Structural basis for Retriever-SNX17 assembly and endosomal sorting.

During endosomal recycling, Sorting Nexin 17 (SNX17) facilitates the transport of numerous membrane cargo proteins by tethering them to the Retriever complex. Despite its importance, the mechanisms underlying this interaction have remained elusive. Here, we report the structure of the Retriever-SNX17 complex determined using cryogenic electron microscopy (cryo-EM). Our structure reveals that the C-terminal tail of SNX17 engages with a highly conserved interface between the VPS35L and VPS26C subunits of Retriever. Through comprehensive biochemical, cellular, and proteomic analyses, we demonstrate that disrupting this interface impairs the Retriever-SNX17 interaction, subsequently affecting the recycling of SNX17-dependent cargos and altering the composition of the plasma membrane proteome. Intriguingly, we find that the SNX17-binding pocket on Retriever can be utilized by other ligands that share a consensus acidic C-terminal tail motif. By showing how SNX17 is linked to Retriever, our findings uncover a fundamental mechanism underlying endosomal trafficking of critical cargo proteins and reveal a mechanism by which Retriever can engage with other regulatory factors.

Preparation and characterization of chitosan/polyvinyl alcohol antibacterial sponge materials.

This study utilized the freeze-drying method to create a chitosan (CS) and polyvinyl alcohol (PVA) sponge. To enhance its antibacterial properties, curcumin and nano silver (Cur@Ag) were added for synergistic antibacterial. After adding curcumin and nano silver, the mechanical properties of the composite sponge dressing (CS-PVA-Cur@Ag) were improved. The porosity of the composite sponge dressing was closed to 80%, which was helpful for drug release, and it had good water absorption and water retention rate. The nano silver diameter was 50-80 nm, which was optimal for killing bacteria. Antibacterial tests usedEscherichia coliandStaphylococcus aureusdemonstrated that little nano silver was required to eliminate bacteria. Finally, in the rat full-thickness skin wound model, the composite sponge dressing can promote wound healing in a short time. In summary, CS-PVA-Cur@Ag wound dressing could protect from bacterial infection and accelerate wound healing. Thus, it had high potential application value for wound dressing.

The NADPH oxidase 2 subunit p47phox binds to the WAVE regulatory complex and p22phox in a mutually exclusive manner.

The actin cytoskeleton and reactive oxygen species (ROS) both play crucial roles in various cellular processes. Previous research indicated a direct interaction between two key components of these systems: the WAVE1 subunit of the WAVE regulatory complex (WRC), which promotes actin polymerization and the p47phox subunit of the NADPH oxidase 2 complex (NOX2), which produces ROS. Here, using carefully characterized recombinant proteins, we find that activated p47phox uses its dual Src homology 3 domains to bind to multiple regions within the WAVE1 and Abi2 subunits of the WRC, without altering WRC's activity in promoting Arp2/3-mediated actin polymerization. Notably, contrary to previous findings, p47phox uses the same binding pocket to interact with both the WRC and the p22phox subunit of NOX2, albeit in a mutually exclusive manner. This observation suggests that when activated, p47phox may separately participate in two distinct processes: assembling into NOX2 to promote ROS production and engaging with WRC to regulate the actin cytoskeleton.

Predictors for early-onset psychotic symptoms in patients newly diagnosed with Parkinson's disease without psychosis at baseline: A 5-year cohort study.

