Unraveling brain aging through the lens of oral microbiota.

ABSTRACT: The oral cavity is a complex physiological community encompassing a wide range of microorganisms. Dysbiosis of oral microbiota can lead to various oral infectious diseases, such as periodontitis and tooth decay, and even affect systemic health, including brain aging and neurodegenerative diseases. Recent studies have highlighted how oral microbes might be involved in brain aging and neurodegeneration, indicating potential avenues for intervention strategies. In this review, we summarize clinical evidence demonstrating a link between oral microbes/oral infectious diseases and brain aging/neurodegenerative diseases, and dissect potential mechanisms by which oral microbes contribute to brain aging and neurodegeneration. We also highlight advances in therapeutic development grounded in the realm of oral microbes, with the goal of advancing brain health and promoting healthy aging.

An in-situ peptide-antibody self-assembly to block CD47 and CD24 signaling enhances macrophage-mediated phagocytosis and anti-tumor immune responses.

Targeted immunomodulation for reactivating innate cells, especially macrophages, holds great promise to complement current adaptive immunotherapy. Nevertheless, there is still a lack of high-performance therapeutics for blocking macrophage phagocytosis checkpoint inhibitors in solid tumors. Herein, a peptide-antibody combo-supramolecular in situ assembled CD47 and CD24 bi-target inhibitor (PAC-SABI) is described, which undergoes biomimetic surface propagation on cancer cell membranes through ligand-receptor binding and enzyme-triggered reactions. By simultaneously blocking CD47 and CD24 signaling, PAC-SABI enhances the phagocytic ability of macrophages in vitro and in vivo, promoting anti-tumor responses in breast and pancreatic cancer mouse models. Moreover, building on the foundation of PAC-SABI-induced macrophage repolarization and increased CD8+ T cell tumor infiltration, sequential anti-PD-1 therapy further suppresses 4T1 tumor progression, prolonging survival rate. The in vivo construction of PAC-SABI-based nano-architectonics provides an efficient platform for bridging innate and adaptive immunity to maximize therapeutic potency.

Injectable alginate-based zwitterionic hydrogels promoting endometrial repair and restoring fertility.

The development of novel therapeutic approaches to facilitate endometrial repair and regeneration while preventing adhesion recurrence is a crucial research objective aimed at enhancing clinical outcomes for women with intrauterine adhesions (IUA). In this study, we introduced an injectable Alg-GMA/PTSB zwitterionic hydrogel, characterized by excellent biocompatibility, anti-protein adsorption properties, and biodegradability. In a rat model, the hydrogel significantly promoted the regeneration and angiogenesis of damaged endometrial tissue, leading to improved recovery of epithelial cells, glands, proliferation, and vascularization. Furthermore, it exhibited the ability to suppress cellular apoptosis and collagen deposition, thereby mitigating fibrosis. Additionally, the hydrogel restored the expression of estrogen/progesterone receptors and endometrial receptivity markers, contributing to enhanced embryo implantation and fertility. These findings underscore the potential of the hydrogel as a promising therapeutic strategy for addressing endometrial injury, reducing fibrosis, restoring fertility, and ultimately improving outcomes for women with IUA.

Reproducibility and reliability of pancreatic pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging.

BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with an extended Tofts linear (ETL) model for tissue and tumor evaluation has been established, but its effectiveness in evaluating the pancreas remains uncertain. PURPOSE: To understand the pharmacokinetics of normal pancreas and serve as a reference for future studies of pancreatic diseases. MATERIAL AND METHODS: Pancreatic pharmacokinetic parameters of 54 volunteers were calculated using DCE-MRI with the ETL model. First, intra- and inter-observer reliability was assessed through the use of the intra-class correlation coefficient (ICC) and coefficient of variation (CoV). Second, a subgroup analysis of the pancreatic DCE-MRI pharmacokinetic parameters was carried out by dividing the 54 individuals into three groups based on the pancreatic region, three groups based on age, and two groups based on sex. RESULTS: There was excellent agreement and low variability of intra- and inter-observer to pancreatic DCE-MRI pharmacokinetic parameters. The intra- and inter-observer ICCs of Ktrans, kep, ve, and vp were 0.971, 0.952, 0.959, 0.944 and 0.947, 0.911, 0.978, 0.917, respectively. The intra- and inter-observer CoVs of Ktrans, kep, ve, vp were 9.98%, 5.99%, 6.47%, 4.76% and 10.15%, 5.22%, 6.28%, 5.40%, respectively. Only the pancreatic ve of the older group was higher than that of the young and middle-aged groups (P = 0.042, 0.001), and the vp of the pancreatic head was higher than that of the pancreatic body and tail (P = 0.014, 0.043). CONCLUSION: The application of DCE-MRI with an ETL model provides a reliable, robust, and reproducible means of non-invasively quantifying pancreatic pharmacokinetic parameters.

