(51:3), eicosanoic acid(20:1), methyl-D-galactoside and TG(50:3) contributed most to the prediction model for MCR-III.InterpretationPre-dementia syndrome of MCR has distinct metabolic subtypes, and SCCs and SG may cause different metabolic changes to develop MCR.

Abstract Objective To investigate the association between sleep duration and cognitive frailty among older adults dwelling in western China. Methods We used the baseline data from West China Health and Aging Trend (WCHAT) study. Sleep duration was classified as short sleep duration (< 6 h), normal sleep duration (6–8 h) and long sleep duration (≥ 9 h). Fried frailty criteria and Short Portable Mental Status Questionnaire were used to measure cognitive frailty. Multinomial logistic regression was conducted to estimate odds ratio (OR) and 95% confidence interval (CI). Results A total of 4093 older adults (age = 67.8 ± 5.9 years, 1708 males and 2385 females) were included in the analysis. The prevalence of cognitive frailty was 11.8% among older adults in western China. Approximately 11.9% participants had short sleep duration (< 6 h); 22.2% had a long sleep duration (≥ 9 h). After adjusting for covariates, only long sleep duration was significantly associated with high risk of cognitive frailty (OR = 2.07, 95%CI = 1.60–2.68, P < 0.001) in western China older adults compared to normal sleep duration. Conclusions Long sleep duration was significantly related to cognitive frailty in older adults. Intervention for long sleep duration may be helpful to prevent cognitive frailty. Trial registration Chinese Clinical Trial Registry: ChiCTR1800018895 .

Abstract Backgrounds Vitamin D deficiency and insufficiency in older adults seems to be common, but the prevalence estimates are lacking in West China. Previous studies suggested that low vitamin D status was associated with obesity. However, most of them evaluated obesity based on body mass index (BMI) and there are no studies at present exploring the association between vitamin D status and different obesity markers. The present study aims to investigate the prevalence of low vitamin D status and evaluate the association between the vitamin D status and different obesity markers among older adults in West China. Methods Data was based on the baseline of West China Health and Aging Trends study (WCHAT). All of the participants were older than 60 years old in the present study. Vitamin D status was based on laboratory data, and obesity markers were assessed by bioelectrical impedance analysis (BIA) using the InBody 770 analyzer. Multiple linear regression was performed to find the association between the vitamin D status and various obesity markers. Results The study included 2661 individuals (mean age: 67.7 ± 6.0 years; males: 41 %). The mean vitamin D level was 18.8 ± 6.3 ng/ml (range: 5 to 59 ng/ml); 5.2 % of participants had a sufficient level of vitamin D, 31.8 % had vitamin D insufficiency, and 63.0 % had vitamin D deficiency. Our results showed that vitamin D status was negatively associated with fat mass index (FMI), visceral fat area (VFA), and waist-hip ratio (WHR) in both sexes. Comparing to other obesity markers, WHR had the strongest correlation with vitamin D status in both sexes (β = -6.090, P = 0.046 in males; β = -11.253, P < 0.001 in females). No significant association was found between vitamin D status and BMI in males. Conclusion The prevalence of vitamin D insufficiency and deficiency among older adults in West China was high. Among the older adults in west China, WHR showed stronger association with vitamin D status and was better for the prediction of vitamin D insufficiency or deficiency in both sexes, compared to BMI. Trial registration Chinese Clinical Trial Registry: ChiCTR1800018895 .