AIMS: To investigate the risk factors for early-onset psychosis in Parkinson's disease (PD) in a cohort of patients from the Parkinson's Progression Markers Initiative. METHODS: Longitudinal data on motor and non-motor features, dopamine transporter (DAT) imaging, and cerebrospinal fluid (CSF) measurements were collected. The survival probability of psychotic symptoms, potential risk factors for psychosis development over a 5-year follow-up period, and the performance of the prediction model were evaluated. RESULTS: Among the 338 newly diagnosed patients with PD, 83 developed psychotic symptoms. Gastrointestinal autonomic dysfunction, presence of probable rapid-eye-movement sleep behavior disorder, and the ratio Aß42: total-tau could independently predict onset of psychosis in PD (hazard ratio (HR) = 1.157, 95% confidence interval (CI) 1.022-1.309, p = 0.021, HR = 2.596, 95% CI 1.287-5.237, p = 0.008, and HR = 0.842, 95% CI 0.723-0.980, p = 0.027, respectively). The combined model integrating baseline clinical predictors, DAT imaging, and CSF measurements achieved better sensitivity than the clinical predictors alone (area under the curve = 0.770 [95% CI 0.672-0.868] vs. 0.714 [95% CI 0.625-0.802], p = 0.098). CONCLUSION: We identified clinical and CSF predictors of early-onset psychosis in patients with PD. Our study provides evidence and implications for prognostic stratification and therapeutic approaches for PD psychosis.

Structural organization of the retriever-CCC endosomal recycling complex.

The recycling of membrane proteins from endosomes to the cell surface is vital for cell signaling and survival. Retriever, a trimeric complex of vacuolar protein-sorting-associated protein (VPS)35L, VPS26C and VPS29, together with the CCC complex comprising coiled-coil domain-containing (CCDC)22, CCDC93 and copper metabolism domain-containing (COMMD) proteins, plays a crucial role in this process. The precise mechanisms underlying retriever assembly and its interaction with CCC have remained elusive. Here, we present a high-resolution structure of retriever in humans determined using cryogenic electron microscopy. The structure reveals a unique assembly mechanism, distinguishing it from its remotely related paralog retromer. By combining AlphaFold predictions and biochemical, cellular and proteomic analyses, we further elucidate the structural organization of the entire retriever-CCC complex across evolution and uncover how cancer-associated mutations in humans disrupt complex formation and impair membrane protein homeostasis. These findings provide a fundamental framework for understanding the biological and pathological implications associated with retriever-CCC-mediated endosomal recycling.

Correlation of slow-wave sleep with motor and nonmotor progression in Parkinson's disease.

OBJECTIVE: This study aimed to explore the association between slow-wave sleep and the progression of motor and nonmotor symptoms in patients with PD. METHODS: Data were collected from the Parkinson's Progression Markers Initiative study. Slow-wave sleep, also known as deep non-rapid eye movement (DNREM) sleep, was objectively assessed using the Verily Study Watch. Motor function was assessed using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III score, Hoehn and Yahr stage, freezing of gait, motor fluctuations, and dyskinesia severity. Comprehensive assessments were conducted on nonmotor symptoms, including depression, anxiety, global cognitive function, and autonomic dysfunction. Statistical analyses involved repeated-measures analysis of variance and linear regression. RESULTS: A total of 102 patients with PD were included in the study, with a median follow-up duration of 3.4 years. In the long DNREM sleep duration group (n = 55), better motor function (DNREM × time interaction: F(1,100) = 4.866, p = 0.030), less severe sexual dysfunction (p = 0.026), and improved activities of daily living (p = 0.033) were observed at the last follow-up visit compared with the short DNREM sleep duration group (n = 47). Reduced DNREM sleep duration is a risk factor for motor progression (ß = -0.251, p = 0.021; 95% confidence interval = -0.465 to -0.038). INTERPRETATION: The findings suggest an association between longer DNREM sleep duration and slower motor and nonmotor progression in patients with PD.

Trehalose-6-Phosphate Synthase Contributes to Rapid Cold Hardening in the Invasive Insect Lissorhoptrus oryzophilus (Coleoptera: Curculionidae) by Regulating Trehalose Metabolism.