Consistent Individual Differences Drive Collective Movements in a Tibetan Macaque Group.

Collective movement has emerged as a key area of interest in animal behavior. While individual differences are often viewed as a potential threat to group cohesion, growing evidence suggests that these differences can actually influence an animal's behavior as an initiator or follower during collective movements, thereby driving the group's movement and decision-making processes. To resolve the divergence, we asked how personality can affect the dynamics of collective movements in one group of free-ranging Tibetan macaques (Macaca thibetana) in Huangshan, China. We assessed individual personality using principal component analysis and applied the generalized linear mixed model and linear mixed model to examine the influence of personality on decision making during collective movements. Our findings reveled three distinct personality types among Tibetan macaques: sociability, boldness, and anxiousness. Individuals with higher sociability scores and rank, or those with lower anxiousness scores, were more likely to initiate successful collective movements. Older individuals were less successful in initiating movements compared to young adults. Leaders with lower anxiousness scores or higher rank attracted more followers, with females attracting larger groups than males. As for followers, individuals with higher rank tended to join the collective movement earlier. Additionally, individuals with higher sociability or boldness scores had shorter joining latency in collective movement. Finally, there was a longer joining latency for middle-aged adults compared to young adults. These results suggest that individual differences are a potential driver of collective movements. We provide some insights into the relationships between personality and decision making in Tibetan macaques.

Co-assembly of cisplatin and dasatinib in hyaluronan nanogel to combat triple negative breast cancer with reduced side effects.

Treatment for triple negative breast cancer (TNBC) remains a huge challenge due to the lack of targeted therapeutics and tumor heterogenicity. Cisplatin (Cis) have demonstrated favorable therapeutic response in TNBC and thus is used together with various kinase inhibitors to fight the heterogenicity of TNBC. The combination of Cis with SRC inhibitor dasatinib (DAS) has shown encouraging anti-TNBC efficacy although the additive toxicity was commonly observed. To overcome the severe side effects of this Cis involved therapy, here we co-encapsulated Cis and DAS into a self-assembled hyaluronan (HA) nanogel (designated as HA/Cis/DAS (HCD) nanogel) to afford the TNBC targeted delivery by using the 4T1 mouse model. The acquired HCD nanogel was around 181 nm in aqueous solution, demonstrating the pharmacological activities of both Cis and DAS. Taking advantages of HA's targeting capability towards CD44 that is overexpressed on many TNBC cells, the HCD could well maintain the anticancer efficacy of the Cis and DAS combination, significantly increase the maximum tolerated dose and relieve the renal toxicity in vivo. The current HCD nanogel provides a potent strategy to improve the therapeutic outcome of Cis and DAS combination and thus representing a new targeted treatment option for TNBC.

Multimodal Omics Approaches to Aging and Age-Related Diseases.

Aging is associated with a progressive decline in physiological capacities and an increased risk of aging-associated disorders. An increasing body of experimental evidence shows that aging is a complex biological process coordinately regulated by multiple factors at different molecular layers. Thus, it is difficult to delineate the overall systematic aging changes based on single-layer data. Instead, multimodal omics approaches, in which data are acquired and analyzed using complementary omics technologies, such as genomics, transcriptomics, and epigenomics, are needed for gaining insights into the precise molecular regulatory mechanisms that trigger aging. In recent years, multimodal omics sequencing technologies that can reveal complex regulatory networks and specific phenotypic changes have been developed and widely applied to decode aging and age-related diseases. This review summarizes the classification and progress of multimodal omics approaches, as well as the rapidly growing number of articles reporting on their application in the field of aging research, and outlines new developments in the clinical treatment of age-related diseases based on omics technologies.

Targeting aging and age-related diseases with vaccines.

