Background: This study aimed to investigate the association of high-sensitivity C-reactive protein (hs-CRP) with incident frailty as well as its effects on pre-frailty progression and regression among middle-aged and older adults. Methods: Based on the frailty index (FI) calculated with 41 items, 6890 eligible participants without frailty at baseline from China Health and Retirement Longitudinal Study (CHARLS) were categorized into health, pre-frailty, and frailty groups. Logistic regression models were used to estimate the longitudinal association between baseline hs-CRP and incident frailty. Furthermore, a series of genetic approaches were conducted to confirm the causal relationship between CRP and frailty, including Linkage disequilibrium score regression (LDSC), pleiotropic analysis, and Mendelian randomization (MR). Finally, we evaluated the association of hs-CRP with pre-frailty progression and regression. Results: The risk of developing frailty was 1.18 times (95% CI: 1.03–1.34) higher in participants with high levels of hs-CRP at baseline than low levels of hs-CRP participants during the 3-year follow-up. MR analysis suggested that genetically determined hs-CRP was potentially positively associated with the risk of frailty (OR: 1.06, 95% CI: 1.03–1.08). Among 5241 participants with pre-frailty at baseline, we found pre-frailty participants with high levels of hs-CRP exhibit increased odds of progression to frailty (OR: 1.39, 95% CI: 1.09–1.79) and decreased odds of regression to health (OR: 0.84, 95% CI: 0.72–0.98) when compared with participants with low levels of hs-CRP. Conclusions: Our results suggest that reducing systemic inflammation is significant for developing strategies for frailty prevention and pre-frailty reversion in the middle-aged and elderly population.

Osteoporosis is a complex skeletal disorder characterized by low bone mineral density (BMD). Compared with classical epigenetic modifications, such as DNA methylation and histone modifications, the participation of chromatin-remodeling complexes in osteoporosis remains less explored. To identify chromatin remodeling factors causally associated with bone mineral density (BMD), here we conducted a systematic analysis of 87 genes encoding components of four major chromatin-remodeling complexes using Summary-data-based Mendelian randomization (SMR) analysis. Candidate chromatin-remodeling factors were further cross-referenced with publicly available skeletal phenotyping data from the International Mouse Phenotyping Consortium (IMPC) database. Functional validation revealed that non-canonical BAF (ncBAF) subunit BRD9 is essential for osteoblast differentiation using both in vitro cell culture and in vivo zebrafish models. RNA-Sequencing (RNA-Seq) demonstrated that BRD9 orchestrates osteogenic differentiation by modulating Wnt/β-catenin signaling activity. Mechanistically, the osteogenic master transcription factor Sp7 was identified as a direct transcriptional target of BRD9, whose expression is coordinately controlled through the synergistic interplay between BRD9 and Wnt/β-catenin signaling during osteogenesis. Collectively, this study established a comprehensive framework for identifying causal genes implicated in osteoporosis and elucidated the previously unrecognized regulatory role of BRD9 in osteogenesis.

Background Glucosamine is a widely used supplement for treating osteoarthritis and joint pain. New evidence suggests a potential association between glucosamine and type 2 diabetes, inflammation and cardiometabolic risk. We aimed to prospectively evaluate the association of habitual glucosamine use with risk of diabetic microvascular complications based on data from the large-scale nationwide prospective UK Biobank cohort study. Methods This analysis included 21,171 participants with type 2 diabetes who were free of microvascular complications from the UK Biobank. Incidence of diabetic microvascular complications was ascertained via electronic health records. The Cox proportional hazards model was used to assess the relationship between glucosamine use and the risk of diabetic microvascular complications. Subgroup analyses and sensitivity analyses were performed to explore the potential effect modifications and the robustness of the main findings. Results At baseline, 14.5% of the participants reported habitual use of glucosamine supplements. During a median follow-up of 12.3 years, 4399 people developed diabetic microvascular complications, including 2084 cases of incident diabetic nephropathy, 2401 incident diabetic retinopathy, and 831 incident diabetic neuropathy. Glucosamine use was significantly associated with lower risks of composite microvascular complications (hazard ratio (HR) 0.89, 95% CI: 0.81 to 0.97) and diabetic nephropathy (HR 0.87, 95% CI: 0.76 to 0.98) in fully adjusted models. However, there was no significant inverse association between glucosamine use and the risk of diabetic retinopathy (HR 0.94, 95% CI: 0.83 to 1.06) or diabetic neuropathy (HR 0.88, 95% CI: 0.71 to 1.08). Conclusions Habitual use of glucosamine supplement was significantly associated with lower risks of composite microvascular complications and diabetic nephropathy but not retinopathy or neuropathy in individuals with type 2 diabetes.

Dietary antioxidants and phytochemicals are believed to support cognitive health, but evidence on composite dietary indices remains limited. This cross-sectional study of 1845 community-dwelling older adults in China investigated the associations of the composite dietary antioxidant index (CDAI) and dietary phytochemical index (DPI) with cognitive function and mild cognitive impairment (MCI). Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA; Beijing version). MCI was diagnosed through a two-stage procedure: MoCA-based preliminary screening (with education-stratified cutoffs: 13/14 for illiterate, 19/20 for 1–6 years, 24/25 for ≥7 years) followed by neurologist confirmation. CDAI was calculated as the sum of the standardized intakes of six antioxidants (selenium, zinc, carotenoids, vitamin A, vitamin C, vitamin E); DPI was defined as the percentage of the total energy intake from phytochemical-rich foods (fruits, vegetables excluding potatoes, legumes including soy products, nuts, seeds, and whole grains). Multivariable linear regression, logistic regression, and receiver operating characteristic (ROC) curve analyses were performed. The basal metabolic rate (BMR) and systemic immune-inflammation index (SII; platelets × neutrophils/lymphocytes) were tested as potential statistical mediators. Each one-unit increase in CDAI was associated with a 0.068-point higher MoCA score (95% CI: 0.012–0.123), and each one-unit increase in DPI was associated with a 0.029-point higher MoCA score (95% CI: 0.008–0.050). BMR and SII partially mediated the association between CDAI and MoCA score, but temporal ordering remains unclear due to the cross-sectional design. When both CDAI and DPI were in the highest quartile, participants had a 46.3% lower risk of MCI compared with those with both indices in the lowest quartile (OR = 0.537, 95% CI: 0.308–0.935). A predictive model incorporating CDAI, inflammatory markers, and red blood cell parameters showed moderate discriminatory ability in this study sample (apparent AUC = 0.731, bootstrap-corrected AUC = 0.728). These findings suggest that a higher combined dietary antioxidant and phytochemical intake may be jointly associated with better cognitive function, although the cross-sectional design precludes causal inference.