Rapid cold hardening (RCH) is known to rapidly enhance the cold tolerance of insects. Trehalose has been demonstrated to be a cryoprotectant in Lissorhoptrus oryzophilus, an important invasive pest of rice in China. Trehalose synthesis mainly occurs through the Trehalose-6-phosphate synthase (TPS)/trehalose-6-phosphate phosphatase (TPP) pathway in insects. In this study, the TPS gene from L. oryzophilus (LoTPS) was cloned and characterized for the first time. Its expression and trehalose content changes elicited by RCH were investigated. Our results revealed that RCH not only increased the survival rate of adults but also upregulated the expression level of LoTPS and increased the trehalose content under low temperature. We hypothesized that upregulated LoTPS promoted trehalose synthesis and accumulation to protect adults from low-temperature damage. To further verify the function of the LoTPS gene, we employed RNA interference (RNAi) technology. Our findings showed that RCH efficiency disappeared and the survival rate did not increase when the adults were fed dsRNA of LoTPS. Additionally, inhibiting LoTPS expression resulted in no significant difference in trehalose content between the RCH and non-RCH treatments. Furthermore, the expression patterns of trehalose transporter (TRET) and trehalase (TRE) were also affected. Collectively, these results indicate the critical role of LoTPS in L. oryzophilus cold resistance after RCH induction. LoTPS can enhance survival ability by regulating trehalose metabolism. These findings contribute to further understanding the role of TPS in insect cold resistance and the invasiveness of L. oryzophilus. Moreover, RNAi of LoTPS opens up possibilities for novel control strategies against L. oryzophilus in the future.

Dose-response effects of resistance training on physical function in frail older Chinese adults: A randomized controlled trial.

BACKGROUND: Effective exercise for the frail elderly has been found to contribute to healthy aging; the corresponding relationship between intensity and volume of exercise and health effects remains unclear. The present study aimed to investigate the dose-response effects of resistance training on muscle strength and physical fitness in frail older adults. METHODS: In this randomized controlled trial, participants were randomized into seven groups: moderate-volume low-intensity, moderate-volume moderate-intensity, moderate-volume high-intensity, high-volume low-intensity, high-volume moderate-intensity, high-volume high-intensity and routine care, receiving 12 weeks of resistance training of different intensities and volumes of exercise. The outcomes were muscle strength (assessed by ergonomics force gauges) and physical fitness function (assessed by the 6-min walking test [6MWT], the 30-s sit-to-stand test [30sSTST] and the 8-foot up-and-go test [8-FUGT]) before and at 6 and 12 weeks of intervention. RESULTS: A total of 161 participants completed the exercise intervention. There were no significant differences in age, sex, height, body weight and body mass index among the seven groups. The exercise volume of resistance training showed linear relationships with muscle strength of the lower limbs, 30sSTST and 6MWT results and a non-linear relationship with 8-FUGT. Resistance training intensity was found to have a linear relationship with muscle strength of the lower limbs and 6MWT and non-linear relationships with 30sSTST and 8-FUGT. The mixed linear model analysis revealed that the lower limb muscle strength differed significantly before and during the intervention (W = 8571.5, Padj  < 0.001), before and after the intervention (W = 6968, Padj  = 0.001) and during and after the intervention (W = 2834.5, Padj  < 0.001); that the 6MWT performance differed during and after the intervention (W = 3184, Padj  < 0.001); and that the 30sSTST was different between before and during the intervention (W = 2350.5, Padj  = 0.012) and between during and after the intervention (W = 2290.5, Padj  = 0.045). CONCLUSIONS: Resistance training was found to be associated with muscle strength and physical fitness in frail older adults in a dose-dependent manner. High-intensity resistance training could be more effective for improving the muscle strength of frail older adults, and the improvement of 6MWT performance was even higher. High-volume resistance training significantly improved muscle strength, with even greater improvement in the 30sSTST and 6MWT performances. Both the intensity and volume of exercise were found to greatly value physical function in frail older adults. Low-moderate-intensity resistance training and low-moderate-volume resistance training also had some advantages in terms of safety, efficacy and acceptance in elderly with frailty.

Synthetic control of actin polymerization and symmetry breaking in active protocells.