Aging is a major risk factor for numerous chronic diseases. Vaccination offers a promising strategy to combat these age-related diseases by targeting specific antigens and inducing immune responses. Here, we provide a comprehensive overview of recent advances in vaccine-based interventions targeting these diseases, including Alzheimer's disease, type II diabetes, hypertension, abdominal aortic aneurysm, atherosclerosis, osteoarthritis, fibrosis and cancer, summarizing current approaches for identifying disease-associated antigens and inducing immune responses against these targets. Further, we reflect on the recent development of vaccines targeting senescent cells, as a strategy for more broadly targeting underlying causes of aging and associated pathologies. In addition to highlighting recent progress in these areas, we discuss important next steps to advance the therapeutic potential of these vaccines, including improving and robustly demonstrating efficacy in human clinical trials, as well as rigorously evaluating the safety and long-term effects of these vaccine strategies.

Single-nucleus transcriptomics uncovers a geroprotective role of YAP in primate gingival aging.

Aging has a profound impact on the gingiva and significantly increases its susceptibility to periodontitis, a worldwide prevalent inflammatory disease. However, a systematic characterization and comprehensive understanding of the regulatory mechanism underlying gingival aging is still lacking. Here, we systematically dissected the phenotypic characteristics of gingiva during aging in primates and constructed the first single-nucleus transcriptomic landscape of gingival aging, by which a panel of cell type-specific signatures were elucidated. Epithelial cells were identified as the most affected cell types by aging in the gingiva. Further analyses pinpointed the crucial role of YAP in epithelial self-renew and homeostasis, which declined during aging in epithelial cells, especially in basal cells. The decline of YAP activity during aging was confirmed in the human gingival tissues, and downregulation of YAP in human primary gingival keratinocytes recapitulated the major phenotypic defects observed in the aged primate gingiva while overexpression of YAP showed rejuvenation effects. Our work provides an in-depth understanding of gingival aging and serves as a rich resource for developing novel strategies to combat aging-associated gingival diseases, with the ultimate goal of advancing periodontal health and promoting healthy aging.

DNA methylation clocks for estimating biological age in Chinese cohorts.

Epigenetic clocks are accurate predictors of human chronological age based on the analysis of DNA methylation at specific CpG sites. However, available DNA methylation (DNAm) age predictors are based on datasets with limited ethnic representation. Moreover, a systematic comparison between DNAm data and other omics datasets has not yet been performed. To address these knowledge gaps, we generated and analyzed DNA methylation datasets from two independent Chinese cohorts, revealing age-related DNAm changes. Additionally, a DNA methylation (DNAm) aging clock (iCAS-DNAmAge) and a group of DNAm-based multi-modal clocks for Chinese individuals were developed, with most of them demonstrating strong predictive capabilities for chronological age. The clocks were further employed to predict factors influencing aging rates. The DNAm aging clock, derived from multi-modal aging features (compositeAge-DNAmAge), exhibited a close association with multi-omics changes, lifestyles, and disease status, underscoring its robust potential for precise biological age assessment. Our findings offer novel insights into the regulatory mechanism of age-related DNAm changes and extend the application of the DNAm clock for measuring biological age and aging pace, providing basis for evaluating aging intervention strategies.

Aging induces region-specific dysregulation of hormone synthesis in the primate adrenal gland.

Adrenal glands, vital for steroid secretion and the regulation of metabolism, stress responses and immune activation, experience age-related decline, impacting systemic health. However, the regulatory mechanisms underlying adrenal aging remain largely uninvestigated. Here we established a single-nucleus transcriptomic atlas of both young and aged primate suprarenal glands, identifying lipid metabolism and steroidogenic pathways as core processes impacted by aging. We found dysregulation in centripetal adrenocortical differentiation in aged adrenal tissues and cells in the zona reticularis region, responsible for producing dehydroepiandrosterone sulfate (DHEA-S), were highly susceptible to aging, reflected by senescence, exhaustion and disturbed hormone production. Remarkably, LDLR was downregulated in all cell types of the outer cortex, and its targeted inactivation in human adrenal cells compromised cholesterol uptake and secretion of dehydroepiandrosterone sulfate, as observed in aged primate adrenal glands. Our study provides crucial insights into endocrine physiology, holding therapeutic promise for addressing aging-related adrenal insufficiency and delaying systemic aging.