Non-linear biomolecular interactions on the membranes drive membrane remodeling that underlies fundamental biological processes including chemotaxis, cytokinesis, and endocytosis. The multitude of biomolecules, the redundancy in their interactions, and the importance of spatiotemporal context in membrane organization hampers understanding the physical principles governing membrane mechanics. A minimal, in vitro system that models the functional interactions between molecular signaling and membrane remodeling, while remaining faithful to cellular physiology and geometry is powerful yet remains unachieved. Here, inspired by the biophysical processes underpinning chemotaxis, we reconstituted externally-controlled actin polymerization inside giant unilamellar vesicles, guiding self-organization on the membrane. We show that applying undirected external chemical inputs to this system results in directed actin polymerization and membrane deformation that are uncorrelated with upstream biochemical cues, indicating symmetry breaking. A biophysical model of the dynamics and mechanics of both actin polymerization and membrane shape suggests that inhomogeneous distributions of actin generate membrane shape deformations in a non-linear fashion, a prediction consistent with experimental measurements and subsequent local perturbations. The active protocellular system demonstrates the interplay between actin dynamics and membrane shape in a symmetry breaking context that is relevant to chemotaxis and a suite of other biological processes.

The intrinsically disordered cytoplasmic tail of a dendrite branching receptor uses two distinct mechanisms to regulate the actin cytoskeleton.

Dendrite morphogenesis is essential for neural circuit formation, yet the molecular mechanisms underlying complex dendrite branching remain elusive. Previous studies on the highly branched Caenorhabditis elegans PVD sensory neuron identified a membrane co-receptor complex that links extracellular signals to intracellular actin remodeling machinery, promoting high-order dendrite branching. In this complex, the claudin-like transmembrane protein HPO-30 recruits the WAVE regulatory complex (WRC) to dendrite branching sites, stimulating the Arp2/3 complex to polymerize actin. We report here our biochemical and structural analysis of this interaction, revealing that the intracellular domain (ICD) of HPO-30 is intrinsically disordered and employs two distinct mechanisms to regulate the actin cytoskeleton. First, HPO-30 ICD binding to the WRC requires dimerization and involves the entire ICD sequence, rather than a short linear peptide motif. This interaction enhances WRC activation by the GTPase Rac1. Second, HPO-30 ICD directly binds to the sides and barbed end of actin filaments. Binding to the barbed end requires ICD dimerization and inhibits both actin polymerization and depolymerization, resembling the actin capping protein CapZ. These dual functions provide an intriguing model of how membrane proteins can integrate distinct mechanisms to fine-tune local actin dynamics.

Structural Organization of the Retriever-CCC Endosomal Recycling Complex.

The recycling of membrane proteins from endosomes to the cell surface is vital for cell signaling and survival. Retriever, a trimeric complex of VPS35L, VPS26C and VPS29, together with the CCC complex comprising CCDC22, CCDC93, and COMMD proteins, plays a crucial role in this process. The precise mechanisms underlying Retriever assembly and its interaction with CCC have remained elusive. Here, we present the first high-resolution structure of Retriever determined using cryogenic electron microscopy. The structure reveals a unique assembly mechanism, distinguishing it from its remotely related paralog, Retromer. By combining AlphaFold predictions and biochemical, cellular, and proteomic analyses, we further elucidate the structural organization of the entire Retriever-CCC complex and uncover how cancer-associated mutations disrupt complex formation and impair membrane protein homeostasis. These findings provide a fundamental framework for understanding the biological and pathological implications associated with Retriever-CCC-mediated endosomal recycling.

Structural Organization of the Retriever-CCC Endosomal Recycling Complex.

The recycling of membrane proteins from endosomes to the cell surface is vital for cell signaling and survival. Retriever, a trimeric complex of VPS35L, VPS26C and VPS29, together with the CCC complex comprising CCDC22, CCDC93, and COMMD proteins, plays a crucial role in this process. The precise mechanisms underlying Retriever assembly and its interaction with CCC have remained elusive. Here, we present the first high-resolution structure of Retriever determined using cryogenic electron microscopy. The structure reveals a unique assembly mechanism, distinguishing it from its remotely related paralog, Retromer. By combining AlphaFold predictions and biochemical, cellular, and proteomic analyses, we further elucidate the structural organization of the entire Retriever-CCC complex and uncover how cancer-associated mutations disrupt complex formation and impair membrane protein homeostasis. These findings provide a fundamental framework for understanding the biological and pathological implications associated with Retriever-CCC-mediated endosomal recycling.

PPP2R1A regulates migration persistence through the NHSL1-containing WAVE Shell Complex.

The RAC1-WAVE-Arp2/3 signaling pathway generates branched actin networks that power lamellipodium protrusion of migrating cells. Feedback is thought to control protrusion lifetime and migration persistence, but its molecular circuitry remains elusive. Here, we identify PPP2R1A by proteomics as a protein differentially associated with the WAVE complex subunit ABI1 when RAC1 is activated and downstream generation of branched actin is blocked. PPP2R1A is found to associate at the lamellipodial edge with an alternative form of WAVE complex, the WAVE Shell Complex, that contains NHSL1 instead of the Arp2/3 activating subunit WAVE, as in the canonical WAVE Regulatory Complex. PPP2R1A is required for persistence in random and directed migration assays and for RAC1-dependent actin polymerization in cell extracts. PPP2R1A requirement is abolished by NHSL1 depletion. PPP2R1A mutations found in tumors impair WAVE Shell Complex binding and migration regulation, suggesting that the coupling of PPP2R1A to the WAVE Shell Complex is essential to its function.

Research progress on the mechanism of curcumin in cerebral ischemia/reperfusion injury: a narrative review.

Cerebral ischemia/reperfusion (I/R) injury can result in different levels of cerebral impairment, and in severe cases, death. Curcumin, an essential bioactive component of turmeric, has a rich history as a traditional medicine for various ailments in numerous countries. Experimental and clinical research has established that curcumin offers a protective effect against cerebral I/R injury. Curcumin exerts its protective effects by acting on specific mechanisms such as antioxidant, anti-inflammatory, inhibition of ferroptosis and pyroptosis, protection of mitochondrial function and structure, reduction of excessive autophagy, and improvement of endoplasmic reticulum (ER) stress, which ultimately help to preserve the blood-brain barrier (BBB) and reducing apoptosis. There is currently a shortage of drugs undergoing clinical trials for the treatment of cerebral I/R injury, highlighting the pressing need for research and development of novel treatments to address this injury. The primary objective of this study is to establish a theoretical basis for future clinical applications of curcumin by delineating the mechanisms and protective effects of curcumin against cerebral I/R injury. Adapted with permission from [1].

Genetics of mirror movements identifies a multifunctional complex required for Netrin-1 guidance and lateralization of motor control.

Mirror movements (MM) disorder is characterized by involuntary movements on one side of the body that mirror intentional movements on the opposite side. We performed genetic characterization of a family with autosomal dominant MM and identified ARHGEF7, a RhoGEF, as a candidate MM gene. We found that Arhgef7 and its partner Git1 bind directly to Dcc. Dcc is the receptor for Netrin-1, an axon guidance cue that attracts commissural axons to the midline, promoting the midline crossing of axon tracts. We show that Arhgef7 and Git1 are required for Netrin-1-mediated axon guidance and act as a multifunctional effector complex. Arhgef7/Git1 activates Rac1 and Cdc42 and inhibits Arf1 downstream of Netrin-1. Furthermore, Arhgef7/Git1, via Arf1, mediates the Netrin-1-induced increase in cell surface Dcc. Mice heterozygous for Arhgef7 have defects in commissural axon trajectories and increased symmetrical paw placements during skilled walking, a MM-like phenotype. Thus, we have delineated how ARHGEF7 mutation causes MM.

Thinking more wisely: using the Socratic method to develop critical thinking skills amongst healthcare students.