The sirtuin-associated human senescence program converges on the activation of placenta-specific gene PAPPA.

Sirtuins are pro-longevity genes with chromatin modulation potential, but how these properties are connected is not well understood. Here, we generated a panel of isogeneic human stem cell lines with SIRT1-SIRT7 knockouts and found that any sirtuin deficiency leads to accelerated cellular senescence. Through large-scale epigenomic analyses, we show how sirtuin deficiency alters genome organization and that genomic regions sensitive to sirtuin deficiency are preferentially enriched in active enhancers, thereby promoting interactions within topologically associated domains and the formation of de novo enhancer-promoter loops. In all sirtuin-deficient human stem cell lines, we found that chromatin contacts are rewired to promote aberrant activation of the placenta-specific gene PAPPA, which controls the pro-senescence effects associated with sirtuin deficiency and serves as a potential aging biomarker. Based on our survey of the 3D chromatin architecture, we established connections between sirtuins and potential target genes, thereby informing the development of strategies for aging interventions.

Outer-Surface Functionalized Solid-State Nanochannels for Enhanced Sensing Properties: Progress and Perspective.

Solid-state nanochannel-based sensing systems have been established as vigorous tools for sensing plentiful biomarkers due to their label-free, highly sensitive, and high-throughput screening. However, research on solid-state nanochannels has predominantly centered on the functional groups modified on the inner wall, neglecting investigations into the outer surface. Actually, the outer surface, as a part of the nanochannels, also plays a key role in regulating ionic current. When the target nears the entrance of the nanochannel and prepares to pass through, it would also interact with functional groups located on the nanochannel's outer surface, leading to subsequent alterations in the ionic current. Recently, the probes on the outer surface have experimentally demonstrated their ability to independently regulate ionic current, unveiling advantages in in situ target detection, especially for targets larger than the diameter of the nanochannels that cannot pass through them. Here, we review the progress over the past decade in nanochannels featuring diverse outer-surface functionalization aimed at enhanced sensing performance, including charge modification, wettability adjustment, and probe immobilization. In addition, we present the promises and challenges posed by outer-surface functionalized nanochannels and discuss possible directions for their future deployments.

Low SAA4 gene expression is associated with advanced HCC stage and a poor prognosis.

At present, although there are tumor markers for hepatocellular carcinoma (HCC), markers with better predictive efficiency are needed. SAA4 gene expression in liver tumor and paracancerous tissues was analyzed using The Cancer Genome Atlas database. The differentially expressed genes (DEGs) were analyzed and visualized by heatmap and volcano plot. Survival analysis was performed based on SAA4 expression. SAA4 expression was compared in patients grouped based on clinicopathological features, and gene set enrichment analysis (GSEA) was conducted. Immunohistochemical staining was used to verify the SAA4 protein staining intensity from The Human Protein Atlas database and our center's samples. The diagnostic value of SAA4 for HCC was evaluated by receiver operating characteristic curves. SAA4 was expressed at low levels in HCC tissues, and low SAA4 expression was associated with a poor prognosis in HCC. In addition, SAA4 expression decreased with HCC progression. There were 188 upregulated DEGs and 1551 downregulated DEGs between the high and low SAA4 expression groups. Complement and coagulation cascades, fatty acid metabolism, and ECM receptor interaction were significantly enriched in the GSEA. SAA4 had good predictive efficacy for HCC and even early HCC and was superior to AFP. In general, low SAA4 expression was associated with advanced HCC stage and a poor prognosis. In addition, SAA4 may be helpful for the diagnosis of early HCC and may become a novel tumor marker with good predictive power for HCC.

Emerging epigenetic insights into aging mechanisms and interventions.

Epigenetic dysregulation emerges as a critical hallmark and driving force of aging. Although still an evolving field with much to explore, it has rapidly gained significance by providing valuable insights into the mechanisms of aging and potential therapeutic opportunities for age-related diseases. Recent years have witnessed remarkable strides in our understanding of the epigenetic landscape of aging, encompassing pivotal elements, such as DNA methylation, histone modifications, RNA modifications, and noncoding (nc) RNAs. Here, we review the latest discoveries that shed light on new epigenetic mechanisms and critical targets for predicting and intervening in aging and related disorders. Furthermore, we explore burgeoning interventions and exemplary clinical trials explicitly designed to foster healthy aging, while contemplating the potential ramifications of epigenetic influences.