BACKGROUND: In medicine, critical thinking is required for managing and tolerating medical uncertainty, as well as solving professional problems and treating diseases. However, the core of Confucianism, teacher-centered and exam-oriented settings in middle and high school education may pose challenges to developing critical thinking in Han Chinese or Taiwanese students. Students may be adversely affected by these pedagogies since student-centered settings were more effective in stimulating their critical and reflective thinking, as well as a sense of responsibility, in the ever-changing world. Therefore, guiding students with less stable foundations of critical thinking might require a different approach. A review article highlighted the potential utility of the Socratic method as a tool for teaching critical thinking in the healthcare field. The method involves posing a series of questions to students. More importantly, medical students and residents in clinical teaching are familiar with the method. Almost all healthcare students must complete a biochemistry laboratory course as part of their basic science training. Thus, we aimed to train students to develop critical thinking in the biochemistry laboratory course by using learning sheets and teacher guidance based on the Socratic method and questioning. METHOD: We recruited second-year students from a medical school, of whom 32 had medical science and biotechnology majors (MSB), 27 had pharmaceutical science majors (PS), and 85 were medical undergraduate (MU) students. An exercise in critical thinking was conducted during a biochemistry laboratory course, which consisted of five different biochemical experiments, along with learning sheets that contained three or four critical thinking questions. Then, the teacher evaluated the students' ability to think critically based on nine intellectual dimensions (clarity, accuracy, precision, relevance, depth, breadth, logic, fairness, and significance) based on the universal intellectual standards developed by Prof. Linda Elder and Richard Paul. In the following analysis, regression models and multivariate analysis were used to determine how students improved over time, and trajectory analysis were carried out in order to observe the trends in students' critical thinking skills construction. RESULTS: Clarity and logic dimensions were identified as the key elements to facilitate the development of critical thinking skills through learning sheets and teacher guidance in students across all three different healthcare majors. The results showed that metacognitive monitoring via Socratic questioning learning sheets have demonstrated potential encourage students to develop critical thinking skills in all dimensions. Another unique contribution of current study was present the heterogeneous learning patterns and progress trajectories of clarity and logic dimensions within classes. CONCLUSION: Using the Socratic learning model could effectively develop students' critical thinking skills so they can more effectively care for their patients.

Predictors of cognitive impairment in newly diagnosed Parkinson's disease with normal cognition at baseline: A 5-year cohort study.

Background and objective: Cognitive impairment (CI) is a substantial contributor to the disability associated with Parkinson's disease (PD). We aimed to assess the clinical features and explore the underlying biomarkers as predictors of CI in patients with newly diagnosed PD (NDPD; less than 2 years). Methods: We evaluated the cognitive function status using the Montreal Cognitive Assessment (MoCA) and a battery of neuropsychological tests at baseline and subsequent annual follow-up for 5 years from the Parkinson's Progression Markers Initiative (PPMI) database. We assessed the baseline clinical features, apolipoprotein (APO) E status, ß-glucocerebrosidase (GBA) mutation status, cerebrospinal fluid findings, and dopamine transporter imaging results. Using a diagnosis of CI (combined mild cognitive impairment and dementia) developed during the 5-year follow-up as outcome measures, we assessed the predictive values of baseline clinical variables and biomarkers. We also constructed a predictive model for the diagnosis of CI using logistic regression analysis. Results: A total of 409 patients with NDPD with 5-year follow-up were enrolled, 232 with normal cognitive function at baseline, and 94 patients developed CI during the 5-year follow-up. In multivariate analyses, age, current diagnosis of hypertension, baseline MoCA scores, Movement disorder society Unified PD Rating Scale part III (MDS-UPDRS III) scores, and APOE status were associated with the development of CI. Predictive accuracy of CI using age alone improved by the addition of clinical variables and biomarkers (current diagnosis of hypertension, baseline MoCA scores, and MDS-UPDRS III scores, APOE status; AUC 0.80 [95% CI 0.74-0.86] vs. 0.71 [0.64-0.77], p = 0.008). Cognitive domains that had higher frequencies of impairment were found in verbal memory (12.6 vs. 16.8%) and attention/processing speed (12.7 vs. 16.9%), however, no significant difference in the prevalence of CI at annual follow-up was found during the 5-year follow-up in NDPD patients. Conclusion: In NDPD, the development of CI during the 5-year follow-up can be predicted with good accuracy using a model combining age, current diagnosis of hypertension, baseline MoCA scores, MDS-UPDRS III scores, and APOE status. Our study underscores the need for the earlier identification of CI in NDPD patients in our clinical practice.