CRL2APPBP2-mediated TSPYL2 degradation counteracts human mesenchymal stem cell senescence.

Cullin-RING E3 ubiquitin ligases (CRLs), the largest family of multi-subunit E3 ubiquitin ligases in eukaryotic cells, represent core cellular machinery for executing protein degradation and maintaining proteostasis. Here, we asked what roles Cullin proteins play in human mesenchymal stem cell (hMSC) homeostasis and senescence. To this end, we conducted a comparative aging phenotype analysis by individually knocking down Cullin members in three senescence models: replicative senescent hMSCs, Hutchinson-Gilford Progeria Syndrome hMSCs, and Werner syndrome hMSCs. Among all family members, we found that CUL2 deficiency rendered hMSCs the most susceptible to senescence. To investigate CUL2-specific underlying mechanisms, we then applied CRISPR/Cas9-mediated gene editing technology to generate CUL2-deficient human embryonic stem cells (hESCs). When we differentiated these into hMSCs, we found that CUL2 deletion markedly accelerates hMSC senescence. Importantly, we identified that CUL2 targets and promotes ubiquitin proteasome-mediated degradation of TSPYL2 (a known negative regulator of proliferation) through the substrate receptor protein APPBP2, which in turn down-regulates one of the canonical aging marker-P21waf1/cip1, and thereby delays senescence. Our work provides important insights into how CRL2APPBP2-mediated TSPYL2 degradation counteracts hMSC senescence, providing a molecular basis for directing intervention strategies against aging and aging-related diseases.

A Single Set of Well-Designed Aptamer Probes for Reliable On-site Qualitative and Ultra-Sensitive Quantitative Detection.

Aptamer-based probes are pivotal components in various sensing strategies, owing to their exceptional specificity and versatile programmable structure. Nevertheless, numerous aptamer-based probes usually offer only a single function, limiting their capacity to meet the diverse requirements of multi-faceted sensing systems. Here, we introduced supersandwich DNA probes (SSW-DNA), designed and modified on the outer surface of nanochannels with hydrophobic inner walls, enabling dual functionality: qualitative detection for on-site analysis and quantitative detection for precise analysis. The fragmented DNAs resulting from the target recognition, are subsequently identified through lateral flow assays, enabling robust on-site qualitative detection of microcystin-LR with an impressively low limit of detection (LOD) at 0.01 µg/L. Meanwhile, the nanochannels enable highly sensitive quantification of microcystin-LR through the current analysis, achieving an exceptionally low LOD at 2.5×10-7  µg/L, with a broad dynamic range spanning from 1×10-6 to 1×102  µg/L. Furthermore, the process of target recognition introduces just a single potential error propagation, which reduces the overall risk of errors during the entire qualitative and quantitative detection process. This sensing strategy broadens the scope of applications for aptamer-based composite probes, holding promising implications across diverse fields, such as medical diagnosis, food safety, and environmental protection.

FOXP3+ regulatory T cell perturbation mediated by the IFNγ-STAT1-IFITM3 feedback loop is essential for anti-tumor immunity.

Targeting tumor-infiltrating regulatory T cells (Tregs) is an efficient way to evoke an anti-tumor immune response. However, how Tregs maintain their fragility and stability remains largely unknown. IFITM3 and STAT1 are interferon-induced genes that play a positive role in the progression of tumors. Here, we showed that IFITM3-deficient Tregs blunted tumor growth by strengthening the tumor-killing response and displayed the Th1-like Treg phenotype with higher secretion of IFNγ. Mechanistically, depletion of IFITM3 enhances the translation and phosphorylation of STAT1. On the contrary, the decreased IFITM3 expression in STAT1-deficient Tregs indicates that STAT1 conversely regulates the expression of IFITM3 to form a feedback loop. Blocking the inflammatory cytokine IFNγ or directly depleting STAT1-IFITM3 axis phenocopies the restored suppressive function of tumor-infiltrating Tregs in the tumor model. Overall, our study demonstrates that the perturbation of tumor-infiltrating Tregs through the IFNγ-IFITM3-STAT1 feedback loop is essential for anti-tumor immunity and constitutes a targetable vulnerability of cancer immunotherapy.