Arf GTPase activates the WAVE regulatory complex through a distinct binding site.

Cross-talk between Rho- and Arf-family guanosine triphosphatases (GTPases) plays an important role in linking the actin cytoskeleton to membrane protrusions, organelle morphology, and vesicle trafficking. The central actin regulator, WAVE regulatory complex (WRC), integrates Rac1 (a Rho-family GTPase) and Arf signaling to promote Arp2/3-mediated actin polymerization in many processes, but how WRC senses Arf signaling is unknown. Here, we have reconstituted a direct interaction between Arf and WRC. This interaction is greatly enhanced by Rac1 binding to the D site of WRC. Arf1 binds to a previously unidentified, conserved surface on the Sra1 subunit of WRC, which, in turn, drives WRC activation using a mechanism distinct from that of Rac1. Mutating the Arf binding site abolishes Arf1-WRC interaction, disrupts Arf1-mediated WRC activation, and impairs lamellipodia formation and cell migration. This work uncovers a new mechanism underlying WRC activation and provides a mechanistic foundation for studying how WRC-mediated actin polymerization links Arf and Rac signaling in cells.

Impact of frailty, mild cognitive impairment and cognitive frailty on adverse health outcomes among community-dwelling older adults: A systematic review and meta-analysis.

Aims: This study analyzes the impact of frailty, mild cognitive impairment, and cognitive frailty on adverse outcomes in community-dwelling older adults. Methods: This systematic review and meta-analysis were conducted using the PRISMA guidelines and MOOSE statement. We developed a specific search strategy for each electronic database and searched PubMed, Web of Science, MEDLINE, and Embase from initial records to July 2021. The studies on adverse outcomes of frailty, pre-frailty, mild cognitive impairment, and mild cognitive impairment with pre-frailty and cognitive frailty were included. Two researchers independently extracted data based on a spreadsheet and assessed the risk of bias. The primary outcomes were mortality, dementia, disability, and hospitalization. The second outcome included quality of life and falls. All analysis was conducted by using Review Manager (RevMan) 5.3 software. Results: A total of 22 cohort studies (71,544 older adults with mean age ranging from 65.1 to 93.6 years) were included with a low risk of bias and high methodological quality with a NOS score ≥7. Compared to robust elders, individuals identified as frailty were associated with a higher risk of mortality (RR = 2.11, 95% CI: 1.57-2.83) and disability (RR = 5.91, 95% CI: 2.37-14.74). Mild cognitive impairment with pre-frailty was associated with mortality (RR = 1.74, 95% CI: 1.48-2.05) and dementia (RR = 4.15, 95% CI: 1.87-9.20). Pre-frailty was associated with a higher risk of mortality (RR = 1.29, 95% CI: 1.11-1.50). Cognitive frailty was associated with higher risk of incident mortality (RR = 2.41, 95% CI: 1.97-2.94), dementia (RR = 3.67, 95% CI: 2.81-4.78), disability (RR = 11.32, 95% CI: 4.14-30.97), and hospitalization (RR = 2.30, 95% CI: 1.60-3.32), as well as poor quality of life. Conclusion: Cognitive frailty could be a comprehensive psychosomatic predictor for adverse outcomes among older people. Interactions between frailty, mild cognitive impairment, and cognitive frailty on adverse outcomes must be further explored. Systematic review registration: [https://inplasy.com/inplasy-2022-5-0064/], identifier [INPLASY202250064].